27081 lines
2.7 MiB
27081 lines
2.7 MiB
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- *602421 - CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; CFTR
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*602421</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602421">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000001626;t=ENST00000003084" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=1080" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=602421" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000001626;t=ENST00000003084" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000492" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000492" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=602421" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=03883&isoform_id=03883_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/CFTR" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/180281,180286,180295,180332,306538,553225,1100102,1100104,1809238,4262090,13236881,13236882,37674391,47775729,47775731,47775733,47775735,47775737,47775739,47775741,47775743,47775745,47775747,47775749,47775751,47775753,47775755,47775757,47775759,47775761,47775763,47775765,47775767,47775769,47775771,47775773,47775775,47775777,47775779,47775781,47775783,47775785,47775787,47775789,47775791,47775793,47775795,47775797,47775799,47775801,47775803,47775805,47775807,47775809,47775811,47775813,47775815,47775817,47775819,47775821,47775823,47775825,47775827,47775829,47775831,47775833,47775835,47775837,47775839,47775841,47775843,47775845,47775847,47775849,47775851,47775853,47775855,47775857,47775893,47776132,47776134,47776136,47776138,47776140,47776142,47776144,47776146,47776148,47776150,47776152,47776154,47776156,47776158,47776160,47776162,47776164,47776166,47776168,47776170,47776172,47776174,47776176,47776178,47776180,47776182,47776184,47776186,47776188,47776190,47776192,47776194,47776196,47776198,47776200,47776202,47776204,47776206,47776208,47776210,47776212,47776214,47776216,47776218,47776220,47776222,47776224,47776226,47776228,47776230,47776232,51095110,57116330,57116332,57116334,57116336,57116338,57116614,85724370,85724373,85724376,85724379,86169626,86169629,86169632,86169635,86169638,86169641,86169644,86169647,89348130,89348133,89348136,89348139,89348142,89348145,89348148,89348151,89348154,89348157,89348160,89348163,89348166,89348169,89348172,89348175,89348178,89348181,90421313,104530252,119603935,119603936,119603937,134142360,147744553,400177525,400177527,649719499,685506010,685506012,688446279,688446284,693268774,693268776,693268778,693268780,693268782,693268784,693268786,693268788,693268790,732666180,1018198517,1041521606,1041521608,1278156095" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P13569" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=1080" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000001626;t=ENST00000003084" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=CFTR" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=CFTR" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+1080" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/CFTR" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:1080" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/1080" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr7&hgg_gene=ENST00000003084.11&hgg_start=117480025&hgg_end=117668665&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:1884" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/cftr" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=602421[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=602421[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/CFTR/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000001626" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=CFTR" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=CFTR" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CFTR" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.genet.sickkids.on.ca/cftr/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CFTR&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA109" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:1884" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:88388" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/CFTR#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:88388" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/1080/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA001794/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=1080" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00000477;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050517-20" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:602421" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:1080" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=CFTR&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 190905008<br />
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<strong>ICD10CM:</strong> E84, E84.9<br />
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<strong>ICD9CM:</strong> 277.0<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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602421
|
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</span>
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</span>
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</div>
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</div>
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; CFTR
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 7; ABCC7
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CFTR" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CFTR</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/7/609?start=-3&limit=10&highlight=609">7q31.2</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:117480025-117668665&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">7:117,480,025-117,668,665</a> </span>
|
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</em>
|
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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<a href="/clinicalSynopsis/table?mimNumber=211400,167800,277180,219700," class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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View Clinical Synopses
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</a>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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<a href="/geneMap/7/609?start=-3&limit=10&highlight=609">
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7q31.2
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<span class="mim-font">
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{Bronchiectasis with or without elevated sweat chloride 1, modifier of}
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<a href="/entry/211400"> 211400 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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{Hypertrypsinemia, neonatal}
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<span class="mim-font">
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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{Pancreatitis, hereditary}
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<span class="mim-font">
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<a href="/entry/167800"> 167800 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Congenital bilateral absence of vas deferens
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<span class="mim-font">
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<a href="/entry/277180"> 277180 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Cystic fibrosis
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<a href="/entry/219700"> 219700 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Sweat chloride elevation without CF
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/602421" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/602421" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>The CFTR gene encodes an ATP-binding cassette (ABC) transporter that functions as a low conductance Cl(-)-selective channel gated by cycles of ATP binding and hydrolysis at its nucleotide-binding domains (NBDs) and regulated tightly by an intrinsically disordered protein segment distinguished by multiple consensus phosphorylation sites termed the regulatory domain (summary by <a href="#265" class="mim-tip-reference" title="Wang, Y., Wrennall, J. A., Cai, Z., Li, H., Sheppard, D. N. <strong>Understanding how cystic fibrosis mutations disrupt CFTR function: from single molecules to animal models.</strong> Int. J. Biochem. Cell Biol. 52: 47-57, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24727426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24727426</a>] [<a href="https://doi.org/10.1016/j.biocel.2014.04.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24727426">Wang et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24727426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Cloning and Expression</strong>
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<p><a href="#198" class="mim-tip-reference" title="Riordan, J. R., Rommens, J. M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J. L., Drumm, M. L., Iannuzzi, M. C., Collins, F. S., Tsui, L.-C. <strong>Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.</strong> Science 245: 1066-1073, 1989. Note: Erratum: Science 245: 1437 only, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2475911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2475911</a>] [<a href="https://doi.org/10.1126/science.2475911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2475911">Riordan et al. (1989)</a> isolated overlapping cDNA clones from epithelial cell libraries with a genomic DNA segment containing a portion of the putative gene causing cystic fibrosis (CF; <a href="/entry/219700">219700</a>). Transcripts approximately 6,500 nucleotides in size were detectable in the tissues affected in patients with CF. The predicted protein consists of 2 similar motifs, each with a domain having properties consistent with membrane-association, and a domain believed to be involved in ATP binding. In CF patients, a deleted phenylalanine residue occurs at the center of the putative first nucleotide-binding fold (NBF). The predicted protein has 1,480 amino acids with a molecular mass of 168,138 Da. The characteristics are remarkably similar to those of the mammalian multidrug resistant P-glycoprotein (<a href="/entry/171050">171050</a>), which also maps to 7q, and to a number of other membrane-associated proteins. To avoid confusion with the previously named CF antigen (<a href="/entry/123885">123885</a>), <a href="#198" class="mim-tip-reference" title="Riordan, J. R., Rommens, J. M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J. L., Drumm, M. L., Iannuzzi, M. C., Collins, F. S., Tsui, L.-C. <strong>Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.</strong> Science 245: 1066-1073, 1989. Note: Erratum: Science 245: 1437 only, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2475911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2475911</a>] [<a href="https://doi.org/10.1126/science.2475911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2475911">Riordan et al. (1989)</a> referred to the protein as cystic fibrosis transmembrane conductance regulator (CFTR). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2475911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Cystic fibrosis represents the first genetic disorder elucidated strictly by the process of reverse genetics (later called positional cloning), i.e., on the basis of map location but without the availability of chromosomal rearrangements or deletions such as those that have greatly facilitated previous success in the cloning of human disease genes in Duchenne muscular dystrophy (<a href="/entry/310200">310200</a>), retinoblastoma (<a href="/entry/180200">180200</a>), and chronic granulomatous disease (<a href="/entry/306400">306400</a>), for example. By use of a combination of chromosome walking and jumping, <a href="#205" class="mim-tip-reference" title="Rommens, J. M., Iannuzzi, M. C., Kerem, B., Drumm, M. L., Melmer, G., Dean, M., Rozmahel, R., Cole, J. L., Kennedy, D., Hidaka, N., Zsiga, M., Buchwald, M., Riordan, J. R., Tsui, L.-C., Collins, F. S. <strong>Identification of the cystic fibrosis gene: chromosome walking and jumping.</strong> Science 245: 1059-1065, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2772657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2772657</a>] [<a href="https://doi.org/10.1126/science.2772657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2772657">Rommens et al. (1989)</a> succeeded in covering the CF region on 7q. The jumping technique was particularly useful in bypassing 'unclonable' regions, which are estimated to constitute 5% of the human genome. (Yeast artificial chromosome (YAC) vectors represent an alternative strategy.) The identification of undermethylated CpG islands was 1 tip-off; another was screening of a cDNA library constructed from cultured sweat gland cells of a non-CF individual. The CF gene proved to be about 250,000 bp long, a surprising finding since the absence of apparent genomic rearrangements in CF chromosomes and the evidence of a limited number of CF mutations predicted a small mutational target. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2772657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#112" class="mim-tip-reference" title="Green, E. D., Olson, M. V. <strong>Chromosomal region of the cystic fibrosis gene in yeast artificial chromosomes: a model for human genome mapping.</strong> Science 250: 94-98, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2218515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2218515</a>] [<a href="https://doi.org/10.1126/science.2218515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2218515">Green and Olson (1990)</a> described a general strategy for cloning and mapping large regions of human DNA with yeast artificial chromosomes (YACs). By analyzing 30 YAC clones from the region of chromosome 7 containing the CFTR gene, a contig map spanning more than 1.5 Mbp was assembled. Individual YACs as large as 790 kb and containing the entire CF gene were constructed in vivo by meiotic recombination in yeast between pairs of overlapping YACs. <a href="#5" class="mim-tip-reference" title="Anand, R., Ogilvie, D. J., Butler, R., Riley, J. H., Finniear, R. S., Powell, S. J., Smith, J. C., Markham, A. F. <strong>A yeast artificial chromosome contig encompassing the cystic fibrosis locus.</strong> Genomics 9: 124-130, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1706309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1706309</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90229-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1706309">Anand et al. (1991)</a> described the physical mapping of a 1.5-Mbp region encompassing 2 genetic loci flanking the CF locus and contained within a series of YAC clones. The entire CFTR gene was included within 1 of these YACs, a 310-kb clone also containing flanking sequence in both the 5-prime and 3-prime directions from the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1706309+2218515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#198" class="mim-tip-reference" title="Riordan, J. R., Rommens, J. M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J. L., Drumm, M. L., Iannuzzi, M. C., Collins, F. S., Tsui, L.-C. <strong>Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.</strong> Science 245: 1066-1073, 1989. Note: Erratum: Science 245: 1437 only, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2475911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2475911</a>] [<a href="https://doi.org/10.1126/science.2475911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2475911">Riordan et al. (1989)</a> identified 24 exons in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2475911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>With the hope of identifying conserved regions of biologic interest by sequence comparison, <a href="#90" class="mim-tip-reference" title="Ellsworth, R. E., Jamison, D. C., Touchman, J. W., Chissoe, S. L., Maduro, V. V. B., Bouffard, G. G., Dietrich, N. L., Beckstrom-Sternberg, S. M., Iyer, L. M., Weintraub, L. A., Cotton, M., Courtney, L., and 18 others. <strong>Comparative genomic sequence analysis of the human and mouse cystic fibrosis transmembrane conductance regulator genes.</strong> Proc. Nat. Acad. Sci. 97: 1172-1177, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655503</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10655503[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.97.3.1172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655503">Ellsworth et al. (2000)</a> sought to establish the sequence of the chromosomal segments encompassing the human CFTR and mouse Cftr genes. Bacterial clone-based physical maps of the relevant human and mouse genomic regions were constructed, and minimally overlapping sets of clones were selected and sequenced. Analyses of the resulting data provided insights about the organization of the CFTR/Cftr genes and potential sequence elements regulating their expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10655503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#198" class="mim-tip-reference" title="Riordan, J. R., Rommens, J. M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J. L., Drumm, M. L., Iannuzzi, M. C., Collins, F. S., Tsui, L.-C. <strong>Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.</strong> Science 245: 1066-1073, 1989. Note: Erratum: Science 245: 1437 only, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2475911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2475911</a>] [<a href="https://doi.org/10.1126/science.2475911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2475911">Riordan et al. (1989)</a> mapped the CFTR gene to chromosome 7q. For additional information on the mapping of the gene for cystic fibrosis, see <a href="/entry/219700">219700</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2475911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The mapping of the murine equivalent of the WNT2 and MET (<a href="/entry/164860">164860</a>) genes to mouse chromosome 6 (<a href="#35" class="mim-tip-reference" title="Chan, A. M.-L., Hilkens, J., Kroezen, V., Mitchell, P. J., Scambler, P., Wainwright, B. J., Williamson, R., Cooper, C. S. <strong>Molecular cloning and localization to chromosome 6 of mouse INT1L1 gene.</strong> Somat. Cell Molec. Genet. 15: 555-562, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2531931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2531931</a>] [<a href="https://doi.org/10.1007/BF01534916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2531931">Chan et al., 1989</a>) strongly indicated that the mouse equivalent of the cystic fibrosis gene is also located on chromosome 6. By Southern analysis of mouse/Chinese hamster somatic cell hybrid DNAs, <a href="#137" class="mim-tip-reference" title="Kelley, K. A., Stamm, S., Kozak, C. A. <strong>Expression and chromosome localization of the murine cystic fibrosis transmembrane conductance regulator.</strong> Genomics 13: 381-388, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1377165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1377165</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90257-s" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1377165">Kelley et al. (1992)</a> mapped the Cftr gene to chromosome 6. Using restriction fragment length variants (RFLVs) in the study of interspecific backcrosses, <a href="#232" class="mim-tip-reference" title="Siegel, D., Irving, N. G., Friedman, J. M., Wainwright, B. J. <strong>Localization of the cystic fibrosis transmembrane conductance regulator (Cftr) to mouse chromosome 6.</strong> Cytogenet. Cell Genet. 61: 184-185, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1385049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1385049</a>] [<a href="https://doi.org/10.1159/000133404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1385049">Siegel et al. (1992)</a> demonstrated that the Cftr gene in the mouse is close to Met and Cola-2. <a href="#248" class="mim-tip-reference" title="Trezise, A. E. O., Szpirer, C., Buchwald, M. <strong>Localization of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) in the rat to chromosome 4 and implications for the evolution of mammalian chromosomes.</strong> Genomics 14: 869-874, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1282491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1282491</a>] [<a href="https://doi.org/10.1016/s0888-7543(05)80107-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1282491">Trezise et al. (1992)</a> demonstrated that the Cftr locus is on rat chromosome 4. Study of other loci suggested that an ancestral mammalian chromosome is represented by the present-day rat chromosome 4: 5 genes are syntenic on rat chromosome 4 and mouse chromosome 6 but are divided between human chromosomes 7 and 12. Another 5 genes that are syntenic on rat chromosome 4 and human chromosome 7 are divided between chromosomes 5 and 6 in the mouse. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1377165+1282491+2531931+1385049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In addition to functioning as a chloride channel, CFTR controls the regulation of other transport pathways. For example, patients with CF and the homozygous CFTR-deficient mouse have enhanced sodium ion absorption; this enhanced sodium ion absorption is corrected by addition of a wildtype copy of CFTR. CFTR and outwardly rectifying chloride channels (ORCCs) are distinct channels but are linked functionally via an unknown regulatory mechanism. <a href="#221" class="mim-tip-reference" title="Schwiebert, E. M., Egan, M. E., Hwang, T.-H., Fulmer, S. B., Allen, S. S., Cutting, G. R., Guggino, W. B. <strong>CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP.</strong> Cell 81: 1063-1073, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7541313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7541313</a>] [<a href="https://doi.org/10.1016/s0092-8674(05)80011-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7541313">Schwiebert et al. (1995)</a> presented results from whole-cell and single-channel patch-clamp recordings, short-circuit current recordings, and ATP-release assays of normal, CF, and wildtype or mutant CFTR-transfected CF airway cultured epithelial cells indicating that CFTR regulates ORCCs by triggering the transport of the potent agonist, ATP, out of the cell. The results suggested that CFTR functions to regulate other chloride ion secretory pathways in addition to conducting chloride ion itself. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7541313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>A quality control system that rapidly degrades abnormal membrane and secretory protein is stringently applied to the CFTR protein; approximately 75% of the wildtype precursor and 100% of the delF508 variant (<a href="#0001">602421.0001</a>) are rapidly degraded before exiting from the endoplasmic reticulum (ER). <a href="#130" class="mim-tip-reference" title="Jensen, T. J., Loo, M. A., Pind, S., Williams, D. B., Goldberg, A. L., Riordan, J. R. <strong>Multiple proteolytic systems, including the proteasome, contribute to CFTR processing.</strong> Cell 83: 129-135, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553864</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90241-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553864">Jensen et al. (1995)</a> demonstrated that CFTR and presumably other intrinsic membrane proteins are substrates for proteasomal degradation during their maturation within the endoplasmic reticulum. <a href="#37" class="mim-tip-reference" title="Chang, X., Cui, L., Hou, Y., Jensen, T. J., Aleksandrov, A. A., Mengos, A., Riordan, J. R. <strong>Removal of multiple arginine-framed trafficking signals overcomes misprocessing of delta-F508 CFTR present in most patients with cystic fibrosis.</strong> Molec. Cell 4: 137-142, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10445036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10445036</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80196-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10445036">Chang et al. (1999)</a> showed that export-incompetent CFTR proteins display multiple arginine-framed tripeptide sequences. Inactivation of 4 of these motifs by replacement of arginine residues at positions R29, R516, R555, and R766 with lysine residues simultaneously caused mutant delF508 CFTR protein to escape ER quality control and function at the cell surface. <a href="#37" class="mim-tip-reference" title="Chang, X., Cui, L., Hou, Y., Jensen, T. J., Aleksandrov, A. A., Mengos, A., Riordan, J. R. <strong>Removal of multiple arginine-framed trafficking signals overcomes misprocessing of delta-F508 CFTR present in most patients with cystic fibrosis.</strong> Molec. Cell 4: 137-142, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10445036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10445036</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80196-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10445036">Chang et al. (1999)</a> suggested that interference with recognition of these signals may be helpful in the management of CF. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10445036+7553864" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#282" class="mim-tip-reference" title="Younger, J. M., Chen, L., Ren, H.-Y., Rosser, M. F. N., Turnbull, E. L., Fan, C.-Y., Patterson, C., Cyr, D. M. <strong>Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator.</strong> Cell 126: 571-582, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16901789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16901789</a>] [<a href="https://doi.org/10.1016/j.cell.2006.06.041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16901789">Younger et al. (2006)</a> identified an ER membrane-associated ubiquitin ligase complex containing the E3 RMA1 (RNF5; <a href="/entry/602677">602677</a>), the E2 UBC6E (UBE2J1), and derlin-1 (DERL1; <a href="/entry/608813">608813</a>) that cooperated with the cytosolic HSC70 (HSPA8; <a href="/entry/600816">600816</a>)/CHIP (STUB1; <a href="/entry/607207">607207</a>) E3 complex to triage CFTR and delFl508. Derlin-1 retained CFTR in the ER membrane and interacted with RMA1 and UBC6E to promote proteasomal degradation of CFTR. RMA1 could recognize folding defects in delF508 coincident with translation, whereas CHIP appeared to act posttranslationally. A folding defect in delF508 detected by RMA1 involved the inability of the second membrane-spanning domain of CFTR to productively interact with N-terminal domains. <a href="#282" class="mim-tip-reference" title="Younger, J. M., Chen, L., Ren, H.-Y., Rosser, M. F. N., Turnbull, E. L., Fan, C.-Y., Patterson, C., Cyr, D. M. <strong>Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator.</strong> Cell 126: 571-582, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16901789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16901789</a>] [<a href="https://doi.org/10.1016/j.cell.2006.06.041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16901789">Younger et al. (2006)</a> concluded that the RMA1 and CHIP E3 ubiquitin ligases act sequentially in ER membrane and cytosol to monitor the folding status of CFTR and delF508. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16901789" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#193" class="mim-tip-reference" title="Randak, C., Neth, P., Auerswald, E. A., Eckerskorn, C., Assfalg-Machleidt, I., Machleidt, W. <strong>A recombinant polypeptide model of the second nucleotide-binding fold of the cystic fibrosis transmembrane conductance regulator functions as an active ATPase, GTPase and adenylate kinase.</strong> FEBS Lett. 410: 180-186, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9237625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9237625</a>] [<a href="https://doi.org/10.1016/s0014-5793(97)00574-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9237625">Randak et al. (1997)</a> expressed NBF2 of CFTR as a soluble protein fused to maltose-binding protein in E. coli and found that it catalyzed hydrolysis of ATP to form ADP and Pi. The ADP product inhibited ATPase activity. NBF2 also hydrolyzed GTP to GDP and Pi. In the presence of AMP, however, the ATPase reaction was superseded by adenylate kinase activity, resulting in formation of 2 ADP molecules from ATP and AMP. <a href="#193" class="mim-tip-reference" title="Randak, C., Neth, P., Auerswald, E. A., Eckerskorn, C., Assfalg-Machleidt, I., Machleidt, W. <strong>A recombinant polypeptide model of the second nucleotide-binding fold of the cystic fibrosis transmembrane conductance regulator functions as an active ATPase, GTPase and adenylate kinase.</strong> FEBS Lett. 410: 180-186, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9237625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9237625</a>] [<a href="https://doi.org/10.1016/s0014-5793(97)00574-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9237625">Randak et al. (1997)</a> identified a typical adenylate kinase-like AMP-binding site in NBF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9237625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine the structural basis for the ATPase activity of CFTR, <a href="#191" class="mim-tip-reference" title="Ramjeesingh, M., Li, C., Garami, E., Huan, L.-J., Galley, K., Wang, Y., Bear, C. E. <strong>Walker mutations reveal loose relationship between catalytic and channel-gating activities of purified CFTR (cystic fibrosis transmembrane conductance regulator).</strong> Biochemistry 38: 1463-1468, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931011</a>] [<a href="https://doi.org/10.1021/bi982243y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931011">Ramjeesingh et al. (1999)</a> studied the effect of mutations in the Walker A consensus motifs on ATP hydrolysis by the purified, intact protein. Mutation of the lysine residue in the Walker A motif of either NBF inhibited the ATPase activity of purified, intact CFTR protein by greater than 50%, suggesting that the 2 NBFs function cooperatively in catalysis. Surprisingly, the rate of channel gating was significantly inhibited only when the mutation was in the second NBF, suggesting that ATPase activity may not be tightly coupled to channel gating. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9931011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#194" class="mim-tip-reference" title="Randak, C., Welsh, M. J. <strong>An intrinsic adenylate kinase activity regulates gating of the ABC transporter CFTR.</strong> Cell 115: 837-850, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14697202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14697202</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00983-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14697202">Randak and Welsh (2003)</a> demonstrated that full-length CFTR and the isolated nucleotide-binding domain-2 (NBD2) had ATPase and adenylate kinase activities following expression in HeLa cells. The adenylate kinase inhibitor Ap5A inhibited CFTR Cl- currents, and it inhibited channel activity by binding an ATP site and an AMP site. Adding AMP switched enzymatic activity of the NBD2 polypeptide from ATPase to adenylate kinase. ATP and AMP appeared to induce dimerization between NBD1 and NBD2, causing the channel to open. <a href="#194" class="mim-tip-reference" title="Randak, C., Welsh, M. J. <strong>An intrinsic adenylate kinase activity regulates gating of the ABC transporter CFTR.</strong> Cell 115: 837-850, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14697202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14697202</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00983-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14697202">Randak and Welsh (2003)</a> hypothesized that at physiologic AMP concentrations, the predominant reaction regulating channel activity is likely adenylate kinase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14697202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#131" class="mim-tip-reference" title="Jiang, Q., Engelhardt, J. F. <strong>Cellular heterogeneity of CFTR expression and function in the lung: implications for gene therapy of cystic fibrosis.</strong> Europ. J. Hum. Genet. 6: 12-31, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9781011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9781011</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9781011">Jiang and Engelhardt (1998)</a> reviewed the cellular heterogeneity of CFTR expression and function in the lung and the important implications for gene therapy of cystic fibrosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9781011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Cystic fibrosis is characterized by persistent Pseudomonas aeruginosa colonization of the conducting airways leading to the migration of inflammatory cells, including polymorphonuclear leukocytes (PMNs), into the airways of CF patients. PMNs release a potent chemokinetic and chemoattractant, leukotriene B, during an inflammatory response, resulting in the further migration of inflammatory cells. <a href="#59" class="mim-tip-reference" title="Cromwell, O., Walport, M. J., Morris, H. R., Taylor, G. W., Hodson, M. E., Batten, J., Kay, A. B. <strong>Identification of leukotrienes D and B in sputum from cystic fibrosis patients.</strong> Lancet 318: 164-165, 1981. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6114241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6114241</a>] [<a href="https://doi.org/10.1016/s0140-6736(81)90353-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6114241">Cromwell et al. (1981)</a> demonstrated the existence of leukotrienes in the sputum of CF patients. The oxidative metabolites of arachidonic acid and the inflammatory cell-derived proteases have been implicated in the destruction and shedding of the airway epithelia observed in CF. Based on these observations, it has been proposed that antiinflammatory drugs might be useful in CF therapy. The nonsteroidal antiinflammatory drug (NSAID) ibuprofen inhibits 5-lipoxygenase and hence leukotriene formation, suggesting that ibuprofen may be useful in the treatment of CF. Its possible benefit in CF, with no apparent adverse effects, was reported by <a href="#146" class="mim-tip-reference" title="Konstan, M. W., Byard, P. J., Hoppel, C. L., Davis, P. B. <strong>Effect of high-dose ibuprofen in patients with cystic fibrosis.</strong> New Eng. J. Med. 332: 848-854, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7503838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7503838</a>] [<a href="https://doi.org/10.1056/NEJM199503303321303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7503838">Konstan et al. (1995)</a>. However, other effects of ibuprofen may counteract therapeutic strategies designed to increase CFTR expression and/or function in secretory epithelia. <a href="#76" class="mim-tip-reference" title="Devor, D. C., Schultz, B. D. <strong>Ibuprofen inhibits cystic fibrosis transmembrane conductance regulator-mediated CI(-) secretion.</strong> J. Clin. Invest. 102: 679-687, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9710435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9710435</a>] [<a href="https://doi.org/10.1172/JCI2614" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9710435">Devor and Schultz (1998)</a> evaluated the acute effects of ibuprofen and salicylic acid on cAMP-mediated Cl- secretion in both colonic and airway epithelia and found that at a pharmacologically relevant concentration the drugs inhibited chloride ion secretion across these epithelia and that this inhibition was due at least in part to the blocking of the CFTR Cl- channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7503838+9710435+6114241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#268" class="mim-tip-reference" title="Wei, L., Vankeerberghen, A., Cuppens, H., Droogmans, G., Cassiman, J.-J., Nilius, B. <strong>Phosphorylation site independent single R-domain mutations affect CFTR channel activity.</strong> FEBS Lett. 439: 121-126, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9849891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9849891</a>] [<a href="https://doi.org/10.1016/s0014-5793(98)01351-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9849891">Wei et al. (1998)</a> studied CFTR channel activity of mature R-domain mutants with point mutations at sites other than the predicted phosphorylation sites. Whole-cell chloride conduction was increased in Xenopus oocytes injected with H620Q-CFTR mRNA, but decreased in the E822K and E826K mutants compared to wildtype CFTR. Anion permeability and single-channel conductances did not differ from wildtype for any of the mutants. Cell-attached single channel studies in COS cells revealed that both open channel probability and/or the number of functional channels were either higher (H260Q) or lower (E822K and E826K) than in wildtype CFTR. These results suggested that sites other than the phosphorylation sites in the R-domain influence gating. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9849891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Chanson, M., Scerri, I., Suter, S. <strong>Defective regulation of gap junctional coupling in cystic fibrosis pancreatic duct cells.</strong> J. Clin. Invest. 103: 1677-1684, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10377174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10377174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10377174[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI5645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10377174">Chanson et al. (1999)</a> compared gap junctional coupling in a human pancreatic cell line harboring the delF508 mutation in CFTR and in the same cell line in which the defect was corrected by transfection with wildtype CFTR. Exposure to agents that elevate intracellular cAMP or specifically activate protein kinase A evoked chloride ion currents and markedly increased junctional conductance of CFTR-expressing cell pairs, but not in the parental cells. Thus, the expression of functional CFTR restored the cAMP-dependent regulation of junctional conductance as well as the chloride ion channel in CF cells. Consequently, defective regulation of gap junction channels may contribute to the altered functions of tissues affected in CF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10377174" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#195" class="mim-tip-reference" title="Reddy, M. M., Light, M. J., Quinton, P. M. <strong>Activation of the epithelial Na(+) channel (ENaC) requires CFTR CI(-) channel function.</strong> Nature 402: 301-304, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10580502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10580502</a>] [<a href="https://doi.org/10.1038/46297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10580502">Reddy et al. (1999)</a> demonstrated that in freshly isolated normal sweat ducts, epithelial sodium channel (ENaC; see <a href="/entry/600228">600228</a>) activity is dependent on, and increases with, CFTR activity. <a href="#195" class="mim-tip-reference" title="Reddy, M. M., Light, M. J., Quinton, P. M. <strong>Activation of the epithelial Na(+) channel (ENaC) requires CFTR CI(-) channel function.</strong> Nature 402: 301-304, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10580502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10580502</a>] [<a href="https://doi.org/10.1038/46297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10580502">Reddy et al. (1999)</a> also found that the primary defect in chloride permeability in cystic fibrosis is accompanied secondarily by a sodium conductance in this tissue that cannot be activated. Thus, reduced salt absorption in cystic fibrosis is due not only to poor chloride conductance but also to poor sodium conductance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10580502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#269" class="mim-tip-reference" title="Weixel, K. M., Bradbury, N. A. <strong>The carboxyl terminus of the cystic fibrosis transmembrane conductance regulator binds to AP-2 clathrin adaptors.</strong> J. Biol. Chem. 275: 3655-3660, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10652362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10652362</a>] [<a href="https://doi.org/10.1074/jbc.275.5.3655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10652362">Weixel and Bradbury (2000)</a> used in vivo cross-linking and in vitro pull-down assays to show that full-length CFTR binds to the endocytic adaptor complex AP2 (see <a href="/entry/601024">601024</a>). Substitution of an alanine residue for tyrosine at position 1424 significantly reduced the ability of AP2 to bind the C terminus of CFTR. However, mutation to a phenylalanine residue, which is normally found in dogfish CFTR at this position, did not perturb AP2 binding. Taken together, these data suggest that the C terminus of CFTR contains a tyrosine-based internalization signal that interacts with the endocytic adaptor complex AP2 to facilitate efficient entry of CFTR into clathrin-coated vesicles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10652362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#262" class="mim-tip-reference" title="Wang, S., Yue, H., Derin, R. B., Guggino, W. B., Li, M. <strong>Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity.</strong> Cell 103: 169-179, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11051556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11051556</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)00096-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11051556">Wang et al. (2000)</a> identified a hydrophilic CFTR-binding protein, CAP70, which is concentrated on the apical surfaces. CAP70 had previously been identified by <a href="#145" class="mim-tip-reference" title="Kocher, O., Comella, N., Tognazzi, K., Brown, L. F. <strong>Identification and partial characterization of PDZK1: a novel protein containing PDZ interaction domains.</strong> Lab. Invest. 78: 117-125, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9461128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9461128</a>]" pmid="9461128">Kocher et al. (1998)</a> as PDZK1 (<a href="/entry/603831">603831</a>). The protein contains 4 PDZ domains, 3 of which are capable of binding to the CFTR C terminus. Linking at least 2 CFTR molecules via cytoplasmic C-terminal binding by either multivalent CAP70 or a bivalent monoclonal antibody potentiates the CFTR chloride channel activity. Thus, the CFTR channel can be switched to a more active conducting state via a modification of intermolecular CFTR-CFTR contact that is enhanced by an accessory protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9461128+11051556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#167" class="mim-tip-reference" title="Moyer, B. D., Duhaime, M., Shaw, C., Denton, J., Reynolds, D., Karlson, K. H., Pfeiffer, J., Wang, S., Mickle, J. E., Milewski, M., Cutting, G. R., Guggino, W. B., Li, M., Stanton, B. A. <strong>The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane.</strong> J. Biol. Chem. 275: 27069-27074, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852925</a>] [<a href="https://doi.org/10.1074/jbc.M004951200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10852925">Moyer et al. (2000)</a> reported that the C terminus of CFTR constitutes a PDZ-interacting domain that is required for CFTR polarization to the apical plasma membrane and interaction with the PDZ domain-containing protein EBP50 (<a href="/entry/604990">604990</a>). PDZ-interacting domains are typically composed of the C-terminal 3 to 5 amino acids, which in CFTR are gln-asp-thr-arg-leu. Point substitution of the leucine at position 0 with alanine abrogated apical polarization of CFTR, interaction between CFTR and EBP50, efficient expression of CFTR in the apical membrane, and chloride secretion. Point substitution of the threonine at position -2 with alanine or valine had no effect on the apical polarization of CFTR, but reduced interaction between CFTR and EBP50, efficient expression of CFTR in the apical membrane, and chloride secretion. By contrast, individual point substitution of any of the other amino acids in the PDZ domain had no effect on measured parameters. <a href="#167" class="mim-tip-reference" title="Moyer, B. D., Duhaime, M., Shaw, C., Denton, J., Reynolds, D., Karlson, K. H., Pfeiffer, J., Wang, S., Mickle, J. E., Milewski, M., Cutting, G. R., Guggino, W. B., Li, M., Stanton, B. A. <strong>The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane.</strong> J. Biol. Chem. 275: 27069-27074, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852925</a>] [<a href="https://doi.org/10.1074/jbc.M004951200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10852925">Moyer et al. (2000)</a> concluded that mutations that delete the C terminus of CFTR may cause cystic fibrosis because CFTR is not polarized, complexed with EBP50, or efficiently expressed in the apical membrane of epithelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10852925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>CFTR regulates other transporters, including chloride-coupled bicarbonate transport. Alkaline fluids are secreted by normal tissues, whereas acidic fluids are secreted by mutant CFTR-expressing tissues, indicating the importance of this activity. Bicarbonate and pH affect mucin viscosity and bacterial binding. <a href="#48" class="mim-tip-reference" title="Choi, J. Y., Muallem, D., Kiselyov, K., Lee, M. G., Thomas, P. J., Muallem, S. <strong>Aberrant CFTR-dependent HCO(-3) transport in mutations associated with cystic fibrosis.</strong> Nature 410: 94-97, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242048</a>] [<a href="https://doi.org/10.1038/35065099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242048">Choi et al. (2001)</a> examined chloride-coupled bicarbonate transport by CFTR mutants that retain substantial or normal chloride channel activity. <a href="#48" class="mim-tip-reference" title="Choi, J. Y., Muallem, D., Kiselyov, K., Lee, M. G., Thomas, P. J., Muallem, S. <strong>Aberrant CFTR-dependent HCO(-3) transport in mutations associated with cystic fibrosis.</strong> Nature 410: 94-97, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242048</a>] [<a href="https://doi.org/10.1038/35065099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242048">Choi et al. (2001)</a> demonstrated that mutants reported to be associated with cystic fibrosis with pancreatic insufficiency do not support bicarbonate transport, and those associated with pancreatic sufficiency show reduced bicarbonate transport. <a href="#48" class="mim-tip-reference" title="Choi, J. Y., Muallem, D., Kiselyov, K., Lee, M. G., Thomas, P. J., Muallem, S. <strong>Aberrant CFTR-dependent HCO(-3) transport in mutations associated with cystic fibrosis.</strong> Nature 410: 94-97, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242048</a>] [<a href="https://doi.org/10.1038/35065099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242048">Choi et al. (2001)</a> concluded that their findings demonstrate the importance of bicarbonate transport in the function of secretory epithelia and in CF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#208" class="mim-tip-reference" title="Rowntree, R. K., Vassaux, G., McDowell, T. L., Howe, S., McGuigan, A., Phylactides, M., Huxley, C., Harris, A. <strong>An element in intron 1 of the CFTR gene augments intestinal expression in vivo.</strong> Hum. Molec. Genet. 10: 1455-1464, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11448937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11448937</a>] [<a href="https://doi.org/10.1093/hmg/10.14.1455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11448937">Rowntree et al. (2001)</a> showed that removal of a DNase I hypersensitive site (DHS) in intron 1 (185+10 kb) of CFTR abolished the activity of this DHS in transient transfection assays of reporter/enhancer gene constructs. Stable transfections of a human colon carcinoma cell line with CFTR-containing YACs showed that transcription from the DHS element-deleted YAC was reduced by 60% compared to the intact construct. In transgenic mice, deletion of the intron 1 DHS had no effect on expression in the lung, but reduced expression in the intestine by 60%. The authors concluded that the regulatory element associated with the intron 1 DHS is tissue-specific and is required for normal CFTR expression levels in the intestinal epithelium in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11448937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Callen, A., Diener-West, M., Zeitlin, P. L., Rubenstein, R. C. <strong>A simplified cyclic adenosine monophosphate-mediated sweat rate test for quantitative measure of cystic fibrosis transmembrane regulator (CFTR) function.</strong> J. Pediat. 137: 849-855, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113843</a>] [<a href="https://doi.org/10.1067/mpd.2000.109198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113843">Callen et al. (2000)</a> developed a cAMP-mediated sweat rate test that allows the quantitative discrimination of CFTR function, thereby indicating CF genotype: CF, CF carrier, and non-CF. <a href="#29" class="mim-tip-reference" title="Callen, A., Diener-West, M., Zeitlin, P. L., Rubenstein, R. C. <strong>A simplified cyclic adenosine monophosphate-mediated sweat rate test for quantitative measure of cystic fibrosis transmembrane regulator (CFTR) function.</strong> J. Pediat. 137: 849-855, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11113843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11113843</a>] [<a href="https://doi.org/10.1067/mpd.2000.109198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11113843">Callen et al. (2000)</a> remarked that this test may be helpful in the diagnosis of ambiguous cases and in studies of new agents to increase the function of CFTR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11113843" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In CFTR, an abbreviated polypyrimidine tract between the branch point A and the 3-prime splice site is associated with increased exon skipping and disease. However, many exons, both in CFTR and in other genes, have short polypyrimidine tracts in their 3-prime splice sites, yet they are not skipped. <a href="#122" class="mim-tip-reference" title="Hefferon, T. W., Broackes-Carter, F. C., Harris, A., Cutting, G. R. <strong>Atypical 5-prime splice sites cause CFTR exon 9 to be vulnerable to skipping.</strong> Am. J. Hum. Genet. 71: 294-303, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12068373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12068373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12068373[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/341664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12068373">Hefferon et al. (2002)</a> examined the molecular basis of the skipping of constitutive exons in mRNAs and the skipping of exon 9 in the CFTR gene. They reported observations in human, mouse, and sheep that placed renewed emphasis on deviations at 3-prime splice sites in nucleotides other than the invariant GT, particularly when such changes are found in conjunction with other altered splicing sequences, such as a shortened polypyrimidine tract. <a href="#122" class="mim-tip-reference" title="Hefferon, T. W., Broackes-Carter, F. C., Harris, A., Cutting, G. R. <strong>Atypical 5-prime splice sites cause CFTR exon 9 to be vulnerable to skipping.</strong> Am. J. Hum. Genet. 71: 294-303, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12068373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12068373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12068373[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/341664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12068373">Hefferon et al. (2002)</a> suggested that careful inspection of entire 5-prime splice sites may identify constitutive exons that are vulnerable to skipping. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12068373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a quantitative mRNA assay at 14 time points through ovine gestation, <a href="#21" class="mim-tip-reference" title="Broackes-Carter, F. C., Mouchel, N., Gill, D., Hyde, S., Bassett, J., Harris, A. <strong>Temporal regulation of CFTR expression during ovine lung development: implications for CF gene therapy.</strong> Hum. Molec. Genet. 11: 125-131, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11809721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11809721</a>] [<a href="https://doi.org/10.1093/hmg/11.2.125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11809721">Broackes-Carter et al. (2002)</a> determined that CFTR expression was highest at the start of the second trimester followed by a gradual decline through to term. In contrast, epithelial sodium channel (SCNN1A; <a href="/entry/600228">600228</a>) expression increased from the start of the third trimester. The authors proposed a role for CFTR in differentiation of the respiratory epithelium and suggested that its expression levels are not merely reflecting major changes in the sodium/chloride bulk flow close to term. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11809721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#88" class="mim-tip-reference" title="Eidelman, O., BarNoy, S., Razin, M., Zhang, J., McPhie, P., Lee, G., Huang, Z., Sorscher, E. J., Pollard, H. B. <strong>Role for phospholipid interactions in the trafficking defect of delta-F508-CFTR.</strong> Biochemistry 41: 11161-11170, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12220181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12220181</a>] [<a href="https://doi.org/10.1021/bi020289s" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12220181">Eidelman et al. (2002)</a> found that NBF1 of CFTR interacted selectively with phosphatidylserine rather than phosphatidylcholine. In contrast, NBF1 with the delta-F508 mutation lost the ability to discriminate between these phospholipids. In mouse L cells expressing delta-F508 CFTR, replacement of phosphatidylcholine by noncharged analogs led to increased CFTR protein expression, suggesting that aberrant interaction between the delta-F508 NFB1 domain and phospholipid chaperones may contribute to the processing defect of the delta-F508 CFTR mutant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12220181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Plasma membrane expression of delta-F508 CFTR can be rescued in epithelial cells by culturing them at 27 degrees Celsius for 24 hours. By screening 100,000 diverse small molecules, <a href="#277" class="mim-tip-reference" title="Yang, H., Shelat, A. A., Guy, R. K., Gopinath, V. S., Ma, T., Du, K., Lukacs, G. L., Taddei, A., Folli, C., Pedemonte, N., Galietta, L. J. V., Verkman, A. S. <strong>Nanomolar affinity small molecule correctors of defective delta-F508-CFTR chloride channel gating.</strong> J. Biol. Chem. 278: 35079-35085, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12832418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12832418</a>] [<a href="https://doi.org/10.1074/jbc.M303098200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12832418">Yang et al. (2003)</a> found that tetrahydrobenzothiophenes could activate cold-induced membrane-associated delta-F508 CFTR, resulting in reversible Cl- conductance in transfected rat thyroid epithelial cells. Single-cell voltage clamp analysis showed characteristic CFTR currents. Activation required low concentrations of a cAMP agonist, mimicking the normal physiologic response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12832418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#196" class="mim-tip-reference" title="Reddy, M. M., Quinton, P. M. <strong>Control of dynamic CFTR selectivity by glutamate and ATP in epithelial cells.</strong> Nature 423: 756-760, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12802335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12802335</a>] [<a href="https://doi.org/10.1038/nature01694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12802335">Reddy and Quinton (2003)</a> reported phosphorylation- and ATP-independent activation of CFTR by cytoplasmic glutamate that exclusively elicits chloride but not bicarbonate conductance in the human sweat duct. They also showed that the anion selectivity of glutamate-activated CFTR is not intrinsically fixed, but can undergo a dynamic shift to conduct bicarbonate by a process involving ATP hydrolysis. Duct cells from patients with the delta-F508 CFTR mutation showed no glutamate/ATP-activated chloride or bicarbonate conductance. In contrast, duct cells from heterozygous patients with R117H (<a href="#0005">602421.0005</a>)/delta-F508 mutations also lost most of the chloride conductance, yet retained significant bicarbonate conductance. <a href="#196" class="mim-tip-reference" title="Reddy, M. M., Quinton, P. M. <strong>Control of dynamic CFTR selectivity by glutamate and ATP in epithelial cells.</strong> Nature 423: 756-760, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12802335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12802335</a>] [<a href="https://doi.org/10.1038/nature01694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12802335">Reddy and Quinton (2003)</a> concluded that not only does glutamate control neuronal ion channels, but it can also regulate anion conductance and selectivity of CFTR in native epithelial cells. They proposed that the loss of this uniquely regulated bicarbonate conductance is most likely responsible for the more severe forms of cystic fibrosis pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12802335" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#263" class="mim-tip-reference" title="Wang, X. F., Zhou, C. X., Shi, Q. X., Yuan, Y. Y., Yu, M. K., Ajonuma, L. C., Ho, L. S., Lo, P. S., Tsang, L. L., Liu, Y., Lam, S. Y., Chan, L. N., Zhao, W. C., Chung, Y. W., Chan, H. C. <strong>Involvement of CFTR in uterine bicarbonate secretion and the fertilizing capacity of sperm.</strong> Nature Cell Biol. 5: 902-906, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14515130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14515130</a>] [<a href="https://doi.org/10.1038/ncb1047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14515130">Wang et al. (2003)</a> demonstrated that endometrial epithelial cells possess a CFTR-mediated bicarbonate transport mechanism. Coculture of sperm with endometrial cells treated with antisense oligonucleotide against CFTR, or with bicarbonate secretion-defective CF epithelial cells, resulted in lower sperm capacitation and egg-fertilizing ability. These results were considered consistent with a critical role of CFTR in controlling uterine bicarbonate secretion and the fertilizing capacity of sperm, providing a link between defective CFTR and lower female fertility in CF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14515130" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Sheep and human CFTR genes show a gradual decline in expression during lung development, from the early midtrimester through to term. <a href="#166" class="mim-tip-reference" title="Mouchel, N., Broackes-Carter, F., Harris, A. <strong>Alternative 5-prime exons of the CFTR gene show developmental regulation.</strong> Hum. Molec. Genet. 12: 759-769, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12651871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12651871</a>] [<a href="https://doi.org/10.1093/hmg/ddg079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12651871">Mouchel et al. (2003)</a> identified a novel 5-prime exon of the sheep CFTR gene (ov1a) that occurs in 2 splice forms (ov1aL and ov1aS), which are both mutually exclusive with exon 1. CFTR transcripts, including ov1aL and ov1aS, were present at low levels in many sheep tissues; however, ov1aS showed temporal and spatial regulation during fetal lung development, being most abundant when CFTR expression starts to decline. Alternative 5-prime exons -1a and 1a in the human CFTR gene also showed changes in expression levels through lung development. Structural evaluation of ov1aL and ov1aS revealed the potential to form extremely stable secondary structures which would cause ribosomal subunit detachment. Further, the loss of exon 1 from the CFTR transcript removed motifs that are thought crucial for normal trafficking of the CFTR protein. <a href="#166" class="mim-tip-reference" title="Mouchel, N., Broackes-Carter, F., Harris, A. <strong>Alternative 5-prime exons of the CFTR gene show developmental regulation.</strong> Hum. Molec. Genet. 12: 759-769, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12651871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12651871</a>] [<a href="https://doi.org/10.1093/hmg/ddg079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12651871">Mouchel et al. (2003)</a> hypothesized that recruitment of these alternative upstream exons may represent a novel mechanism of developmental regulation of CFTR expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12651871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#96" class="mim-tip-reference" title="Fischer, H., Schwarzer, C., Illek, B. <strong>Vitamin C controls the cystic fibrosis transmembrane conductance regulator chloride channel.</strong> Proc. Nat. Acad. Sci. 101: 3691-3696, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14993613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14993613</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14993613[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0308393100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14993613">Fischer et al. (2004)</a> found that vitamin C induced the opening of CFTR chloride channels by increasing the average open probability in the absence of detectable increased cAMP levels. Exposure of the apical airway surface to physiologic concentrations of vitamin C stimulated transepithelial chloride secretion. When instilled into the nasal epithelium of human subjects, vitamin C activated chloride transport. <a href="#96" class="mim-tip-reference" title="Fischer, H., Schwarzer, C., Illek, B. <strong>Vitamin C controls the cystic fibrosis transmembrane conductance regulator chloride channel.</strong> Proc. Nat. Acad. Sci. 101: 3691-3696, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14993613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14993613</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14993613[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0308393100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14993613">Fischer et al. (2004)</a> concluded that cellular vitamin C, via its apical vitamin C transporter, is a biologic regulator of CFTR-mediated chloride secretion in epithelia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14993613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#254" class="mim-tip-reference" title="Vergani, P., Lockless, S. W., Nairn, A. C., Gadsby, D. C. <strong>CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains.</strong> Nature 433: 876-880, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15729345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15729345</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15729345[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature03313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15729345">Vergani et al. (2005)</a> used single-channel recording methods on intact CFTR molecules to directly follow opening and closing of the channel gates, and related these occurrences to ATP-mediated events in the nucleotide binding domains (NBDs). They found that energetic coupling between 2 CFTR residues, expected to lie on opposite sides of its predicted NBD1-NBD2 dimer interface, changes in concert with channel gating status. The 2 monitored side chains are independent of each other in closed channels but become coupled as the channels open. <a href="#254" class="mim-tip-reference" title="Vergani, P., Lockless, S. W., Nairn, A. C., Gadsby, D. C. <strong>CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains.</strong> Nature 433: 876-880, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15729345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15729345</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15729345[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature03313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15729345">Vergani et al. (2005)</a> concluded that their results directly link ATP-driven tight dimerization of CFTR's cytoplasmic nucleotide binding domains to opening of the ion channel in the transmembrane domains. This establishes a molecular mechanism, involving dynamic restructuring of the NBD dimer interface, that is probably common to all members of the ABC protein superfamily. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15729345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using proteomics to assess global CFTR protein interactions, <a href="#264" class="mim-tip-reference" title="Wang, X., Venable, J., LaPointe, P., Hutt, D. M., Koulov, A. V., Coppinger, J., Gurkan, C., Kellner, W., Matteson, J., Plutner, H., Riordan, J. R., Kelly, J. W., Yates, J. R., III, Balch, W. E. <strong>Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis.</strong> Cell 127: 803-815, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17110338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17110338</a>] [<a href="https://doi.org/10.1016/j.cell.2006.09.043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17110338">Wang et al. (2006)</a> showed that HSP90 (see <a href="/entry/140571">140571</a>) cochaperones modulated HSP90-dependent stability of CFTR protein folding in the ER. Small interfering RNA-mediated partial silencing of the HSP90 cochaperone ATPase regulator AHA1 (AHSA1; <a href="/entry/608466">608466</a>) in human embryonic kidney and lung cell lines rescued delivery of CFTR delta-F508 to the cell surface. <a href="#264" class="mim-tip-reference" title="Wang, X., Venable, J., LaPointe, P., Hutt, D. M., Koulov, A. V., Coppinger, J., Gurkan, C., Kellner, W., Matteson, J., Plutner, H., Riordan, J. R., Kelly, J. W., Yates, J. R., III, Balch, W. E. <strong>Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis.</strong> Cell 127: 803-815, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17110338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17110338</a>] [<a href="https://doi.org/10.1016/j.cell.2006.09.043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17110338">Wang et al. (2006)</a> proposed that failure of CFTR delta-F508 to achieve an energetically favorable fold in response to steady-state dynamics of the chaperone folding environment is responsible for the pathophysiology of CF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17110338" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using proteomic approaches, <a href="#246" class="mim-tip-reference" title="Thelin, W. R., Chen, Y., Gentzsch, M., Kreda, S. M., Sallee, J. L., Scarlett, C. O., Borchers, C. H., Jacobson, K., Stutts, M. J., Milgram, S. L. <strong>Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR.</strong> J. Clin. Invest. 117: 364-374, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235394</a>] [<a href="https://doi.org/10.1172/JCI30376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235394">Thelin et al. (2007)</a> showed that filamin (FLNA; <a href="/entry/300017">300017</a>) associates with the extreme CFTR N terminus, and found that the disease-causing S13F mutation disrupts this interaction. Cell studies revealed that FLNA tethers plasma membrane CFTR to the underlying actin network, stabilizing CFTR at the cell surface and regulating the plasma membrane dynamics and confinement of the channel. In the absence of filamin binding, CFTR is rapidly internalized from the cell surface, where it accumulates prematurely in lysosomes and is ultimately degraded. <a href="#246" class="mim-tip-reference" title="Thelin, W. R., Chen, Y., Gentzsch, M., Kreda, S. M., Sallee, J. L., Scarlett, C. O., Borchers, C. H., Jacobson, K., Stutts, M. J., Milgram, S. L. <strong>Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR.</strong> J. Clin. Invest. 117: 364-374, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235394</a>] [<a href="https://doi.org/10.1172/JCI30376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235394">Thelin et al. (2007)</a> concluded that the CFTR N terminus plays a role in the regulation of the plasma membrane stability and metabolic stability of CFTR, and stated that S13F is the first missense mutation in CFTR found to disrupt a protein-protein interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17235394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Coimmunoprecipitation analysis and immunofluorescence microscopy by <a href="#44" class="mim-tip-reference" title="Cheng, J., Moyer, B. D., Milewski, M., Loffing, J., Ikeda, M., Mickle, J. E., Cutting, G. R., Li, M., Stanton, B. A., Guggino, W. B. <strong>A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression.</strong> J. Biol. Chem. 277: 3520-3529, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11707463/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11707463</a>] [<a href="https://doi.org/10.1074/jbc.M110177200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11707463">Cheng et al. (2002)</a> showed that CAL (GOPC; <a href="/entry/606845">606845</a>) interacted with the C terminus of CFTR in the Golgi. Functional analysis indicated that the CAL-CFTR interaction resulted in a reduction of the CFTR chloride current by a selective inhibition of cell surface CFTR expression; this could be reversed by competition from NHERF (<a href="/entry/604990">604990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11707463" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#43" class="mim-tip-reference" title="Cheng, J., Cebotaru, V., Cebotaru, L., Guggino, W. B. <strong>Syntaxin 6 and CAL mediate the degradation of the cystic fibrosis transmembrane conductance regulator.</strong> Molec. Biol. Cell 21: 1178-1187, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20130090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20130090</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20130090[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1091/mbc.e09-03-0229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20130090">Cheng et al. (2010)</a> showed that both syntaxin-6 (STX6; <a href="/entry/603944">603944</a>) and CAL were involved in downregulation of CFTR via lysosome-mediated degradation. STX6 bound the N terminus of CFTR, and CAL independently bound the C terminus of CFTR. Overexpression of STX6 reduced cell surface expression of CFTR and caused its instability, but not in the absence of CAL and not in the presence of a lysosome inhibitor. Conversely, overexpression of a dominant-negative STX6 mutant or knockdown of STX6 resulted in CFTR stability. STX6 and CAL had no effect on the stability of delta-F508 CFTR, which is retained in the ER and undergoes ER-associated degradation. <a href="#43" class="mim-tip-reference" title="Cheng, J., Cebotaru, V., Cebotaru, L., Guggino, W. B. <strong>Syntaxin 6 and CAL mediate the degradation of the cystic fibrosis transmembrane conductance regulator.</strong> Molec. Biol. Cell 21: 1178-1187, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20130090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20130090</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20130090[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1091/mbc.e09-03-0229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20130090">Cheng et al. (2010)</a> concluded that STX6 and CAL function in the trans-Golgi network and direct trafficking of CFTR to the lysosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20130090" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By coimmunoprecipitation of transfected COS-7 and CHO-K1 cells, <a href="#199" class="mim-tip-reference" title="Rode, B., Dirami, T., Bakouh, N., Rizk-Rabin, M., Norez, C., Lhuillier, P., Lores, P., Jollivet, M., Melin, P., Zvetkova, I., Bienvenu, T., Becq, F., Planelles, G., Edelman, A., Gacon, G., Toure, A. <strong>The testis anion transporter TAT1 (SLC26A8) physically and functionally interacts with the cystic fibrosis transmembrane conductance regulator channel: a potential role during sperm capacitation.</strong> Hum. Molec. Genet. 21: 1287-1298, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22121115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22121115</a>] [<a href="https://doi.org/10.1093/hmg/ddr558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22121115">Rode et al. (2012)</a> found that human testis anion transporter-1 (TAT1, or SLC26A8; <a href="/entry/608480">608480</a>) interacted with the Cl- and HCO3- conductor CFTR. The 2 proteins colocalized at the equatorial segment of the human sperm head, with partial colocalization at the annulus. Similar colocalization was observed in mouse sperm. Voltage clamp experiments showed that TAT1 enhanced PKA (see <a href="/entry/188830">188830</a>)-stimulated currents in CFTR-expressing Xenopus oocytes and stimulated cAMP-dependent CFTR-mediated iodide efflux in transfected CHO-K1 cells. TAT1 alone did not mediate iodide efflux in CHO-K1 cells and did not affect whole-cell conductance in Xenopus oocytes, suggesting that TAT1 is an electroneutral anion exchanger. <a href="#199" class="mim-tip-reference" title="Rode, B., Dirami, T., Bakouh, N., Rizk-Rabin, M., Norez, C., Lhuillier, P., Lores, P., Jollivet, M., Melin, P., Zvetkova, I., Bienvenu, T., Becq, F., Planelles, G., Edelman, A., Gacon, G., Toure, A. <strong>The testis anion transporter TAT1 (SLC26A8) physically and functionally interacts with the cystic fibrosis transmembrane conductance regulator channel: a potential role during sperm capacitation.</strong> Hum. Molec. Genet. 21: 1287-1298, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22121115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22121115</a>] [<a href="https://doi.org/10.1093/hmg/ddr558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22121115">Rode et al. (2012)</a> concluded that TAT1 and CFTR cooperate in the regulation of Cl-/HCO3- fluxes required for sperm motility and capacitation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22121115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By overexpression and knockdown analyses, <a href="#181" class="mim-tip-reference" title="Ousingsawat, J., Kongsuphol, P., Schreiber, R., Kunzelmann, K. <strong>CFTR and TMEM16A are separate but functionally related Cl- channels.</strong> Cell. Physiol. Biochem. 28: 715-724, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22178883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22178883</a>] [<a href="https://doi.org/10.1159/000335765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22178883">Ousingsawat et al. (2011)</a> showed that TMEM16A (<a href="/entry/610108">610108</a>) formed Ca(2+)-activated Cl- channels (CaCCs) in human airway epithelial cells and that TMEM16A was inhibited by CFTR (<a href="/entry/602421">602421</a>). However, knockdown analysis in HEK293 cells revealed that CFTR currents were largely independent of other TMEM16 isoforms. CFTR and TMEM16A had an inverse relationship, as CFTR currents were attenuated by additional expression of TMEM16A in HEK293 cells. CFTR and TMEM16A localized to the membrane and appeared to interact physically. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22178883" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#89" class="mim-tip-reference" title="El Khouri, E., Le Pavec, G., Toledano, M. B., Delaunay-Moisan, A. <strong>RNF185 is a novel E3 ligase of endoplasmic reticulum-associated degradation (ERAD) that targets cystic fibrosis transmembrane conductance regulator (CFTR).</strong> J. Biol. Chem. 288: 31177-31191, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24019521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24019521</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24019521[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M113.470500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24019521">El Khouri et al. (2013)</a> found that the RING-dependent E3 ligase RNF185 (<a href="/entry/620096">620096</a>) was transcriptionally induced during the unfolded protein response (UPR) and was associated with ER-associated degradation (ERAD). RNF185 targeted CFTR to ERAD to regulate CFTR turnover by inducing ubiquitin-proteasome-dependent degradation of CFTR proteins during translation. Further analysis indicated that RNF5 and RNF185 had redundant function in the control of CFTR stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24019521" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Benedetto, R., Ousingsawat, J., Wanitchakool, P., Zhang, Y., Holtzman, M. J., Amaral, M., Rock, J. R., Schreiber, R., Kunzelmann, K. <strong>Epithelial chloride transport by CFTR requires TMEM16A.</strong> Sci. Rep. 7: 12397, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28963502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28963502</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28963502[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41598-017-10910-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28963502">Benedetto et al. (2017)</a> found that Ca(2+)-activated and cAMP-stimulated Cftr-dependent chloride secretion depended on Tmem16a expression, as knockout of Tmem16a eliminated Cftr currents in mouse intestinal epithelial cells and mouse respiratory epithelial cells. Analysis with human airway epithelial cells further established that Cl- currents by CFTR and TMEM16A were functionally linked and interdependent. Mechanistically, TMEM16A enhanced Ca(2+) store release to provide Ca(2+) for activation of CFTR in the presence of cAMP through Ca(2+)-dependent adenylate cyclases. TMEM16A also regulated membrane expression of CFTR. Further analysis revealed that CFTR and TMEM16A interacted, likely with the help of adaptor proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28963502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using single-cell RNA sequencing and in vivo lineage tracing to study the composition and hierarchy of the mouse tracheal epithelium, <a href="#164" class="mim-tip-reference" title="Montoro, D. T., Haber, A. L., Biton, M., Vinarsky, V., Lin, B., Birket, S. E., Yuan, F., Chen, S., Leung, H. M., Villoria, J., Rogel, N., Burgin, G., and 17 others. <strong>A revised airway epithelial hierarchy includes CFTR-expressing ionocytes.</strong> Nature 560: 319-324, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30069044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30069044</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30069044[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0393-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30069044">Montoro et al. (2018)</a> identified a rare cell type, the Foxi1 (<a href="/entry/601093">601093</a>)-positive pulmonary ionocyte; functional variations in club cells based on their location; a distinct cell type in high turnover squamous epithelial structures that they termed 'hillocks'; and disease-relevant subsets of tuft and goblet cells. <a href="#164" class="mim-tip-reference" title="Montoro, D. T., Haber, A. L., Biton, M., Vinarsky, V., Lin, B., Birket, S. E., Yuan, F., Chen, S., Leung, H. M., Villoria, J., Rogel, N., Burgin, G., and 17 others. <strong>A revised airway epithelial hierarchy includes CFTR-expressing ionocytes.</strong> Nature 560: 319-324, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30069044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30069044</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30069044[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0393-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30069044">Montoro et al. (2018)</a> developed 'pulse-seq,' combining single-cell RNA-seq and lineage tracing, to show that tuft, neuroendocrine, and ionocyte cells are continually and directly replenished by basal progenitor cells. Ionocytes are the major source of transcripts of the CFTR in both mouse and human. Knockout of Foxi1 in mouse ionocytes caused loss of Cftr expression and disrupted airway fluid and mucus physiology, phenotypes that are characteristic of cystic fibrosis. <a href="#164" class="mim-tip-reference" title="Montoro, D. T., Haber, A. L., Biton, M., Vinarsky, V., Lin, B., Birket, S. E., Yuan, F., Chen, S., Leung, H. M., Villoria, J., Rogel, N., Burgin, G., and 17 others. <strong>A revised airway epithelial hierarchy includes CFTR-expressing ionocytes.</strong> Nature 560: 319-324, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30069044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30069044</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30069044[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0393-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30069044">Montoro et al. (2018)</a> concluded that by associating cell type-specific expression programs with key disease genes, they had established a new cellular narrative for airway disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30069044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#190" class="mim-tip-reference" title="Plasschaert, L. W., Zilionis, R., Choo-Wing, R., Savova, V., Knehr, J., Roma, G., Klein, A. M., Jaffe, A. B. <strong>A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte.</strong> Nature 560: 377-381, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30069046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30069046</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30069046[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0394-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30069046">Plasschaert et al. (2018)</a> performed single-cell profiling of human bronchial epithelial cells and mouse tracheal epithelial cells to obtain a comprehensive census of cell types in the conducting airway and their behavior in homeostasis and regeneration. The analysis revealed cell states that represent known and novel cell populations, delineated their heterogeneity, and identified distinct differentiation trajectories during homeostasis and tissue repair. In addition, <a href="#190" class="mim-tip-reference" title="Plasschaert, L. W., Zilionis, R., Choo-Wing, R., Savova, V., Knehr, J., Roma, G., Klein, A. M., Jaffe, A. B. <strong>A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte.</strong> Nature 560: 377-381, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30069046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30069046</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30069046[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0394-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30069046">Plasschaert et al. (2018)</a> identified a novel, rare cell type that they called the 'pulmonary ionocyte,' which coexpresses FOXI1, multiple subunits of the vacuolar-type H(+)-ATPase (V-ATPase), and CFTR. Using immunofluorescence, modulation of signaling pathways, and electrophysiology, <a href="#190" class="mim-tip-reference" title="Plasschaert, L. W., Zilionis, R., Choo-Wing, R., Savova, V., Knehr, J., Roma, G., Klein, A. M., Jaffe, A. B. <strong>A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte.</strong> Nature 560: 377-381, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30069046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30069046</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30069046[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0394-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30069046">Plasschaert et al. (2018)</a> showed that Notch signaling (see <a href="/entry/190198">190198</a>) is necessary and FOXI1 expression is sufficient to drive the production of the pulmonary ionocyte, and that the pulmonary ionocyte is a major source of CFTR activity in the conducting airway epithelium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30069046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#223" class="mim-tip-reference" title="Serohijos, A. W. R., Hegedus, T., Aleksandrov, A. A., He, L., Cui, L., Dokholyan, N. V., Riordan, J. R. <strong>Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function.</strong> Proc. Nat. Acad. Sci. 105: 3256-3261, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18305154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18305154</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18305154[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0800254105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18305154">Serohijos et al. (2008)</a> presented a 3-dimensional structure of CFTR, constructed by molecular modeling and supported biochemically, in which phe508 mediates a tertiary interaction between the surface of the N-terminal nucleotide-binding domain and cytoplasmic loop-4 in the C-terminal membrane-spanning domain. This crucial cytoplasmic membrane interface is involved in regulation of channel gating and explains the sensitivity of CFTR assembly to disease-associated mutations in cytoplasmic loop-4, as well as in the N-terminal nucleotide-binding domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18305154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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<a href="#155" class="mim-tip-reference" title="Liu, F., Zhang, Z., Levit, A., Levring, J., Touhara, K. K., Shoichet, B. K., Chen, J. <strong>Structural identification of a hotspot on CFTR for potentiation.</strong> Science 364: 1184-1188, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31221859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31221859</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31221859[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aaw7611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31221859">Liu et al. (2019)</a> reported 2 cryoelectron microscopy structures of human CFTR in complex with potentiators: one with ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These 2 drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggested that in both cases, hydrogen bonds provided by the protein are important for drug recognition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31221859" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#138" class="mim-tip-reference" title="Kerem, B., Rommens, J. M., Buchanan, J. A., Markiewicz, D., Cox, T. K., Chakravarti, A., Buchwald, M., Tsui, L.-C. <strong>Identification of the cystic fibrosis gene: genetic analysis.</strong> Science 245: 1073-1080, 1989. Note: Erratum: Science 245: 1437 only, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2570460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2570460</a>] [<a href="https://doi.org/10.1126/science.2570460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2570460">Kerem et al. (1989)</a> found that approximately 70% of the mutations in CF patients correspond to a specific deletion of 3 basepairs, which results in the loss of a phenylalanine residue at amino acid position 508 of the putative product of the CF gene (F508del; <a href="#0001">602421.0001</a>). Haplotype data based on DNA markers closely linked to the putative disease gene locus suggested that the remainder of the CF mutant gene pool consists of multiple, different mutations. A small set of these latter mutant alleles (about 8%) may confer residual pancreatic exocrine function in a subgroup of patients who are pancreatic sufficient. The discovery that the most common CF abnormality gives rise to the loss of a single amino acid residue in a functional domain suggests that the phenotype of CF is not due to complete loss of function of the gene product. The situation may be comparable to that in sickling disorders, in which a specific subset of mutations in the beta-globin gene gives rise to an altered protein with unusual behavior. Complete absence of function of the beta-globin gene gives rise to a different phenotype, namely, beta-0-thalassemia; similarly, homozygous loss of function of the CF gene may lead to a distinctive phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2570460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#247" class="mim-tip-reference" title="Trapnell, B. C., Chu, C.-S., Paakko, P. K., Banks, T. C., Yoshimura, K., Ferrans, V. J., Chernick, M. S., Crystal, R. G. <strong>Expression of the cystic fibrosis transmembrane conductance regulator gene in the respiratory tract of normal individuals and individuals with cystic fibrosis.</strong> Proc. Nat. Acad. Sci. 88: 6565-6569, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1713683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1713683</a>] [<a href="https://doi.org/10.1073/pnas.88.15.6565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1713683">Trapnell et al. (1991)</a> studied CFTR mRNA transcripts in respiratory tract epithelial cells recovered by fiberoptic bronchoscopy with a cytology brush. They found that the transcripts reflected the normal and the delta-F508 alleles in appropriate proportions. CFTR mRNA transcripts were expressed in nasal, tracheal, and bronchial epithelial cells in about 1 to 2 copies per cell, more than 100-fold greater than in pharyngeal epithelium. <a href="#284" class="mim-tip-reference" title="Zeitlin, P. L., Crawford, I., Lu, L., Woel, S., Cohen, M. E., Donowitz, M., Montrose, M. H., Hamosh, A., Cutting, G. R., Gruenert, D., Huganir, R., Maloney, P., Guggino, W. B. <strong>CFTR protein expression in primary and cultured epithelia.</strong> Proc. Nat. Acad. Sci. 89: 344-347, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1370353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1370353</a>] [<a href="https://doi.org/10.1073/pnas.89.1.344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1370353">Zeitlin et al. (1992)</a> identified a polyclonal antibody that was used to detect the CFTR glycoprotein in biopsied human nasal and bronchial tissues and in the apical membrane fraction of ileal villus tissue. Levels of the protein were modulated pharmacologically. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1713683+1370353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#287" class="mim-tip-reference" title="Zielenski, J., Markiewicz, D., Rininsland, F., Rommens, J., Tsui, L.-C. <strong>A cluster of highly polymorphic dinucleotide repeats in intron 17b of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Am. J. Hum. Genet. 49: 1256-1262, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1720926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1720926</a>]" pmid="1720926">Zielenski et al. (1991)</a> found a cluster of highly polymorphic dinucleotide repeats in intron 17b of the CFTR gene, 200 bp downstream from the preceding exon. At least 24 alleles, with sizes ranging from 7 to 56 units of a TA repeat, were identified in a panel of 92 unrelated carriers of CF. The common alleles had 7, 30, and 31 dinucleotide units, with frequencies of 0.22, 0.19, and 0.12, respectively, among the non-CF chromosomes. A less polymorphic dinucleotide cluster, a CA repeat, was also detected in a region 167 bp downstream from the TA repeat. This varied from 11 to 17 dinucleotide units and appeared to bear an inverse relationship to that of the TA repeats. These repeats were considered to be useful in genetic linkage studies, in counseling CF families with unknown mutations, and in tracing the origins of various mutant CF alleles. <a href="#165" class="mim-tip-reference" title="Morral, N., Nunes, V., Casals, T., Estivill, X. <strong>CA/GT microsatellite alleles within the cystic fibrosis transmembrane conductance regulator (CFTR) gene are not generated by unequal crossing-over.</strong> Genomics 10: 692-698, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1716244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1716244</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90454-m" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1716244">Morral et al. (1991)</a> and <a href="#41" class="mim-tip-reference" title="Chehab, F. F., Johnson, J., Louie, E., Goossens, M., Kawasaki, E., Erlich, H. <strong>A dimorphic 4-bp repeat in the cystic fibrosis gene is in absolute disequilibrium with the delta-F508 mutation: implications for prenatal diagnosis and mutation origin.</strong> Am. J. Hum. Genet. 48: 223-226, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1990833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1990833</a>]" pmid="1990833">Chehab et al. (1991)</a> also described repeats within introns of the CFTR gene. The significance of the inverse correlation between the lengths of the 2 repeat regions was not investigated; length compensation may be involved and may have functional importance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1716244+1990833+1720926" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Chalkley, G., Harris, A. <strong>A cystic fibrosis patient who is homozygous for the G85E mutation has very mild disease.</strong> J. Med. Genet. 28: 875-877, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1757965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1757965</a>] [<a href="https://doi.org/10.1136/jmg.28.12.875" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1757965">Chalkley and Harris (1991)</a> made use of 'ectopic' or 'illegitimate' transcription of CF mRNA in leukocytes in the detection of CF mutations. By use of PCR, it was possible to detect such ectopic transcription as in the case of other genes such as those for dystrophin (<a href="/entry/300377">300377</a>) and factor VIII (<a href="/entry/300841">300841</a>). <a href="#97" class="mim-tip-reference" title="Fonknechten, N., Chelly, J., Lepercq, J., Kahn, A., Kaplan, J.-C., Kitzis, A., Chomel, J.-C. <strong>CFTR illegitimate transcription in lymphoid cells: quantification and applications to the investigation of pathological transcripts.</strong> Hum. Genet. 88: 508-512, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1372586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1372586</a>] [<a href="https://doi.org/10.1007/BF00219336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1372586">Fonknechten et al. (1992)</a> extended these observations, using the PCR reaction for detecting CFTR mutations in the study of lymphocytes and lymphoblasts. <a href="#95" class="mim-tip-reference" title="Ferrie, R. M., Schwarz, M. J., Robertson, N. H., Vaudin, S., Super, M., Malone, G., Little, S. <strong>Development, multiplexing, and application of ARMS tests for common mutations in the CFTR gene.</strong> Am. J. Hum. Genet. 51: 251-262, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1379414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1379414</a>]" pmid="1379414">Ferrie et al. (1992)</a> applied the amplification refractory mutation system (ARMS) to the detection of mutations in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1379414+1757965+1372586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#65" class="mim-tip-reference" title="Cutting, G. R., Kasch, L. M., Rosenstein, B. J., Zielenski, J., Tsui, L.-C., Antonarakis, S. E., Kazazian, H. H., Jr. <strong>A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.</strong> Nature 346: 366-369, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1695717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1695717</a>] [<a href="https://doi.org/10.1038/346366a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1695717">Cutting et al. (1990)</a> sought mutations in the 2 NBFs of CFTR by nucleotide sequencing of exons 9, 10, 11, and 12 (encoding the first NBF) and exons 20, 21, and 22 (encoding most of the second NBF) from 20 Caucasian and 18 American black CF patients. They found a cluster of 4 mutations in a 30-bp region of exon 11. Three of the mutations caused amino acid substitutions at residues that are highly conserved among the CFTR protein, the multiple-drug-resistance proteins, and ATP-binding membrane-associated transport proteins. The fourth mutation created a premature termination signal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1695717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To explore the molecular mechanisms responsible for defective chloride transport in patients with CF, <a href="#278" class="mim-tip-reference" title="Yang, Y., Devor, D. C., Engelhardt, J. F., Ernst, S. A., Strong, T. V., Collins, F. S., Cohn, J. A., Frizzell, R. A., Wilson, J. M. <strong>Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR.</strong> Hum. Molec. Genet. 2: 1253-1261, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7691345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7691345</a>] [<a href="https://doi.org/10.1093/hmg/2.8.1253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7691345">Yang et al. (1993)</a> studied the processing, localization, and function of wildtype, delF508 (<a href="#0001">602421.0001</a>) and G551D (<a href="#0013">602421.0013</a>) CFTR in retrovirus transduced L cells. They concluded that the molecular pathology of G551D is explained by an abnormality in channel activity, while the defect in delF508 is a combination of mislocalization and instability of the protein in addition to partial defects in channel function. Some of their observations suggested the possibility of pharmacologic therapies for CF based on activating latent CFTR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7691345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Not only is there heterogeneity in the mutations causing cystic fibrosis, but the pathogenetic mechanisms also vary. Deletion of phenylalanine-508 appears to cause disease by abrogating normal biosynthetic processing and thereby resulting in retention and degradation of the mutant protein within the endoplasmic reticulum. Other mutations, such as the relatively common gly551-to-asp mutation, appear to be normally processed and, therefore, must cause disease through some other mechanism. Because both delta-F508 and G551D occur within a predicted nucleotide-binding domain (NBD) of CFTR, <a href="#156" class="mim-tip-reference" title="Logan, J., Hiestand, D., Daram, P., Huang, Z., Muccio, D. D., Hartman, J., Haley, B., Cook, W. J., Sorscher, E. J. <strong>Cystic fibrosis transmembrane conductance regulator mutations that disrupt nucleotide binding.</strong> J. Clin. Invest. 94: 228-236, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7518829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7518829</a>] [<a href="https://doi.org/10.1172/JCI117311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7518829">Logan et al. (1994)</a> tested the influence of these mutations on nucleotide binding by the protein. They found that G551D and the corresponding mutation in the CFTR second nucleotide binding domain, gly1349-to-asp (G1349D), led to decreased nucleotide binding by CFTR NBDs, while the delta-F508 mutation did not alter nucleotide binding. These results implicated defective ATP-binding as the pathogenic mechanism of a relatively common mutation leading to CF and suggested that structural integrity of a highly conserved region present in over 30 prokaryotic and eukaryotic nucleotide-binding domains may be critical for normal nucleotide binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7518829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>There is a polymorphic string of thymidines at the end of intron 8 of the CFTR gene; 3 different alleles can be found depending on the number of thymidines (5, 7, or 9) present at this site (<a href="#51" class="mim-tip-reference" title="Chu, C.-S., Trapnell, B. C., Murtagh, J. J., Jr., Moss, J., Dalemans, W., Jallat, S., Mercenier, A., Pavirani, A., Lecocq, J.-P., Cutting, G. R., Guggino, W. B., Crystal, R. G. <strong>Variable detection of exon 9 coding sequences in cystic fibrosis transmembrane conductance regulator gene mRNA transcripts in normal bronchial epithelium.</strong> EMBO J. 10: 1355-1363, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1709095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1709095</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1991.tb07655.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1709095">Chu et al., 1991</a>). The number of thymidines determines the efficiency by which the intron 8 splice acceptor site is used. The efficiency decreases when a shorter stretch of thymidine residues is found. A higher proportion of CFTR transcripts that lack exon 9 sequences, which encode part of the functionally important first nucleotide-binding domain, will therefore be found when a shorter stretch of thymidine residues is present (<a href="#50" class="mim-tip-reference" title="Chu, C.-S., Trapnell, B. C., Curristin, S., Cutting, G. R., Crystal, R. G. <strong>Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA.</strong> Nature Genet. 3: 151-156, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7684646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7684646</a>] [<a href="https://doi.org/10.1038/ng0293-151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7684646">Chu et al., 1993</a>). If a CFTR gene with the arg117-to-his (R117H) mutation (<a href="#0005">602421.0005</a>) harbors a T5 allele, the mutant gene will be responsible for CF. An R117H mutant CFTR gene that harbors a T7 allele can either result in CF or CBAVD (<a href="#142" class="mim-tip-reference" title="Kiesewetter, S., Macek, M., Jr., Davis, C., Curristin, S. M., Chu, C.-S., Graham, C., Shrimpton, A. E., Cashman, S. M., Tsui, L.-C., Mickle, J., Amos, J., Highsmith, W. E., Shuber, A., Witt, D. R., Crystal, R. G., Cutting, G. R. <strong>A mutation in CFTR produces different phenotypes depending on chromosomal background.</strong> Nature Genet. 5: 274-278, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7506096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7506096</a>] [<a href="https://doi.org/10.1038/ng1193-274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7506096">Kiesewetter et al., 1993</a>). <a href="#243" class="mim-tip-reference" title="Teng, H., Jorissen, M., Van Poppel, H., Legius, E., Cassiman, J.-J., Cuppens, H. <strong>Increased proportion of exon 9 alternatively spliced CFTR transcripts in vas deferens compared with nasal epithelial cells.</strong> Hum. Molec. Genet. 6: 85-90, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9002674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9002674</a>] [<a href="https://doi.org/10.1093/hmg/6.1.85" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9002674">Teng et al. (1997)</a> noted that the T5 allele results in the most inefficient use of this splice acceptor site. Most CFTR transcripts from a T5 allele will therefore lack exon 9 sequencing. Such exon 9-deficient CFTR transcripts are known to be translated into CFTR proteins that will not mature, and will therefore not function as chloride channels in the apical membrane of epithelial cells. Among CBAVD patients, the frequency of this T5 allele is 4- to 6-fold higher than in the control population (see <a href="#0005">602421.0005</a>). <a href="#243" class="mim-tip-reference" title="Teng, H., Jorissen, M., Van Poppel, H., Legius, E., Cassiman, J.-J., Cuppens, H. <strong>Increased proportion of exon 9 alternatively spliced CFTR transcripts in vas deferens compared with nasal epithelial cells.</strong> Hum. Molec. Genet. 6: 85-90, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9002674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9002674</a>] [<a href="https://doi.org/10.1093/hmg/6.1.85" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9002674">Teng et al. (1997)</a> analyzed CFTR transcripts qualitatively and quantitatively in nasal epithelial and vas deferens cells. Alternative splicing of exon 9, which had been known to occur in nasal epithelial cells, also occurred in vas deferens cells. The extent of this alternative splicing was determined by the allele present at the Tn locus at the end of intron 8 of the CFTR gene. However, the proportion of transcripts lacking exon 9 sequences was increased in vas deferens cells compared with nasal epithelial cells, independent of the Tn genotype. Thus, <a href="#243" class="mim-tip-reference" title="Teng, H., Jorissen, M., Van Poppel, H., Legius, E., Cassiman, J.-J., Cuppens, H. <strong>Increased proportion of exon 9 alternatively spliced CFTR transcripts in vas deferens compared with nasal epithelial cells.</strong> Hum. Molec. Genet. 6: 85-90, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9002674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9002674</a>] [<a href="https://doi.org/10.1093/hmg/6.1.85" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9002674">Teng et al. (1997)</a> postulated that tissue-specific differences in the proportion of CFTR transcripts lacking exon 9 sequences may contribute to the tissue-specific disease phenotype observed in individuals with CBAVD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9002674+7506096+1709095+7684646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Besides the polymorphic Tn locus, more than 120 polymorphisms have been described in the CFTR gene. <a href="#60" class="mim-tip-reference" title="Cuppens, H., Lin, W., Jaspers, M., Costes, B., Teng, H., Vankeerberghen, A., Jorissen, M., Droogmans, G., Reynaert, I., Goossens, M., Nilius, B., Cassiman, J.-J. <strong>Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes: the polymorphic (TG)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation.</strong> J. Clin. Invest. 101: 487-496, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9435322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9435322</a>] [<a href="https://doi.org/10.1172/JCI639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9435322">Cuppens et al. (1998)</a> hypothesized that the combination of particular alleles at several polymorphic loci might result in less functional or even insufficient CFTR protein. Analysis of 3 polymorphic loci with frequent alleles in the general population showed that, in addition to the known effect of the Tn locus, the quantity and quality of CFTR transcripts and/or proteins were affected by 2 other polymorphic loci: M470V (<a href="#0023">602421.0023</a>) and a dinucleotide repeat polymorphism (TG)m. On a T7 background, the (TG)11 allele gave a 2.8-fold increase in the proportion of CFTR transcripts that lacked exon 9, and (TG)12 gave a 6-fold increase, compared with the (TG)10 allele. T5 CFTR genes derived from patients were found to carry a high number of TG repeats, while T5 CFTR genes derived from healthy CF fathers harbored a low number of TG repeats. Moreover, it was found that M470 CFTR proteins matured more slowly, and that they had a 1.7-fold increased intrinsic chloride channel activity compared with V470 CFTR proteins, suggesting that the M470V locus might also play a role in the partial penetrance of T5 as a disease mutation. Such polyvalent mutant genes could explain why apparently normal CFTR genes cause disease. Moreover, they might be responsible for variation in the phenotypic expression of CFTR mutations. This study suggested that genetic and functional studies of polymorphisms in relation to genetic diseases will become of major interest, in relation both to monogenic disorders and complex traits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9435322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 9 of 16 cases of disseminated bronchiectasis (56%), <a href="#188" class="mim-tip-reference" title="Pignatti, P. F., Bombieri, C., Benetazzo, M., Casartelli, A., Trabetti, E., Gile, L. S., Martinati, L. C., Boner, A. L., Luisetti, M. <strong>CFTR gene variant IVS8-5T in disseminated bronchiectasis. (Letter)</strong> Am. J. Hum. Genet. 58: 889-892, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644755</a>]" pmid="8644755">Pignatti et al. (1996)</a> found the 5T allele in intron 8 (IVS8-5T) and/or a CFTR gene mutation. The results confirmed, at the molecular genetic level, a clinical connection between CF and one obstructive pulmonary disease, disseminated bronchiectasis of unknown origin. Similarly, <a href="#106" class="mim-tip-reference" title="Girodon, E., Cazeneuve, C., Lebargy, F., Chinet, T., Costes, B., Ghanem, N., Martin, J., Lemay, S., Scheid, P., Housset, B., Bignon, J., Goossens, M. <strong>CFTR gene mutations in adults with disseminated bronchiectasis.</strong> Europ. J. Hum. Genet. 5: 149-155, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9272738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9272738</a>]" pmid="9272738">Girodon et al. (1997)</a> studied 32 patients with disseminated bronchiectasis and a clinically isolated respiratory syndrome. Analysis of all CFTR gene exons and their flanking regions demonstrated 13 CFTR gene mutations in 16 different alleles. Six of these mutations, which had previously been reported as CF defects, were found in 9 alleles. Four patients were compound heterozygotes; 6 were heterozygous for a mutation. <a href="#106" class="mim-tip-reference" title="Girodon, E., Cazeneuve, C., Lebargy, F., Chinet, T., Costes, B., Ghanem, N., Martin, J., Lemay, S., Scheid, P., Housset, B., Bignon, J., Goossens, M. <strong>CFTR gene mutations in adults with disseminated bronchiectasis.</strong> Europ. J. Hum. Genet. 5: 149-155, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9272738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9272738</a>]" pmid="9272738">Girodon et al. (1997)</a> concluded that CFTR gene mutations may play a role in bronchiectatic lung disease, possibly in a multifactorial context. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9272738+8644755" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>It has been proposed that in heterozygous state mutations of the CFTR gene provide increased resistance to infectious diseases, thereby maintaining mutant CFTR alleles at high levels in selected populations. <a href="#186" class="mim-tip-reference" title="Pier, G. B., Grout, M., Zaidi, T., Meluleni, G., Mueschenborn, S. S., Banting, G., Ratcliff, R., Evans, M. J., Colledge, W. H. <strong>Salmonella typhi uses CFTR to enter intestinal epithelial cells.</strong> Nature 393: 79-82, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590693</a>] [<a href="https://doi.org/10.1038/30006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590693">Pier et al. (1998)</a> investigated whether typhoid fever could be one such disease. This disease is initiated when Salmonella typhi enters gastrointestinal epithelial cells for submucosal translocation. They found that S. typhi, but not the related murine pathogen S. typhimurium, uses CFTR for entry into epithelial cells. Cells expressing wildtype CFTR internalized more S. typhi than isogenic cells expressing the most common CFTR mutation, delta-F508 (<a href="#0001">602421.0001</a>). Monoclonal antibodies and synthetic peptides containing a sequence corresponding to the first predicted extracellular domain of CFTR inhibited uptake of S. typhi. Heterozygous delta-F508 Cftr mice translocated 86% fewer S. typhi into the gastrointestinal submucosa than did wildtype Cftr mice; no translocation occurred in delta-F508 Cftr homozygous mice. The Cftr genotype had no effect on the translocation of S. typhimurium. Immunoelectron microscopy revealed that more CFTR bound S. typhi in the submucosa of Cftr wildtype mice than in delta-F508 heterozygous mice. <a href="#186" class="mim-tip-reference" title="Pier, G. B., Grout, M., Zaidi, T., Meluleni, G., Mueschenborn, S. S., Banting, G., Ratcliff, R., Evans, M. J., Colledge, W. H. <strong>Salmonella typhi uses CFTR to enter intestinal epithelial cells.</strong> Nature 393: 79-82, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590693</a>] [<a href="https://doi.org/10.1038/30006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590693">Pier et al. (1998)</a> concluded that diminished levels of CFTR in heterozygotes decreases susceptibility to typhoid fever. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#249" class="mim-tip-reference" title="van de Vosse, E., Ali, S., de Visser, A. W., Surjadi, C., Widjaja, S., Vollaard, A. M., van Dissel, J. T. <strong>Susceptibility to typhoid fever is associated with a polymorphism in the cystic fibrosis transmembrane conductance regulator (CFTR).</strong> Hum. Genet. 118: 138-140, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16078047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16078047</a>] [<a href="https://doi.org/10.1007/s00439-005-0005-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16078047">Van de Vosse et al. (2005)</a> tested the hypothesis that CFTR heterozygotes have a selective advantage against typhoid, which may be conferred through reduced attachment of S. typhi to the intestinal mucosa. They genotyped patients and controls in a typhoid endemic area in Indonesia for 2 highly polymorphic markers in CFTR and the most common CF mutation, F508del. Consistent with the apparently very low incidence of CF in Indonesia, the F508del mutation was not present in any patients or controls. However, they found significant association between a common polymorphism in intron 8 (16 or 17 CA repeats) and selective advantage against typhoid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16078047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#224" class="mim-tip-reference" title="Sharer, N., Schwarz, M., Malone, G., Howarth, A., Painter, J., Super, M., Braganza, J. <strong>Mutations of the cystic fibrosis gene in patients with chronic pancreatitis.</strong> New Eng. J. Med. 339: 645-652, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9725921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9725921</a>] [<a href="https://doi.org/10.1056/NEJM199809033391001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9725921">Sharer et al. (1998)</a> studied 134 consecutive patients with chronic pancreatitis (<a href="/entry/167800">167800</a>) (alcohol-related disease in 71, hyperparathyroidism in 2, hypertriglyceridemia in 1, and idiopathic disease in 60). DNA was examined for 22 mutations of the CFTR gene that together account for 95% of all mutations in patients with cystic fibrosis in the northwest of England where the study was performed. They also determined the length of the noncoding sequence of thymidines in intron 8, since the shorter the sequence, the lower the proportion of normal CFTR mRNA. None of the patients had a mutation on both copies of the CFTR gene. Eighteen patients (13.4%), including 12 without alcoholism, had a CFTR mutation on 1 chromosome, as compared with a frequency of 5.3% among 600 local unrelated partners of persons with a family history of cystic fibrosis (P less than 0.001). A total of 10.4% of the patients had the 5T allele in intron 8 (14 of 134), which is twice the expected frequency (P = 0.008). Four patients were heterozygous for both a CFTR mutation and the 5T allele. Patients with a CFTR mutation were younger than those with no mutations (P = 0.03). None had the combination of sinopulmonary disease, high sweat electrolyte concentrations, and low nasal potential-difference values that is diagnostic of cystic fibrosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9725921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Similarly, <a href="#56" class="mim-tip-reference" title="Cohn, J. A., Friedman, K. J., Noone, P. G., Knowles, M. R., Silverman, L. M., Jowell, P. S. <strong>Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.</strong> New Eng. J. Med. 339: 653-658, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9725922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9725922</a>] [<a href="https://doi.org/10.1056/NEJM199809033391002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9725922">Cohn et al. (1998)</a> studied 27 patients (mean age at diagnosis, 36 years), 22 of whom were female, who had been referred for an evaluation of idiopathic pancreatitis. DNA was tested for 17 CFTR mutations and for the 5T allele in intron 8. The 5T allele reduces the level of functional CFTR and is associated with an inherited form of infertility in males, CBAVD. <a href="#56" class="mim-tip-reference" title="Cohn, J. A., Friedman, K. J., Noone, P. G., Knowles, M. R., Silverman, L. M., Jowell, P. S. <strong>Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.</strong> New Eng. J. Med. 339: 653-658, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9725922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9725922</a>] [<a href="https://doi.org/10.1056/NEJM199809033391002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9725922">Cohn et al. (1998)</a> found that 10 patients with idiopathic chronic pancreatitis (37%) had at least 1 abnormal CFTR allele. Eight CFTR mutations were detected. In 3 patients both alleles were affected. These 3 patients did not have lung disease typical of cystic fibrosis on the basis of sweat testing, spirometry, or base-line nasal potential-difference measurements. Nonetheless, each had abnormal nasal cyclic AMP-mediated chloride transport. The genotypes of the 3 patients were delF508/wildtype (<a href="#0001">602421.0001</a>), 9T/5T in 2, and delF508/R117H (<a href="#0005">602421.0005</a>), 9T/7T in 1. These are the 2 most common genotypes in patients with CBAVD. These genotypes do not typically cause lung disease. In contrast, lung disease is present in patients with a genotype of delF508/R117H, 9T/5T. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9725922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>An abbreviated tract of 5T in intron 8 of the CFTR gene is found in approximately 10% of individuals. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, <a href="#115" class="mim-tip-reference" title="Groman, J. D., Hefferon, T. W., Casals, T., Bassas, L., Estivill, X., Georges, M. D., Guittard, C., Koudova, M., Fallin, M. D., Nemeth, K., Fekete, G., Kadasi, L., and 15 others. <strong>Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.</strong> Am. J. Hum. Genet. 74: 176-179, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14685937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14685937</a>] [<a href="https://doi.org/10.1086/381001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14685937">Groman et al. (2004)</a> determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens (<a href="/entry/277180">277180</a>), 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P less than 0.00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1-103.7.7, P less than 0.00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14685937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#151" class="mim-tip-reference" title="Lee, J. H., Choi, J. H., Namkung, W., Hanrahan, J. W., Chang, J., Song, S. Y., Park, S. W., Kim, D. S., Yoon, J.-H., Suh, Y., Jang, I.-J., Nam, J. H., Kim, S. J., Cho, M.-O., Lee, J.-E., Kim, K. H., Lee, M. G. <strong>A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases.</strong> Hum. Molec. Genet. 12: 2321-2332, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12952861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12952861</a>] [<a href="https://doi.org/10.1093/hmg/ddg243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12952861">Lee et al. (2003)</a> haplotyped 117 Korean controls and 75 CF patients having bronchiectasis or chronic pancreatitis using 11 polymorphisms in CFTR. Several haplotypes, especially those with Q1352H (<a href="#0133">602421.0133</a>), IVS8 T5 (<a href="#0086">602421.0086</a>), and E217G (<a href="#0134">602421.0134</a>), were found to have disease associations in a case-control study. The common M470V polymorphism (<a href="#0023">602421.0023</a>) appeared to affect the intensity of the disease association. The T5-V470 haplotype showed higher disease association than T5-M470, but the Q1352H mutation in a V470 background showed the strongest disease association. Nonsynonymous E217G and Q1352H mutations in the M470 background caused a 60 to 80% reduction in CFTR-dependent chloride currents and bicarbonate transport activities. The M470V polymorphic variant in combination with the Q1352H mutation completely abolished CFTR-dependent anion transport activities. The results revealed that interactions between multiple genetic variants in cis affected the final function of the gene products. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12952861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Buratti, E., Dork, T., Zucatto, E., Pagani, R., Romano, M., Baralle, F. E. <strong>Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping.</strong> EMBO J. 20: 1774-1784, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11285240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11285240</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11285240[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/20.7.1774" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11285240">Buratti et al. (2001)</a> showed that nuclear factor TDP43 (<a href="/entry/605078">605078</a>) binds specifically to the UG repeat sequence of CFTR pre-mRNA and, in this way, promotes skipping of CFTR exon 9. <a href="#260" class="mim-tip-reference" title="Wang, H.-Y., Wang, I.-F., Bose, J., Shen, C.-K. J. <strong>Structural diversity and functional implications of the eukaryotic TDP gene family.</strong> Genomics 83: 130-139, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14667816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14667816</a>] [<a href="https://doi.org/10.1016/s0888-7543(03)00214-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14667816">Wang et al. (2004)</a> found that the mouse homolog of human TDP43 also inhibits human CFTR exon 9 splicing in a minigene system. <a href="#25" class="mim-tip-reference" title="Buratti, E., Brindisi, A., Pagani, F., Baralle, F. E. <strong>Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance. (Letter)</strong> Am. J. Hum. Genet. 74: 1322-1325, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15195661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15195661</a>] [<a href="https://doi.org/10.1086/420978" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15195661">Buratti et al. (2004)</a> described experiments consistent with the model in which the TG repeats in the CFTR intron 8 bind to TDP43, and this protein, in turn, inhibits splicing of exon 9. They suggested that their results provide a mechanistic explanation for the association data of <a href="#115" class="mim-tip-reference" title="Groman, J. D., Hefferon, T. W., Casals, T., Bassas, L., Estivill, X., Georges, M. D., Guittard, C., Koudova, M., Fallin, M. D., Nemeth, K., Fekete, G., Kadasi, L., and 15 others. <strong>Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.</strong> Am. J. Hum. Genet. 74: 176-179, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14685937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14685937</a>] [<a href="https://doi.org/10.1086/381001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14685937">Groman et al. (2004)</a> and also an explanation for the variable phenotypic penetrance of the TG repeats. Individual and tissue-specific variability in the concentration of this inhibitory splicing factor may even determine whether an individual will develop multisystemic (non-classic CF) or monosymptomatic (CBAVD) disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14685937+11285240+15195661+14667816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Audrezet, M.-P., Chen, J.-M., Le Marechal, C., Ruszniewski, P., Robaszkiewicz, M., Raguenes, O., Quere, I., Scotet, V., Ferec, C. <strong>Determination of the relative contribution of three genes--the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene--to the etiology of idiopathic chronic pancreatitis.</strong> Europ. J. Hum. Genet. 10: 100-106, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11938439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11938439</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200786" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11938439">Audrezet et al. (2002)</a> analyzed the entire coding sequence and exon/intron junctions of the CFTR gene by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing in 39 white French patients with idiopathic chronic pancreatitis. A total of 18 mutant alleles were identified in 14 patients (35.9%), among whom 4 were compound heterozygotes. None of the 4 compound heterozygotes were found to have unrecognized CF-related pulmonary symptoms following reevaluation. However, a sweat test done retrospectively was positive in 2 of them. The 5T allele of the polymorphic string of thymidines at the end of intron 8 of the CFTR gene was present in 7 of the 36 patients tested, an allele frequency (9.7%) nearly 2 times greater than the rate of 5% in the general population (P = 0.09). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11938439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The molecular pathogenesis of cystic fibrosis has been investigated by analysis of delF508 CFTR in different heterologous systems, revealing an abrogation of CFTR expression by defective protein maturation. Mutant CFTR was found arrested in an early wildtype intermediate, unable to adopt a protease-resistant mature conformation (<a href="#45" class="mim-tip-reference" title="Cheng, S. H., Gregory, R. J., Marshall, J., Paul, S., Souza, D. W., White, G. A., O'Riordan, C. R., Smith, A. E. <strong>Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis.</strong> Cell 63: 827-834, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1699669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1699669</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90148-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1699669">Cheng et al., 1990</a>; <a href="#113" class="mim-tip-reference" title="Gregory, R. J., Rich, D. P., Cheng, S. H., Souza, D. W., Paul, S., Manavalan, P., Anderson, M. P., Welsh, M. J., Smith, A. E. <strong>Maturation and function of cystic fibrosis transmembrane conductance regulator variants bearing mutations in putative nucleotide-binding domains 1 and 2.</strong> Molec. Cell. Biol. 11: 3886-3893, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1712898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1712898</a>] [<a href="https://doi.org/10.1128/mcb.11.8.3886-3893.1991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1712898">Gregory et al., 1991</a>; <a href="#285" class="mim-tip-reference" title="Zhang, F., Kartner, N., Lukacs, G. L. <strong>Limited proteolysis as a probe for arrested conformational maturation of deltaF508 CFTR.</strong> Nature Struct. Biol. 5: 180-183, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9501909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9501909</a>] [<a href="https://doi.org/10.1038/nsb0398-180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9501909">Zhang et al., 1998</a>) that enables exit from the endoplasmic reticulum and processing in the Golgi compartment. Prolonged interaction of immature delF508 CFTR with the chaperones calnexin (CANX; <a href="/entry/114217">114217</a>) and Hsp70 (see <a href="/entry/140550">140550</a>) in experiments by <a href="#189" class="mim-tip-reference" title="Pind, S., Riordan, J. R., Williams, D. B. <strong>Participation of the endoplasmic reticulum chaperone calnexin (p88,IP90) in the biogenesis of the cystic fibrosis transmembrane conductance regulator.</strong> J. Biol. Chem. 269: 12784-12788, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7513695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7513695</a>]" pmid="7513695">Pind et al. (1994)</a> and <a href="#279" class="mim-tip-reference" title="Yang, Y., Janich, S., Cohn, J. A., Wilson, J. M. <strong>The common variant of cystic fibrosis transmembrane conductance regulator is recognized by hsp70 and degraded in a pre-Golgi nonlysosomal compartment.</strong> Proc. Nat. Acad. Sci. 90: 9480-9484, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7692448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7692448</a>] [<a href="https://doi.org/10.1073/pnas.90.20.9480" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7692448">Yang et al. (1993)</a>, respectively, indicated that the aberrant protein is recognized by the cell's quality control and that premature degradation by the ubiquitin-proteasome pathway occurs in a pre-Golgi compartment (<a href="#130" class="mim-tip-reference" title="Jensen, T. J., Loo, M. A., Pind, S., Williams, D. B., Goldberg, A. L., Riordan, J. R. <strong>Multiple proteolytic systems, including the proteasome, contribute to CFTR processing.</strong> Cell 83: 129-135, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553864</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90241-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553864">Jensen et al., 1995</a>; <a href="#216" class="mim-tip-reference" title="Sato, S., Ward, C. L., Kopito, R. R. <strong>Cotranslational ubiquitination of cystic fibrosis transmembrane conductance regulator in vitro.</strong> J. Biol. Chem. 273: 7189-7192, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9516408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9516408</a>] [<a href="https://doi.org/10.1074/jbc.273.13.7189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9516408">Sato et al., 1998</a>). Reduction of temperature (<a href="#74" class="mim-tip-reference" title="Denning, G. M., Anderson, M. P., Amara, J. F., Marshall, J., Smith, A. E., Welsh, M. J. <strong>Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive.</strong> Nature 358: 761-764, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1380673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1380673</a>] [<a href="https://doi.org/10.1038/358761a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1380673">Denning et al., 1992</a>) and addition of chemical chaperones such as glycerol (<a href="#217" class="mim-tip-reference" title="Sato, S., Ward, C. L., Krouse, M. E., Wine, J. J., Kopito, R. R. <strong>Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation.</strong> J. Biol. Chem. 271: 635-638, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8557666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8557666</a>] [<a href="https://doi.org/10.1074/jbc.271.2.635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8557666">Sato et al., 1996</a>) and trimethylamine-N-oxide (<a href="#23" class="mim-tip-reference" title="Brown, C. R., Hong-Brown, L. Q., Biwersi, J., Verkman, A. S., Welsh, W. J. <strong>Chemical chaperones correct the mutant phenotype of the deltaF508 cystic fibrosis transmembrane conductance regulator protein.</strong> Cell Stress Chaperones 1: 117-125, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9222597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9222597</a>] [<a href="https://doi.org/10.1379/1466-1268(1996)001<0117:ccctmp>2.3.co;2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9222597">Brown et al., 1996</a>) overcame impediments in the folding pathway of delF508 CFTR and allowed proper targeting, thus demonstrating that the mutant protein is still capable of assuming a mature conformation. However, at the cell surface, the chloride channel formed therefrom showed a decreased half-life and reduced open probability and sensitivity to stimulation with cAMP agonists. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1712898+1380673+7553864+9501909+1699669+7513695+8557666+7692448+9516408+9222597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#136" class="mim-tip-reference" title="Kalin, N., Claass, A., Sommer, M., Puchelle, E., Tummler, B. <strong>Delta-F508 CFTR protein expression in tissues from patients with cystic fibrosis.</strong> J. Clin. Invest. 103: 1379-1389, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330420</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10330420[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI5731" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330420">Kalin et al. (1999)</a> investigated endogenous CFTR expression in skin biopsies and respiratory and intestinal tissue specimens from delF508 homozygous patients and non-CF persons, using immunohistochemical and immunoblot analyses with a panel of CFTR antibodies. CFTR expression was detected at the luminal surface of reabsorptive sweat ducts and airway submucosal glands, at the apex of ciliated cells in pseudostratified respiratory epithelia and of isolated cells of the villi of duodenum and jejunum, and within intracellular compartments of intestinal goblet cells. In delF508 homozygous patients, expression of the mutant protein proved to be tissue specific. Whereas delF508 CFTR was undetectable in sweat glands, the expression in the respiratory and intestinal tracts could not be distinguished from the wildtype by signal intensity or localization. The tissue-specific variation of delF508 CFTR expression from null to apparently normal amounts indicated that delF508 CFTR maturation can be modulated and suggested that determinants other than CFTR mislocalization should play a role in delF508 CF respiratory and intestinal disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10330420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#270" class="mim-tip-reference" title="Welsh, M. J., Smith, A. E. <strong>Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis.</strong> Cell 73: 1251-1254, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7686820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7686820</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90353-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7686820">Welsh and Smith (1993)</a> provided a classification of the mechanisms by which mutations in CFTR cause cystic fibrosis. The grouping of mutations into 5 classes was based on their functional effect: (I) defective protein production; (II) defective protein processing; (III) defective protein regulation; (IV) defective protein conductance; and (V) reduced amounts of functional CFTR protein. Class I, II, and III mutations have been associated with typical severe multiorgan disease on the basis of clinical studies. In contrast, class IV and V mutations appeared to confer sufficient functional CFTR to result in a mild phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7686820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#118" class="mim-tip-reference" title="Haardt, M., Benharouga, M., Lechardeur, D., Kartner, N., Lukacs, G. L. <strong>C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis: a novel class of mutation.</strong> J. Biol. Chem. 274: 21873-21877, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10419506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10419506</a>] [<a href="https://doi.org/10.1074/jbc.274.31.21873" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10419506">Haardt et al. (1999)</a> reviewed the various classes of CF-associated mutations and added a tentative additional class VI. They suggested that the mutations can be grouped into 2 major categories. The first group includes those mutants that are unable to accumulate at the cell surface, either because of impaired biosynthesis (class I and class V), or because of defective folding at the endoplasmic reticulum (class II). Mutants that belong to the second category are expressed at the cell surface but fail to translocate chloride ions because of a defect in activation (class IV) or channel conductance (class III). Because the biosynthetic processing and macroscopic chloride channel function of some of the truncated CFTR constructs appear to be normal but the biologic stability of their mature, complex-glycosylated form is dramatically reduced, <a href="#118" class="mim-tip-reference" title="Haardt, M., Benharouga, M., Lechardeur, D., Kartner, N., Lukacs, G. L. <strong>C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis: a novel class of mutation.</strong> J. Biol. Chem. 274: 21873-21877, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10419506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10419506</a>] [<a href="https://doi.org/10.1074/jbc.274.31.21873" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10419506">Haardt et al. (1999)</a> proposed a class VI, which would include stability mutants such as those characterized by their experiments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10419506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To study the consequences that disease-causing mutations have on the regulatory function of CFTR, <a href="#163" class="mim-tip-reference" title="Mickle, J. E., Milewski, M. I., Macek, M., Jr., Cutting, G. R. <strong>Effects of cystic fibrosis and congenital bilateral absence of the vas deferens-associated mutations on cystic fibrosis transmembrane conductance regulator-mediated regulation of separate channels.</strong> Am. J. Hum. Genet. 66: 1485-1495, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10762539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10762539</a>] [<a href="https://doi.org/10.1086/302893" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10762539">Mickle et al. (2000)</a> transiently expressed CFTR-bearing mutations associated with CF or its milder phenotype, congenital bilateral absence of the vas deferens (<a href="/entry/277180">277180</a>), and determined whether mutant CFTR could regulate outwardly rectifying chloride channels (ORCCs). CFTR bearing a CF-associated mutation in the first nucleotide-binding domain, delta-F508del (<a href="#0001">602421.0001</a>), functioned as a chloride channel but did not regulate ORCCs. However, CFTR that had disease-associated mutations in other domains retained both functions, regardless of the associated phenotype. Thus, a relationship between loss of CFTR regulatory function and disease severity is evident for NBD1, a region of CFTR that appears important for regulation of separate channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10762539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Bronsveld, I., Mekus, F., Bijman, J., Ballmann, M., de Jonge, H. R., Laabs, U., Halley, D. J., Ellemunter, H., Mastella, G., Thomas, S., Veeze, H. J., Tummler, B. <strong>Chloride conductance and genetic background modulate the cystic fibrosis phenotype of delta-F508 homozygous twins and siblings.</strong> J. Clin. Invest. 108: 1705-1715, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11733566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11733566</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11733566[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI12108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11733566">Bronsveld et al. (2001)</a> determined chloride transport properties of the respiratory and intestinal tracts in delta-F508 twins and sibs. In respiratory tissue, the expression of basal CFTR-mediated chloride conductance, demonstrated by 30% of delta-F508 homozygotes, was identified as a positive predictor of milder CF. In intestinal tissue, 4,4-prime-diisothiocyanatostilbene-2,2-prime-disulfonic acid (DIDS)-insensitive chloride secretion, which is indicative of functional CFTR channels, correlated with a milder phenotype, whereas DIDS-sensitive chloride secretion was observed mainly in more severely affected patients. <a href="#22" class="mim-tip-reference" title="Bronsveld, I., Mekus, F., Bijman, J., Ballmann, M., de Jonge, H. R., Laabs, U., Halley, D. J., Ellemunter, H., Mastella, G., Thomas, S., Veeze, H. J., Tummler, B. <strong>Chloride conductance and genetic background modulate the cystic fibrosis phenotype of delta-F508 homozygous twins and siblings.</strong> J. Clin. Invest. 108: 1705-1715, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11733566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11733566</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11733566[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI12108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11733566">Bronsveld et al. (2001)</a> concluded that in delta-F508 patients, the ability to secrete chloride in the organs that are primarily involved in the course of CF is predictive of the CF phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11733566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Bobadilla, J. L., Macek, M., Jr., Fine, J. P., Farrell, P. M. <strong>Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening.</strong> Hum. Mutat. 19: 575-606, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12007216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12007216</a>] [<a href="https://doi.org/10.1002/humu.10041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12007216">Bobadilla et al. (2002)</a> determined the distribution of CFTR mutations in as many regions throughout the world as possible in an effort to understand the evolution of the disease in each region and gain insight for decisions regarding screening programs. Although wide mutational heterogeneity was found throughout the world, characterization of the most common mutations in most populations was possible. A significant positive correlation was found between delta-F508 frequency and the CF incidence of regional populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12007216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Primary sclerosing cholangitis (PSC; see <a href="/entry/109720">109720</a>), a slowly progressive cholestatic liver disease characterized by fibroobliterative inflammation of the biliary tract, leads to cirrhosis and portal hypertension and is a major indication for liver transplantation. <a href="#227" class="mim-tip-reference" title="Sheth, S., Shea, J. C., Bishop, M. D., Chopra, S., Regan, M. M., Malmberg, E., Walker, C., Ricci, R., Tsui, L.-C., Durie, P. R., Zielenski, J., Freedman, S. D. <strong>Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis.</strong> Hum. Genet. 113: 286-292, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12783301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12783301</a>] [<a href="https://doi.org/10.1007/s00439-003-0963-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12783301">Sheth et al. (2003)</a> stated that 75 to 80% of cases were associated with inflammatory bowel disease (IBD; <a href="/entry/266600">266600</a>) and that 2.5 to 7.5% of patients with IBD develop PSC (<a href="#152" class="mim-tip-reference" title="Lee, Y.-M., Kaplan, M. M. <strong>Primary sclerosing cholangitis.</strong> New Eng. J. Med. 332: 924-933, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7877651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7877651</a>] [<a href="https://doi.org/10.1056/NEJM199504063321406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7877651">Lee and Kaplan, 1995</a>). <a href="#227" class="mim-tip-reference" title="Sheth, S., Shea, J. C., Bishop, M. D., Chopra, S., Regan, M. M., Malmberg, E., Walker, C., Ricci, R., Tsui, L.-C., Durie, P. R., Zielenski, J., Freedman, S. D. <strong>Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis.</strong> Hum. Genet. 113: 286-292, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12783301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12783301</a>] [<a href="https://doi.org/10.1007/s00439-003-0963-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12783301">Sheth et al. (2003)</a> hypothesized that dysfunction of CFTR may explain why a subset of patients with IBD develop PSC. They prospectively evaluated CFTR genotype and phenotype in 19 patients with PSC compared with 18 patients with IBD and no liver disease, 17 with primary biliary cirrhosis (PBC; <a href="/entry/109720">109720</a>), 81 with CF, and 51 healthy controls. They found an increased prevalence of CFTR abnormalities in heterozygous state in PSC as demonstrated by molecular and functional analyses, and concluded that these abnormalities may contribute to the development of PSC in a subset of patients with IBD. Eighty-nine percent of PSC patients carried genotypes containing the 1540G variant (<a href="#0023">602421.0023</a>) resulting in decreased functional CFTR compared with 57% of disease controls (P = 0.03). Only 1 of 19 PSC patients had neither a CFTR mutation nor the 1540G variant. CFTR chloride channel function assessed by nasal potential difference testing demonstrated a reduced median isoproterenol response in PSC patients compared with disease controls and healthy controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12783301+7877651" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#183" class="mim-tip-reference" title="Pagani, F., Stuani, C., Tzetis, M., Kanavakis, E., Efthymiadou, A., Doudounakis, S., Casals, T., Baralle, F. E. <strong>New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12.</strong> Hum. Molec. Genet. 12: 1111-1120, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12719375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12719375</a>] [<a href="https://doi.org/10.1093/hmg/ddg131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12719375">Pagani et al. (2003)</a> showed that several nucleotide changes in exon 12 of the CFTR gene induced a variable extent of exon skipping, leading to reduced levels of normal transcripts. This was the case in 2 natural mutations--1 of which was gly576 to ala (G576A; <a href="#0061">602421.0061</a>), which had previously been considered a neutral polymorphism--and several site-directed silent substitutions. This phenomenon was due to the interference with a regulatory element, which the authors named composite exonic regulatory element of splicing (CERES). The effect of single-nucleotide substitutions at CERES could not be predicted by either serine-arginine-rich (SR) matrices or enhancer identification. <a href="#183" class="mim-tip-reference" title="Pagani, F., Stuani, C., Tzetis, M., Kanavakis, E., Efthymiadou, A., Doudounakis, S., Casals, T., Baralle, F. E. <strong>New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12.</strong> Hum. Molec. Genet. 12: 1111-1120, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12719375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12719375</a>] [<a href="https://doi.org/10.1093/hmg/ddg131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12719375">Pagani et al. (2003)</a> suggested that appropriate functional splicing assays should be included in genotype screenings to distinguish between polymorphisms and pathogenic mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12719375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By testing 19 synonymous changes in nucleotides 13 to 52 of the human CFTR exon 12, <a href="#182" class="mim-tip-reference" title="Pagani, F., Raponi, M., Baralle, F. E. <strong>Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution.</strong> Proc. Nat. Acad. Sci. 102: 6368-6372, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15840711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15840711</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15840711[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0502288102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15840711">Pagani et al. (2005)</a> found that the probability of inducing exon skipping with a single synonymous substitution was approximately 30%, demonstrating that synonymous substitutions can affect splicing and are not neutral in evolution as they can be constrained by splicing requirements. <a href="#182" class="mim-tip-reference" title="Pagani, F., Raponi, M., Baralle, F. E. <strong>Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution.</strong> Proc. Nat. Acad. Sci. 102: 6368-6372, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15840711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15840711</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15840711[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0502288102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15840711">Pagani et al. (2005)</a> suggested that evolutionary selection of genomic variation takes place at 2 sequential levels: splicing control and protein function optimization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15840711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Aznarez, I., Chan, E. M., Zielenski, J., Blencowe, B. J., Tsui, L.-C. <strong>Characterization of disease-associated mutations affecting an exonic splicing enhancer and two cryptic splice sites in exon 13 of the cystic fibrosis transmembrane conductance regulator gene.</strong> Hum. Molec. Genet. 12: 2031-2040, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12913074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12913074</a>] [<a href="https://doi.org/10.1093/hmg/ddg215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12913074">Aznarez et al. (2003)</a> investigated the consequence of 2 CF disease-causing mutations on the function of a putative exonic splicing enhancer (ESE) in exon 13 of the CFTR gene. Both mutations caused aberrant splicing in a predicted manner, supporting a role for the putative ESE sequence in pre-mRNA splicing. In addition, 3 mutations, including D648V (<a href="#0097">602421.0097</a>), caused aberrant splicing of exon 13 by improving the polypyrimidine tracts of 2 cryptic 3-prime splice sites. The relative levels of 2 splicing factors, Tra2-alpha (TRA2A; <a href="/entry/602718">602718</a>) and SF2/ASF (SFRS1; <a href="/entry/600812">600812</a>), altered the effect on splicing of some of the exon 13 disease mutations. The authors suggested that the severity of CF may be modulated by changes in the fidelity of CFTR pre-mRNA splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12913074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Audrezet, M.-P., Chen, J.-M., Raguenes, O., Chuzhanova, N., Giteau, K., Le Marechal, C., Quere, I., Cooper, D. N., Ferec, C. <strong>Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms.</strong> Hum. Mutat. 23: 343-357, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024729</a>] [<a href="https://doi.org/10.1002/humu.20009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024729">Audrezet et al. (2004)</a> reported the first systematic screening of the 27 exons of the CFTR gene for large genomic rearrangements, by means of the quantitative multiplex PCR of short fluorescent fragments (QMPSF). Although many disease alleles of CFTR had previously been identified, up to 30% of disease alleles still remained to be identified in some populations, and it had been suggested that gross genomic rearrangements could account for these unidentified alleles. <a href="#10" class="mim-tip-reference" title="Audrezet, M.-P., Chen, J.-M., Raguenes, O., Chuzhanova, N., Giteau, K., Le Marechal, C., Quere, I., Cooper, D. N., Ferec, C. <strong>Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms.</strong> Hum. Mutat. 23: 343-357, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024729</a>] [<a href="https://doi.org/10.1002/humu.20009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024729">Audrezet et al. (2004)</a> studied a well-characterized cohort of 39 patients with classic CF carrying at least 1 unidentified allele. Using QMPSF, approximately 16% of the previously unidentified CF mutant alleles were identified and characterized, including 5 novel mutations (1 large deletion and 4 insertions/deletions). The breakpoints of these 5 mutations were precisely determined. Although nonhomologous recombination may be invoked to explain all 5 complex lesions, each mutation appeared to have arisen through a different mechanism. One of the insertions/deletions was highly unusual in that it involved the insertion of a short 41-bp sequence with partial homology to a retrotranspositionally-competent LINE-1 element. <a href="#10" class="mim-tip-reference" title="Audrezet, M.-P., Chen, J.-M., Raguenes, O., Chuzhanova, N., Giteau, K., Le Marechal, C., Quere, I., Cooper, D. N., Ferec, C. <strong>Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms.</strong> Hum. Mutat. 23: 343-357, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024729</a>] [<a href="https://doi.org/10.1002/humu.20009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15024729">Audrezet et al. (2004)</a> suggested that the insertion of this ultra-short LINE-1 element (dubbed a 'hyphen element') may constitute a novel type of mutation associated with human genetic disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15024729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Dinucleotide repeats are ubiquitous features of eukaryotic genomes. The highly variable nature of dinucleotide repeats makes them particularly interesting candidates for modifiers of RNA splicing when they are found near splicing signals. An example of a variable dinucleotide repeat that affects splicing is a TG repeat located in the splice acceptor of exon 9 of the CFTR gene. Higher repeat numbers result in reduced exon 9 splicing efficiency and, in some instances, the reduction in full-length transcript is sufficient to cause male infertility due to congenital bilateral absence of the vas deferens (<a href="/entry/277180">277180</a>) or nonclassic cystic fibrosis. Using a CFTR minigene system, <a href="#123" class="mim-tip-reference" title="Hefferon, T. W., Groman, J. D., Yurk, C. E., Cutting, G. R. <strong>A variable dinucleotide repeat in the CFTR gene contributes to phenotype diversity by forming RNA secondary structures that alter splicing.</strong> Proc. Nat. Acad. Sci. 101: 3504-3509, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14993601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14993601</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14993601[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0400182101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14993601">Hefferon et al. (2004)</a> studied TG tract variation and observed the same correlation between dinucleotide repeat number and exon 9 splicing efficiency seen in vivo. Placement of the TG dinucleotide tract in the minigene with random sequence abolished splicing of exon 9. Replacement of the TG tract with sequences that can self-basepair suggested that the formation of an RNA secondary structure was associated with efficient splicing; however, splicing efficiency was inversely correlated with the predicted thermodynamic stability of such structures, demonstrating that intermediate stability was optimal. Finally, substitution with TA repeats of differing length confirmed that stability of the RNA secondary structure, not sequence content, correlated with splicing efficiency. <a href="#123" class="mim-tip-reference" title="Hefferon, T. W., Groman, J. D., Yurk, C. E., Cutting, G. R. <strong>A variable dinucleotide repeat in the CFTR gene contributes to phenotype diversity by forming RNA secondary structures that alter splicing.</strong> Proc. Nat. Acad. Sci. 101: 3504-3509, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14993601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14993601</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14993601[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0400182101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14993601">Hefferon et al. (2004)</a> concluded that dinucleotide repeats can form secondary structures that have variable effects on RNA splicing efficiency and clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14993601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#276" class="mim-tip-reference" title="Wong, L.-J. C., Alper, O. M., Wang, B.-T., Lee, M.-H., Lo, S.-Y. <strong>Two novel null mutations in a Taiwanese cystic fibrosis patient and a survey of East Asian CFTR mutations. (Letter)</strong> Am. J. Med. Genet. 120A: 296-298, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12833420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12833420</a>] [<a href="https://doi.org/10.1002/ajmg.a.20039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12833420">Wong et al. (2003)</a> described pancreatic-insufficient CF in a child whose father was from Taiwan and mother from Vietnam. The child had 2 different null mutations, glu7 to ter (<a href="#0131">602421.0131</a>) in exon 1 and a 1-bp insertion, 989A (<a href="#0132">602421.0132</a>), which caused frameshift and a truncated CFTR protein of 306 amino acids. <a href="#276" class="mim-tip-reference" title="Wong, L.-J. C., Alper, O. M., Wang, B.-T., Lee, M.-H., Lo, S.-Y. <strong>Two novel null mutations in a Taiwanese cystic fibrosis patient and a survey of East Asian CFTR mutations. (Letter)</strong> Am. J. Med. Genet. 120A: 296-298, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12833420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12833420</a>] [<a href="https://doi.org/10.1002/ajmg.a.20039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12833420">Wong et al. (2003)</a> commented on the fact that East Asian CF patients did not share mutations with patients of other ethnic backgrounds. Even within East Asians, the CFTR mutation spectrum in Chinese patients is distinct from that of Japanese patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12833420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Chang, M.-C., Chang, Y.-T., Wei, S.-C., Tien, Y.-W., Liang, P.-C., Jan, I.-S., Su, Y.-N., Wong, J.-M. <strong>Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis.</strong> Clin. Genet. 71: 530-539, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17539902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17539902</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00813.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17539902">Chang et al. (2007)</a> identified mutations in the CFTR gene in 14.1% of total alleles and 24.4% of 78 Chinese/Taiwanese patients with idiopathic chronic pancreatitis (ICP; <a href="/entry/167800">167800</a>) compared to 4.8% of total alleles and 9.5% of 200 matched controls. The findings indicated that heterozygous carriers of CFTR mutations have an increased risk of developing ICP. The mutations identified were different from those usually observed in Western countries. The T5 allele with 12 or 13 TG repeats was significantly associated with earlier age at onset in patients with ICP, although the frequency of this allele did not differ between patients and controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17539902" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#241" class="mim-tip-reference" title="Sun, W., Anderson, B., Redman, J., Milunsky, A., Buller, A., McGinniss, M. J., Quan, F., Anguiano, A., Huang, S., Hantash, F., Strom, C. <strong>CFTR 5T variant has a low penetrance in females that is partially attributable to its haplotype.</strong> Genet. Med. 8: 339-345, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16778595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16778595</a>] [<a href="https://doi.org/10.1097/01.gim.0000223549.57443.16" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16778595">Sun et al. (2006)</a> analyzed the polymorphic TG dinucleotide repeat adjacent to the 5T variant in intron 8 and the codon 470 in exon 10. Patients selected for this study were positive for both the 5T variant and the major cystic fibrosis mutation, delta-F508. Almost all delta-F508 mutations occur in a 10TG-9T-470M haplotype. Therefore, it is possible to determine the haplotype of the 5T variant in trans. Of the 74 samples analyzed, 41 (55%) were 11TG-5T-470M, 31 (42%) were 12TG-5T-470V, and 2 (3%) were 13TG-5T-470M. Of the 49 cases for which they had clinical information, <a href="#241" class="mim-tip-reference" title="Sun, W., Anderson, B., Redman, J., Milunsky, A., Buller, A., McGinniss, M. J., Quan, F., Anguiano, A., Huang, S., Hantash, F., Strom, C. <strong>CFTR 5T variant has a low penetrance in females that is partially attributable to its haplotype.</strong> Genet. Med. 8: 339-345, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16778595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16778595</a>] [<a href="https://doi.org/10.1097/01.gim.0000223549.57443.16" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16778595">Sun et al. (2006)</a> reported that 17.6% of females (6 of 34) and 66.7% of males (10 of 15) showed symptoms resembling atypical cystic fibrosis. The haplotype with the highest penetrance in females (42%, or 5 of 12) and more than 80% (5 of 6) in males was 12TG-5T-470V. The authors also evaluated 12 males affected with congenital bilateral absence of vas deferens and positive for the 5T variant; 10 of 12 had the 12TG-5T-470V haplotype. <a href="#241" class="mim-tip-reference" title="Sun, W., Anderson, B., Redman, J., Milunsky, A., Buller, A., McGinniss, M. J., Quan, F., Anguiano, A., Huang, S., Hantash, F., Strom, C. <strong>CFTR 5T variant has a low penetrance in females that is partially attributable to its haplotype.</strong> Genet. Med. 8: 339-345, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16778595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16778595</a>] [<a href="https://doi.org/10.1097/01.gim.0000223549.57443.16" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16778595">Sun et al. (2006)</a> concluded that overall, the 5T variant has a milder clinical consequence than previously estimated in females. The clinical presentations of the 5T variant are associated with the 5T-12TG-470M haplotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16778595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Alonso, M. J., Heine-Suner, D., Calvo, M., Rosell, J., Gimenez, J., Ramos, M. D., Telleria, J. J., Palacio, A., Estivill, X., Casals, T. <strong>Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry.</strong> Ann. Hum. Genet. 71: 194-201, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17331079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17331079</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2006.00310.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17331079">Alonso et al. (2007)</a> analyzed 1,954 Spanish cystic fibrosis alleles to define the molecular spectrum of mutations. Commercial panels showed a limited detection power, leading to the identification of only 76% of alleles. More sensitive assays identified 12 mutations with frequencies above 1%, the F508del mutation being the most frequent, present on 51% of alleles. In the Spanish population, 18 mutations were needed to achieve a detection rate of 80%. Fifty-one mutations (42%) were observed once. <a href="#3" class="mim-tip-reference" title="Alonso, M. J., Heine-Suner, D., Calvo, M., Rosell, J., Gimenez, J., Ramos, M. D., Telleria, J. J., Palacio, A., Estivill, X., Casals, T. <strong>Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry.</strong> Ann. Hum. Genet. 71: 194-201, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17331079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17331079</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2006.00310.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17331079">Alonso et al. (2007)</a> identified a total of 121 disease-causing mutations that accounted for 96% of CF alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17331079" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Effect of Aminoglycoside Antibiotics</em></strong></p><p>
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In addition to their antimicrobial activity, aminoglycoside antibiotics can suppress premature termination codons by allowing an amino acid to be incorporated in place of the stop codon, thus permitting translation to continue to the normal end of the transcript. The mechanism translation termination is highly conserved among most organisms and is almost always signaled by an amber (UAG), ochre (UAA), or opal (UGA) termination codon. The nucleotide sequence surrounding the termination codon has an important role in determining the efficiency of translation termination. Aminoglycoside antibiotics can reduce the fidelity of translation, predominantly by inhibiting ribosomal 'proofreading,' a mechanism to exclude poorly matched aminoacyl-tRNA from becoming incorporated into the polypeptide chain. In this way aminoglycosides increase the frequency of erroneous insertions at the nonsense codon and permit translation to continue to the end of the gene, as has been shown in eukaryotic cells (<a href="#28" class="mim-tip-reference" title="Burke, J. F., Mogg, A. E. <strong>Suppression of a nonsense mutation in mammalian cells in vivo by the aminoglycoside antibiotics G-418 and paromomycin.</strong> Nucleic Acids Res. 13: 6265-6272, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2995924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2995924</a>] [<a href="https://doi.org/10.1093/nar/13.17.6265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2995924">Burke and Mogg, 1985</a>), including human fibroblasts (<a href="#24" class="mim-tip-reference" title="Buchanan, J. H., Stevens, A., Sidhu, J. <strong>Aminoglycoside antibiotic treatment of human fibroblasts: intracellular accumulation, molecular changes and the loss of ribosomal accuracy.</strong> Europ. J. Cell Biol. 43: 141-147, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3569303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3569303</a>]" pmid="3569303">Buchanan et al., 1987</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2995924+3569303" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#126" class="mim-tip-reference" title="Howard, M., Frizzell, R. A., Bedwell, D. M. <strong>Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations.</strong> Nature Med. 2: 467-469, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8597960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8597960</a>] [<a href="https://doi.org/10.1038/nm0496-467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8597960">Howard et al. (1996)</a> demonstrated that 2 CFTR-associated stop mutations could be suppressed by treating cells with low doses of an aminoglycoside antibiotic. Others demonstrated this effect in cultured cells bearing CFTR nonsense mutations and in connection with stop mutations in muscular dystrophy in mice and in vitro in Hurler syndrome (<a href="/entry/607014">607014</a>), cystinosis (<a href="/entry/219800">219800</a>), and other disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8597960" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a CF bronchial cell line carrying the CFTR W1282X (<a href="#0022">602421.0022</a>) mutation, <a href="#17" class="mim-tip-reference" title="Bedwell, D. M., Kaenjak, A., Benos, D. J., Bebok, Z., Bubien, J. K., Hong, J., Tousson, A., Clancy, J. P., Sorscher, E. J. <strong>Suppression of a CFTR premature stop mutation in a bronchial epithelial cell line.</strong> Nature Med. 3: 1280-1284, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9359706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9359706</a>] [<a href="https://doi.org/10.1038/nm1197-1280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9359706">Bedwell et al. (1997)</a> demonstrated that treatment with the aminoglycosides G418 and gentamicin restored CFTR expression, as shown by the reappearance of cAMP-activated chloride currents, the restoration of CFTR protein at the apical plasma membrane, and an increase in the abundance of CFTR mRNA levels from the W1282X allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9359706" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#275" class="mim-tip-reference" title="Wilschanski, M., Yahav, Y., Yaacov, Y., Blau, H., Bentur, L., Rivlin, J., Aviram, M., Bdolah-Abram, T., Bebok, Z., Shushi, L., Kerem, B., Kerem, E. <strong>Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations.</strong> New Eng. J. Med. 349: 1433-1441, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14534336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14534336</a>] [<a href="https://doi.org/10.1056/NEJMoa022170" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14534336">Wilschanski et al. (2003)</a> performed a double-blind placebo-controlled crossover trial of intranasal gentamicin in patients with stop mutations in CFTR, in comparison with patients homozygous for the delta-F508 mutation. Nasal potential difference was measured at baseline and after each treatment. Gentamicin treatment caused a significant reduction in basal potential difference in 19 patients carrying stop mutations and a significant response to chloride-free isoproterenol solution. This effect of gentamicin on nasal potential difference occurred both in patients who were homozygous for stop mutations and in those who were heterozygous, but not in patients who were homozygous for delta-F508. After gentamicin treatment, a significant increase in peripheral and surface staining for CFTR was observed in the nasal epithelial cells of patients carrying stop mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14534336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#242" class="mim-tip-reference" title="Tata, F., Stanier, P., Wicking, C., Halford, S., Kruyer, H., Lench, N. J., Scambler, P. J., Hansen, C., Braman, J. C., Williamson, R., Wainwright, B. J. <strong>Cloning the mouse homolog of the human cystic fibrosis transmembrane conductance regulator gene.</strong> Genomics 10: 301-307, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1712752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1712752</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90312-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1712752">Tata et al. (1991)</a> cloned the mouse homolog of the human CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1712752" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#160" class="mim-tip-reference" title="McCombie, W. R., Adams, M. D., Kelley, J. M., FitzGerald, M. G., Utterback, T. R., Khan, M., Dubnick, M., Kerlavage, A. R., Venter, J. C., Fields, C. <strong>Caenorhabditis elegans expressed sequence tags identify gene families and potential disease gene homologues.</strong> Nature Genet. 1: 124-131, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302005</a>] [<a href="https://doi.org/10.1038/ng0592-124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302005">McCombie et al. (1992)</a> used expressed sequence tags to identify homologs of human genes, including CFTR and the LDL receptor gene (<a href="/entry/606945">606945</a>), in Caenorhabditis elegans. They suggested that C. elegans, because of the extensive information on the physical and genetic map of the organism, might have unique advantages for the study of the function of normal and mutant genes. The same approach was applied even more extensively by <a href="#266" class="mim-tip-reference" title="Waterston, R., Martin, C., Craxton, M., Huynh, C., Coulson, A., Hillier, L., Durbin, R., Green, P., Shownkeen, R., Halloran, N., Metzstein, M., Hawkins, T., Wilson, R., Berks, M., Du, Z., Thomas, K., Thierry-Mieg, J., Sulston, J. <strong>A survey of expressed genes in Caenorhabditis elegans.</strong> Nature Genet. 1: 114-123, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302004</a>] [<a href="https://doi.org/10.1038/ng0592-114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302004">Waterston et al. (1992)</a> who, by study of a cDNA library, identified about 1,200 of the estimated 15,000 genes of C. elegans. More than 30% of the inferred protein sequences had significant similarity to existing sequences in databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1302004+1302005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#283" class="mim-tip-reference" title="Zeiher, B. G., Eichwald, E., Zabner, J., Smith, J. J., Puga, A. P., McCray, P. B., Jr., Capecchi, M. R., Welsh, M. J., Thomas, K. R. <strong>A mouse model for the delta-F508 allele of cystic fibrosis.</strong> J. Clin. Invest. 96: 2051-2064, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7560099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7560099</a>] [<a href="https://doi.org/10.1172/JCI118253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7560099">Zeiher et al. (1995)</a> noted that the F508del (<a href="#0001">602421.0001</a>) mutation disrupts the biosynthetic processing of CFTR so that the protein is retained in the endoplasmic reticulum and is then degraded. As a result, affected epithelia lack CFTR in the apical membrane and lack cAMP-stimulated chloride ion permeability. <a href="#80" class="mim-tip-reference" title="Dorin, J. R., Dickinson, P., Alton, E. W. F. W., Smith, S. N., Geddes, D. M., Stevenson, B. J., Kimber, W. L., Fleming, S., Clarke, A. R., Hooper, M. L., Anderson, L., Beddington, R. S. P., Porteous, D. J. <strong>Cystic fibrosis in the mouse by targeted insertional mutagenesis.</strong> Nature 359: 211-215, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1382232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1382232</a>] [<a href="https://doi.org/10.1038/359211a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1382232">Dorin et al. (1992)</a> and <a href="#235" class="mim-tip-reference" title="Snouwaert, J. N., Brigman, K. K., Latour, A. M., Malouf, N. N., Boucher, R. C., Smithies, O., Koller, B. H. <strong>An animal model for cystic fibrosis made by gene targeting.</strong> Science 257: 1083-1088, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1380723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1380723</a>] [<a href="https://doi.org/10.1126/science.257.5073.1083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1380723">Snouwaert et al. (1992)</a>, as well as others, disrupted the mouse CFTR gene to create null mutant mice that lack CFTR or express greatly reduced amounts of wildtype protein. To understand the pathophysiology of the disease and to evaluate new therapies, <a href="#283" class="mim-tip-reference" title="Zeiher, B. G., Eichwald, E., Zabner, J., Smith, J. J., Puga, A. P., McCray, P. B., Jr., Capecchi, M. R., Welsh, M. J., Thomas, K. R. <strong>A mouse model for the delta-F508 allele of cystic fibrosis.</strong> J. Clin. Invest. 96: 2051-2064, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7560099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7560099</a>] [<a href="https://doi.org/10.1172/JCI118253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7560099">Zeiher et al. (1995)</a> used a targeting strategy to introduce the F508del mutation into the mouse CFTR gene. Murine CFTR is 78% identical to human CFTR, and it contains a phenylalanine at residue 508 flanked by 28 amino acids identical to those in human CFTR. They could show that affected epithelia from homozygous F508del mice lacked CFTR in the apical membrane and were chloride ion-impermeable. Forty percent of homozygous animals survived into adulthood and displayed several abnormalities found in human disease and in CFTR null mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7560099+1380723+1382232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#250" class="mim-tip-reference" title="Van Doorninck, J. H., French, P. J., Verbeek, E., Peters, R. H. P. C., Morreau, H., Bijman, J., Scholte, B. J. <strong>A mouse model for the cystic fibrosis delta-F508 mutation.</strong> EMBO J. 14: 4403-4411, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7556083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7556083</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1995.tb00119.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7556083">Van Doorninck et al. (1995)</a> generated a mouse model of CF with the phe508del mutation using the 'hit-and-run' mutagenesis procedure. In this model, the intron structure was not disturbed, in contrast to similar models (<a href="#283" class="mim-tip-reference" title="Zeiher, B. G., Eichwald, E., Zabner, J., Smith, J. J., Puga, A. P., McCray, P. B., Jr., Capecchi, M. R., Welsh, M. J., Thomas, K. R. <strong>A mouse model for the delta-F508 allele of cystic fibrosis.</strong> J. Clin. Invest. 96: 2051-2064, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7560099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7560099</a>] [<a href="https://doi.org/10.1172/JCI118253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7560099">Zeiher et al., 1995</a>; <a href="#57" class="mim-tip-reference" title="Colledge, W. H., Abella, B. S., Southern, K. W., Ratcliff, R., Jiang, C., Cheng, S. H., MacVinish, L. J., Anderson, J. R., Cuthbert, A. W., Evans, M. J. <strong>Generation and characterisation of a delta-F508 cystic fibrosis mouse model.</strong> Nature Genet. 10: 445-452, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7545494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7545494</a>] [<a href="https://doi.org/10.1038/ng0895-445" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7545494">Colledge et al., 1995</a>). <a href="#98" class="mim-tip-reference" title="French, P. J., van Doorninck, J. H., Peters, R. H. P. C., Verbeek, E., Ameen, N. A., Marino, C. R., de Jonge, H. R., Bijman, J., Scholte, B. J. <strong>A delta-F508 mutation in mouse cystic fibrosis transmembrane conductance regulator results in a temperature-sensitive processing defect in vivo.</strong> J. Clin. Invest. 98: 1304-1312, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8823295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8823295</a>] [<a href="https://doi.org/10.1172/JCI118917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8823295">French et al. (1996)</a> demonstrated that in this model of CF the mutant CFTR was not processed efficiently to the fully glycosylated form in vivo. However, the mutant protein was expressed as functional chloride channels in the plasma membrane of cells cultured at reduced temperature. Furthermore, they could show that the electrophysiologic characteristics of the mouse phe508del-CFTR channels were indistinguishable from normal. In homozygous mutant mice they did not observe a significant effect of genetic background on the level of residual chloride channel activity. The data showed that like its human homolog, the mouse mutant CFTR is a temperature-sensitive processing mutant, and therefore an authentic model for study of pathophysiology and therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7560099+7556083+8823295+7545494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#79" class="mim-tip-reference" title="Dickinson, P., Smith, S. N., Webb, S., Kilanowski, F. M., Campbell, I. J., Taylor, M. S., Porteous, D. J., Willemsen, R., de Jonge, H. R., Farley, R., Alton, E. W. F. W., Dorin, J. R. <strong>The severe G480C cystic fibrosis mutation, when replicated in the mouse, demonstrates mistrafficking, normal survival and organ-specific bioelectrics.</strong> Hum. Molec. Genet. 11: 243-251, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823443</a>] [<a href="https://doi.org/10.1093/hmg/11.3.243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823443">Dickinson et al. (2002)</a> replicated the G480C mutation (<a href="#0083">602421.0083</a>) in the murine Cftr gene using the 'hit-and-run' double recombination procedure. The G480C cystic fibrosis mouse model expressed the G480C mutant transcript at a level comparable to that of wildtype Cftr. The homozygous mutant mice were fertile and had normal survival, weight, tooth color, and no evidence of cecal blockage, despite mild goblet cell hypertrophy in the intestine. Analysis of the mutant protein revealed that the majority of G480C CFTR was abnormally processed and no G480C CFTR-specific immunostaining in the apical membranes of intestinal cells was detected. The bioelectric phenotype of these mice revealed organ-specific electrophysiological effects. In contrast to delta-F508 'hit-and-run' homozygotes, the classic defect of forskolin-induced chloride ion transport was not replicated in the cecum, but the response to low chloride in the nose was clearly defective in the G480C mutant animals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11823443" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Of importance to any gene-replacement strategy for treatment of CF is the identification of the cell type(s) within the lung milieu that need to be corrected and an indication whether this is sufficient to restore a normal inflammatory response and bacterial clearance. <a href="#174" class="mim-tip-reference" title="Oceandy, D., McMorran, B. J., Smith, S. N., Schreiber, R., Kunzelmann, K., Alton, E. W. F. W., Hume, D. A., Wainwright, B. J. <strong>Gene complementation of airway epithelium in the cystic fibrosis mouse is necessary and sufficient to correct the pathogen clearance and inflammatory abnormalities.</strong> Hum. Molec. Genet. 11: 1059-1067, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11978765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11978765</a>] [<a href="https://doi.org/10.1093/hmg/11.9.1059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11978765">Oceandy et al. (2002)</a> generated G551D CF mice transgenically expressing the human CFTR gene in 2 tissue compartments previously demonstrated to mediate a CFTR-dependent inflammatory response: lung epithelium and alveolar macrophages. Following chronic pulmonary infection with Pseudomonas aeruginosa, CF mice with epithelial-expressed (but not macrophage-specific) CFTR showed an improvement in pathogen clearance and inflammatory markers compared with control CF animals. The authors concluded that there may be a role for CFTR-mediated events in epithelial cells in response of the lung to bacterial pathogens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11978765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#78" class="mim-tip-reference" title="Di, A., Brown, M. E., Deriy, L. V., Li, C., Szeto, F. L., Chen, Y., Huang, P., Tong, J., Naren, A. P., Bindokas, V., Palfrey, H. C., Nelson, D. J. <strong>CFTR regulates phagosome acidification in macrophages and alters bactericidal activity.</strong> Nat. Cell Biol. 8: 933-944, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16921366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16921366</a>] [<a href="https://doi.org/10.1038/ncb1456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16921366">Di et al. (2006)</a> found that alveolar macrophages from Cftr -/- mice retained the ability to phagocytose and generate an oxidative burst, but exhibited defective killing of internalized bacteria. Lysosomes from Cftr -/- macrophages failed to acidify, although they retained normal fusogenic capacity with nascent phagosomes. <a href="#78" class="mim-tip-reference" title="Di, A., Brown, M. E., Deriy, L. V., Li, C., Szeto, F. L., Chen, Y., Huang, P., Tong, J., Naren, A. P., Bindokas, V., Palfrey, H. C., Nelson, D. J. <strong>CFTR regulates phagosome acidification in macrophages and alters bactericidal activity.</strong> Nat. Cell Biol. 8: 933-944, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16921366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16921366</a>] [<a href="https://doi.org/10.1038/ncb1456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16921366">Di et al. (2006)</a> proposed that CFTR contributes to lysosome acidification and that in its absence phagolysosomes acidify poorly, thus providing an environment conducive to bacterial replication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16921366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The delta-F508 CFTR mutation results in the production of a misfolded CFTR protein that is retained in the endoplasmic reticulum and targeted for degradation. Curcumin, a major component of the curry spice turmeric, is a nontoxic calcium-adenosine triphosphatase pump inhibitor that can be administered to humans safely. <a href="#87" class="mim-tip-reference" title="Egan, M. E., Pearson, M., Weiner, S. A., Rajendran, V., Rubin, D., Glockner-Pagel, J., Canny, S., Du, K., Lukacs, G. L., Caplan, M. J. <strong>Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects.</strong> Science 304: 600-602, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15105504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15105504</a>] [<a href="https://doi.org/10.1126/science.1093941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15105504">Egan et al. (2004)</a> found that oral administration of curcumin to homozygous delta-F508 Cftr mice in doses comparable, on a weight-per-weight basis, to those well tolerated by humans corrected these animals' characteristic nasal potential difference defect. These effects were not observed in mice homozygous for a complete knockout of the CFTR gene. Curcumin also induced the functional appearance of delta-F508 CFTR protein in the plasma membranes of transfected baby hamster kidney cells. <a href="#87" class="mim-tip-reference" title="Egan, M. E., Pearson, M., Weiner, S. A., Rajendran, V., Rubin, D., Glockner-Pagel, J., Canny, S., Du, K., Lukacs, G. L., Caplan, M. J. <strong>Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects.</strong> Science 304: 600-602, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15105504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15105504</a>] [<a href="https://doi.org/10.1126/science.1093941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15105504">Egan et al. (2004)</a> concluded that curcumin treatment may be able to correct defects associated with the homozygous expression of the delta-F508 CFTR gene, as it allows for dissociation from ER chaperone proteins and transfer to the cell membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15105504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Delayed puberty is common among individuals with cystic fibrosis and is usually attributed to chronic disease and/or poor nutrition. However, delayed puberty has been reported as a feature of CF even in the setting of good nutritional and clinical status (<a href="#133" class="mim-tip-reference" title="Johannesson, M., Gottlieb, C., Hjelte, L. <strong>Delayed puberty in girls with cystic fibrosis despite good clinical status.</strong> Pediatrics 99: 29-34, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8989333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8989333</a>] [<a href="https://doi.org/10.1542/peds.99.1.29" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8989333">Johannesson et al., 1997</a>). This finding, along with evidence that Cftr is expressed in rat brain, human hypothalamus, and a gonadotropin-releasing hormone secreting line, raised the possibility that some of the pubertal delay in cystic fibrosis could stem directly from alterations in Cftr function that affects the hypothalamic-pituitary-gonadal axis. To examine this hypothesis, <a href="#132" class="mim-tip-reference" title="Jin, R., Hodges, C. A., Drumm, M. L., Palmert, M. R. <strong>The cystic fibrosis transmembrane conductance regulator (Cftr) modulates the timing of puberty in mice. (Letter)</strong> J. Med. Genet. 43: e29, 2006. Note: Electronic Letter.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16740913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16740913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16740913[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.032839" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16740913">Jin et al. (2006)</a> studied pubertal timing in a mouse model of CF engineered to produce a truncated Cftr mRNA and referred to as S489X. Homozygous knockout mice, which have chronic inflammation and gastrointestinal disease, grew more slowly and had later onset of puberty than wildtype animals. <a href="#132" class="mim-tip-reference" title="Jin, R., Hodges, C. A., Drumm, M. L., Palmert, M. R. <strong>The cystic fibrosis transmembrane conductance regulator (Cftr) modulates the timing of puberty in mice. (Letter)</strong> J. Med. Genet. 43: e29, 2006. Note: Electronic Letter.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16740913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16740913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16740913[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.032839" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16740913">Jin et al. (2006)</a> anticipated that the knockout heterozygotes, which have no clinical CF phenotype, might display an intermediate timing of puberty. They found, however, that these mice had earlier onset of puberty, as assessed by vaginal opening (VO), than wildtype. These findings were confirmed in a second independent model of CF engineered to generate the delta-F508 mutation in mice. Again the homozygotes displayed later pubertal timing, and the heterozygotes displayed earlier VO than the wildtype animals. These data provided further evidence that Cftr can directly modulate the reproductive endocrine axis and raised the possibility that heterozygote mutation carriers may have a reproductive advantage. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8989333+16740913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For further information on animal models for CF, see <a href="/entry/219700">219700</a>.</p><p>To investigate the abnormalities that impair elimination when a bacterium lands on the pristine surface of a newborn CF airway, <a href="#185" class="mim-tip-reference" title="Pezzulo, A. A., Tang, X. X., Hoegger, M. J., Alaiwa, M. H., Ramachandran, S., Moninger, T. O., Karp, P. H., Wohlford-Lenane, C. L., Haagsman, H. P., van Eijk, M., Banfi, B., Horswill, A. R., Stolz, D. A., McCray, P. B., Jr., Welsh, M. J., Zabner, J. <strong>Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung.</strong> Nature 487: 109-113, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22763554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22763554</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22763554[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22763554">Pezzulo et al. (2012)</a> interrogated the viability of individual bacteria immobilized on solid grids and placed onto the airway surface. As a model, they studied CF pigs, which spontaneously develop hallmark features of CF lung disease. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. <a href="#185" class="mim-tip-reference" title="Pezzulo, A. A., Tang, X. X., Hoegger, M. J., Alaiwa, M. H., Ramachandran, S., Moninger, T. O., Karp, P. H., Wohlford-Lenane, C. L., Haagsman, H. P., van Eijk, M., Banfi, B., Horswill, A. R., Stolz, D. A., McCray, P. B., Jr., Welsh, M. J., Zabner, J. <strong>Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung.</strong> Nature 487: 109-113, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22763554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22763554</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22763554[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22763554">Pezzulo et al. (2012)</a> showed that in newborn wildtype pigs, the thin layer of airway surface liquid (ASL) rapidly kills bacteria in vivo, when removed from the lung, and in primary epithelial cultures. Lack of CFTR reduces bacterial killing. <a href="#185" class="mim-tip-reference" title="Pezzulo, A. A., Tang, X. X., Hoegger, M. J., Alaiwa, M. H., Ramachandran, S., Moninger, T. O., Karp, P. H., Wohlford-Lenane, C. L., Haagsman, H. P., van Eijk, M., Banfi, B., Horswill, A. R., Stolz, D. A., McCray, P. B., Jr., Welsh, M. J., Zabner, J. <strong>Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung.</strong> Nature 487: 109-113, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22763554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22763554</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22763554[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22763554">Pezzulo et al. (2012)</a> found that the ASL pH was more acidic in CF pigs, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wildtype pigs, and, conversely, increasing ASL pH rescued killing in CF pigs. <a href="#185" class="mim-tip-reference" title="Pezzulo, A. A., Tang, X. X., Hoegger, M. J., Alaiwa, M. H., Ramachandran, S., Moninger, T. O., Karp, P. H., Wohlford-Lenane, C. L., Haagsman, H. P., van Eijk, M., Banfi, B., Horswill, A. R., Stolz, D. A., McCray, P. B., Jr., Welsh, M. J., Zabner, J. <strong>Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung.</strong> Nature 487: 109-113, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22763554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22763554</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22763554[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22763554">Pezzulo et al. (2012)</a> concluded that their results directly linked the initial host defense defect to the loss of CFTR, an anion channel that facilitates bicarbonate transport. Without CFTR, airway epithelial bicarbonate secretion is defective; the ASL pH falls and inhibits antimicrobial function, and thereby impairs the killing of bacteria that enter the newborn lung. <a href="#185" class="mim-tip-reference" title="Pezzulo, A. A., Tang, X. X., Hoegger, M. J., Alaiwa, M. H., Ramachandran, S., Moninger, T. O., Karp, P. H., Wohlford-Lenane, C. L., Haagsman, H. P., van Eijk, M., Banfi, B., Horswill, A. R., Stolz, D. A., McCray, P. B., Jr., Welsh, M. J., Zabner, J. <strong>Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung.</strong> Nature 487: 109-113, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22763554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22763554</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22763554[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22763554">Pezzulo et al. (2012)</a> also concluded that increasing ASL pH might prevent the initial infection in patients with CF, and that assaying bacterial killing could report on the benefit of therapeutic interventions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22763554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>CFTR was one of the genes used by <a href="#159" class="mim-tip-reference" title="Mashal, R. D., Koontz, J., Sklar, J. <strong>Detection of mutations by cleavage of DNA heteroduplexes with bacteriophage resolvases.</strong> Nature Genet. 9: 177-183, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719346</a>] [<a href="https://doi.org/10.1038/ng0295-177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719346">Mashal et al. (1995)</a> to test their method of mutation detection using bacteriophage resolvases, whose function in vivo is to cleave branched DNA and which have the property of recognizing mismatched bases in double-stranded DNA and cutting the DNA at the mismatch. The new method, termed enzyme mismatch cleavage (EMC) by <a href="#281" class="mim-tip-reference" title="Youil, R., Kemper, B. W., Cotton, R. G. H. <strong>Screening for mutations by enzyme mismatch cleavage with T4 endonuclease VII.</strong> Proc. Nat. Acad. Sci. 92: 87-91, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7816853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7816853</a>] [<a href="https://doi.org/10.1073/pnas.92.1.87" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7816853">Youil et al. (1995)</a>, who independently developed the method, takes advantage of this characteristic of resolvases to detect individuals who are heterozygous at a given site. Radiolabeled DNA is cleaved by the resolvase at the site of mismatch in heteroduplex DNA and digestion is monitored on a gel. Thus, both the presence and the estimated position of an alteration is revealed. One may think of the resolvase as a restriction enzyme that only recognizes mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7719346+7816853" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs113993960 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113993960;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs113993960" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs113993960" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007523 OR RCV000007524 OR RCV000058929 OR RCV000119038 OR RCV000626692 OR RCV000626693 OR RCV000785641 OR RCV001004459 OR RCV001642198 OR RCV001787370 OR RCV001787371 OR RCV001831519 OR RCV002243627 OR RCV002251888 OR RCV002490332 OR RCV003227599 OR RCV003444054" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007523, RCV000007524, RCV000058929, RCV000119038, RCV000626692, RCV000626693, RCV000785641, RCV001004459, RCV001642198, RCV001787370, RCV001787371, RCV001831519, RCV002243627, RCV002251888, RCV002490332, RCV003227599, RCV003444054" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007523...</a>
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<p>In individuals with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#138" class="mim-tip-reference" title="Kerem, B., Rommens, J. M., Buchanan, J. A., Markiewicz, D., Cox, T. K., Chakravarti, A., Buchwald, M., Tsui, L.-C. <strong>Identification of the cystic fibrosis gene: genetic analysis.</strong> Science 245: 1073-1080, 1989. Note: Erratum: Science 245: 1437 only, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2570460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2570460</a>] [<a href="https://doi.org/10.1126/science.2570460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2570460">Kerem et al. (1989)</a> identified deletion of 3 basepairs in exon 10 of the CFTR gene, leading to deletion of phenylalanine at codon 508 (delta-F508). The exon in which the delta-F508 mutation occurs has been corrected to exon 11; see, e.g., <a href="#225" class="mim-tip-reference" title="Sharma, H., Mavuduru, R. S., Singh, S. K., Prasad, R. <strong>Heterogeneous spectrum of mutations in CFTR gene from Indian patients with congenital absence of the vas deferens and their association with cystic fibrosis genetic modifiers.</strong> Molec. Hum Reprod. 20: 827-835, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24958810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24958810</a>] [<a href="https://doi.org/10.1093/molehr/gau047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24958810">Sharma et al. (2014)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24958810+2570460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The <a href="#91" class="mim-tip-reference" title="European Working Group on CF Genetics. <strong>Gradient of distribution in Europe of the major CF mutation and of its associated haplotype.</strong> Hum. Genet. 85: 436-445, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2210767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2210767</a>] [<a href="https://doi.org/10.1007/BF02428304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2210767">European Working Group on CF Genetics (1990)</a> published information on the distribution of the delta-F508 mutation in Europe. The data, illustrated with a useful map, indicated a striking cline across Europe from low values of 30% in the southeast (in Turkey) to high values in the northwest (e.g., 88% in Denmark). The group suggested that the spread of the CF gene might have accompanied the migrations of early farmers starting from the Middle East and slowly progressing toward the northwest of Europe. The diffusion of the gene may have been favored by the selective advantage conferred by the gene. Strong association with the so-called haplotype B was demonstrated. The possibility of 'hitchhiking,' i.e., the influence of neighboring genes was discussed. <a href="#211" class="mim-tip-reference" title="Rozen, R., Schwartz, R. H., Hilman, B. C., Stanislovitis, P., Horn, G. T., Klinger, K., Daigneault, J., De Braekeleer, M., Kerem, B., Tsui, L.-C., Fujiwara, T. M., Morgan, K. <strong>Cystic fibrosis mutations in North American populations of French ancestry: analysis of Quebec French-Canadian and Louisiana Acadian families.</strong> Am. J. Hum. Genet. 47: 606-610, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2220803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2220803</a>]" pmid="2220803">Rozen et al. (1990)</a> found the delta-F508 mutation in 71% of CF chromosomes from urban Quebec province French Canadian families, 55% of those from Saguenay-Lac-Saint-Jean region families and in 70% of those from Louisiana Acadian families. <a href="#67" class="mim-tip-reference" title="De Braekeleer, M. <strong>Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada).</strong> Hum. Hered. 41: 141-146, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1937486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1937486</a>] [<a href="https://doi.org/10.1159/000153992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1937486">De Braekeleer (1991)</a> estimated that the frequency at birth of cystic fibrosis is 1/926 in the Saguenay-Lac-Saint-Jean region, giving a carrier rate of 1/15. For the same region, <a href="#66" class="mim-tip-reference" title="Daigneault, J., Aubin, G., Simard, F., De Braekeleer, M. <strong>Genetic epidemiology of cystic fibrosis in Saguenay-Lac-St-Jean (Quebec, Canada).</strong> Clin. Genet. 40: 298-303, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1756602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1756602</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1991.tb03099.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1756602">Daigneault et al. (1991)</a> reported a prevalence of CF at birth of 1/902 liveborns, and a carrier rate of 1/15. <a href="#209" class="mim-tip-reference" title="Rozen, R., De Braekeleer, M., Daigneault, J., Ferreira-Rajabi, L., Gerdes, M., Lamoureux, L., Aubin, G., Simard, F., Fujiwara, T. M., Morgan, K. <strong>Cystic fibrosis mutations in French Canadians: three CFTR mutations are relatively frequent in a Quebec population with an elevated incidence of cystic fibrosis.</strong> Am. J. Med. Genet. 42: 360-364, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1536179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1536179</a>] [<a href="https://doi.org/10.1002/ajmg.1320420322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1536179">Rozen et al. (1992)</a> found that the delta-F508 mutation was present in 58% of Saguenay-Lac-Saint-Jean CF families, with the G-to-T donor splice site mutation after codon 621 being found in 23%, and the A455E mutation (<a href="#0007">602421.0007</a>) in 8%. The latter 2 mutations were not found in urban Quebec families. This provided further evidence of the role of founder effect. Among 293 patients, <a href="#139" class="mim-tip-reference" title="Kerem, B., Zielenski, J., Markiewicz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in regions corresponding to the 2 putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.</strong> Proc. Nat. Acad. Sci. 87: 8447-8451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236053</a>] [<a href="https://doi.org/10.1073/pnas.87.21.8447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236053">Kerem et al. (1990)</a> found that those who were homozygous for the F508 deletion had received a diagnosis of cystic fibrosis at an earlier age and had a greater frequency of pancreatic insufficiency. Pancreatic insufficiency was present in 99% of the homozygous patients, 72% of those heterozygous for the deletion, and only 36% of patients with other mutations. <a href="#267" class="mim-tip-reference" title="Wauters, J. G., Hendrickx, J., Coucke, P., Vits, L., Stuer, K., van Schil, L., van der Auwera, B. J., Van Elsen, A., Dumon, J., Willems, P. J. <strong>Frequency of the phenylalanine deletion (delta-F508) in the CF gene of Belgian cystic fibrosis patients.</strong> Clin. Genet. 39: 89-92, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1673094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1673094</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1991.tb02992.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1673094">Wauters et al. (1991)</a> studied the frequency of the delta-F508 mutation among Belgian patients with CF. The mutation was present in 80% of CF chromosomes from 36 unrelated families. Ninety-three percent of the CF chromosomes carrying the delta-F508 mutation also carried haplotype B in this population. <a href="#104" class="mim-tip-reference" title="Gille, C., Grade, K., Coutelle, C. <strong>A pooling strategy for heterozygote screening of the delta-F508 cystic fibrosis mutation.</strong> Hum. Genet. 86: 289-291, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1997384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1997384</a>] [<a href="https://doi.org/10.1007/BF00202411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1997384">Gille et al. (1991)</a> described a strategy for efficient heterozygote screening for the delta-F508 mutation. They showed that PCR could detect a heterozygote in a pool of up to 49 unrelated DNA samples. <a href="#154" class="mim-tip-reference" title="Lerer, I., Sagi, M., Cutting, G. R., Abeliovich, D. <strong>Cystic fibrosis mutations delta-F508 and G542X in Jewish patients.</strong> J. Med. Genet. 29: 131-133, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1377276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1377276</a>] [<a href="https://doi.org/10.1136/jmg.29.2.131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1377276">Lerer et al. (1992)</a> reported that the delta-F508 mutation accounts for 33.8% of Jewish CF alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2210767+1673094+1997384+1377276+1536179+2236053+1937486+1756602+2220803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The Basque population is thought to be one of the oldest in Europe, having been established in western Europe during the late Paleolithic Age. Euskera, the Basque language, is thought to be pre-Indo-European, originating from the first settlers of Europe. The variable distribution of the delF508 mutation in Europe, with higher frequencies in northern Europe and lower frequencies in southern Europe, has been attributed to a spread of the mutation by early farmers migrating from the Middle East during the Neolithic period. However, a very high frequency of this mutation was found in the Basque Provinces, where the incidence of CF is approximately 1 in 4,500. In a study of 45 CF families from the Basque Provinces, <a href="#31" class="mim-tip-reference" title="Casals, T., Vazquez, C., Lazaro, C., Girbau, E., Gimenez, F. J., Estivill, X. <strong>Cystic fibrosis in the Basque country: high frequency of mutation delF508 in patients of Basque origin.</strong> Am. J. Hum. Genet. 50: 404-410, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1370875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1370875</a>]" pmid="1370875">Casals et al. (1992)</a> found that the frequency of the delF508 mutation was 87% in the chromosomes of individuals of pure Basque extraction and 58% in those of mixed Basque origin. <a href="#31" class="mim-tip-reference" title="Casals, T., Vazquez, C., Lazaro, C., Girbau, E., Gimenez, F. J., Estivill, X. <strong>Cystic fibrosis in the Basque country: high frequency of mutation delF508 in patients of Basque origin.</strong> Am. J. Hum. Genet. 50: 404-410, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1370875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1370875</a>]" pmid="1370875">Casals et al. (1992)</a> proposed that the delF508 mutation was present in Europe more than 10,000 years ago, preceding the agricultural migrations which diluted the mutation rather than introducing it. <a href="#15" class="mim-tip-reference" title="Ballabio, A., Gibbs, R. A., Caskey, C. T. <strong>PCR test for cystic fibrosis deletion. (Letter)</strong> Nature 343: 220 only, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2300168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2300168</a>] [<a href="https://doi.org/10.1038/343220a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2300168">Ballabio et al. (1990)</a> described an allele-specific amplification method for diagnosing the phenylalanine-508 deletion. Among Pueblo and Navajo Native Americans of the U.S. Southwest, <a href="#110" class="mim-tip-reference" title="Grebe, T. A., Doane, W. W., Richter, S. F., Clericuzio, C., Norman, R. A., Seltzer, W. K., Rhodes, S. N., Goldberg, B. E., Hernried, L. S., McClure, M., Kaplan, G. <strong>Mutation analysis of the cystic fibrosis transmembrane regulator gene in Native American populations of the Southwest.</strong> Am. J. Hum. Genet. 51: 736-740, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1384321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1384321</a>]" pmid="1384321">Grebe et al. (1992)</a> found no instance of the delF508 mutation in 12 affected individuals. Clinically, 6 of the affected individuals had growth deficiency and 5 (all from the Zuni Pueblo) had a severe CF phenotype. Four of the 6 Zunis with CF were also microcephalic, a finding not previously noted in CF patients. In an analysis of 640 Spanish cystic fibrosis families, <a href="#30" class="mim-tip-reference" title="Casals, T., Ramos, M. D., Gimenez, J., Larriba, S., Nunes, V., Estivill, X. <strong>High heterogeneity for cystic fibrosis in Spanish families : 75 mutations account for 90% of chromosomes.</strong> Hum. Genet. 101: 365-370, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9439669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9439669</a>] [<a href="https://doi.org/10.1007/s004390050643" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9439669">Casals et al. (1997)</a> found that 75 mutations accounted for 90.2% of CF chromosomes - an extraordinarily high heterozygosity. The frequency of the delta-F508 mutation was 53.2%. The next most frequent mutation was gly542 to ter (<a href="#0009">602421.0009</a>) with a frequency of 8.43%. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1370875+9439669+1384321+2300168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using 3 intragenic microsatellites of the CFTR gene located in introns, <a href="#212" class="mim-tip-reference" title="Russo, M. P., Romeo, G., Devoto, M., Barbujani, G., Cabrini, G., Giunta, A., D'Alcamo, E., Leoni, G., Sangiuolo, F., Magnani, C., Cremonesi, L., Ferrari, M. <strong>Analysis of linkage disequilibrium between different cystic fibrosis mutations and three intragenic microsatellites in the Italian population.</strong> Hum. Mutat. 5: 23-27, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7537148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7537148</a>] [<a href="https://doi.org/10.1002/humu.1380050103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7537148">Russo et al. (1995)</a> evaluated linkage disequilibrium between each marker and various CF mutations on a total of 377 CF and 358 normal chromosomes from Italian subjects. Results were considered consistent with the hypothesis that all del508 chromosomes derived from a single mutational event. The same hypothesis was valid for 3 other mutations which might have originated more recently than del508. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7537148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#111" class="mim-tip-reference" title="Grebe, T. A., Seltzer, W. K., DeMarchi, J., Silva, D. K., Doane, W. W., Gozal, D., Richter, S. F., Bowman, C. M., Norman, R. A., Rhodes, S. N., Hernried, L. S., Murphy, S., Harwood, I. R., Accurso, F. J., Jain, K. D. <strong>Genetic analysis of Hispanic individuals with cystic fibrosis.</strong> Am. J. Hum. Genet. 54: 443-446, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7509564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7509564</a>]" pmid="7509564">Grebe et al. (1994)</a> performed molecular genetic analyses on 129 Hispanic individuals with cystic fibrosis in the southwestern United States. Only 46% (59 of 129) carried mutation F508del (frequency in the general population 67.1%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7509564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 69 Italian patients with CF due to homozygosity for the delF508 mutation, <a href="#69" class="mim-tip-reference" title="De Rose, V., Arduino, C., Cappello, N., Piana, R., Salmin, P., Bardessono, M., Goia, M., Padoan, R., Bignamini, E., Costantini, D., Pizzamiglio, G., Bennato, V., Colombo, C., Giunta, A., Piazza, A. <strong>Fc-gamma receptor IIA genotype and susceptibility to P. aeruginosa infection in patients with cystic fibrosis.</strong> Europ. J. Hum. Genet. 13: 96-101, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15367919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15367919</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15367919">De Rose et al. (2005)</a> found that those who also carried the R131 allele of the immunoglobulin Fc-gamma receptor II gene (FCGR2A; see <a href="/entry/146790#0001">146790.0001</a>) had a 4-fold increased risk of acquiring chronic Pseudomonas aeruginosa infection (p = 0.042). <a href="#69" class="mim-tip-reference" title="De Rose, V., Arduino, C., Cappello, N., Piana, R., Salmin, P., Bardessono, M., Goia, M., Padoan, R., Bignamini, E., Costantini, D., Pizzamiglio, G., Bennato, V., Colombo, C., Giunta, A., Piazza, A. <strong>Fc-gamma receptor IIA genotype and susceptibility to P. aeruginosa infection in patients with cystic fibrosis.</strong> Europ. J. Hum. Genet. 13: 96-101, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15367919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15367919</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15367919">De Rose et al. (2005)</a> suggested that FCGR2A locus variability contributes to this infection susceptibility in CF patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15367919" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 62-year-old woman with idiopathic bronchiectasis (BESC1; <a href="/entry/211400">211400</a>) and elevated sweat chloride but normal nasal potential difference, who carried a heterozygous F508del CFTR mutation, <a href="#92" class="mim-tip-reference" title="Fajac, I., Viel, M., Sublemontier, S., Hubert, D., Bienvenu, T. <strong>Could a defective epithelial sodium channel lead to bronchiectasis.</strong> Respir. Res. 9: 46, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18507830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18507830</a>] [<a href="https://doi.org/10.1186/1465-9921-9-46" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18507830">Fajac et al. (2008)</a> also identified heterozygosity for a missense mutation in the SCNN1B gene (<a href="/entry/600760#0015">600760.0015</a>). The patient had a forced expiratory volume in 1 second (FEV1) that was 89% of predicted. <a href="#92" class="mim-tip-reference" title="Fajac, I., Viel, M., Sublemontier, S., Hubert, D., Bienvenu, T. <strong>Could a defective epithelial sodium channel lead to bronchiectasis.</strong> Respir. Res. 9: 46, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18507830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18507830</a>] [<a href="https://doi.org/10.1186/1465-9921-9-46" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18507830">Fajac et al. (2008)</a> concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18507830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#175" class="mim-tip-reference" title="Okiyoneda, T., Barriere, H., Bagdany, M., Rabeh, W. M., Du, K., Hohfeld, J., Young, J. C., Lukacs, G. L. <strong>Peripheral protein quality control removes unfolded CFTR from the plasma membrane.</strong> Science 329: 805-810, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20595578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20595578</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20595578[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1191542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20595578">Okiyoneda et al. (2010)</a> identified the components of the peripheral protein quality control network that removes unfolded CFTR containing the F508del mutation from the plasma membrane. Based on their results and proteostatic mechanisms at different subcellular locations, <a href="#175" class="mim-tip-reference" title="Okiyoneda, T., Barriere, H., Bagdany, M., Rabeh, W. M., Du, K., Hohfeld, J., Young, J. C., Lukacs, G. L. <strong>Peripheral protein quality control removes unfolded CFTR from the plasma membrane.</strong> Science 329: 805-810, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20595578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20595578</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20595578[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1191542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20595578">Okiyoneda et al. (2010)</a> proposed a model in which the recognition of unfolded cytoplasmic regions of CFTR is mediated by HSC70 (<a href="/entry/600816">600816</a>) in concert with DNAJA1 (<a href="/entry/602837">602837</a>) and possibly by the HSP90 machinery (<a href="/entry/140571">140571</a>). Prolonged interaction with the chaperone-cochaperone complex recruits CHIP (<a href="/entry/607207">607207</a>)-UBCH5C (<a href="/entry/602963">602963</a>) and leads to ubiquitination of conformationally damaged CFTR. This ubiquitination is probably influenced by other E3 ligases and deubiquitinating enzyme activities, culminating in accelerated endocytosis and lysosomal delivery mediated by Ub-binding clathrin adaptors and the endosomal sorting complex required for transport (ESCRT) machinery, respectively. In an accompanying perspective, <a href="#127" class="mim-tip-reference" title="Hutt, D., Balch, W. E. <strong>The proteome in balance.</strong> Science 329: 766-767, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20705837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20705837</a>] [<a href="https://doi.org/10.1126/science.1194160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20705837">Hutt and Balch (2010)</a> commented that the 'yin-yang' balance maintained by the proteostasis network is critical for normal cellular, tissue, and organismal physiology. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20595578+20705837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 1,482 Schmiedeleut (S-leut) Hutterites from the United States, <a href="#49" class="mim-tip-reference" title="Chong, J. X., Ouwenga, R., Anderson, R. L., Waggoner, D. J., Ober, C. <strong>A population-based study of autosomal-recessive disease-causing mutations in a founder population.</strong> Am. J. Hum. Genet. 91: 608-620, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22981120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22981120</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.08.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22981120">Chong et al. (2012)</a> found 32 heterozygotes and no homozygotes for the phe508del mutation in the CFTR gene, for a frequency of 0.022, or 1 in 45.5. This frequency is lower than that for the general population for this mutation, which is 1 in 30. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22981120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#184" class="mim-tip-reference" title="Pankow, S., Bamberger, C., Calzolari, D., Martinez-Bartolome, S., Lavalee-Adam, M., Balch, W. E., Yates, J. R., III. <strong>Delta-F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.</strong> Nature 528: 510-516, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26618866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26618866</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26618866[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature15729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26618866">Pankow et al. (2015)</a> reported the first comprehensive analysis of the CFTR and delta-F508 CFTR interactome and its dynamics during temperature shift and inhibition of histone deacetylases. By using a novel deep proteomic analysis method, they identified 638 individual high-confidence CFTR interactors and discovered a delta-F508 deletion-specific interactome, which is extensively remodeled upon rescue. Detailed analysis of the interactome remodeling identified key novel interactors, whose loss promote delta-F508i CFTR channel function in primary cystic fibrosis epithelia or which are critical for CFTR biogenesis. The results of <a href="#184" class="mim-tip-reference" title="Pankow, S., Bamberger, C., Calzolari, D., Martinez-Bartolome, S., Lavalee-Adam, M., Balch, W. E., Yates, J. R., III. <strong>Delta-F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.</strong> Nature 528: 510-516, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26618866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26618866</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26618866[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature15729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26618866">Pankow et al. (2015)</a> demonstrated that global remodeling of delta-F508 CFTR interactions is crucial for rescue, and provided comprehensive insight into the molecular disease mechanisms of cystic fibrosis caused by deletion of F508. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26618866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Clinical Trials</em></strong></p><p>
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<a href="#258" class="mim-tip-reference" title="Wainwright, C. E., Elborn, J. S., Ramsey, B. W., Marigowda, G., Huang, X., Cipolli, M., Colombo, C., Davies, J. C., De Boeck, K., Flume, P. A., Konstan, M. W., McColley, S. A., McCoy, K., McKone, E. F., Munck, A., Ratjen, F., Rowe, S. M., Waltz, D., Boyle, M. P., TRAFFIC Study Group, TRANSPORT Study Group. <strong>Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.</strong> New Eng. J. Med. 373: 220-231, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25981758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25981758</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25981758[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1409547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25981758">Wainwright et al. (2015)</a> conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator. A total of 1,108 patients 12 years of age or older who were homozygous for the Phe508del CFTR mutation were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary endpoint was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24. In both studies, there were significant improvements in the primary endpoint. The difference between active and placebo with respect to mean absolute improvement in the percentage FEV1 ranged from 2.6 to 4.0 percentage points (p less than 0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (p less than 0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the treated groups than in the placebo group. In addition, the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the treated groups. The incidence of adverse events was similar in the treated and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo. <a href="#258" class="mim-tip-reference" title="Wainwright, C. E., Elborn, J. S., Ramsey, B. W., Marigowda, G., Huang, X., Cipolli, M., Colombo, C., Davies, J. C., De Boeck, K., Flume, P. A., Konstan, M. W., McColley, S. A., McCoy, K., McKone, E. F., Munck, A., Ratjen, F., Rowe, S. M., Waltz, D., Boyle, M. P., TRAFFIC Study Group, TRANSPORT Study Group. <strong>Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.</strong> New Eng. J. Med. 373: 220-231, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25981758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25981758</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25981758[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1409547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25981758">Wainwright et al. (2015)</a> concluded that the combination of a CFTR corrector and potentiator, designed to address the underlying cause of cystic fibrosis by targeting CFTR, can benefit the 45% of patients who are homozygous for the Phe508del mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25981758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908745 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908745;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908745" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908745" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007525 OR RCV000224705 OR RCV000780118 OR RCV001004458 OR RCV001826426 OR RCV002496293 OR RCV003472998" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007525, RCV000224705, RCV000780118, RCV001004458, RCV001826426, RCV002496293, RCV003472998" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007525...</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#139" class="mim-tip-reference" title="Kerem, B., Zielenski, J., Markiewicz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in regions corresponding to the 2 putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.</strong> Proc. Nat. Acad. Sci. 87: 8447-8451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236053</a>] [<a href="https://doi.org/10.1073/pnas.87.21.8447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236053">Kerem et al. (1990)</a> detected deletion of 3 bp in the CFTR gene, resulting in deletion of isoleucine at either position 506 or 507 (delta-I507). <a href="#169" class="mim-tip-reference" title="Nelson, P. V., Carey, W. F., Morris, C. P. <strong>Identification of a cystic fibrosis mutation: deletion of isoleucine-506.</strong> Hum. Genet. 86: 391-393, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1999342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1999342</a>] [<a href="https://doi.org/10.1007/BF00201841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1999342">Nelson et al. (1991)</a> found the same mutation in homozygous state in 2 sibs with severe pancreatic insufficiency. <a href="#178" class="mim-tip-reference" title="Orozco, L., Friedman, K., Chavez, M., Lezana, J. L., Villarreal, M. T., Carnevale, A. <strong>Identification of the I507 deletion by site-directed mutagenesis.</strong> Am. J. Med. Genet. 51: 137-139, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8092189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8092189</a>] [<a href="https://doi.org/10.1002/ajmg.1320510210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8092189">Orozco et al. (1994)</a> commented on the difficulties in recognizing the ile507-to-del mutation in a compound heterozygote with F508del. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1999342+8092189+2236053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs77101217 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77101217;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs77101217?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs77101217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs77101217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007526 OR RCV000727628 OR RCV001004456 OR RCV001835623 OR RCV002288473 OR RCV002496294 OR RCV003472999" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007526, RCV000727628, RCV001004456, RCV001835623, RCV002288473, RCV002496294, RCV003472999" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007526...</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#139" class="mim-tip-reference" title="Kerem, B., Zielenski, J., Markiewicz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in regions corresponding to the 2 putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.</strong> Proc. Nat. Acad. Sci. 87: 8447-8451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236053</a>] [<a href="https://doi.org/10.1073/pnas.87.21.8447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236053">Kerem et al. (1990)</a> detected a C-to-T change in nucleotide 1609 in exon 10 of the CFTR gene that caused a premature stop position 493 (Q493X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2236053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs113993958 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113993958;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs113993958?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs113993958" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs113993958" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007527 OR RCV000058930 OR RCV000660769 OR RCV000780153 OR RCV001004427 OR RCV001009392 OR RCV001835624 OR RCV002247259 OR RCV003473000 OR RCV005042001" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007527, RCV000058930, RCV000660769, RCV000780153, RCV001004427, RCV001009392, RCV001835624, RCV002247259, RCV003473000, RCV005042001" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007527...</a>
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<p>Using the method for identifying single-strand conformation polymorphisms (SSCPs) developed by <a href="#176" class="mim-tip-reference" title="Orita, M., Iwahana, H., Kanazawa, H., Hayashi, K., Sekiya, T. <strong>Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms.</strong> Proc. Nat. Acad. Sci. 86: 2766-2770, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2565038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2565038</a>] [<a href="https://doi.org/10.1073/pnas.86.8.2766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2565038">Orita et al. (1989)</a>, <a href="#71" class="mim-tip-reference" title="Dean, M., White, M. B., Amos, J., Gerrard, B., Stewart, C., Khaw, K.-T., Leppert, M. <strong>Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients.</strong> Cell 61: 863-870, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2344617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2344617</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90196-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2344617">Dean et al. (1990)</a> identified 3 different mutations associated with mild cystic fibrosis (CF; <a href="/entry/219700">219700</a>). All 3 mutations replaced charged amino acids with less polar residues and resulted in changes in the putative transmembrane sections of the molecule. The mutated amino acids were found to be ones conserved in both rodents and amphibians and to lie in a region of CFTR that is believed to form a channel in the membrane. In a family identified as BOS-7, a C-to-G transversion in exon 4 replaced an aspartic acid residue with histidine (D110H). (The Orita method for identifying SSCPs involves amplification of 100-400 bp segments of radiolabeled DNA, which are subsequently denatured and electrophoresed on high resolution, nondenaturing acrylamide gels. Under these conditions each strand of the DNA fragment can fold back on itself in a unique conformation. Mutations within a DNA segment will often alter the secondary structure of the molecule and affect its electrophoretic mobility.) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2565038+2344617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs78655421 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs78655421;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs78655421?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs78655421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs78655421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007528 OR RCV000007529 OR RCV000078997 OR RCV000190992 OR RCV000417156 OR RCV000763151 OR RCV000826137 OR RCV001009478 OR RCV001642199 OR RCV003473001 OR RCV004018585" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007528, RCV000007529, RCV000078997, RCV000190992, RCV000417156, RCV000763151, RCV000826137, RCV001009478, RCV001642199, RCV003473001, RCV004018585" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007528...</a>
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<p>In 2 presumably unrelated families with mild cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#71" class="mim-tip-reference" title="Dean, M., White, M. B., Amos, J., Gerrard, B., Stewart, C., Khaw, K.-T., Leppert, M. <strong>Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients.</strong> Cell 61: 863-870, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2344617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2344617</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90196-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2344617">Dean et al. (1990)</a> found a 482G-A transition in exon 4 of the CFTR gene, resulting in an arg117-to-his (R117H) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2344617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#102" class="mim-tip-reference" title="Gervais, R., Dumur, V., Rigot, J.-M., Lafitte, J.-J., Roussel, P., Claustres, M., Demaille, J. <strong>High frequency of the R117H cystic fibrosis mutation in patients with congenital absence of the vas deferens. (Letter)</strong> New Eng. J. Med. 328: 446-447, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8421472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8421472</a>] [<a href="https://doi.org/10.1056/NEJM199302113280619" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8421472">Gervais et al. (1993)</a> reported that the R117H mutation was present in 4 of 23 patients with congenital absence of the vas deferens (CBAVD; <a href="/entry/277180">277180</a>). Three patients had compound heterozygosity for R117H and delF508 (<a href="#0001">602421.0001</a>), whereas a fourth was a compound heterozygote for R117H and 2322delG. None of the 23 patients had pulmonary evidence of cystic fibrosis. Five patients without the delF508 mutation had unilateral renal agenesis in addition to absence of the vas deferens; these patients may represent a different distinct subset. <a href="#19" class="mim-tip-reference" title="Bienvenu, T., Beldjord, C., Adjiman, M., Kaplan, J. C. <strong>Male infertility as the only presenting sign of cystic fibrosis when homozygous for the mild mutation R117H. (Letter)</strong> J. Med. Genet. 30: 797 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7692051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7692051</a>] [<a href="https://doi.org/10.1136/jmg.30.9.797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7692051">Bienvenu et al. (1993)</a> described for the first time homozygosity for the R117H mutation in a 30-year-old French male with sterility owing to congenital bilateral absence of the vas deferens. The subject had no respiratory or pancreatic involvement and had a normal sweat electrolyte value. His parents were not consanguineous, and there were no other cases of CBAVD or CF in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8421472+7692051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#142" class="mim-tip-reference" title="Kiesewetter, S., Macek, M., Jr., Davis, C., Curristin, S. M., Chu, C.-S., Graham, C., Shrimpton, A. E., Cashman, S. M., Tsui, L.-C., Mickle, J., Amos, J., Highsmith, W. E., Shuber, A., Witt, D. R., Crystal, R. G., Cutting, G. R. <strong>A mutation in CFTR produces different phenotypes depending on chromosomal background.</strong> Nature Genet. 5: 274-278, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7506096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7506096</a>] [<a href="https://doi.org/10.1038/ng1193-274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7506096">Kiesewetter et al. (1993)</a> presented evidence that the chromosome background of the R117H mutation has a profound effect on the phenotype produced. Three length variants of CFTR have been observed with varying degrees of exon 9 splicing depending on variation in the length of the polypyrimidine tract in the splice acceptor site in intron 8 (Chu et al. (<a href="#51" class="mim-tip-reference" title="Chu, C.-S., Trapnell, B. C., Murtagh, J. J., Jr., Moss, J., Dalemans, W., Jallat, S., Mercenier, A., Pavirani, A., Lecocq, J.-P., Cutting, G. R., Guggino, W. B., Crystal, R. G. <strong>Variable detection of exon 9 coding sequences in cystic fibrosis transmembrane conductance regulator gene mRNA transcripts in normal bronchial epithelium.</strong> EMBO J. 10: 1355-1363, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1709095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1709095</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1991.tb07655.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1709095">1991</a>, <a href="#50" class="mim-tip-reference" title="Chu, C.-S., Trapnell, B. C., Curristin, S., Cutting, G. R., Crystal, R. G. <strong>Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA.</strong> Nature Genet. 3: 151-156, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7684646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7684646</a>] [<a href="https://doi.org/10.1038/ng0293-151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7684646">1993</a>)). Varied lengths of a thymidine (T)-tract (5, 7, or 9Ts) were noted in front of the splice acceptor site of intron 8. The 5T variant is present in 5% of the CFTR alleles among Caucasian populations producing almost exclusively (95%) exon 9-minus RNA. The effect of this T-tract polymorphism in CFTR gene expression was also documented by its relationship with the R117H mutation: R117H (5T) is found in typical CF patients with pancreatic sufficiency; R117H (7T) is associated with CBAVD. The R117H mutation has been reported in CF patients, males with congenital bilateral absence of the vas deferens, and in an asymptomatic woman. Furthermore, population screening discovered a 19-fold higher than expected number of carriers of this CF mutation. The situation was compared to that in Gaucher disease in which the severity of neuronopathic disease associated with a missense mutation appears to be altered by additional missense mutations in the same allele (<a href="#149" class="mim-tip-reference" title="Latham, T., Grabowski, G. A., Theophilus, B. D. M., Smith, F. I. <strong>Complex alleles of the acid beta-glucosidase gene in Gaucher disease.</strong> Am. J. Hum. Genet. 47: 79-86, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2349952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2349952</a>]" pmid="2349952">Latham et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2349952+7506096+1709095+7684646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#273" class="mim-tip-reference" title="White, S. M., Lucassen, A., Norbury, G. <strong>Cystic fibrosis: a further case of an asymptomatic compound heterozygote. (Letter)</strong> Am. J. Med. Genet. 103: 342-343, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11746017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11746017</a>]" pmid="11746017">White et al. (2001)</a> reported a healthy 29-year-old female who was found to be an R117H/delF508 heterozygote. The patient had atopic asthma and infertility, but normal height and weight and no pulmonary symptoms of CF. Analysis of the polythymidine tract showed that the R117H mutation was in cis with a 7T tract and the delta-F508 mutation in cis with a 9T tract. The authors concluded that poly-T studies are important in any patient found to have the R117H mutation, and recommended caution in the genetic counseling of such families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11746017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#244" class="mim-tip-reference" title="Thauvin-Robinet, C., Munck, A., Huet, F., Genin, E., Bellis, G., Gautier, E., Audrezet, M.-P., Ferec, C., Lalau, G., Des Georges, M., Claustres, M., Bienvenu, T., and 33 others. <strong>The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening.</strong> J. Med. Genet. 46: 752-758, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19880712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19880712</a>] [<a href="https://doi.org/10.1136/jmg.2009.067215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19880712">Thauvin-Robinet et al. (2009)</a> reported the results of a national collaborative study in France to establish the overall phenotype associated with R117H and to evaluate the disease penetrance of the R117H+F508del genotype. In 184 R117H+F508del individuals of the French population, including 72 newborns, the disease phenotype was predominantly mild; 1 child had classic cystic fibrosis, and 3 adults had severe pulmonary symptoms. In 5,245 healthy adults with no family history of CF, the allelic prevalence of F508del was 1.06%, R117H;T7 0.27%, and R117H;T5 less than 0.01%. The theoretical number of R117H;T7+F508del individuals in the French populations was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classic CF for R117H;T7+F508del was estimated at 0.03% and that of severe CF in adulthood at 0.06%. <a href="#244" class="mim-tip-reference" title="Thauvin-Robinet, C., Munck, A., Huet, F., Genin, E., Bellis, G., Gautier, E., Audrezet, M.-P., Ferec, C., Lalau, G., Des Georges, M., Claustres, M., Bienvenu, T., and 33 others. <strong>The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening.</strong> J. Med. Genet. 46: 752-758, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19880712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19880712</a>] [<a href="https://doi.org/10.1136/jmg.2009.067215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19880712">Thauvin-Robinet et al. (2009)</a> suggested that R117H should be withdrawn from CF mutation panels used for screening programs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19880712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs77932196 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77932196;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs77932196?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs77932196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs77932196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007530 OR RCV001004251 OR RCV001530124 OR RCV001831520 OR RCV002504761 OR RCV003473002" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007530, RCV001004251, RCV001530124, RCV001831520, RCV002504761, RCV003473002" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007530...</a>
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<p>In 3 sibs with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) from a family identified as UT 1446, <a href="#71" class="mim-tip-reference" title="Dean, M., White, M. B., Amos, J., Gerrard, B., Stewart, C., Khaw, K.-T., Leppert, M. <strong>Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients.</strong> Cell 61: 863-870, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2344617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2344617</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90196-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2344617">Dean et al. (1990)</a> found a C-to-G transversion at position 1172 in the CFTR gene, resulting in substitution of proline for aspartic acid (R347P). The mutation destroyed a HhaI restriction site and created a NcoI site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2344617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74551128 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74551128;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74551128?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74551128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74551128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007531 OR RCV000660853 OR RCV000763569 OR RCV001004446 OR RCV001530091 OR RCV001826427 OR RCV003473003" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007531, RCV000660853, RCV000763569, RCV001004446, RCV001530091, RCV001826427, RCV003473003" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007531...</a>
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<p>In 2 chromosomes from patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#139" class="mim-tip-reference" title="Kerem, B., Zielenski, J., Markiewicz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in regions corresponding to the 2 putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.</strong> Proc. Nat. Acad. Sci. 87: 8447-8451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236053</a>] [<a href="https://doi.org/10.1073/pnas.87.21.8447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236053">Kerem et al. (1990)</a> detected a C-to-A change at nucleotide 1496 in exon 9 of the CFTR gene that caused substitution of glutamic acid for alanine at position 455 (A455E). The exon in which the A455E mutation occurs has been corrected to exon 10; see, e.g., <a href="#253" class="mim-tip-reference" title="Vecchio-Pagan, B., Blackman, S., Lee, M., Atalar, M., Pellicore, M. J., Pace, R. G., Franca, A. L., Raraigh, K. S., Sharma, N., Knowles, M. R., Cutting, G. R. <strong>Deep resequencing of CFTR in 762 F508del homozygotes reveals clusters of non-coding variants associated with cystic fibrosis disease traits.</strong> Hum Genome Var. 3: 16038, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27917292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27917292</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27917292[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/hgv.2016.38" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27917292">Vecchio-Pagan et al. (2016)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27917292+2236053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs76713772 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs76713772;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs76713772?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs76713772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs76713772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007532 OR RCV000224919 OR RCV001004462 OR RCV001027893 OR RCV002496295 OR RCV003473004" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007532, RCV000224919, RCV001004462, RCV001027893, RCV002496295, RCV003473004" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007532...</a>
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<p>In a patient with cystic fibrosis, <a href="#139" class="mim-tip-reference" title="Kerem, B., Zielenski, J., Markiewicz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in regions corresponding to the 2 putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.</strong> Proc. Nat. Acad. Sci. 87: 8447-8451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236053</a>] [<a href="https://doi.org/10.1073/pnas.87.21.8447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236053">Kerem et al. (1990)</a> identified a splice mutation in the CFTR gene, a G-to-A change of nucleotide -1 in the acceptor site of intron 10. In a French patient with cystic fibrosis, <a href="#116" class="mim-tip-reference" title="Guillermit, H., Fanen, P., Ferec, C. <strong>A 3-prime splice site consensus sequence mutation in the cystic fibrosis gene.</strong> Hum. Genet. 85: 450-453, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2210769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2210769</a>] [<a href="https://doi.org/10.1007/BF02428306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2210769">Guillermit et al. (1990)</a> detected the same mutation: a G-to-A change in the last nucleotide at the 3-prime end of intron 10 nucleotide 1717 minus one. The mutation destroyed a splice site. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2236053+2210769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs113993959 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113993959;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs113993959?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs113993959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs113993959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007535 OR RCV000058931 OR RCV000119041 OR RCV000763572 OR RCV001004463 OR RCV001826428 OR RCV003473006" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007535, RCV000058931, RCV000119041, RCV000763572, RCV001004463, RCV001826428, RCV003473006" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007535...</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#139" class="mim-tip-reference" title="Kerem, B., Zielenski, J., Markiewicz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in regions corresponding to the 2 putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.</strong> Proc. Nat. Acad. Sci. 87: 8447-8451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236053</a>] [<a href="https://doi.org/10.1073/pnas.87.21.8447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236053">Kerem et al. (1990)</a> found a G-to-T change at nucleotide 1756 in exon 11 of the CFTR gene that was responsible for a stop mutation in codon 542 (G542X). <a href="#61" class="mim-tip-reference" title="Cuppens, H., Marynen, P., De Boeck, C., De Baets, F., Eggermont, E., Van den Berghe, H., Cassiman, J. J. <strong>A child, homozygous for a stop codon in exon 11, shows milder cystic fibrosis symptoms than her heterozygous nephew.</strong> J. Med. Genet. 27: 717-719, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2135388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2135388</a>] [<a href="https://doi.org/10.1136/jmg.27.11.717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2135388">Cuppens et al. (1990)</a> found the same mutation in a Belgian patient. The G542X mutation accounted for 7.3% of the CF chromosomes in Belgium, being probably the second most frequent mutation. (In a sample of Belgian CF patients, 68.1% of all CF chromosomes carried the delta-F508 mutation.) The clinical manifestations were mild in a homozygote but were severe in a first cousin who was a genetic compound for G542X and gly458-to-val (<a href="#0028">602421.0028</a>). <a href="#154" class="mim-tip-reference" title="Lerer, I., Sagi, M., Cutting, G. R., Abeliovich, D. <strong>Cystic fibrosis mutations delta-F508 and G542X in Jewish patients.</strong> J. Med. Genet. 29: 131-133, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1377276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1377276</a>] [<a href="https://doi.org/10.1136/jmg.29.2.131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1377276">Lerer et al. (1992)</a> reported that the gly542-to-ter mutation accounts for 13% of Ashkenazi CF mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1377276+2135388+2236053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Castaldo, G., Rippa, E., Salvatore, D., Sibillo, R., Raia, V., de Ritis, G., Salvatore, F. <strong>Severe liver impairment in a cystic fibrosis-affected child homozygous for the G542X mutation.</strong> Am. J. Med. Genet. 69: 155-158, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9056552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9056552</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19970317)69:2<155::aid-ajmg7>3.0.co;2-o" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9056552">Castaldo et al. (1997)</a> described severe liver involvement associated with pancreatic insufficiency and moderate pulmonary expression of CF in a girl, homozygous for the G542X mutation, who died at the age of 10 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9056552" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#157" class="mim-tip-reference" title="Loirat, F., Hazout, S., Lucotte, G. <strong>G542X as a probable Phoenician cystic fibrosis mutation.</strong> Hum. Biol. 69: 419-425, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9164051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9164051</a>]" pmid="9164051">Loirat et al. (1997)</a> suggested that G542X is probably the Phoenician cystic fibrosis mutation. They showed that the frequency of G542X varies among different towns at regions of origin, being lower in northeastern Europeans than in southwestern Europeans. G542X mutation mapping that they defined by multiple regression of G542X frequencies covered 28 countries (53 geographic points) and was based on data from 50 laboratories. More elevated values of G542X frequency corresponded to ancient sites of occupation by occidental Phoenicians. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9164051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with a severe form of cystic fibrosis, <a href="#218" class="mim-tip-reference" title="Savov, A., Angelicheva, D., Balassopoulou, A., Jordanova, A., Noussia-Arvanitakis, S., Kalaydjieva, L. <strong>Double mutant alleles: are they rare?</strong> Hum. Molec. Genet. 4: 1169-1171, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528204</a>] [<a href="https://doi.org/10.1093/hmg/4.7.1169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528204">Savov et al. (1995)</a> identified compound heterozygosity for the G542X mutation and an allele with a double mutation (S912L and G1244V; <a href="#0135">602421.0135</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908755 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908755;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908755?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908755" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908755" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007536 OR RCV000211264 OR RCV000727629 OR RCV001004465 OR RCV001831522 OR RCV002247260 OR RCV002496296 OR RCV003473007" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007536, RCV000211264, RCV000727629, RCV001004465, RCV001831522, RCV002247260, RCV002496296, RCV003473007" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007536...</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#65" class="mim-tip-reference" title="Cutting, G. R., Kasch, L. M., Rosenstein, B. J., Zielenski, J., Tsui, L.-C., Antonarakis, S. E., Kazazian, H. H., Jr. <strong>A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.</strong> Nature 346: 366-369, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1695717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1695717</a>] [<a href="https://doi.org/10.1038/346366a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1695717">Cutting et al. (1990)</a> detected compound heterozygosity for a G-to-A change at nucleotide 1778 in exon 11 of the CFTR gene, responsible for substitution of asparagine for serine at position 549 (S549N), and a premature termination mutation, also in exon 11 (R553X; <a href="#0014">602421.0014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1695717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#139" class="mim-tip-reference" title="Kerem, B., Zielenski, J., Markiewicz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in regions corresponding to the 2 putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.</strong> Proc. Nat. Acad. Sci. 87: 8447-8451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236053</a>] [<a href="https://doi.org/10.1073/pnas.87.21.8447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236053">Kerem et al. (1990)</a> detected a G-to-T change at nucleotide 1778 in exon 11 of the CFTR gene, responsible for substitution of isoleucine for serine at amino acid 549 (S549I). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2236053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908757 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908757;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908757?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909005 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909005;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909005?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#139" class="mim-tip-reference" title="Kerem, B., Zielenski, J., Markiewicz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in regions corresponding to the 2 putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.</strong> Proc. Nat. Acad. Sci. 87: 8447-8451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236053</a>] [<a href="https://doi.org/10.1073/pnas.87.21.8447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236053">Kerem et al. (1990)</a> detected a T-to-G change at nucleotide 1779 in exon 11 of the CFTR gene, resulting in substitution of arginine for serine at amino acid 549 (S549R). <a href="#215" class="mim-tip-reference" title="Sangiuolo, F., Novelli, G., Murru, S., Dallapiccola, B. <strong>A serine-to-arginine (AGT-to-CGT) mutation in codon 549 of the CFTR gene in an Italian patient with severe cystic fibrosis.</strong> Genomics 9: 788-789, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1903761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1903761</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90380-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1903761">Sangiuolo et al. (1991)</a> found the same ser549-to-arg substitution in an Italian patient with severe cystic fibrosis; however, the substitution was caused by an A-to-C change at nucleotide 1777. Thus, the 2 mutations are AGT-to-AGG and AGT-to-CGT. A T-to-C change at nucleotide 1779 would also change serine to arginine. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2236053+1903761" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#202" class="mim-tip-reference" title="Romey, M.-C., Guittard, C., Carles, S., Demaille, J., Claustres, M., Ramsay, M. <strong>First putative sequence alterations in the minimal CFTR promoter region. (Letter)</strong> J. Med. Genet. 36: 263-264, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10204861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10204861</a>]" pmid="10204861">Romey et al. (1999)</a> reported a novel complex allele in the CFTR gene, combining the S549R mutation due to a T-to-G transversion in exon 11 with the first described sequence change in the minimal CFTR promoter, a T-to-A transversion at position -102 (<a href="#0122">602421.0122</a>). In a separate publication, <a href="#203" class="mim-tip-reference" title="Romey, M.-C., Guittard, C., Chazalette, J.-P., Frossard, P., Dawson, K. P., Patton, M. A., Casals, T., Bazarbachi, T., Girodon, E., Rault, G., Bozon, D., Seguret, F., Demaille, J., Claustres, M. <strong>Complex allele (-102T-to-A+S549R(T-to-G)) is associated with milder forms of cystic fibrosis than allele S549R(T-to-G) alone.</strong> Hum. Genet. 105: 145-150, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10480369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10480369</a>] [<a href="https://doi.org/10.1007/s004399900066" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10480369">Romey et al. (1999)</a> compared the main clinical features of 6 CF patients carrying the complex allele with those of 16 CF patients homozygous for the S549R mutation alone. Age at diagnosis was higher, and current age was significantly higher (P = 0.0032), in the group with the complex allele, compared with the S549R/S549R group. Although the proportion of patients with lung colonization was similar in the 2 groups, the age at onset was significantly higher in the group with the complex allele (P = 0.0022). Patients with the complex allele also had significantly lower sweat test chloride values (P = 0.0028) and better overall clinical scores (P = 0.004). None of the 22 patients involved in this study had meconium ileus. All 16 patients homozygous for S549R, however, were pancreatic insufficient, as compared with 50% of patients carrying the complex allele (P = 0.013). Moreover, the single patient homozygous for the complex allele presented with mild disease at 34 years of age. These observations strongly suggested that the sequence change in the CFTR minimal promoter attenuates the severe clinical phenotype associated with the S549R mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10204861+10480369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#204" class="mim-tip-reference" title="Romey, M.-C., Pallares-Ruiz, N., Mange, A., Mettling, C., Peytavi, R., Demaille, J., Claustres, M. <strong>A naturally occurring sequence variation that creates a YY1 element is associated with increased cystic fibrosis transmembrane conductance regulator gene expression.</strong> J. Biol. Chem. 275: 3561-3567, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10652351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10652351</a>] [<a href="https://doi.org/10.1074/jbc.275.5.3561" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10652351">Romey et al. (2000)</a> postulated that the -102T-A sequence change may attenuate the effects of the severe S549R mutation through regulation of CFTR expression. Analysis of transiently transfected cell lines with wildtype and -102A variant human CFTR-directed luciferase reporter genes demonstrated that constructs containing the -102A variant, which creates a Yin Yang 1 (YY1) core element, increases CFTR expression significantly. Electrophoretic mobility shift assays indicated that the -102 site is located within a region of multiple DNA-protein interactions and that the -102A allele recruits specifically an additional nuclear protein related to YY1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10652351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs75527207 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs75527207;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs75527207?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs75527207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs75527207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007540 OR RCV000119040 OR RCV000211289 OR RCV000301838 OR RCV000763574 OR RCV001004467 OR RCV001831524 OR RCV003473009" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007540, RCV000119040, RCV000211289, RCV000301838, RCV000763574, RCV001004467, RCV001831524, RCV003473009" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007540...</a>
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<p>In 7 patients, including 2 sibs, with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#65" class="mim-tip-reference" title="Cutting, G. R., Kasch, L. M., Rosenstein, B. J., Zielenski, J., Tsui, L.-C., Antonarakis, S. E., Kazazian, H. H., Jr. <strong>A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.</strong> Nature 346: 366-369, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1695717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1695717</a>] [<a href="https://doi.org/10.1038/346366a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1695717">Cutting et al. (1990)</a> detected a G-to-A change at nucleotide 1784 in exon 11 of the CFTR gene that was responsible for substitution of aspartic acid for glycine at amino acid 551 (G551D). In 6 of these patients the delta-F508 mutation (<a href="#0001">602421.0001</a>) was present on the other allele; 3 of these patients, aged 11 to 13 years, had mild lung disease with normal pulmonary function test results. In the seventh patient, with mild lung disease, the mutation on the other allele was unknown. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1695717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#62" class="mim-tip-reference" title="Curtis, A., Nelson, R., Porteous, M., Burn, J., Bhattacharya, S. S. <strong>Association of less common cystic fibrosis mutations with a mild phenotype.</strong> J. Med. Genet. 28: 34-37, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1999830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1999830</a>] [<a href="https://doi.org/10.1136/jmg.28.1.34" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1999830">Curtis et al. (1991)</a> described this mutation in 2 sibs in homozygous state and in an unrelated adult who was a compound heterozygote for G551D and delta-I507 (<a href="#0002">602421.0002</a>). All 3 showed clinically mild disease. The G551D mutation creates an MboI recognition site at codon 551 in the CFTR gene. <a href="#27" class="mim-tip-reference" title="Burger, J., Macek, M., Jr., Stuhrmann, M., Reis, A., Krawczak, M., Schmidtke, J. <strong>Genetic influences in the formation of nasal polyps. (Letter)</strong> Lancet 337: 974, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1678049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1678049</a>] [<a href="https://doi.org/10.1016/0140-6736(91)91603-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1678049">Burger et al. (1991)</a> suggested that heterozygosity for the G551D mutation is a causative factor in recurrent polyposis nasi (nasal polyps). <a href="#119" class="mim-tip-reference" title="Hamosh, A., King, T. M., Rosenstein, B. J., Corey, M., Levison, H., Durie, P., Tsui, L.-C., McIntosh, I., Keston, M., Brock, D. J. H., Macek, M., Jr., Zemkova, D., and 20 others. <strong>Cystic fibrosis patients bearing both the common missense mutation gly-to-asp at codon 551 and the delta-F508 mutation are clinically indistinguishable from delta-F508 homozygotes, except for decreased risk of meconium ileus.</strong> Am. J. Hum. Genet. 51: 245-250, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1379413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1379413</a>]" pmid="1379413">Hamosh et al. (1992)</a> stated that the gly551-to-asp mutation, which is within the first nucleotide-binding fold of the CFTR, is the third most common CF mutation, with a worldwide frequency of 3.1% among CF chromosomes. Regions with a high frequency correspond to areas with large populations of Celtic descent. To determine whether G551D confers a different phenotype than does delta-F508, <a href="#119" class="mim-tip-reference" title="Hamosh, A., King, T. M., Rosenstein, B. J., Corey, M., Levison, H., Durie, P., Tsui, L.-C., McIntosh, I., Keston, M., Brock, D. J. H., Macek, M., Jr., Zemkova, D., and 20 others. <strong>Cystic fibrosis patients bearing both the common missense mutation gly-to-asp at codon 551 and the delta-F508 mutation are clinically indistinguishable from delta-F508 homozygotes, except for decreased risk of meconium ileus.</strong> Am. J. Hum. Genet. 51: 245-250, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1379413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1379413</a>]" pmid="1379413">Hamosh et al. (1992)</a> studied 79 compound heterozygotes for the 2 mutations in comparison with age- and sex-matched delta-F508 homozygotes from 9 CF centers in Europe and North America. There was less meconium ileus among the compound heterozygotes but otherwise no statistically significant difference was found between the 2 groups. Clinical outcome (after survival of meconium ileus) was indistinguishable. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1678049+1999830+1379413" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#73" class="mim-tip-reference" title="Delaney, S. J., Alton, E. W. F. W., Smith, S. N., Lunn, D. P., Farley, R., Lovelock, P. K., Thomson, S. A., Hume, D. A., Lamb, D., Porteous, D. J., Dorin, J. R., Wainwright, B. J. <strong>Cystic fibrosis mice carrying the missense mutation G551D replicate human genotype-phenotype correlations.</strong> EMBO J. 15: 955-963, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8605891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8605891</a>]" pmid="8605891">Delaney et al. (1996)</a> showed that mice carrying the human G551D mutation in the Cftr gene show cystic fibrosis pathology but have a reduced risk of fatal intestinal blockage compared with 'null' mutants, in keeping with the reduced incidence of meconium ileus in G551D patients. The G551D mutant mice showed greatly reduced CFTR-related chloride transport, displaying activity (equivalent to approximately 4% of wildtype Cftr) intermediate between that of 'null' mice and Cftr insertional mutants with residual activity. The authors stated that long-term survival of these animals should provide an excellent model for the study of cystic fibrosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8605891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The G551D allele is associated characteristically with populations of Celtic descent and is seen at its highest prevalence in regions such as Ireland and Brittany. It is seen in diminishing frequencies as one moves to the southern and eastern portions of Europe. An initially puzzling phenomenon was the relatively high incidence of this mutation in the Czech Republic (3.8%). As pointed out by <a href="#20" class="mim-tip-reference" title="Bobadilla, J. L., Macek, M., Jr., Fine, J. P., Farrell, P. M. <strong>Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening.</strong> Hum. Mutat. 19: 575-606, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12007216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12007216</a>] [<a href="https://doi.org/10.1002/humu.10041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12007216">Bobadilla et al. (2002)</a>, however, population movements of the past provide an explanation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12007216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Accurso, F. J., Rowe, S. M., Clancy, J. P., Boyle, M. P., Dunitz, J. M., Durie, P. R., Sagel, S. D., Hornick, D. B., Konstan, K. W., Donaldson, S. H., Moss, R. B., Pilewski, J. M., and 14 others. <strong>Effect of VX-770 in persons with cystic fibrosis and the G155D-CFTR mutation.</strong> New Eng. J. Med. 363: 1991-2003, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21083385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21083385</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21083385[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa0909825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21083385">Accurso et al. (2010)</a> reported the results of a 2-phase clinical trial using VX-770, a CFTR potentiator, in 39 adults with cystic fibrosis and at least 1 G551D allele. Subjects received 150 mg of VX-770 every 12 hours for 28 days in phase 2 of the study. All showed a change in the nasal potential difference from baseline of -3.5 mV (range, -8.3 to 0.5; P = 0.02 for the within-subject comparison; P = 0.13 vs placebo), and the median change in the level of sweat chloride was -59.5 mmol per liter (range, -66.0 to -19.0; P = 0.008 within-subject, P = 0.02 vs placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P = 0.008 within-subject, P = 0.56 vs placebo). The VX-770 was well tolerated. None of the subjects withdrew from the study. All severe adverse events resolved without the discontinuation of VX-770. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21083385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#192" class="mim-tip-reference" title="Ramsey, B. W., Davies, J., McElvaney, N. G., Tullis, E., Bell, S. C., Drevinek, P., Griese, M., McKone, E. F., Wainwright, C. E., Konstan, M. W., Moss, R., Ratjen, F., Sermet-Gaudelus, I., Rowe, S. M., Dong, Q., Rodriguez, S., Yen, K., Ordonez, C., Elborn, J. S. <strong>A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.</strong> New Eng. J. Med. 365: 1663-1672, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22047557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22047557</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22047557[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1105185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22047557">Ramsey et al. (2011)</a> conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770) in subjects 12 years of age or older with cystic fibrosis and at least 1 G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of the drug every 12 hours (84 subjects, of whom 83 received at least 1 dose) or placebo (83, of whom 78 received at least 1 dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of forced expiratory volume in 1 second (FEV1). The change from baseline through week 24 in the percent of predicted FEV1 was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (p less than 0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have pulmonary exacerbation than were patients receiving placebo, through week 48 (p less than 0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory symptoms domain of the Cystic Fibrosis Questionnaire revised instrument (p less than 0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (p less than 0.001). The change from baseline through week 48 in the concentration of sweat chloride with ivacaftor as compared with placebo was -48.1 mmol per liter (p less than 0.001). The incidence of adverse events was similar with treatment and controls, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs 42%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22047557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>On January 31, 2012, the FDA approved Kalydeco, formerly VX-770 (ivacaftor), for use in cystic fibrosis patients with the G551D mutation, as reported by <a href="#150" class="mim-tip-reference" title="Ledford, H. <strong>Drug bests cystic-fibrosis mutation.</strong> Nature 482: 145 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22318583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22318583</a>] [<a href="https://doi.org/10.1038/482145a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22318583">Ledford (2012)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22318583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74597325 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74597325;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74597325?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74597325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74597325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007542 OR RCV000506601 OR RCV000763575 OR RCV000781237 OR RCV001004260 OR RCV001831525 OR RCV003137499" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007542, RCV000506601, RCV000763575, RCV000781237, RCV001004260, RCV001831525, RCV003137499" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007542...</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#65" class="mim-tip-reference" title="Cutting, G. R., Kasch, L. M., Rosenstein, B. J., Zielenski, J., Tsui, L.-C., Antonarakis, S. E., Kazazian, H. H., Jr. <strong>A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.</strong> Nature 346: 366-369, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1695717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1695717</a>] [<a href="https://doi.org/10.1038/346366a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1695717">Cutting et al. (1990)</a> detected a C-to-T change at nucleotide 1789 in exon 11 of the CFTR gene that was responsible for a stop mutation at amino acid 553 (R553X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1695717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Bal, J., Stuhrmann, M., Schloesser, M., Schmidtke, J., Reiss, J. <strong>A cystic fibrosis patient homozygous for the nonsense mutation R553X.</strong> J. Med. Genet. 28: 715-717, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1682496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1682496</a>] [<a href="https://doi.org/10.1136/jmg.28.10.715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1682496">Bal et al. (1991)</a> described a patient homozygous for the arg553-to-ter mutation in exon 11. The patient was moderately severely affected. <a href="#120" class="mim-tip-reference" title="Hamosh, A., Trapnell, B. C., Zeitlin, P. L., Montrose-Rafizadeh, C., Rosenstein, B. J., Crystal, R. G., Cutting, G. R. <strong>Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and W1316X in respiratory epithelial cells of patients with cystic fibrosis.</strong> J. Clin. Invest. 88: 1880-1885, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1721624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1721624</a>] [<a href="https://doi.org/10.1172/JCI115510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1721624">Hamosh et al. (1991)</a> studied a CF patient who was a compound heterozygote for 2 nonsense mutations, R553X and W1316X (<a href="#0029">602421.0029</a>). The patient had undetectable CFTR mRNA in bronchial and nasal epithelial cells associated with severe pancreatic disease but unexpectedly mild pulmonary disease. The R553X mutation has the fourth highest frequency worldwide, 1.5%, according to the CF Consortium (<a href="#120" class="mim-tip-reference" title="Hamosh, A., Trapnell, B. C., Zeitlin, P. L., Montrose-Rafizadeh, C., Rosenstein, B. J., Crystal, R. G., Cutting, G. R. <strong>Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and W1316X in respiratory epithelial cells of patients with cystic fibrosis.</strong> J. Clin. Invest. 88: 1880-1885, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1721624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1721624</a>] [<a href="https://doi.org/10.1172/JCI115510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1721624">Hamosh et al., 1991</a>). The patient was a 22-year-old African American female, 1 of 2 patients with mild pulmonary disease reported by <a href="#64" class="mim-tip-reference" title="Cutting, G. R., Kasch, L. M., Rosenstein, B. J., Tsui, L.-C., Kazazian, H. H., Jr., Antonarakis, S. E. <strong>Two patients with cystic fibrosis, nonsense mutations in each cystic fibrosis gene, and mild pulmonary disease.</strong> New Eng. J. Med. 323: 1685-1689, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2233965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2233965</a>] [<a href="https://doi.org/10.1056/NEJM199012133232407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2233965">Cutting et al. (1990)</a>. <a href="#39" class="mim-tip-reference" title="Cheadle, J., Al-Jader, L., Goodchild, M., Meredith, A. L. <strong>Mild pulmonary disease in a cystic fibrosis child homozygous for R553X.</strong> J. Med. Genet. 29: 597, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1518030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1518030</a>] [<a href="https://doi.org/10.1136/jmg.29.8.597" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1518030">Cheadle et al. (1992)</a> described a child who despite being homozygous for the R553X mutation had only mild pulmonary disease. They raised the possibility that the lack of CFTR protein in airway cells may be less damaging than the presence of an altered protein, a suggestion advanced by <a href="#64" class="mim-tip-reference" title="Cutting, G. R., Kasch, L. M., Rosenstein, B. J., Tsui, L.-C., Kazazian, H. H., Jr., Antonarakis, S. E. <strong>Two patients with cystic fibrosis, nonsense mutations in each cystic fibrosis gene, and mild pulmonary disease.</strong> New Eng. J. Med. 323: 1685-1689, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2233965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2233965</a>] [<a href="https://doi.org/10.1056/NEJM199012133232407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2233965">Cutting et al. (1990)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1682496+1721624+2233965+1518030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Chen, H.-J., Lin, S.-P., Lee, H.-C., Chen, C.-P., Chiu, N.-C., Hung, H.-Y., Chern, S.-R., Chuang, C.-K. <strong>Cystic fibrosis with homozygous R553X mutation in a Taiwanese child.</strong> J. Hum. Genet. 50: 674-678, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16283068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16283068</a>] [<a href="https://doi.org/10.1007/s10038-005-0309-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16283068">Chen et al. (2005)</a> reported a Taiwanese CF patient who was homozygous for the R553X mutation. He had a severe clinical course, with early onset of chronic diarrhea, failure to thrive, and frequent respiratory infections. The parents, who were not related, were both heterozygous for the mutation. Both of their families were native to Taiwan, having been on the island for at least 3 generations. <a href="#42" class="mim-tip-reference" title="Chen, H.-J., Lin, S.-P., Lee, H.-C., Chen, C.-P., Chiu, N.-C., Hung, H.-Y., Chern, S.-R., Chuang, C.-K. <strong>Cystic fibrosis with homozygous R553X mutation in a Taiwanese child.</strong> J. Hum. Genet. 50: 674-678, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16283068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16283068</a>] [<a href="https://doi.org/10.1007/s10038-005-0309-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16283068">Chen et al. (2005)</a> noted that cystic fibrosis is rare among Asians and that homozygosity for R553X had only been reported previously in Caucasian patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16283068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Aznarez, I., Zielenski, J., Rommens, J. M., Blencowe, B. J., Tsui, L.-C. <strong>Exon skipping through the creation of a putative exonic splicing silencer as a consequence of the cystic fibrosis mutation R553X. (Letter)</strong> J. Med. Genet. 44: 341-346, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17475917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17475917</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17475917[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2006.045880" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17475917">Aznarez et al. (2007)</a> performed transcript analysis of 5 CF patients who were compound heterozygous for the R553X and delta-F508 (<a href="#0001">602421.0001</a>) mutations. RT-PCR of patient lymphoblastoid cells showed variable levels of an aberrantly spliced CFTR isoform that corresponded to the skipping of exon 11. Use of a splice reporter construct indicated that the R553X substitution creates a putative exonic splicing silencer (ESS) that may result in exon skipping by preventing selection of the proximal 5-prime splice site. Exon 11 skipping did not result from a nonsense-associated altered splicing mechanism. <a href="#13" class="mim-tip-reference" title="Aznarez, I., Zielenski, J., Rommens, J. M., Blencowe, B. J., Tsui, L.-C. <strong>Exon skipping through the creation of a putative exonic splicing silencer as a consequence of the cystic fibrosis mutation R553X. (Letter)</strong> J. Med. Genet. 44: 341-346, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17475917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17475917</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17475917[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2006.045880" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17475917">Aznarez et al. (2007)</a> concluded that aminoglycoside treatment would not be effective for CF patients with this mutation owing to its effect of skipping exon 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17475917" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs75549581 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs75549581;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs75549581?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs75549581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs75549581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007543 OR RCV000521321 OR RCV001004261 OR RCV001826429 OR RCV002476941 OR RCV003473010" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007543, RCV000521321, RCV001004261, RCV001826429, RCV002476941, RCV003473010" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007543...</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#65" class="mim-tip-reference" title="Cutting, G. R., Kasch, L. M., Rosenstein, B. J., Zielenski, J., Tsui, L.-C., Antonarakis, S. E., Kazazian, H. H., Jr. <strong>A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.</strong> Nature 346: 366-369, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1695717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1695717</a>] [<a href="https://doi.org/10.1038/346366a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1695717">Cutting et al. (1990)</a> detected a G-to-A change at nucleotide 1807 in exon 11 of the CFTR gene that caused a substitution of threonine for alanine at amino acid 559 (A559T). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1695717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80055610 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80055610;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80055610?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80055610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80055610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007533 OR RCV000224789 OR RCV000780134 OR RCV001004262 OR RCV001831521 OR RCV002504762 OR RCV003473005" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007533, RCV000224789, RCV000780134, RCV001004262, RCV001831521, RCV002504762, RCV003473005" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007533...</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#139" class="mim-tip-reference" title="Kerem, B., Zielenski, J., Markiewicz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in regions corresponding to the 2 putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.</strong> Proc. Nat. Acad. Sci. 87: 8447-8451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236053</a>] [<a href="https://doi.org/10.1073/pnas.87.21.8447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236053">Kerem et al. (1990)</a> found a G-to-C change at nucleotide 1811 in exon 11 of the CFTR gene responsible for substitution of threonine for arginine at amino acid 560 (R560T). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2236053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0017" class="mim-anchor"></a>
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<strong>.0017 CYSTIC FIBROSIS</strong>
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CFTR, TYR563ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909006 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909006;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909006?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007534 OR RCV001004266 OR RCV001009533 OR RCV002254258 OR RCV004566688 OR RCV004734501 OR RCV005042002" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007534, RCV001004266, RCV001009533, RCV002254258, RCV004566688, RCV004734501, RCV005042002" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007534...</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#139" class="mim-tip-reference" title="Kerem, B., Zielenski, J., Markiewicz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in regions corresponding to the 2 putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.</strong> Proc. Nat. Acad. Sci. 87: 8447-8451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236053</a>] [<a href="https://doi.org/10.1073/pnas.87.21.8447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236053">Kerem et al. (1990)</a> found a T-to-A change at nucleotide 1819 in exon 12 of the CFTR gene responsible for substitution of asparagine for tyrosine at amino acid 563 (Y563N). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2236053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0018" class="mim-anchor"></a>
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<strong>.0018 CYSTIC FIBROSIS</strong>
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CFTR, PRO574HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908758 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908758;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908758?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007539 OR RCV001004269 OR RCV001009367 OR RCV001831523 OR RCV002254259 OR RCV002490333 OR RCV003473008" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007539, RCV001004269, RCV001009367, RCV001831523, RCV002254259, RCV002490333, RCV003473008" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007539...</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#139" class="mim-tip-reference" title="Kerem, B., Zielenski, J., Markiewicz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in regions corresponding to the 2 putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.</strong> Proc. Nat. Acad. Sci. 87: 8447-8451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236053</a>] [<a href="https://doi.org/10.1073/pnas.87.21.8447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236053">Kerem et al. (1990)</a> detected a C-to-A change at nucleotide 1853 in exon 12 of the CFTR gene responsible for substitution of histidine for proline at amino acid 574 (P574H). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2236053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0019" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0019 CYSTIC FIBROSIS</strong>
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CFTR, 2-BP INS, 2566AT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906359 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906359;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000190991" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190991" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190991</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#271" class="mim-tip-reference" title="White, M. B., Amos, J., Hsu, J. M. C., Gerrard, B., Finn, P., Dean, M. <strong>A frame-shift mutation in the cystic fibrosis gene.</strong> Nature 344: 665-667, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1691449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1691449</a>] [<a href="https://doi.org/10.1038/344665a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1691449">White et al. (1990)</a> detected insertion of 2 nucleotides, AT, after nucleotide 2566 (2566insAT) in exon 13 of the CFTR gene, responsible for a frameshift. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1691449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0020" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0020 CYSTIC FIBROSIS</strong>
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CFTR, 1-BP DEL, 3659C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908811 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908811;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908811?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007544 OR RCV001004502 OR RCV001831526 OR RCV003473011 OR RCV004558238 OR RCV005031406" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007544, RCV001004502, RCV001831526, RCV003473011, RCV004558238, RCV005031406" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007544...</a>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#139" class="mim-tip-reference" title="Kerem, B., Zielenski, J., Markiewicz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in regions corresponding to the 2 putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.</strong> Proc. Nat. Acad. Sci. 87: 8447-8451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236053</a>] [<a href="https://doi.org/10.1073/pnas.87.21.8447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236053">Kerem et al. (1990)</a> detected deletion of a C at nucleotide 3659 in exon 19 of the (3659delC) CFTR gene resulting in a frameshift. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2236053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0021" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0021 CYSTIC FIBROSIS</strong>
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CFTR, SER1255TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs76649725 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs76649725;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs76649725?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs76649725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs76649725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007545 OR RCV000781247 OR RCV001810834 OR RCV001831527 OR RCV003473012" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007545, RCV000781247, RCV001810834, RCV001831527, RCV003473012" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007545...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In an 11-year-old black boy with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#64" class="mim-tip-reference" title="Cutting, G. R., Kasch, L. M., Rosenstein, B. J., Tsui, L.-C., Kazazian, H. H., Jr., Antonarakis, S. E. <strong>Two patients with cystic fibrosis, nonsense mutations in each cystic fibrosis gene, and mild pulmonary disease.</strong> New Eng. J. Med. 323: 1685-1689, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2233965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2233965</a>] [<a href="https://doi.org/10.1056/NEJM199012133232407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2233965">Cutting et al. (1990)</a> detected a C-to-A change at nucleotide 3896 in exon 20 of the CFTR gene responsible for a stop mutation at amino acid 1255 (S1255X). The boy inherited this mutation from his father. The chromosome inherited from his mother carried another nonsense mutation, gly542-to-ter (<a href="#0009">602421.0009</a>). The patient had serious pancreatic disease but only mild pulmonary involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2233965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0022 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs77010898 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77010898;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs77010898?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs77010898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs77010898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007549 OR RCV000271658 OR RCV000763161 OR RCV000780159 OR RCV001004509 OR RCV001731145 OR RCV002228015 OR RCV002255994 OR RCV003473013" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007549, RCV000271658, RCV000763161, RCV000780159, RCV001004509, RCV001731145, RCV002228015, RCV002255994, RCV003473013" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007549...</a>
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<p>In a French patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#256" class="mim-tip-reference" title="Vidaud, M., Fanen, P., Martin, J., Ghanem, N., Nicolas, S., Goossens, M. <strong>Three point mutations in the CFTR gene in French cystic fibrosis patients: identification by denaturing gradient gel electrophoresis.</strong> Hum. Genet. 85: 446-449, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2210768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2210768</a>] [<a href="https://doi.org/10.1007/BF02428305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2210768">Vidaud et al. (1990)</a> identified the substitution of tryptophan-1282 by a termination codon in the CFTR gene. The other chromosome carried the delta-F508 mutation (<a href="#0001">602421.0001</a>). In another French patient with cystic fibrosis, <a href="#256" class="mim-tip-reference" title="Vidaud, M., Fanen, P., Martin, J., Ghanem, N., Nicolas, S., Goossens, M. <strong>Three point mutations in the CFTR gene in French cystic fibrosis patients: identification by denaturing gradient gel electrophoresis.</strong> Hum. Genet. 85: 446-449, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2210768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2210768</a>] [<a href="https://doi.org/10.1007/BF02428305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2210768">Vidaud et al. (1990)</a> found precisely the same mutation on one chromosome but the mutation on the other chromosome was unknown. A G-to-A substitution at nucleotide 3978 was responsible for the trp1282-to-ter change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2210768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#120" class="mim-tip-reference" title="Hamosh, A., Trapnell, B. C., Zeitlin, P. L., Montrose-Rafizadeh, C., Rosenstein, B. J., Crystal, R. G., Cutting, G. R. <strong>Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and W1316X in respiratory epithelial cells of patients with cystic fibrosis.</strong> J. Clin. Invest. 88: 1880-1885, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1721624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1721624</a>] [<a href="https://doi.org/10.1172/JCI115510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1721624">Hamosh et al. (1991)</a> cited evidence that the W1282X mutation, located in exon 20, is the most common CF mutation in the Ashkenazi Jewish population where it is present on 50% of CF chromosomes. In Israel, <a href="#228" class="mim-tip-reference" title="Shoshani, T., Augarten, A., Gazit, E., Bashan, N., Yahav, Y., Rivlin, Y., Tal, A., Seret, H., Yaar, L., Kerem, E., Kerem, B. <strong>Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease.</strong> Am. J. Hum. Genet. 50: 222-228, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1370365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1370365</a>]" pmid="1370365">Shoshani et al. (1992)</a> found the W1282X mutation in 63 chromosomes from 97 CF families. Sixteen patients homozygous for the W1282X mutation and 22 patients heterozygous for the delta-F508 and W1282X mutations had similarly severe disease, reflected by pancreatic insufficiency, high incidence of meconium ileus (37% and 27%, respectively), early age at diagnosis, poor nutritional status, and variable pulmonary function. Again, the W1282X mutation was the most common form in Ashkenazi Jewish patients in Israel. In the Jewish Ashkenazi patient population, 60% of the CF chromosomes carry the W1282X nonsense mutation. Patients homozygous for this mutation have severe disease with variable pulmonary complications. Studies by <a href="#229" class="mim-tip-reference" title="Shoshani, T., Augarten, A., Yahav, J., Gazit, E., Kerem, B. <strong>Two novel mutations in the CFTR gene: W1089X in exon 17B and 4010delTATT in exon 21.</strong> Hum. Molec. Genet. 3: 657-658, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7520798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7520798</a>] [<a href="https://doi.org/10.1093/hmg/3.4.657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7520798">Shoshani et al. (1994)</a> demonstrated that CFTR mRNA levels in patients homozygous for the W1282X mutation are not significantly decreased by the mutation. In patients heterozygous for the mutation, the relative levels of mRNA with the W1282X allele and either the delta-F508 or the normal allele were similar in each patient. These results indicated that the severe clinical phenotype of patients carrying the W1282X mutation is not due to a severe deficiency of mRNA. The severity, progression, and variability of the pulmonary disease appear to be affected by other, as yet unknown factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1370365+7520798+1721624" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#147" class="mim-tip-reference" title="Kulczycki, L. L., Kostuch, M., Bellanti, J. A. <strong>A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype-phenotype manifestations.</strong> Am. J. Med. Genet. 116A: 262-267, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12503104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12503104</a>] [<a href="https://doi.org/10.1002/ajmg.a.10886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12503104">Kulczycki et al. (2003)</a> described their oldest patient with cystic fibrosis, a 71-year-old white male who had been diagnosed at the age of 27 years because of recurrent nasal polyposis, elevated sweat sodium and chloride, and a history of CF in his sister. Urologic examination demonstrated congenital bilateral absence of the vas deferens (<a href="/entry/277180">277180</a>). At the age of 60 years, genetic testing indicated compound heterozygosity for a severe W1282X mutation and a mild ala445-to-glu (<a href="#0130">602421.0130</a>) mutation in the CFTR gene. (In the article by <a href="#147" class="mim-tip-reference" title="Kulczycki, L. L., Kostuch, M., Bellanti, J. A. <strong>A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype-phenotype manifestations.</strong> Am. J. Med. Genet. 116A: 262-267, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12503104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12503104</a>] [<a href="https://doi.org/10.1002/ajmg.a.10886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12503104">Kulczycki et al. (2003)</a>, the W1282X mutation was erroneously cited as H1282X.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12503104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0023 CFTR POLYMORPHISM</strong>
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CFTR, MET470VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs213950 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs213950;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs213950?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs213950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs213950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007550 OR RCV000036517 OR RCV001095216 OR RCV001810835" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007550, RCV000036517, RCV001095216, RCV001810835" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007550...</a>
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<p><a href="#139" class="mim-tip-reference" title="Kerem, B., Zielenski, J., Markiewicz, D., Bozon, D., Gazit, E., Yahav, J., Kennedy, D., Riordan, J. R., Collins, F. S., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in regions corresponding to the 2 putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.</strong> Proc. Nat. Acad. Sci. 87: 8447-8451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2236053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2236053</a>] [<a href="https://doi.org/10.1073/pnas.87.21.8447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2236053">Kerem et al. (1990)</a> found 'normal' A or G variation at nucleotide 1540 resulting in methionine or valine, respectively, at position 470. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2236053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1800091 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800091;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1800091?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1800091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1800091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007551 OR RCV000245320 OR RCV000759754 OR RCV001282755" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007551, RCV000245320, RCV000759754, RCV001282755" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007551...</a>
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<p>This variant in the CFTR gene was found by <a href="#144" class="mim-tip-reference" title="Kobayashi, K., Knowles, M. R., Boucher, R. C., O'Brien, W. E., Beaudet, A. L. <strong>Benign missense variations in the cystic fibrosis gene.</strong> Am. J. Hum. Genet. 47: 611-615, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1977306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1977306</a>]" pmid="1977306">Kobayashi et al. (1990)</a> in a compound heterozygote with delta-F508 (<a href="#0001">602421.0001</a>). Clinical and epithelial physiologic studies yielded normal results, indicating that the I506V mutation is benign. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1977306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74571530 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74571530;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74571530?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74571530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74571530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007546 OR RCV000078978 OR RCV001009496 OR RCV001281707 OR RCV001327947 OR RCV001642200 OR RCV001731144 OR RCV002255993" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007546, RCV000078978, RCV001009496, RCV001281707, RCV001327947, RCV001642200, RCV001731144, RCV002255993" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007546...</a>
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<p>This mutation was found by <a href="#144" class="mim-tip-reference" title="Kobayashi, K., Knowles, M. R., Boucher, R. C., O'Brien, W. E., Beaudet, A. L. <strong>Benign missense variations in the cystic fibrosis gene.</strong> Am. J. Hum. Genet. 47: 611-615, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1977306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1977306</a>]" pmid="1977306">Kobayashi et al. (1990)</a> in a compound heterozygote with delta-F508 (<a href="#0001">602421.0001</a>). Clinical and epithelial physiologic studies yielded normal results, indicating that the F508C mutation is benign. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1977306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0026" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0026 CYSTIC FIBROSIS</strong>
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CFTR, TRP846TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267606722 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606722;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267606722?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267606722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267606722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007547 OR RCV001004480 OR RCV001826430 OR RCV004566689 OR RCV005042003" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007547, RCV001004480, RCV001826430, RCV004566689, RCV005042003" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007547...</a>
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<p>In a French patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#256" class="mim-tip-reference" title="Vidaud, M., Fanen, P., Martin, J., Ghanem, N., Nicolas, S., Goossens, M. <strong>Three point mutations in the CFTR gene in French cystic fibrosis patients: identification by denaturing gradient gel electrophoresis.</strong> Hum. Genet. 85: 446-449, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2210768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2210768</a>] [<a href="https://doi.org/10.1007/BF02428305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2210768">Vidaud et al. (1990)</a> found a replacement of tryptophan-846 by a stop codon on one chromosome; the nature of the mutation on the other chromosome was unidentified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2210768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0027" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0027 CYSTIC FIBROSIS</strong>
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</h4>
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CFTR, TYR913CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909008 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909008;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909008?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007548 OR RCV001004485 OR RCV004566690 OR RCV005031407" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007548, RCV001004485, RCV004566690, RCV005031407" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007548...</a>
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</span>
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<span class="mim-text-font">
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<p>In a French patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#256" class="mim-tip-reference" title="Vidaud, M., Fanen, P., Martin, J., Ghanem, N., Nicolas, S., Goossens, M. <strong>Three point mutations in the CFTR gene in French cystic fibrosis patients: identification by denaturing gradient gel electrophoresis.</strong> Hum. Genet. 85: 446-449, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2210768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2210768</a>] [<a href="https://doi.org/10.1007/BF02428305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2210768">Vidaud et al. (1990)</a> identified substitution of tyrosine-913 by cysteine. The other chromosome carried the delta-F508 mutation. An A-to-G substitution at position 2870 was responsible for the tyr913-to-cys change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2210768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0028" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0028 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, GLY458VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909009 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909009;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007552" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007552" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007552</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#61" class="mim-tip-reference" title="Cuppens, H., Marynen, P., De Boeck, C., De Baets, F., Eggermont, E., Van den Berghe, H., Cassiman, J. J. <strong>A child, homozygous for a stop codon in exon 11, shows milder cystic fibrosis symptoms than her heterozygous nephew.</strong> J. Med. Genet. 27: 717-719, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2135388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2135388</a>] [<a href="https://doi.org/10.1136/jmg.27.11.717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2135388">Cuppens et al. (1990)</a> described compound heterozygosity for the G542X mutation (<a href="#0009">602421.0009</a>) and a change of glycine-458 to valine (G458V). The patient died at the age of 12 years of respiratory insufficiency and right heart failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2135388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
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<a id="0029" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0029 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, TRP1316TER
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909010 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909010;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007553" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007553" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007553</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 21-year-old black woman with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) with substantial pancreatic disease but only mild pulmonary involvement, <a href="#64" class="mim-tip-reference" title="Cutting, G. R., Kasch, L. M., Rosenstein, B. J., Tsui, L.-C., Kazazian, H. H., Jr., Antonarakis, S. E. <strong>Two patients with cystic fibrosis, nonsense mutations in each cystic fibrosis gene, and mild pulmonary disease.</strong> New Eng. J. Med. 323: 1685-1689, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2233965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2233965</a>] [<a href="https://doi.org/10.1056/NEJM199012133232407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2233965">Cutting et al. (1990)</a> found an A-to-G substitution at nucleotide 4079 in exon 21, leading to replacement of tryptophan at codon 1316 by a termination signal. The mutation appeared to have been inherited from the father; from the mother the patient had inherited the arg553-to-ter mutation (<a href="#0014">602421.0014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2233965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<a id="0030" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0030 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, 2-BP INS, 1154TC
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906360 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906360;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906360" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906360" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007554 OR RCV000723429 OR RCV000780169 OR RCV001004249 OR RCV001831528 OR RCV003473014 OR RCV005031408" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007554, RCV000723429, RCV000780169, RCV001004249, RCV001831528, RCV003473014, RCV005031408" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007554...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 37-year-old woman with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) who had a high sweat chloride level, pancreatic insufficiency since infancy, and mild lung disease, <a href="#128" class="mim-tip-reference" title="Iannuzzi, M. C., Stern, R. C., Collins, F. S., Tom Hon, C., Hidaka, N., Strong, T., Becker, L., Drumm, M. L., White, M. B., Gerrard, B., Dean, M. <strong>Two frameshift mutations in the cystic fibrosis gene.</strong> Am. J. Hum. Genet. 48: 227-231, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1990834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1990834</a>]" pmid="1990834">Iannuzzi et al. (1991)</a> identified insertion of 2 nucleotides, T and C, at position 1154 of the CFTR gene, predicting a shift in the reading frame of the protein and the introduction of a UAA(ochre) termination codon at residue 369. The patient carried delta-F508 (<a href="#0001">602421.0001</a>) on the other allele. <a href="#4" class="mim-tip-reference" title="Alper, O. M., Wong, L.-J. C., Hostetter, G., Cook, J., Tenenholz, B., Hsu, E., Woo, M. S. <strong>1154insTC is not a rare CFTR mutation. (Letter)</strong> Am. J. Med. Genet. 120A: 294-295, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12833419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12833419</a>] [<a href="https://doi.org/10.1002/ajmg.a.20038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12833419">Alper et al. (2003)</a> described the truncated protein as lacking ATP binding domains, the regulatory domain, and the second transmembrane domain and as thought to be nonfunctional. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1990834+12833419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Screening 80 CFTR patients, <a href="#4" class="mim-tip-reference" title="Alper, O. M., Wong, L.-J. C., Hostetter, G., Cook, J., Tenenholz, B., Hsu, E., Woo, M. S. <strong>1154insTC is not a rare CFTR mutation. (Letter)</strong> Am. J. Med. Genet. 120A: 294-295, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12833419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12833419</a>] [<a href="https://doi.org/10.1002/ajmg.a.20038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12833419">Alper et al. (2003)</a> found two 1154insTC mutations, both in Caucasians, accounting for 1.25% of the CF chromosomes. They also reported compound heterozygosity with delF508 (<a href="#0001">602421.0001</a>) in CF with pancreatic insufficiency and meconium ileus in a Caucasian male. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12833419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906361 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906361;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906361?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007555 OR RCV001009522 OR RCV001831529 OR RCV003466826" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007555, RCV001009522, RCV001831529, RCV003466826" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007555...</a>
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<p>In 2 sibs with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#128" class="mim-tip-reference" title="Iannuzzi, M. C., Stern, R. C., Collins, F. S., Tom Hon, C., Hidaka, N., Strong, T., Becker, L., Drumm, M. L., White, M. B., Gerrard, B., Dean, M. <strong>Two frameshift mutations in the cystic fibrosis gene.</strong> Am. J. Hum. Genet. 48: 227-231, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1990834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1990834</a>]" pmid="1990834">Iannuzzi et al. (1991)</a> identified deletion of thymine at position 1213, which was predicted to shift the reading frame of the protein and to introduce a UAA(ochre) termination codon at residue 368. The patients had mildly impaired lung function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1990834" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80034486 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80034486;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80034486?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80034486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80034486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007556 OR RCV000224445 OR RCV001004513 OR RCV001831530 OR RCV002255995 OR RCV002287325 OR RCV003473015 OR RCV005042004" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007556, RCV000224445, RCV001004513, RCV001831530, RCV002255995, RCV002287325, RCV003473015, RCV005042004" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007556...</a>
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<p>On 4 of 52 chromosomes from patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), including 2 sibs, <a href="#179" class="mim-tip-reference" title="Osborne, L., Knight, R., Santis, G., Hodson, M. <strong>A mutation in the second nucleotide binding fold of the cystic fibrosis gene.</strong> Am. J. Hum. Genet. 48: 608-612, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1998343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1998343</a>]" pmid="1998343">Osborne et al. (1991)</a> identified a C-to-G change at nucleotide 4041 of the CFTR gene resulting in a change from asparagine to lysine at amino acid position 1303 (N1303K). This mutation was found exclusively in heterozygous state and no correlation could be made between clinical phenotype and the presence of the gene. Pooling laboratories throughout Europe and the United States, <a href="#180" class="mim-tip-reference" title="Osborne, L., Santis, G., Schwarz, M., Klinger, K., Dork, T., McIntosh, I., Schwartz, M., Nunes, V., Macek, M., Jr., Reiss, J., and 46 others. <strong>Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene.</strong> Hum. Genet. 89: 653-658, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1380943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1380943</a>] [<a href="https://doi.org/10.1007/BF00221957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1380943">Osborne et al. (1992)</a> identified 216 examples of N1303K among nearly 15,000 CF chromosomes tested, a frequency of 1.5%. The frequency was greater in southern than in northern Europe; it was not found in U.K. Asians, American blacks, or Australians. Ten patients were homozygous, whereas 106 of the remainder carried 1 of 12 known CF mutations in the other allele. <a href="#180" class="mim-tip-reference" title="Osborne, L., Santis, G., Schwarz, M., Klinger, K., Dork, T., McIntosh, I., Schwartz, M., Nunes, V., Macek, M., Jr., Reiss, J., and 46 others. <strong>Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene.</strong> Hum. Genet. 89: 653-658, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1380943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1380943</a>] [<a href="https://doi.org/10.1007/BF00221957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1380943">Osborne et al. (1992)</a> concluded that N1303K is a 'severe' mutation with respect to the pancreas, but could find no correlation between this mutation in either the homozygous or heterozygous state and the severity of lung disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1380943+1998343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0033 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74767530 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74767530;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74767530?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74767530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74767530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007557 OR RCV000508142 OR RCV000780138 OR RCV001004500 OR RCV001831531 OR RCV002504763 OR RCV003473016 OR RCV004720229" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007557, RCV000508142, RCV000780138, RCV001004500, RCV001831531, RCV002504763, RCV003473016, RCV004720229" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007557...</a>
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<p>In a study of cystic fibrosis (CF; <a href="/entry/219700">219700</a>) mutations in south European cases, <a href="#101" class="mim-tip-reference" title="Gasparini, P., Nunes, V., Savoia, A., Dognini, M., Morral, N., Gaona, A., Bonizzato, A., Chillon, M., Sangiuolo, F., Novelli, G., Dallapiccola, B., Pignatti, P. F., Estivill, X. <strong>The search for south European cystic fibrosis mutations: identification of two new mutations, four variants, and intronic sequences.</strong> Genomics 10: 193-200, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2045102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2045102</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90500-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2045102">Gasparini et al. (1991)</a> found a nonsense mutation in exon 19 due to a C-to-T substitution at nucleotide 3616. The normal codon CGA, which codes for arginine at position 1162, was changed to a stop codon UGA (R1162X). It was detected in 2 of 16 non-delta-F508 chromosomes. In 9 patients homozygous for this mutation, <a href="#99" class="mim-tip-reference" title="Gasparini, P., Borgo, G., Mastella, G., Bonizzato, A., Dognini, M., Pignatti, P. F. <strong>Nine cystic fibrosis patients homozygous for the CFTR nonsense mutation R1162X have mild or moderate lung disease.</strong> J. Med. Genet. 29: 558-562, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1381442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1381442</a>] [<a href="https://doi.org/10.1136/jmg.29.8.558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1381442">Gasparini et al. (1992)</a> found mild lung disease. They had expected that the interruption in the synthesis of the CFTR protein would result in a severe clinical course. The findings of mild to moderate involvement of the lungs (although pancreatic insufficiency was present in all) suggested to them that this form of truncated CFTR protein, still containing the regulatory region, the first ATP binding domain, and both transmembrane domains, could be partially working in lung tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2045102+1381442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0034 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909011 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909011;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909011?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007559 OR RCV000224060 OR RCV000763567 OR RCV001000033 OR RCV001004246 OR RCV001826431 OR RCV003473017" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007559, RCV000224060, RCV000763567, RCV001000033, RCV001004246, RCV001826431, RCV003473017" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007559...</a>
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<p>In the course of a study of cystic fibrosis (CF; <a href="/entry/219700">219700</a>) mutations in south European cases, <a href="#101" class="mim-tip-reference" title="Gasparini, P., Nunes, V., Savoia, A., Dognini, M., Morral, N., Gaona, A., Bonizzato, A., Chillon, M., Sangiuolo, F., Novelli, G., Dallapiccola, B., Pignatti, P. F., Estivill, X. <strong>The search for south European cystic fibrosis mutations: identification of two new mutations, four variants, and intronic sequences.</strong> Genomics 10: 193-200, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2045102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2045102</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90500-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2045102">Gasparini et al. (1991)</a> found a C-to-T substitution at nucleotide 1132 in exon 7. This point mutation changed an arginine codon to a tryptophan at position 334 of the putative first transmembrane domain of the protein (R334W). The patient was a compound heterozygote for mutations R334X and N1303K (<a href="#0032">602421.0032</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2045102" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Antinolo, G., Borrego, S., Gili, M., Dapena, J., Alfageme, I., Reina, F. <strong>Genotype-phenotype relationship in 12 patients carrying cystic fibrosis mutation R334W.</strong> J. Med. Genet. 34: 89-91, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039981</a>] [<a href="https://doi.org/10.1136/jmg.34.2.89" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9039981">Antinolo et al. (1997)</a> compared the phenotype of 12 patients with cystic fibrosis caused by the R334W mutation with those of homozygous delF508 patients. Current age and age at diagnosis were significantly higher in the R334W mutation group. They found a lower rate of Pseudomonas aeruginosa colonization in patients carrying the R334W mutation, although the difference was not statistically significant. However, they found a statistically significant higher age of onset of Pseudomonas aeruginosa colonization in the group of patients with the R334W mutation. Pancreatic insufficiency was found in a lower percentage of R334W patients (33%). The body weight expressed as a percentage of ideal weight for height was significantly higher in patients with the R334W mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9039981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0035 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908776 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908776;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908776" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908776" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007560 OR RCV001528991 OR RCV001813963 OR RCV001826432 OR RCV003473018" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007560, RCV001528991, RCV001813963, RCV001826432, RCV003473018" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007560...</a>
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<p>In both parents of a sibship in which 3 children with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) had died within months of birth (2 with pneumonia and 1 with presumed meconium ileus), <a href="#129" class="mim-tip-reference" title="Ivaschenko, T. E., White, M. B., Dean, M., Baranov, V. S. <strong>A deletion of two nucleotides in exon 10 of the CFTR gene in a Soviet family with cystic fibrosis causing early infant death.</strong> Genomics 10: 298-299, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1710601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1710601</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90517-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1710601">Ivaschenko et al. (1991)</a> found the same mutation, namely, deletion of 2 nucleotides (TA) at position 1677. As a result of the deletion, the protein reading frame was shifted, introducing a termination codon (TAG) at amino acid position 515 in the resulting transcript. The family was from a small Soviet ethnic group called the Megrals in western Georgia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1710601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909012 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909012;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007561 OR RCV001004481 OR RCV001831532 OR RCV002476942 OR RCV003473019" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007561, RCV001004481, RCV001831532, RCV002476942, RCV003473019" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007561...</a>
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<p>In a compound heterozygote with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#272" class="mim-tip-reference" title="White, M. B., Leppert, M., Nielsen, D., Zielenski, J., Gerrard, B., Stewart, C., Dean, M. <strong>A de novo cystic fibrosis mutation: CGA (arg) to TGA (stop) at codon 851 of the CFTR gene.</strong> Genomics 11: 778-779, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1723056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1723056</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90092-s" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1723056">White et al. (1991)</a> found a de novo mutation which converted codon 851 (CGA;ARG) to a stop codon (TGA). The mother lacked any CFTR mutation and the father was heterozygous for the common delta-F508 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1723056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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CFTR, GLY551SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909013 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909013;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909013?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007562 OR RCV000211256 OR RCV000224595 OR RCV001831533 OR RCV002247261 OR RCV003473020" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007562, RCV000211256, RCV000224595, RCV001831533, RCV002247261, RCV003473020" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007562...</a>
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<p>In 2 sisters with mild cystic fibrosis (CF; <a href="/entry/219700">219700</a>), the offspring of second-cousin parents, <a href="#239" class="mim-tip-reference" title="Strong, T. V., Smit, L. S., Turpin, S. V., Cole, J. L., Tom Hon, C., Markiewicz, D., Petty, T. L., Craig, M. W., Rosenow, E. C., III, Tsui, L.-C., Iannuzzi, M. C., Knowles, M. R., Collins, F. S. <strong>Cystic fibrosis gene mutation in two sisters with mild disease and normal sweat electrolyte levels.</strong> New Eng. J. Med. 325: 1630-1634, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1944451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1944451</a>] [<a href="https://doi.org/10.1056/NEJM199112053252307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1944451">Strong et al. (1991)</a> found a G-to-A substitution at basepair 1783 resulting in substitution of a serine for a glycine residue at the highly conserved position of amino acid 551. The proposita was a 50-year-old woman with a chronic productive cough. She had frequent pulmonary infections. Her sweat electrolyte concentrations were borderline normal. The patient had 2 normal pregnancies and deliveries and raised these children while working as a truck inspector. The patient had a sister who died of respiratory failure at the age of 48. She had delivered 4 healthy children without difficulty, had no evidence of malabsorption, and was in good health until the age of 23 when she had an episode of hemoptysis. At that time she was reported to have digital clubbing and bronchiectasis on chest roentgenography. Several sweat tests were normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1944451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0038 CYSTIC FIBROSIS</strong>
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CFTR, GLY85GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs75961395 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs75961395;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs75961395?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs75961395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs75961395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007563 OR RCV000224170 OR RCV001004234 OR RCV001831534 OR RCV002490334 OR RCV003473021" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007563, RCV000224170, RCV001004234, RCV001831534, RCV002490334, RCV003473021" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007563...</a>
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<p>In an 11-year-old boy of Iranian extraction with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#33" class="mim-tip-reference" title="Chalkley, G., Harris, A. <strong>A cystic fibrosis patient who is homozygous for the G85E mutation has very mild disease.</strong> J. Med. Genet. 28: 875-877, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1757965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1757965</a>] [<a href="https://doi.org/10.1136/jmg.28.12.875" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1757965">Chalkley and Harris (1991)</a> found homozygosity for a G-to-A mutation at nucleotide 386 in exon 3 of the CFTR gene, resulting in substitution of glutamic acid for glycine-85. The diagnosis of CF was made when the patient presented with a nasal polyp. He had sweat sodium values of 90 mmol per liter and mild lung disease and was pancreatic sufficient. The G85E mutation was first defined by <a href="#286" class="mim-tip-reference" title="Zielenski, J., Bozon, D., Kerem, B., Markiewicz, D., Durie, P., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in exons 1 through 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Genomics 10: 229-235, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1710599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1710599</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90504-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1710599">Zielenski et al. (1991)</a> in a French Canadian patient who was a compound heterozygote. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1757965+1710599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0039" class="mim-anchor"></a>
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<strong>.0039 CYSTIC FIBROSIS</strong>
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CFTR, ARG1158TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs79850223 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs79850223;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs79850223?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs79850223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs79850223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007564 OR RCV000579152 OR RCV000763158 OR RCV001004499 OR RCV001831535 OR RCV003473022" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007564, RCV000579152, RCV000763158, RCV001004499, RCV001831535, RCV003473022" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007564...</a>
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<p>In an Italian patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) known to be a genetic compound, <a href="#206" class="mim-tip-reference" title="Ronchetto, P., Telleria Orriols, J. J., Fanen, P., Cremonesi, L., Ferrari, M., Magnani, C., Seia, M., Goossens, M., Romeo, G., Devoto, M. <strong>A nonsense mutation (R1158X) and a splicing mutation (3849+4A-to-G) in exon 19 of the cystic fibrosis transmembrane conductance regulator gene.</strong> Genomics 12: 417-418, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1371265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1371265</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90396-a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1371265">Ronchetto et al. (1992)</a> found a C-to-T transition at nucleotide 3604 of the CFTR gene, which changed an arginine residue at position 1158 to a stop codon (R1158X). The patient carried an unknown mutation on the other chromosome and was pancreatic sufficient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1371265" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0040 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906362 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906362;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007558" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007558" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007558</a>
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<p>In an Italian patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) with pancreatic insufficiency but mild pulmonary disease, <a href="#206" class="mim-tip-reference" title="Ronchetto, P., Telleria Orriols, J. J., Fanen, P., Cremonesi, L., Ferrari, M., Magnani, C., Seia, M., Goossens, M., Romeo, G., Devoto, M. <strong>A nonsense mutation (R1158X) and a splicing mutation (3849+4A-to-G) in exon 19 of the cystic fibrosis transmembrane conductance regulator gene.</strong> Genomics 12: 417-418, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1371265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1371265</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90396-a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1371265">Ronchetto et al. (1992)</a> found an A-to-G transition located at the 5-prime end of intron 19 of the CFTR gene, which changed the consensus sequence of the donor site from GTGAGA to GTGGGA (3849+4A-G). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1371265" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0041" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0041 CYSTIC FIBROSIS</strong>
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CFTR, 22-BP DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908804 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908804;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007565 OR RCV001826433" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007565, RCV001826433" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007565...</a>
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<p>As part of a search for additional mutations causing cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#72" class="mim-tip-reference" title="Dean, M., White, M. B., Gerrard, B., Amos, J., Milunsky, A. <strong>A 22-bp deletion in the coding region of the cystic fibrosis gene.</strong> Genomics 13: 235-236, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1374361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1374361</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90233-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1374361">Dean et al. (1992)</a> used flanking primers for exon 6A to amplify DNA from over 150 CF patients who lacked the delta-F508 mutation on at least 1 chromosome. In 1 individual, a 22-bp deletion, beginning at nucleotide 852 and stopping 2 bp before the end of the exon, was found. The deletion was predicted to alter the reading frame of the protein, causing the introduction of an in-frame termination codon, TGA, at amino acid 253. <a href="#72" class="mim-tip-reference" title="Dean, M., White, M. B., Gerrard, B., Amos, J., Milunsky, A. <strong>A 22-bp deletion in the coding region of the cystic fibrosis gene.</strong> Genomics 13: 235-236, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1374361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1374361</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90233-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1374361">Dean et al. (1992)</a> stated that were no documented cases of large deletions and only 1 report of a de novo mutation in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1374361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0042" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0042 CYSTIC FIBROSIS</strong>
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</h4>
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CFTR, 1-BP DEL, 556A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906363 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906363;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007566 OR RCV001826434" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007566, RCV001826434" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007566...</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) with pancreatic insufficiency, <a href="#286" class="mim-tip-reference" title="Zielenski, J., Bozon, D., Kerem, B., Markiewicz, D., Durie, P., Rommens, J. M., Tsui, L.-C. <strong>Identification of mutations in exons 1 through 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Genomics 10: 229-235, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1710599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1710599</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90504-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1710599">Zielenski et al. (1991)</a> identified an exon 4 mutation in CFTR that created a new BglI site, a frameshift due to deletion of nucleotide 556, an A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1710599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0043" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0043 CYSTIC FIBROSIS</strong>
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</h4>
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CFTR, 1-BP DEL, 557T
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906364 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906364;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007567 OR RCV001831536 OR RCV005031409" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007567, RCV001831536, RCV005031409" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007567...</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) with relatively mild symptoms, <a href="#108" class="mim-tip-reference" title="Graham, C. A., Goon, P. K.-C., Hill, A. J. M., Nevin, N. C. <strong>Identification of a frameshift mutation (557 del T) in exon 4 of the CFTR gene.</strong> Genomics 12: 854-855, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1374052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1374052</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90327-o" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1374052">Graham et al. (1992)</a> identified deletion of a single nucleotide, a T, in the T tract from base 557 to 561 in exon 4 of the CFTR gene. Like the 556A deletion (<a href="#0042">602421.0042</a>), the mutation created a new BglI site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1374052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0044" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0044 CYSTIC FIBROSIS</strong>
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CFTR, 84-BP DEL, NT1949
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908777 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908777;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000046486 OR RCV004558294 OR RCV005042130" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000046486, RCV004558294, RCV005042130" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000046486...</a>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#109" class="mim-tip-reference" title="Granell, R., Solera, J., Carrasco, S., Molano, J. <strong>Identification of a nonframeshift 84-bp deletion in exon 13 of the cystic fibrosis gene.</strong> Am. J. Hum. Genet. 50: 1022-1026, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1373934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1373934</a>]" pmid="1373934">Granell et al. (1992)</a> identified an 84-bp deletion in exon 13 of the CFTR gene by DNA amplification and direct sequencing of 500 bp of the 5-prime end of exon 13. The deletion was in the maternal allele, and the patient's paternal allele bore the delta-F508 deletion (<a href="#0001">602421.0001</a>). The deletion spanned from a 4-A cluster in positions 1949-1952 to another 4-A cluster in positions 2032-2035. The mutation resulted in the loss of 28 amino acid residues in the R domain of the CFTR protein. Since this in-frame mutation, the largest identified to that time, began after nucleotide 1949, it was referred to as 1949del84. Out of 340 Spanish CF patients, <a href="#171" class="mim-tip-reference" title="Nunes, V., Casals, T., Gaona, A., Antinolo, G., Ferrer-Calvete, J., Perez-Frias, J., Tardio, E., Molano, J., Estivill, X. <strong>Cystic fibrosis patients with mutation 1949del84 in exon 13 of the CFTR gene have a similar clinical severity as delF508 homozygotes.</strong> Hum. Mutat. 1: 375-379, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284539</a>] [<a href="https://doi.org/10.1002/humu.1380010505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284539">Nunes et al. (1992)</a> found 3 patients who were compound heterozygotes for the 1949del84 and delF508 mutations and 1 for 1949del84 and an unknown mutation. The patients had a similar severity of disease to that in delF508 homozygous patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1373934+1284539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0045 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908788 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908788;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007569 OR RCV001826435 OR RCV002490335" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007569, RCV001826435, RCV002490335" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007569...</a>
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<p>In 5 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#170" class="mim-tip-reference" title="Nunes, V., Bonizzato, A., Gaona, A., Dognini, M., Chillon, M., Casals, T., Pignatti, P. F., Novelli, G., Estivill, X., Gasparini, P. <strong>A frameshift mutation (2869insG) in the second transmembrane domain of the CFTR gene: identification, regional distribution, and clinical presentation. (Letter)</strong> Am. J. Hum. Genet. 50: 1140-1142, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1373935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1373935</a>]" pmid="1373935">Nunes et al. (1992)</a> identified a frameshift mutation resulting from insertion of a guanine (G) after nucleotide 2869 in exon 15. One patient was homozygous for the mutation and the other 4 were compound heterozygous. Direct sequencing of the person homozygous for this mutation showed that the mutation resulted in a TGA stop codon at the site of insertion, followed by another stop signal at the beginning of exon 16. The mutation created a new restriction site for the MboI endonuclease. <a href="#170" class="mim-tip-reference" title="Nunes, V., Bonizzato, A., Gaona, A., Dognini, M., Chillon, M., Casals, T., Pignatti, P. F., Novelli, G., Estivill, X., Gasparini, P. <strong>A frameshift mutation (2869insG) in the second transmembrane domain of the CFTR gene: identification, regional distribution, and clinical presentation. (Letter)</strong> Am. J. Hum. Genet. 50: 1140-1142, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1373935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1373935</a>]" pmid="1373935">Nunes et al. (1992)</a> demonstrated that the mutation was present in 6 of 191 non-delF508 chromosomes in the Spanish population and in none of 86 Italian non-delF508 chromosomes. All chromosomes carrying the mutation had the same haplotype. A homozygous patient had a moderately severe clinical course. (This mutation is also referred to as 2869insG.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1373935" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0046 CYSTIC FIBROSIS</strong>
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CFTR, VAL520PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs77646904 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77646904;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs77646904?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs77646904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs77646904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007570 OR RCV000781233 OR RCV001004460 OR RCV001528232 OR RCV001826436 OR RCV003473023" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007570, RCV000781233, RCV001004460, RCV001528232, RCV001826436, RCV003473023" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007570...</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#134" class="mim-tip-reference" title="Jones, C. T., McIntosh, I., Keston, M., Ferguson, A., Brock, D. J. H. <strong>Three novel mutations in the cystic fibrosis gene detected by chemical cleavage: analysis of variant splicing and a nonsense mutation.</strong> Hum. Molec. Genet. 1: 11-17, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284466</a>] [<a href="https://doi.org/10.1093/hmg/1.1.11" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284466">Jones et al. (1992)</a> used the chemical cleavage mismatch technique to demonstrate a V520F mutation which resulted from a G-to-T transversion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0047 CYSTIC FIBROSIS</strong>
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CFTR, CYS524TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908754 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908754;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908754?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007571 OR RCV001831537 OR RCV003466827" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007571, RCV001831537, RCV003466827" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007571...</a>
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<p>Using the chemical cleavage mismatch technique for the study of DNA from a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#134" class="mim-tip-reference" title="Jones, C. T., McIntosh, I., Keston, M., Ferguson, A., Brock, D. J. H. <strong>Three novel mutations in the cystic fibrosis gene detected by chemical cleavage: analysis of variant splicing and a nonsense mutation.</strong> Hum. Molec. Genet. 1: 11-17, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284466</a>] [<a href="https://doi.org/10.1093/hmg/1.1.11" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284466">Jones et al. (1992)</a> discovered a nonsense C524X mutation resulting from a C-to-A transversion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0048" class="mim-anchor"></a>
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<h4>
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<strong>.0048 CYSTIC FIBROSIS</strong>
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CFTR, GLN1291HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909015 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909015;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909015?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007572 OR RCV000780123 OR RCV002228016 OR RCV003473024" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007572, RCV000780123, RCV002228016, RCV003473024" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007572...</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#134" class="mim-tip-reference" title="Jones, C. T., McIntosh, I., Keston, M., Ferguson, A., Brock, D. J. H. <strong>Three novel mutations in the cystic fibrosis gene detected by chemical cleavage: analysis of variant splicing and a nonsense mutation.</strong> Hum. Molec. Genet. 1: 11-17, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284466</a>] [<a href="https://doi.org/10.1093/hmg/1.1.11" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284466">Jones et al. (1992)</a> demonstrated a Q1291H mutation caused by a G-to-C transversion at the last nucleotide of exon 20 using the chemical cleavage mismatch technique. Further study, involving RNA-based PCR, demonstrated that the Q1291H is also a splice mutation. Both correctly and aberrantly spliced mRNAs were produced by the Q1291H allele. The incorrectly spliced product resulted from the use of a nearby cryptic splice site 29 bases into the adjacent intron. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0049" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0049 CYSTIC FIBROSIS</strong>
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CFTR, PHE311LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909016 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909016;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909016" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909016" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007573 OR RCV001642201 OR RCV003473025" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007573, RCV001642201, RCV003473025" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007573...</a>
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<p>Using DGGE in a systematic study of cystic fibrosis (CF; <a href="/entry/219700">219700</a>) mutations in a Celtic population in Brittany, <a href="#94" class="mim-tip-reference" title="Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Quere, I., Verlingue, C. <strong>Detection of over 98% cystic fibrosis mutations in a Celtic population.</strong> Nature Genet. 1: 188-191, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284639</a>] [<a href="https://doi.org/10.1038/ng0692-188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284639">Ferec et al. (1992)</a> identified a C-to-G mutation at nucleotide 1065 of the CFTR gene changing codon 311 from phenylalanine to leucine. The mutation was found in a compound heterozygous child who was classified as pancreatic insufficient; the other allele was gly551-to-asp (<a href="#0013">602421.0013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0050" class="mim-anchor"></a>
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<strong>.0050 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906365 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906365;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007574 OR RCV003473026" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007574, RCV003473026" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007574...</a>
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<p>In a systematic study of 365 cystic fibrosis (CF; <a href="/entry/219700">219700</a>) chromosomes in the Celtic population in Brittany, <a href="#94" class="mim-tip-reference" title="Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Quere, I., Verlingue, C. <strong>Detection of over 98% cystic fibrosis mutations in a Celtic population.</strong> Nature Genet. 1: 188-191, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284639</a>] [<a href="https://doi.org/10.1038/ng0692-188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284639">Ferec et al. (1992)</a> detected a frameshift mutation in exon 7. The patient, who was severely pancreatic insufficient, was a compound heterozygote for a deletion of 2 nucleotides at position 1221. The other allele had a deletion of T at 1078. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0051 CYSTIC FIBROSIS</strong>
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CFTR, SER492PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909017 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909017;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909017?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007575 OR RCV000763571 OR RCV001004455 OR RCV001810836 OR RCV003473027 OR RCV004734502" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007575, RCV000763571, RCV001004455, RCV001810836, RCV003473027, RCV004734502" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007575...</a>
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<p>In a systematic study of 365 cystic fibrosis (CF; <a href="/entry/219700">219700</a>) chromosomes in the Celtic population in Brittany, <a href="#94" class="mim-tip-reference" title="Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Quere, I., Verlingue, C. <strong>Detection of over 98% cystic fibrosis mutations in a Celtic population.</strong> Nature Genet. 1: 188-191, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284639</a>] [<a href="https://doi.org/10.1038/ng0692-188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284639">Ferec et al. (1992)</a> identified a ser492-to-phe mutation, due to a change at nucleotide 1607 from C to T, in a child classified as pancreatic sufficient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0052 CYSTIC FIBROSIS</strong>
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CFTR, ARG560LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80055610 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80055610;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80055610?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80055610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80055610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007576 OR RCV003466828" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007576, RCV003466828" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007576...</a>
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<span class="mim-text-font">
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<p>In a systematic study of 365 cystic fibrosis (CF; <a href="/entry/219700">219700</a>) chromosomes in the Celtic population in Brittany, <a href="#94" class="mim-tip-reference" title="Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Quere, I., Verlingue, C. <strong>Detection of over 98% cystic fibrosis mutations in a Celtic population.</strong> Nature Genet. 1: 188-191, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284639</a>] [<a href="https://doi.org/10.1038/ng0692-188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284639">Ferec et al. (1992)</a> identified an arg560-to-lys mutation at the 3-prime end of exon 11, resulting from a G-to-A transition at nucleotide 1811. As well as resulting in an amino acid change in the protein product, the substitution in the last residue of the exon may represent a splice mutation; a similar change in exon 1 of the human beta-globin gene diminishes RNA splicing (<a href="#257" class="mim-tip-reference" title="Vidaud, M., Gattoni, R., Stevenin, J., Vidaud, D., Amselem, S., Chibani, J., Rosa, J., Goossens, M. <strong>A 5-prime splice-region G-to-C mutation in exon 1 of the human beta-globin gene inhibits pre-mRNA splicing: a mechanism for beta(+)-thalassemia.</strong> Proc. Nat. Acad. Sci. 86: 1041-1045, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2915972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2915972</a>] [<a href="https://doi.org/10.1073/pnas.86.3.1041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2915972">Vidaud et al., 1989</a>; see hemoglobin Kairouan; HBB, ARG30THR; <a href="/entry/141900#0144">141900.0144</a>). The patient was pancreatic insufficient. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2915972+1284639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0053" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0053 CYSTIC FIBROSIS</strong>
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</h4>
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CFTR, GLU827TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909018 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909018;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007577" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007577" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007577</a>
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</span>
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<span class="mim-text-font">
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<p>In a child with pancreatic-insufficient cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in the Celtic population of Brittany, <a href="#94" class="mim-tip-reference" title="Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Quere, I., Verlingue, C. <strong>Detection of over 98% cystic fibrosis mutations in a Celtic population.</strong> Nature Genet. 1: 188-191, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284639</a>] [<a href="https://doi.org/10.1038/ng0692-188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284639">Ferec et al. (1992)</a> identified a G-to-T change at position 2611 in exon 13 leading to change of glutamic acid-827 to a stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<a id="0054" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0054 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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CFTR, ARG1066HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909019 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909019;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909019?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909019" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909019" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007578 OR RCV000506781 OR RCV000592350 OR RCV001004299 OR RCV001831538 OR RCV002496297 OR RCV003473028" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007578, RCV000506781, RCV000592350, RCV001004299, RCV001831538, RCV002496297, RCV003473028" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007578...</a>
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<span class="mim-text-font">
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<p>In a pancreatic-insufficient cystic fibrosis (CF; <a href="/entry/219700">219700</a>) patient in the Celtic population of Brittany, <a href="#94" class="mim-tip-reference" title="Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Quere, I., Verlingue, C. <strong>Detection of over 98% cystic fibrosis mutations in a Celtic population.</strong> Nature Genet. 1: 188-191, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284639</a>] [<a href="https://doi.org/10.1038/ng0692-188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284639">Ferec et al. (1992)</a> found an arg1066-to-his mutation resulting from a G-to-A transition at nucleotide 3329. This CpG dinucleotide is a known hotspot for mutations. <a href="#94" class="mim-tip-reference" title="Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Quere, I., Verlingue, C. <strong>Detection of over 98% cystic fibrosis mutations in a Celtic population.</strong> Nature Genet. 1: 188-191, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284639</a>] [<a href="https://doi.org/10.1038/ng0692-188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284639">Ferec et al. (1992)</a> quoted unpublished results indicating that another mutation, C3328 to T leading to arg1066-to-cys, had been discovered (<a href="#0058">602421.0058</a>). The child with the arg1066-to-his mutation was a compound heterozygote, the other allele having a deletion of T at nucleotide 1078. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0055" class="mim-anchor"></a>
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<strong>.0055 CYSTIC FIBROSIS</strong>
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CFTR, ALA1067THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909020 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909020;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909020?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007579 OR RCV000078995 OR RCV000660774 OR RCV000723610 OR RCV001831539" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007579, RCV000078995, RCV000660774, RCV000723610, RCV001831539" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007579...</a>
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<p>In a pancreatic-insufficient child with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in the Celtic population in Brittany, <a href="#94" class="mim-tip-reference" title="Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Quere, I., Verlingue, C. <strong>Detection of over 98% cystic fibrosis mutations in a Celtic population.</strong> Nature Genet. 1: 188-191, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284639</a>] [<a href="https://doi.org/10.1038/ng0692-188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284639">Ferec et al. (1992)</a> found a G-to-A transition at position 3331 resulting in an ala1067-to-thr substitution. The modification replaced a nonpolar residue with a polar residue. The other chromosome carried the delta-F508 mutation (<a href="#0001">602421.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0056 CYSTIC FIBROSIS</strong>
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CFTR, IVS20, G-A, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs143570767 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs143570767;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs143570767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs143570767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007580 OR RCV001004510 OR RCV001831540 OR RCV002496298 OR RCV003736536" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007580, RCV001004510, RCV001831540, RCV002496298, RCV003736536" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007580...</a>
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<span class="mim-text-font">
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<p>In a pancreatic-insufficient patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in the Celtic population of Brittany, <a href="#94" class="mim-tip-reference" title="Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Quere, I., Verlingue, C. <strong>Detection of over 98% cystic fibrosis mutations in a Celtic population.</strong> Nature Genet. 1: 188-191, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284639</a>] [<a href="https://doi.org/10.1038/ng0692-188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284639">Ferec et al. (1992)</a> identified a G-to-A mutation in the first nucleotide of the splice donor site of intron 20. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0057" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0057 CYSTIC FIBROSIS</strong>
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CFTR, 5-BP DUP, NT3320
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906366 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906366;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007581" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007581" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007581</a>
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<span class="mim-text-font">
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<p>In a pancreatic-insufficient patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in the Celtic population of Brittany, <a href="#94" class="mim-tip-reference" title="Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Quere, I., Verlingue, C. <strong>Detection of over 98% cystic fibrosis mutations in a Celtic population.</strong> Nature Genet. 1: 188-191, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284639</a>] [<a href="https://doi.org/10.1038/ng0692-188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284639">Ferec et al. (1992)</a> found duplication of 5 nucleotides (CTATG) after nucleotide 3320, creating a frameshift. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0058" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0058 CYSTIC FIBROSIS</strong>
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CFTR, ARG1066CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs78194216 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs78194216;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs78194216?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs78194216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs78194216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007582 OR RCV000723839 OR RCV001001063 OR RCV001004298 OR RCV001831541 OR RCV002496299 OR RCV003473029" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007582, RCV000723839, RCV001001063, RCV001004298, RCV001831541, RCV002496299, RCV003473029" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007582...</a>
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</span>
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<span class="mim-text-font">
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<p><a href="#94" class="mim-tip-reference" title="Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Quere, I., Verlingue, C. <strong>Detection of over 98% cystic fibrosis mutations in a Celtic population.</strong> Nature Genet. 1: 188-191, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284639</a>] [<a href="https://doi.org/10.1038/ng0692-188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284639">Ferec et al. (1992)</a> cited unpublished results of P. Fanen: a C-to-T transition at nucleotide 3328 led to an arg1066-to-cys substitution. This CpG dinucleotide is a hotspot for mutations; see <a href="#0054">602421.0054</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0059" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0059 CYSTIC FIBROSIS</strong>
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</h4>
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CFTR, 1-BP DEL, 1078T
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908744 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908744;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908744?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs75528968 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs75528968;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs75528968" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs75528968" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007583 OR RCV000079016 OR RCV001826437 OR RCV003473030" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007583, RCV000079016, RCV001826437, RCV003473030" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007583...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>See <a href="#0050">602421.0050</a>. <a href="#54" class="mim-tip-reference" title="Claustres, M., Gerrard, B., White, M. B., Desgeorges, M., Kjellberg, P., Rollin, B., Dean, M. <strong>A new mutation (1078delT) in exon 7 of the CFTR gene in a southern French adult with cystic fibrosis.</strong> Genomics 13: 907-908, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1379211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1379211</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90187-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1379211">Claustres et al. (1992)</a> found this mutation in exon 7 in a CF patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) from southern France. <a href="#200" class="mim-tip-reference" title="Romey, M.-C., Aguilar-Martinez, P., Demaille, J., Claustres, M. <strong>Rapid detection of single nucleotide deletions: application to the beta-6 (-A) mutation of the beta-globin gene and to cystic fibrosis.</strong> Hum. Genet. 92: 627-628, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8262525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8262525</a>] [<a href="https://doi.org/10.1007/BF00420951" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8262525">Romey et al. (1993)</a> described an improved procedure that allows the detection of single basepair deletions on nondenaturing polyacrylamide gels and demonstrated its applicability for identifying this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8262525+1379211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0060 VAS DEFERENS, CONGENITAL BILATERAL ABSENCE OF</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs11971167 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11971167;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs11971167?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs11971167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs11971167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007584 OR RCV000046985 OR RCV000176372 OR RCV000480239 OR RCV000587433 OR RCV001158873 OR RCV001255580 OR RCV005031410" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007584, RCV000046985, RCV000176372, RCV000480239, RCV000587433, RCV001158873, RCV001255580, RCV005031410" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007584...</a>
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<p>In a study of 25 unrelated, unselected white azoospermic men with clinically diagnosed congenital bilateral absence of the vas deferens (CBAVD; <a href="/entry/277180">277180</a>), aged 24 to 43 years, <a href="#6" class="mim-tip-reference" title="Anguiano, A., Oates, R. D., Amos, J. A., Dean, M., Gerrard, B., Stewart, C., Maher, T. A., White, M. B., Milunsky, A. <strong>Congenital bilateral absence of the vas deferens: a primarily genital form of cystic fibrosis.</strong> JAMA 267: 1794-1797, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1545465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1545465</a>]" pmid="1545465">Anguiano et al. (1992)</a> found 2 in whom there was heterozygosity for the phe508-to-del mutation (<a href="#0001">602421.0001</a>) with another rare mutation on the other chromosome. In 1 patient, of English/Italian extraction, the second mutation was a G-to-A transition resulting in substitution of asparagine for aspartic acid at amino acid 1270 (D1270N). The patient had a normal chest x-ray and sweat electrolytes well within the normal range. There were no signs of pulmonary or gastrointestinal disease and no signs of overt malabsorption. Thus, the patient had a primarily genital form of cystic fibrosis. Both this mutation and the G576A mutation (<a href="#0061">602421.0061</a>) occur within the adenosine triphosphate-binding domains of the CFTR protein. These domains are believed to play a role in the regulation of chloride transport. It is possible that the cells of the developing wolffian duct have regulatory pathways functionally associated to CFTR that are different from the lung, pancreas, or sweat duct. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1545465" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1800098 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800098;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1800098?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1800098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1800098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007585 OR RCV000029486 OR RCV000078981 OR RCV000155472 OR RCV000582695 OR RCV000584175 OR RCV001009484 OR RCV001089864 OR RCV001172493 OR RCV005031411" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007585, RCV000029486, RCV000078981, RCV000155472, RCV000582695, RCV000584175, RCV001009484, RCV001089864, RCV001172493, RCV005031411" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007585...</a>
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<p>In a man with isolated congenital bilateral absence of the vas deferens (<a href="/entry/277180">277180</a>), <a href="#6" class="mim-tip-reference" title="Anguiano, A., Oates, R. D., Amos, J. A., Dean, M., Gerrard, B., Stewart, C., Maher, T. A., White, M. B., Milunsky, A. <strong>Congenital bilateral absence of the vas deferens: a primarily genital form of cystic fibrosis.</strong> JAMA 267: 1794-1797, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1545465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1545465</a>]" pmid="1545465">Anguiano et al. (1992)</a> found compound heterozygosity for the phe508-to-del (<a href="#0001">602421.0001</a>) mutation and another rare mutation: a GGA-to-GCA transversion in codon 576 in exon 12, predicted to cause a substitution of alanine for glycine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1545465" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs75039782 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs75039782;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs75039782?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs75039782" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs75039782" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007586 OR RCV000507372 OR RCV000727872 OR RCV000763159 OR RCV001009390 OR RCV001826438 OR RCV002257359" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007586, RCV000507372, RCV000727872, RCV000763159, RCV001009390, RCV001826438, RCV002257359" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007586...</a>
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<p><a href="#1" class="mim-tip-reference" title="Abeliovich, D., Lavon, I. P., Lerer, I., Cohen, T., Springer, C., Avital, A., Cutting, G. R. <strong>Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population.</strong> Am. J. Hum. Genet. 51: 951-956, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1384328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1384328</a>]" pmid="1384328">Abeliovich et al. (1992)</a> found that among 94 Ashkenazi Jewish patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in Israel, 5 mutations accounted for 97% of mutant CFTR alleles. Four of these were delF508 (<a href="#0001">602421.0001</a>), G542X (<a href="#0009">602421.0009</a>), W1282X (<a href="#0022">602421.0022</a>), and N1303K (<a href="#0032">602421.0032</a>). The fifth, which accounted for 4% of alleles, was an unusual mutation found by <a href="#125" class="mim-tip-reference" title="Highsmith, W. E., Jr. <strong>Personal Communication.</strong> Chapel Hill, N.C. 1991."None>Highsmith (1991)</a>. Referred to as 3849+10kbC-T, it was detected by cleavage of a PCR product by HphI. <a href="#124" class="mim-tip-reference" title="Highsmith, W. E., Burch, L. H., Boat, T. F., Boucher, R. C., Silverman, L. M., Knowles, M. R. <strong>Identification of a homozygous point mutation in intron 19 in an inbred CF patient with mild disease and normal sweat chloride: creation of an alternative splice site resulting in base-sequence insertion in CFTR coding region between exons 19 and 20. (Abstract)</strong> Pediat. Pulmonol. Suppl. 6: 22A, 1991."None>Highsmith et al. (1991)</a> detected the 3849+10kbC-T mutation in a 19-year-old Pakistani woman with mild manifestations of CF and normal sweat chloride values. To explain the milder course of the disease in patients with this mutation, <a href="#124" class="mim-tip-reference" title="Highsmith, W. E., Burch, L. H., Boat, T. F., Boucher, R. C., Silverman, L. M., Knowles, M. R. <strong>Identification of a homozygous point mutation in intron 19 in an inbred CF patient with mild disease and normal sweat chloride: creation of an alternative splice site resulting in base-sequence insertion in CFTR coding region between exons 19 and 20. (Abstract)</strong> Pediat. Pulmonol. Suppl. 6: 22A, 1991."None>Highsmith et al. (1991)</a> hypothesized that the C-to-T base substitution created an alternative splice site, which resulted in insertion of 84 basepairs into the CFTR coding region. This change may cause synthesis of a protein with normal CFTR function together with a nonfunctional protein. Alternatively, this mutation might lead to production of a protein that is only partly functional and causes milder disease. In Israel, <a href="#11" class="mim-tip-reference" title="Augarten, A., Kerem, B.-S., Yahav, Y., Noiman, S., Rivlin, Y., Tal, A., Blau, H., Ben-Tur, L., Szeinberg, A., Kerem, E., Gazit, E. <strong>Mild cystic fibrosis and normal or borderline sweat test in patients with the 3849 + 10 kb C-to-T mutation.</strong> Lancet 342: 25-26, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8100293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8100293</a>] [<a href="https://doi.org/10.1016/0140-6736(93)91885-p" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8100293">Augarten et al. (1993)</a> investigated 15 patients with CF and this mutation, all Ashkenazi Jews. Their clinical features were compared with those of CF patients with mutations known to be associated with severe disease. Patients with the 3849+10kbC-T mutation were older, had been diagnosed as having CF at a more advanced age, and were in a better nutritional state. Sweat chloride values were normal in 5 of the 15 patients; 4 of these patients and 6 others had normal pancreatic function. However, age-adjusted pulmonary function did not differ between these patients and those with mutations known to cause severe disease. None of the patients with the 3849+10kbC-T mutation had had meconium ileus and none had liver disease or diabetes mellitus. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8100293+1384328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs77902683 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77902683;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs77902683?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs77902683" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs77902683" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007587 OR RCV001731145 OR RCV001831542" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007587, RCV001731145, RCV001831542" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007587...</a>
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<p>In 3 pancreatic-insufficient patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#40" class="mim-tip-reference" title="Cheadle, J. P., Meredith, A. L., Al-Jader, L. N. <strong>A new missense mutation (R1283M) in exon 20 of the cystic fibrosis transmembrane conductance regulator gene.</strong> Hum. Molec. Genet. 1: 123-125, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284468</a>] [<a href="https://doi.org/10.1093/hmg/1.2.123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284468">Cheadle et al. (1992)</a> identified a novel CFTR mutation which, like the trp1282-to-ter mutation (<a href="#0022">602421.0022</a>), abolishes an MnlII restriction site. The new mutation was found to be a G-to-T transversion at position 3980 resulting in replacement of arginine by methionine at residue 1283 (R1283M). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0064 CYSTIC FIBROSIS</strong>
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CFTR, IVS12, G-A, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908748 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908748;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908748?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007588 OR RCV000985681 OR RCV001002343 OR RCV001004273 OR RCV001027908 OR RCV002496300 OR RCV003473031" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007588, RCV000985681, RCV001002343, RCV001004273, RCV001027908, RCV002496300, RCV003473031" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007588...</a>
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<p>In 2 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#238" class="mim-tip-reference" title="Strong, T. V., Smit, L. S., Nasr, S., Wood, D. L., Cole, J. L., Iannuzzi, M. C., Stern, R. C., Collins, F. S. <strong>Characterization of an intron 12 splice donor mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Hum. Mutat. 1: 380-387, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1284540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1284540</a>] [<a href="https://doi.org/10.1002/humu.1380010506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1284540">Strong et al. (1992)</a> used chemical mismatch cleavage and subsequent DNA sequencing to identify a splice mutation at the 5-prime end of intron 12 of the CFTR gene. A G-to-A transition at position 1 of the donor-splice site resulted in skipping of exon 12. The mutation was found in compound heterozygous state with the delF508 mutation (<a href="#0001">602421.0001</a>) in a 39-year-old white male and a 9-year-old female with typical pulmonary and gastrointestinal changes of CF. Both were pancreatic insufficient. The male had a history of liver disease requiring splenorenal shunt for portal hypertension at age 14 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1284540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0065" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0065 CYSTIC FIBROSIS</strong>
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</h4>
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<div style="float: left;">
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CFTR, GLN359LYS AND THR360LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs75053309 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs75053309;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs75053309?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs75053309" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs75053309" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs76879328 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs76879328;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs76879328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs76879328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007589 OR RCV001293471 OR RCV001293472 OR RCV002247262 OR RCV002415404 OR RCV002420286" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007589, RCV001293471, RCV001293472, RCV002247262, RCV002415404, RCV002420286" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007589...</a>
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</span>
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<p><a href="#230" class="mim-tip-reference" title="Shoshani, T., Berkun, Y., Yahav, Y., Augarten, A., Bashan, N., Rivlin, Y., Gazit, E., Sereth, H., Kerem, E., Kerem, B. <strong>A new mutation in the CFTR gene, composed of two adjacent DNA alterations, is a common cause of cystic fibrosis among Georgian Jews.</strong> Genomics 15: 236-237, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7679367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7679367</a>] [<a href="https://doi.org/10.1006/geno.1993.1046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7679367">Shoshani et al. (1993)</a> found that 88% of identified cystic fibrosis (CF; <a href="/entry/219700">219700</a>) chromosomes among CF patients who were Jews from Soviet Georgia had a double mutation in adjacent codons: one alteration was a C-to-A transversion at nucleotide position 1207, changing the glutamine codon to lysine (Q359K); the second alteration was a C-to-A transversion at nucleotide position 1211, changing the threonine codon to lysine (T360K). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7679367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0066" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0066 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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CFTR, IVS6, 12-BP DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906367 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906367;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007590" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007590" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007590</a>
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</span>
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<span class="mim-text-font">
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<p>In a pancreatic-insufficient cystic fibrosis (CF; <a href="/entry/219700">219700</a>) patient, <a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> found compound heterozygosity for a delta-F508 mutation and a novel mutation which they designated 876--14 del 12 NT: a large deletion which began at position -14 of exon 6b corresponded to a loss of 12 nucleotides. Because the mutation involved a 4-bp repeat (GATT), the deletion could involve 8 nucleotides depending on the allele in which it occurred. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7683952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0067" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0067 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, ARG347LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs77932196 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77932196;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs77932196?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs77932196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs77932196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007591 OR RCV001004252 OR RCV003466829 OR RCV005031412" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007591, RCV001004252, RCV003466829, RCV005031412" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007591...</a>
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<p>In a 2-year-old girl with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) detected during a systematic neonatal screening who was up to that time symptom free and pancreatic sufficient, <a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> found a G-to-T transversion at bp 1172 changing arginine (an amino acid with a basic side chain) to leucine (bearing a nonpolar side chain) at residue 347. <a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> pointed out that 2 other mutations involving nucleotide 1172 have been observed, one leading to R347P (<a href="#0006">602421.0006</a>) and the other to R347H (<a href="#0078">602421.0078</a>). Both are associated with pancreatic sufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7683952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0068" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0068 CYSTIC FIBROSIS</strong>
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</h4>
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CFTR, ALA349VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909021 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909021;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909021?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007592 OR RCV000728852 OR RCV000780115 OR RCV001004253 OR RCV002247263 OR RCV003466830" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007592, RCV000728852, RCV000780115, RCV001004253, RCV002247263, RCV003466830" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007592...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In the course of screening the normal husband of a heterozygous woman, <a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> found a C-to-T transition at nucleotide 1178 predicting substitution of valine for alanine at residue 349. Since both of these amino acids carry a nonpolar side chain, it was not obvious that the variation would lead to a CF allele. However, this nucleotide change was not observed on more than 300 normal chromosomes screened, and alanine at position 349 is conserved in the CFTR gene of human, Xenopus, and cow. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7683952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0069" class="mim-anchor"></a>
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<strong>.0069 CYSTIC FIBROSIS</strong>
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CFTR, ALA534GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909022 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909022;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906368 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906368;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906368?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007593 OR RCV000755924 OR RCV001831543 OR RCV002482841 OR RCV003234896" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007593, RCV000755924, RCV001831543, RCV002482841, RCV003234896" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007593...</a>
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<p>In a screening of 48 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) and 12 obligate carriers, <a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> observed a C-to-T transition at nucleotide 1733 leading to substitution of glutamic acid for alanine-534 (A534E). The change is a drastic one since it replaces an acidic residue with one that is nonpolar. Observed in heterozygotes, the mutation is probably of functional significance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7683952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0070" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0070 CYSTIC FIBROSIS</strong>
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CFTR, LYS716TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909023 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909023;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007594" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007594" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007594</a>
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<p>In a screening of 48 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) and 12 obligate carriers, <a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> found an A-to-T transversion at nucleotide 2278 resulting in a stop codon at lysine-716. The mutation was detected in the heterozygous father of a deceased child; no clinical data were available. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7683952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0071" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0071 CYSTIC FIBROSIS</strong>
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CFTR, IVS13, G-A, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs141158996 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs141158996;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs141158996?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs141158996" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs141158996" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007595 OR RCV001509317 OR RCV001826439 OR RCV005031413" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007595, RCV001509317, RCV001826439, RCV005031413" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007595...</a>
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<p>In a 2-year-old child with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) who carried the delta-F508 mutation (<a href="#0001">602421.0001</a>) and manifested classic symptoms of CF, namely, pancreatic insufficiency and pulmonary disease, <a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> detected on the other chromosome a G-to-A transition in the first nucleotide in the 5-prime splice site of intron 13. <a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> referred to this mutation as 2622 +1 G-to-A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7683952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0072" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0072 CYSTIC FIBROSIS</strong>
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CFTR, GLN1238TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908766 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908766;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908766?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007596" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007596" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007596</a>
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<span class="mim-text-font">
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<p>In a patient with classic pancreatic-insufficient CF (CF; <a href="/entry/219700">219700</a>), <a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> found a C-to-T transition at nucleotide 3844 creating a stop codon (TAG) in place of glutamine (CAG). The other chromosome carried the G542X mutation (<a href="#0009">602421.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7683952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0073" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0073 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, IVS19, G-A, -1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906369 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906369;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007597 OR RCV001831544 OR RCV003996079" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007597, RCV001831544, RCV003996079" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007597...</a>
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</span>
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<div>
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<p>In 3 children with classic cystic fibrosis (CF; <a href="/entry/219700">219700</a>), all with pancreatic insufficiency, <a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> observed a G-to-A transition at nucleotide -1 of intron 19, involving the splice acceptor site (3850, -1, G-to-A). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7683952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0074 CYSTIC FIBROSIS</strong>
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CFTR, 1-BP INS, 3898C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906370 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906370;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906370?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007598" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007598" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007598</a>
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<p>In a severely affected, pancreatic-insufficient, 20-year-old patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> found insertion of a C after nucleotide 3898 resulting in frameshift. The other chromosome carried the R1162X mutation (<a href="#0033">602421.0033</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7683952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0075" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0075 CYSTIC FIBROSIS</strong>
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CFTR, TRP57TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909025 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909025;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007599 OR RCV001826440" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007599, RCV001826440" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007599...</a>
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</span>
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<span class="mim-text-font">
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<p>In 2 patients with pancreatic-insufficient cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> found compound heterozygosity for a G-to-A transition at nucleotide 302 in exon 3 converting codon 57 from TGG (trp) to TGA (stop). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7683952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0076" class="mim-anchor"></a>
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<strong>.0076 CYSTIC FIBROSIS</strong>
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CFTR, GLN1313TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909026 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909026;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909026?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007600 OR RCV001826441 OR RCV003473032" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007600, RCV001826441, RCV003473032" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007600...</a>
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</span>
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<span class="mim-text-font">
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<p>In a severely affected, pancreatic-insufficient patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> found homozygosity for a C-to-T transition at nucleotide 4069 in exon 21 converting gln1313 to a stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7683952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0077" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0077 CYSTIC FIBROSIS</strong>
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</h4>
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CFTR, GLU92LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908751 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908751;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908751?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007601 OR RCV001009395 OR RCV001093484 OR RCV001831545 OR RCV003473033" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007601, RCV001009395, RCV001093484, RCV001831545, RCV003473033" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007601...</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a Spanish patient with mild cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#172" class="mim-tip-reference" title="Nunes, V., Chillon, M., Dork, T., Tummler, B., Casals, T., Estivill, X. <strong>A new missense mutation (E92K) in the first transmembrane domain of the CFTR gene causes a benign cystic fibrosis phenotype.</strong> Hum. Molec. Genet. 2: 79-80, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683954</a>] [<a href="https://doi.org/10.1093/hmg/2.1.79" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683954">Nunes et al. (1993)</a> found a G-to-A transition at nucleotide 406 resulting in a change of codon 92 in exon 4 from glutamic acid to lysine. The same mutation was found in homozygous state in a Turkish patient with consanguineous parents living in Germany. Both patients were pancreatic sufficient and had normal fat excretion. In both cases physical activity led rapidly to excessive sweating and fatigue; the mother of the Turkish boy reported that after 1 hour of sports the boy's skin and hair became covered with a white salty crust which required 2 or 3 showers to remove. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7683954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<div>
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<a id="0078" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0078 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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CFTR, ARG347HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs77932196 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77932196;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs77932196?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs77932196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs77932196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007602 OR RCV000224726 OR RCV000508504 OR RCV001004250 OR RCV001009366 OR RCV001027909 OR RCV003473034 OR RCV005042005" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007602, RCV000224726, RCV000508504, RCV001004250, RCV001009366, RCV001027909, RCV003473034, RCV005042005" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007602...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p><a href="#8" class="mim-tip-reference" title="Audrezet, M. P., Mercier, B., Guillermit, H., Quere, I., Verlingue, C., Rault, G., Ferec, C. <strong>Identification of 12 novel mutations in the CFTR gene.</strong> Hum. Molec. Genet. 2: 51-54, 1993. Note: Erratum: Hum. Molec. Genet. 2: 496 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7683952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7683952</a>] [<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7683952">Audrezet et al. (1993)</a> referred to an R347H mutation causing pancreatic-sufficient cystic fibrosis (CF; <a href="/entry/219700">219700</a>). This is 1 of 3 mutations that involve nucleotide 1172, the others being R347P (<a href="#0006">602421.0006</a>) and R347L (<a href="#0067">602421.0067</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7683952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0079 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908750 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908750;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908750?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007603 OR RCV001831546 OR RCV004566691" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007603, RCV001831546, RCV004566691" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007603...</a>
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<p>In a study of 87 non-delF508 chromosomes of Breton origin, <a href="#117" class="mim-tip-reference" title="Guillermit, H., Jehanne, M., Quere, I., Audrezet, M. P., Mercier, B., Ferec, C. <strong>A novel mutation in exon 3 of the CFTR gene.</strong> Hum. Genet. 91: 233-235, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7682984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7682984</a>] [<a href="https://doi.org/10.1007/BF00218262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7682984">Guillermit et al. (1993)</a> found a G91R mutation in 3 pancreatic-sufficient cystic fibrosis patients (CF; <a href="/entry/219700">219700</a>). The 3 patients were compound heterozygous for the G91R mutation and delF508 (<a href="#0001">602421.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7682984" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0080 CYSTIC FIBROSIS</strong>
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CFTR, PHE1286SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909028 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909028;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007604" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007604" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007604</a>
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<p>In an analysis of 160 cystic fibrosis (CF; <a href="/entry/219700">219700</a>) chromosomes, <a href="#84" class="mim-tip-reference" title="Dorval, I., Odent, S., Jezequel, P., Journel, H., Chauvel, B., Dabadie, A., Roussey, M., Le Gall, J. Y., Le Marec, B., David, V., Blayau, M. <strong>Analysis of 160 CF chromosomes: detection of a novel mutation in exon 20.</strong> Hum. Genet. 91: 254-256, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8097485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8097485</a>] [<a href="https://doi.org/10.1007/BF00218266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8097485">Dorval et al. (1993)</a> detected an F1286S mutation in exon 20 of the CFTR gene using denaturing gel electrophoresis followed by direct sequencing of the PCR products. A T-to-C transition at nucleotide 3989 was responsible for the change from phenylalanine to serine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8097485" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0081 CYSTIC FIBROSIS</strong>
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CFTR, 1-BP INS, 2307A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908787 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908787;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs746418935 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs746418935;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs746418935?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs746418935" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs746418935" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007605 OR RCV000727574 OR RCV000781235 OR RCV001004471 OR RCV001826442 OR RCV003473035" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007605, RCV000727574, RCV000781235, RCV001004471, RCV001826442, RCV003473035" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007605...</a>
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<p>By chemical mismatch cleavage in an African American patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#233" class="mim-tip-reference" title="Smit, L. S., Nasr, S. Z., Iannuzzi, M. C., Collins, F. S. <strong>An African-American cystic fibrosis patient homozygous for a novel frameshift mutation associated with reduced CFTR mRNA levels.</strong> Hum. Mutat. 2: 148-151, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7686423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7686423</a>] [<a href="https://doi.org/10.1002/humu.1380020217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7686423">Smit et al. (1993)</a> found homozygosity for insertion of an adenine after nucleotide 2307 in exon 13. The resulting shift of the reading frame at codon 726 introduced 2 consecutive stop codons at amino acid positions 729 and 730. To examine the mRNA level associated with the 2307insA mutation, RNA from nasal epithelial cells of the patient and a normal subject were reverse transcribed. Subsequent amplification of the cDNA demonstrated that the CFTR message level associated with 2307insA was markedly reduced compared to the normal control, while both the patient and the normal subject showed similar levels of expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7686423" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0082" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0082 CYSTIC FIBROSIS</strong>
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CFTR, GLU92TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908751 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908751;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908751?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007606 OR RCV001004423 OR RCV001009515 OR RCV001826443 OR RCV003473036" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007606, RCV001004423, RCV001009515, RCV001826443, RCV003473036" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007606...</a>
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<p>In each of 4 German patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#274" class="mim-tip-reference" title="Will, K., Dork, T., Stuhrmann, M., Meitinger, T., Bertele-Harms, R., Tummler, B., Schmidtke, J. <strong>A novel exon in the cystic fibrosis transmembrane conductance regulator gene activated by the nonsense mutation E92X in airway epithelial cells of patients with cystic fibrosis.</strong> J. Clin. Invest. 93: 1852-1859, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7512993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7512993</a>] [<a href="https://doi.org/10.1172/JCI117172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7512993">Will et al. (1994)</a> found a G-to-T transversion that affected the first base of exon 4 and created a termination codon glu92-to-ter. Lymphocyte RNA of patients heterozygous for the E92X mutation were found to contain the wildtype sequence and a differentially spliced isoform lacking exon 4. On the other hand, RNA derived from nasal epithelial cells of these patients showed a third fragment of longer length. Sequencing revealed the presence of E92X and an additional 183-bp fragment, inserted between exons 3 and 4. The 183-bp sequence was mapped to intron 3 of the CFTR gene. It was flanked by acceptor and donor splice sites. <a href="#274" class="mim-tip-reference" title="Will, K., Dork, T., Stuhrmann, M., Meitinger, T., Bertele-Harms, R., Tummler, B., Schmidtke, J. <strong>A novel exon in the cystic fibrosis transmembrane conductance regulator gene activated by the nonsense mutation E92X in airway epithelial cells of patients with cystic fibrosis.</strong> J. Clin. Invest. 93: 1852-1859, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7512993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7512993</a>] [<a href="https://doi.org/10.1172/JCI117172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7512993">Will et al. (1994)</a> concluded that the 183-bp fragment in intron 3 is a cryptic CFTR exon that can be activated in epithelial cells by the presence of the E92X mutation. E92X abolishes correctly spliced CFTR mRNA and leads to severe cystic fibrosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7512993" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0083" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0083 CYSTIC FIBROSIS</strong>
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CFTR, GLY480CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs79282516 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs79282516;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs79282516?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs79282516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs79282516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a pancreatic-insufficient African American CF (CF; <a href="/entry/219700">219700</a>) patient, <a href="#234" class="mim-tip-reference" title="Smit, L. S., Strong, T. V., Wilkinson, D. J., Macek, M., Jr., Mansoura, M. K., Wood, D. L., Cole, J. L., Cutting, G. R., Cohn, J. A., Dawson, D. C., Collins, F. S. <strong>Missense mutation (G480C) in the CFTR gene associated with protein mislocalization but normal chloride channel activity.</strong> Hum. Molec. Genet. 4: 269-273, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7757078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7757078</a>] [<a href="https://doi.org/10.1093/hmg/4.2.269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7757078">Smit et al. (1995)</a> found a novel CFTR missense mutation associated with a protein trafficking defect in mammalian cells but normal chloride channel properties in a Xenopus oocyte assay. The mutation resulted in substitution of a cysteine for glycine at residue 480. In mammalian cells, the encoded mutant protein was not fully glycosylated and failed to reach the plasma membrane, suggesting that the G480C protein was subject to defective intracellular processing. However, in Xenopus oocytes, a system in which mutant CFTR proteins are less likely to experience an intracellular processing/trafficking deficit, expression of G480C CFTR was associated with a chloride conductance that exhibited a sensitivity to activation by forskolin and 3-isobutyl-1-methylxanthine (IBMX) that was similar to that of wildtype CFTR. This appeared to be the first identification of a CFTR mutant in which the sole basis for disease was mislocation of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7757078" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908752 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908752;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908752?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908752" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908752" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007611 OR RCV000079011 OR RCV000660772 OR RCV000763156 OR RCV001004443 OR RCV001009388 OR RCV001831547 OR RCV003473037" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007611, RCV000079011, RCV000660772, RCV000763156, RCV001004443, RCV001009388, RCV001831547, RCV003473037" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007611...</a>
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<p>The leu206-to-trp (L206W) mutation of the CFTR gene was first identified in 3 cystic fibrosis (CF; <a href="/entry/219700">219700</a>) patients from South France (<a href="#55" class="mim-tip-reference" title="Claustres, M., Laussel, M., Desgeorges, M., Giansily, M., Culard, J.-F., Razakatsara, G., Demaille, J. <strong>Analysis of the 27 exons and flanking regions of the cystic fibrosis gene: 40 different mutations account for 91.2% of the mutant alleles in Southern France.</strong> Hum. Molec. Genet. 2: 1209-1213, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7691344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7691344</a>] [<a href="https://doi.org/10.1093/hmg/2.8.1209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7691344">Claustres et al., 1993</a>). <a href="#210" class="mim-tip-reference" title="Rozen, R., Ferreira-Rajabi, L., Robb, L., Colman, N. <strong>L206W mutation of the cystic fibrosis gene, relatively frequent in French Canadians, is associated with atypical presentations of cystic fibrosis.</strong> Am. J. Med. Genet. 57: 437-439, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7545869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7545869</a>] [<a href="https://doi.org/10.1002/ajmg.1320570314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7545869">Rozen et al. (1995)</a> reported that it is relatively frequent in French Canadians from Quebec. On the basis of findings in 7 French Canadian probands, they suggested that this mutation is likely to be present in patients with atypical forms of CF and may be present in otherwise healthy men and women with infertility. Their group contained 47-year-old and 48-year-old sisters and their 30-year-old brother. The women were thought to have reduced fertility and the man had absence of the vas deferentia. The man and 1 sister had normal pulmonary function and high-resolution CT scan of the chest. The 47-year-old sister had had left upper lobectomy for presumed bronchiectasis at the age of 20 years and had had frequent pulmonary infections but had surprisingly well-preserved lung function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7691344+7545869" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Clain, J., Lehmann-Che, J., Dugueperoux, I., Arous, N., Girodon, E., Legendre, M., Goossens, M., Edelman, A., de Braekeleer, M., Teulon, J., Fanen, P. <strong>Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype.</strong> Hum. Mutat. 25: 360-371, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15776432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15776432</a>] [<a href="https://doi.org/10.1002/humu.20156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15776432">Clain et al. (2005)</a> noted that the L206W mutation can result in variable disease phenotypes. Individuals bearing this mutation in trans with the severe CF-causing mutation F508del (<a href="#0001">602421.0001</a>) may have CF or isolated congenital bilateral absence of the vas deferens (<a href="/entry/277180">277180</a>). <a href="#52" class="mim-tip-reference" title="Clain, J., Lehmann-Che, J., Dugueperoux, I., Arous, N., Girodon, E., Legendre, M., Goossens, M., Edelman, A., de Braekeleer, M., Teulon, J., Fanen, P. <strong>Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype.</strong> Hum. Mutat. 25: 360-371, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15776432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15776432</a>] [<a href="https://doi.org/10.1002/humu.20156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15776432">Clain et al. (2005)</a> studied the effect of the L206W mutation on CFTR protein production and function and examined the genotype-phenotype correlation of L206W/F508del compound heterozygote patients. They showed that L206W is a processing (class II) mutation, as the CFTR biosynthetic pathway was severely impaired, whereas single-channel measurements indicated ion conductance similar to the wildtype protein. These data raised the larger question of the phenotypic variability of class II mutants, including F508del. <a href="#52" class="mim-tip-reference" title="Clain, J., Lehmann-Che, J., Dugueperoux, I., Arous, N., Girodon, E., Legendre, M., Goossens, M., Edelman, A., de Braekeleer, M., Teulon, J., Fanen, P. <strong>Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype.</strong> Hum. Mutat. 25: 360-371, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15776432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15776432</a>] [<a href="https://doi.org/10.1002/humu.20156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15776432">Clain et al. (2005)</a> concluded that since multiple potential properties could modify the processing of the CFTR protein during its course to the cell surface, environmental and other genetic factors might contribute to this variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15776432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906371 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906371;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007608" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007608" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007608</a>
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<p><a href="#251" class="mim-tip-reference" title="Varon, R., Magdorf, K., Staab, D., Wahn, H.-U., Krawczak, M., Sperling, K., Reis, A. <strong>Recurrent nasal polyps as a monosymptomatic form of cystic fibrosis associated with a novel in-frame deletion (591del18) in the CFTR gene.</strong> Hum. Molec. Genet. 4: 1463-1464, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581390</a>] [<a href="https://doi.org/10.1093/hmg/4.8.1463" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581390">Varon et al. (1995)</a> described recurrent nasal polyps as a monosymptomatic form of cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in association with a novel in-frame mutation, deletion of 18 bp in exon 4 of the CFTR gene. Since the deletion started with nucleotide 591 of their cDNA clone, the mutation was symbolized 591del18. It was found in male twins of Turkish origin. The twins inherited the 591del18 mutation from their mother. On the paternal allele, they carried the nonsense mutation glu831-to-ter (<a href="#255" class="mim-tip-reference" title="Verlingue, C., Mercier, B., Lecoq, I., Audrezet, M. P., Laroche, D., Travert, G., Ferec, C. <strong>Retrospective study of the cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Guthrie cards from a large cohort of neonatal screening for cystic fibrosis.</strong> Hum. Genet. 93: 429-434, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7513292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7513292</a>] [<a href="https://doi.org/10.1007/BF00201669" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7513292">Verlingue et al., 1994</a>). The patients had been diagnosed as having CF at the age of 10 years due to persistent nasal polyps and elevated sweat electrolytes. Nasal polyps had been surgically removed on 4 occasions. The neonatal period and early infancy were completely uneventful. They were pancreatic sufficient and had no lung disease or other CF-related problems. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7513292+7581390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Burger, J., Macek, M., Jr., Stuhrmann, M., Reis, A., Krawczak, M., Schmidtke, J. <strong>Genetic influences in the formation of nasal polyps. (Letter)</strong> Lancet 337: 974, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1678049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1678049</a>] [<a href="https://doi.org/10.1016/0140-6736(91)91603-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1678049">Burger et al. (1991)</a> suggested that heterozygosity for the G551D mutation (<a href="#0013">602421.0013</a>) is a causative factor in recurrent nasal polyps. Presentation with a nasal polyp was the basis of the diagnosis of cystic fibrosis in an 11-year-old boy of Iranian extraction in whom <a href="#33" class="mim-tip-reference" title="Chalkley, G., Harris, A. <strong>A cystic fibrosis patient who is homozygous for the G85E mutation has very mild disease.</strong> J. Med. Genet. 28: 875-877, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1757965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1757965</a>] [<a href="https://doi.org/10.1136/jmg.28.12.875" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1757965">Chalkley and Harris (1991)</a> found homozygosity for a gly85-to-glu mutation (<a href="#0038">602421.0038</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1678049+1757965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1805177 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1805177;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1805177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1805177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007609 OR RCV000007610 OR RCV000155619 OR RCV000173692 OR RCV000190992 OR RCV000405075 OR RCV001009378 OR RCV001010359 OR RCV001706280 OR RCV002243923 OR RCV003330602 OR RCV003483594" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007609, RCV000007610, RCV000155619, RCV000173692, RCV000190992, RCV000405075, RCV001009378, RCV001010359, RCV001706280, RCV002243923, RCV003330602, RCV003483594" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007609...</a>
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<p><a href="#288" class="mim-tip-reference" title="Zielenski, J., Patrizio, P., Corey, M., Handelin, B., Markiewicz, D., Asch, R., Tsui, L.-C. <strong>CFTR gene variant for patients with congenital absence of vas deferens. (Letter)</strong> Am. J. Hum. Genet. 57: 958-960, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7573058/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7573058</a>]" pmid="7573058">Zielenski et al. (1995)</a> estimated that CBAVD (<a href="/entry/277180">277180</a>) is associated with the 5T variant at the 3-prime end of intron 8 of the CFTR gene with a penetrance of 0.60 in males. <a href="#50" class="mim-tip-reference" title="Chu, C.-S., Trapnell, B. C., Curristin, S., Cutting, G. R., Crystal, R. G. <strong>Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA.</strong> Nature Genet. 3: 151-156, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7684646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7684646</a>] [<a href="https://doi.org/10.1038/ng0293-151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7684646">Chu et al. (1993)</a> noted varied lengths of a thymidine (T)-tract (5, 7, or 9T) in front of the splice-acceptor site of intron 8. The length appeared to correlate with the efficiency of exon 9 splicing, with the 5T variant that is present in 5% of the CFTR alleles among the Caucasian population producing almost exclusively (95%) exon 9-minus mRNA. The effect of this T-tract polymorphism in CFTR gene expression was also documented by its relationship with the CF mutation R117H (<a href="#0005">602421.0005</a>): while R117H (5T) is found in typical CF patients with pancreatic sufficiency, R117H (7T) is associated with CBAVD (<a href="#142" class="mim-tip-reference" title="Kiesewetter, S., Macek, M., Jr., Davis, C., Curristin, S. M., Chu, C.-S., Graham, C., Shrimpton, A. E., Cashman, S. M., Tsui, L.-C., Mickle, J., Amos, J., Highsmith, W. E., Shuber, A., Witt, D. R., Crystal, R. G., Cutting, G. R. <strong>A mutation in CFTR produces different phenotypes depending on chromosomal background.</strong> Nature Genet. 5: 274-278, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7506096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7506096</a>] [<a href="https://doi.org/10.1038/ng1193-274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7506096">Kiesewetter et al., 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7573058+7506096+7684646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#58" class="mim-tip-reference" title="Costes, B., Girodon, E., Ghanem, N., Flori, E., Jardin, A., Soufir, J. C., Goossens, M. <strong>Frequent occurrence of the CFTR intron 8 (TG)n 5T allele in men with congenital bilateral absence of the vas deferens.</strong> Europ. J. Hum. Genet. 3: 285-293, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8556303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8556303</a>] [<a href="https://doi.org/10.1159/000472312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8556303">Costes et al. (1995)</a> studied the CFTR gene in 45 azoospermic individuals with isolated CBAVD. They detected a CFTR gene defect in 86% of chromosomes from these subjects. In addition to identifying 9 novel CFTR gene mutations, they found that 84% of men with CBAVD who were heterozygous for a CF mutation carried the intron 8 polypyrimidine 5T CFTR allele on 1 chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8556303" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#68" class="mim-tip-reference" title="de Meeus, A., Guittard, C., Desgeorges, M., Carles, S., Demaille, J., Claustres, M. <strong>Linkage disequilibrium between the M470V variant and the IVS8 polyT alleles of the CFTR gene in CBAVD.</strong> J. Med. Genet. 35: 594-596, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9678705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9678705</a>] [<a href="https://doi.org/10.1136/jmg.35.7.594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9678705">De Meeus et al. (1998)</a> found linkage disequilibrium between the 5T allele and the val allele of the met470-to-val polymorphism (<a href="#0023">602421.0023</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9678705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#115" class="mim-tip-reference" title="Groman, J. D., Hefferon, T. W., Casals, T., Bassas, L., Estivill, X., Georges, M. D., Guittard, C., Koudova, M., Fallin, M. D., Nemeth, K., Fekete, G., Kadasi, L., and 15 others. <strong>Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.</strong> Am. J. Hum. Genet. 74: 176-179, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14685937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14685937</a>] [<a href="https://doi.org/10.1086/381001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14685937">Groman et al. (2004)</a> demonstrated that the number of TG repeats adjacent to 5T influences disease penetrance. They determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. They found that those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats. Thus, determination of TG repeat number will allows for more accurate prediction of benign versus pathogenic 5T alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14685937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The TG repeat located at the splice acceptor site of exon 9 of the CFTR gene is an example of a variable dinucleotide repeat that affects splicing. Higher repeat numbers result in reduced exon 9 splicing efficiency and, in some instances, the reduction in full-length transcript is sufficient to cause male infertility due to congenital bilateral absence of the vas deferens or nonclassic cystic fibrosis. Using a CFTR minigene system, <a href="#123" class="mim-tip-reference" title="Hefferon, T. W., Groman, J. D., Yurk, C. E., Cutting, G. R. <strong>A variable dinucleotide repeat in the CFTR gene contributes to phenotype diversity by forming RNA secondary structures that alter splicing.</strong> Proc. Nat. Acad. Sci. 101: 3504-3509, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14993601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14993601</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14993601[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0400182101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14993601">Hefferon et al. (2004)</a> studied TG tract variation and observed the same correlation between dinucleotide repeat number and exon 9 splicing efficiency seen in vivo. Replacement of the TG dinucleotide tract in the minigene with random sequence abolished splicing of exon 9. Replacements of the TG tract with sequences that can self-basepair suggested that the formation of an RNA secondary structure was associated with efficient splicing. However, splicing efficiency was inversely correlated with the predicted thermodynamic stability of such structures, demonstrating that intermediate stability was optimal. Finally, substitution of TA repeats of differing lengths confirmed that stability of the RNA secondary structure, not sequence content, correlated with splicing efficiency. Taken together, these data indicated that dinucleotide repeats can form secondary structures that have variable effects on RNA splicing efficiency and clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14993601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 66-year-old woman and an unrelated 67-year-old man with idiopathic bronchiectasis (BESC1; <a href="/entry/211400">211400</a>), who were heterozygous for the 5T CFTR variant, <a href="#92" class="mim-tip-reference" title="Fajac, I., Viel, M., Sublemontier, S., Hubert, D., Bienvenu, T. <strong>Could a defective epithelial sodium channel lead to bronchiectasis.</strong> Respir. Res. 9: 46, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18507830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18507830</a>] [<a href="https://doi.org/10.1186/1465-9921-9-46" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18507830">Fajac et al. (2008)</a> also identified heterozygosity for a missense mutation in the SCNN1B gene (<a href="/entry/600760#0015">600760.0015</a>). The woman had a borderline elevated sweat chloride, normal nasal potential difference (PD), and FEV1 that was 77% of predicted. The man had normal sweat chloride and nasal PD, and FEV1 that was 80% of predicted. <a href="#92" class="mim-tip-reference" title="Fajac, I., Viel, M., Sublemontier, S., Hubert, D., Bienvenu, T. <strong>Could a defective epithelial sodium channel lead to bronchiectasis.</strong> Respir. Res. 9: 46, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18507830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18507830</a>] [<a href="https://doi.org/10.1186/1465-9921-9-46" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18507830">Fajac et al. (2008)</a> concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18507830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs77409459 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77409459;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs77409459?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs77409459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs77409459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007614 OR RCV000506655 OR RCV001009472 OR RCV001269654 OR RCV003473038 OR RCV005042006" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007614, RCV000506655, RCV001009472, RCV001269654, RCV003473038, RCV005042006" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007614...</a>
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<p>In all 8 children of Sardinian descent seen because of hypotonic dehydration associated with hyponatremia, hypochloremia, hypokalemia, and metabolic alkalosis, <a href="#153" class="mim-tip-reference" title="Leoni, G., Pitzalis, S., Podda, R., Zanda, M., Silvetti, M., Caocci, L., Cao, A., Rosatelli, M. C. <strong>A specific cystic fibrosis mutation (T338I) associated with the phenotype of isolated hypotonic dehydration.</strong> J. Pediat. 127: 281-283, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7543567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7543567</a>] [<a href="https://doi.org/10.1016/s0022-3476(95)70310-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7543567">Leoni et al. (1995)</a> found a T338I mutation either in homozygosity or compound heterozygosity with another CF mutation. None had pulmonary or pancreatic involvement. The T338I mutation was not detected in patients with CF who had classic symptoms or in healthy persons of the same descent. Their data suggested that the T338I mutation is associated with a specific mild cystic fibrosis (CF; <a href="/entry/219700">219700</a>) phenotype. The patients were seen at ages varying between 2 months and 7 years of age. Three of the patients had failed to thrive. The sweat chloride concentration was high in all patients but 1, who at 3 months of age had borderline values. All the patients had normal steatocrit values for their age, and none of them required pancreatic enzyme supplements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7543567" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs78802634 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs78802634;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs78802634?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs78802634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs78802634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 of 138 alleles in Jewish patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#229" class="mim-tip-reference" title="Shoshani, T., Augarten, A., Yahav, J., Gazit, E., Kerem, B. <strong>Two novel mutations in the CFTR gene: W1089X in exon 17B and 4010delTATT in exon 21.</strong> Hum. Molec. Genet. 3: 657-658, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7520798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7520798</a>] [<a href="https://doi.org/10.1093/hmg/3.4.657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7520798">Shoshani et al. (1994)</a> identified a G-to-A transition at nucleotide 3398 of exon 17b of the CFTR gene. This substitution results in a termination codon (TAG) instead of tryptophan at residue 1089. Both mutant chromosomes carry the same extra- and intragenic haplotype, A112. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7520798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906373 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906373;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000047015 OR RCV001831781 OR RCV003474594 OR RCV004998162 OR RCV005031516" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000047015, RCV001831781, RCV003474594, RCV004998162, RCV005031516" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000047015...</a>
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<p>In a patient of Arab origin with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#229" class="mim-tip-reference" title="Shoshani, T., Augarten, A., Yahav, J., Gazit, E., Kerem, B. <strong>Two novel mutations in the CFTR gene: W1089X in exon 17B and 4010delTATT in exon 21.</strong> Hum. Molec. Genet. 3: 657-658, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7520798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7520798</a>] [<a href="https://doi.org/10.1093/hmg/3.4.657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7520798">Shoshani et al. (1994)</a> detected a 4-bp deletion in the CFTR gene, TATT, at position 4010 of the coding sequence using direct sequencing of exon 21. This frameshift mutation is expected to create a termination codon (TAG) 34 amino acids downstream of the mutation. This alteration is likely to be a disease-causing mutation since it is predicted to create a truncated polypeptide that lacks the second ATP binding domain. The patient inherited this deletion from her father. The CFTR chromosome carries the D121 haplotype. Her other CFTR chromosome has the asn1303-to-lys mutation (<a href="#0032">602421.0032</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7520798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0090 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs75789129 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs75789129;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs75789129?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs75789129" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs75789129" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007617 OR RCV000046398 OR RCV000174251 OR RCV001009505" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007617, RCV000046398, RCV000174251, RCV001009505" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007617...</a>
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<p>This variant, formerly titled CYSTIC FIBROSIS, has been reclassified based on a review of the gnomAD database by <a href="#121" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 5/3/2018."None>Hamosh (2018)</a>.</p><p>In a study of 224 non-F508del cystic fibrosis (CF; <a href="/entry/219700">219700</a>) chromosomes, <a href="#103" class="mim-tip-reference" title="Ghanem, N., Costes, B., Girodon, E., Martin, J., Fanen, P., Goossens, M. <strong>Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Genomics 21: 434-436, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7522211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7522211</a>] [<a href="https://doi.org/10.1006/geno.1994.1290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7522211">Ghanem et al. (1994)</a> identified a C-to-T substitution at nucleotide 223, changing arginine to cysteine at position 31, in a French couple with cystic fibrosis and one affected child. Since their apparently unaffected 6-year-old child was found to be homozygous for this mutation, it is probably a polymorphism. The father and the affected child had another substitution changing an isoleucine-556 to valine in exon 11. This mutation can be detected by restriction analysis since it abolishes a HhaI recognition sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7522211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#121" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 5/3/2018."None>Hamosh (2018)</a> found that the I556V variant was present in heterozygous state in 914 of 276,478 alleles and in 28 homozygotes in the gnomAD database, with an allelic frequency of 0.0033 (May 3, 2018).</p>
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<strong>.0091 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909031 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909031;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007618 OR RCV003473040" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007618, RCV003473040" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007618...</a>
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<p>In a 16-year-old girl with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) diagnosed at age 9 months who has remained pancreatic-sufficient, <a href="#219" class="mim-tip-reference" title="Schaedel, C., Kristoffersson, A.-C., Kornfalt, R., Holmberg, L. <strong>A novel cystic fibrosis mutation, Y109C, in the first transmembrane domain of CFTR.</strong> Hum. Molec. Genet. 3: 1001-1002, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7524909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7524909</a>] [<a href="https://doi.org/10.1093/hmg/3.6.1001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7524909">Schaedel et al. (1994)</a> identified an A-to-G substitution at nucleotide 458 in exon 4 of the CFTR gene, converting tyrosine-109 to cysteine (Y109C). Her second mutation was 3659delC (<a href="#0020">602421.0020</a>) in exon 19. The 3659delC mutation is associated with the pancreatic insufficiency phenotype. The authors concluded that tyr109-to-cys is the mutation conferring pancreatic sufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7524909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0092" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0092 CYSTIC FIBROSIS</strong>
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CFTR, ARG352GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908753 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908753;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908753?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007619 OR RCV000660773 OR RCV000763568 OR RCV000985669 OR RCV001004254 OR RCV001826444 OR RCV003473041" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007619, RCV000660773, RCV000763568, RCV000985669, RCV001004254, RCV001826444, RCV003473041" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007619...</a>
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<p>In a systematic study of 133 cystic fibrosis (CF; <a href="/entry/219700">219700</a>) patients in northern Italy, <a href="#100" class="mim-tip-reference" title="Gasparini, P., Marigo, C., Bisceglia, G., Nicolis, E., Zelante, L., Bombieri, C., Borgo, G., Pignatti, P. F., Cabrini, G. <strong>Screening of 62 mutations in the cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes.</strong> Hum. Mutat. 2: 389-394, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7504969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7504969</a>] [<a href="https://doi.org/10.1002/humu.1380020511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7504969">Gasparini et al. (1993)</a> identified an arg352-to-glu mutation in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7504969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0093" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0093 CYSTIC FIBROSIS</strong>
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CFTR, IVS3, A-G, +4
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906374 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906374;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906374?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906374" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906374" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007620 OR RCV001753408 OR RCV001831548 OR RCV002281699" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007620, RCV001753408, RCV001831548, RCV002281699" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007620...</a>
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<p><a href="#103" class="mim-tip-reference" title="Ghanem, N., Costes, B., Girodon, E., Martin, J., Fanen, P., Goossens, M. <strong>Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Genomics 21: 434-436, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7522211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7522211</a>] [<a href="https://doi.org/10.1006/geno.1994.1290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7522211">Ghanem et al. (1994)</a> identified an A-to-G substitution at the fourth nucleotide of the donor splice site of intron 3. It is not known if this mutation is drastic enough to cause aberrant splicing. It could simply be sufficient for a cryptic splice site to be used. This mutation was found on the maternal cystic fibrosis (CF; <a href="/entry/219700">219700</a>) chromosome in an African family originating from Cameroon. The CF-affected child, a 9-year-old girl, had no pancreatic insufficiency and no serious lung disease, but suffered from asthma. The sweat chloride was elevated (90 to 110 mmol per liter). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7522211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0094" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0094 CYSTIC FIBROSIS</strong>
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CFTR, GLN524HIS
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007612" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007612" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007612</a>
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<p>In a systematic study of 133 cystic fibrosis (CF; <a href="/entry/219700">219700</a>) individuals in northern Italy, <a href="#100" class="mim-tip-reference" title="Gasparini, P., Marigo, C., Bisceglia, G., Nicolis, E., Zelante, L., Bombieri, C., Borgo, G., Pignatti, P. F., Cabrini, G. <strong>Screening of 62 mutations in the cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes.</strong> Hum. Mutat. 2: 389-394, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7504969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7504969</a>] [<a href="https://doi.org/10.1002/humu.1380020511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7504969">Gasparini et al. (1993)</a> identified a gln524-to-his (Q524H) mutation in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7504969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0095" class="mim-anchor"></a>
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<strong>.0095 CYSTIC FIBROSIS</strong>
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CFTR, GLY542TER
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007535 OR RCV000058931 OR RCV000119041 OR RCV000763572 OR RCV001004463 OR RCV001826428 OR RCV003473006" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007535, RCV000058931, RCV000119041, RCV000763572, RCV001004463, RCV001826428, RCV003473006" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007535...</a>
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<span class="mim-text-font">
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<p>In a systematic study of 133 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in northern Italy, <a href="#100" class="mim-tip-reference" title="Gasparini, P., Marigo, C., Bisceglia, G., Nicolis, E., Zelante, L., Bombieri, C., Borgo, G., Pignatti, P. F., Cabrini, G. <strong>Screening of 62 mutations in the cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes.</strong> Hum. Mutat. 2: 389-394, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7504969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7504969</a>] [<a href="https://doi.org/10.1002/humu.1380020511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7504969">Gasparini et al. (1993)</a> found a point mutation creating a stop codon in place of glycine-542. In molecular genetic analyses on 129 Hispanic individuals with cystic fibrosis in the southwestern United States, <a href="#111" class="mim-tip-reference" title="Grebe, T. A., Seltzer, W. K., DeMarchi, J., Silva, D. K., Doane, W. W., Gozal, D., Richter, S. F., Bowman, C. M., Norman, R. A., Rhodes, S. N., Hernried, L. S., Murphy, S., Harwood, I. R., Accurso, F. J., Jain, K. D. <strong>Genetic analysis of Hispanic individuals with cystic fibrosis.</strong> Am. J. Hum. Genet. 54: 443-446, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7509564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7509564</a>]" pmid="7509564">Grebe et al. (1994)</a> found that 5.4% (7 of 129) individuals carried this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7504969+7509564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0096" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0096 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, GLN552TER
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs76554633 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs76554633;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs76554633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs76554633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007622 OR RCV001826445 OR RCV003473042" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007622, RCV001826445, RCV003473042" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007622...</a>
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</span>
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<span class="mim-text-font">
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<p>In a cystic fibrosis (CF; <a href="/entry/219700">219700</a>) patient with severe pancreatic insufficiency, <a href="#100" class="mim-tip-reference" title="Gasparini, P., Marigo, C., Bisceglia, G., Nicolis, E., Zelante, L., Bombieri, C., Borgo, G., Pignatti, P. F., Cabrini, G. <strong>Screening of 62 mutations in the cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes.</strong> Hum. Mutat. 2: 389-394, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7504969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7504969</a>] [<a href="https://doi.org/10.1002/humu.1380020511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7504969">Gasparini et al. (1993)</a> found a mutation in the CFTR gene that created a stop codon in place of glutamine-552. This mutation was found in 3 of 225 cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7504969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0097" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0097 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, ASP648VAL
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909033 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909033;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007623" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007623" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007623</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a systematic study of 133 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in northern Italy, <a href="#100" class="mim-tip-reference" title="Gasparini, P., Marigo, C., Bisceglia, G., Nicolis, E., Zelante, L., Bombieri, C., Borgo, G., Pignatti, P. F., Cabrini, G. <strong>Screening of 62 mutations in the cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes.</strong> Hum. Mutat. 2: 389-394, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7504969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7504969</a>] [<a href="https://doi.org/10.1002/humu.1380020511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7504969">Gasparini et al. (1993)</a> identified an asp648-to-val mutation in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7504969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<div>
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<a id="0098" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0098 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, LYS710TER
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs75115087 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs75115087;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs75115087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs75115087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007624 OR RCV000759034 OR RCV001004470 OR RCV001826446 OR RCV003473043" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007624, RCV000759034, RCV001004470, RCV001826446, RCV003473043" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007624...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a systematic study of 133 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in northern Italy, <a href="#100" class="mim-tip-reference" title="Gasparini, P., Marigo, C., Bisceglia, G., Nicolis, E., Zelante, L., Bombieri, C., Borgo, G., Pignatti, P. F., Cabrini, G. <strong>Screening of 62 mutations in the cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes.</strong> Hum. Mutat. 2: 389-394, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7504969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7504969</a>] [<a href="https://doi.org/10.1002/humu.1380020511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7504969">Gasparini et al. (1993)</a> found a point mutation creating a stop codon in place of lysine-710 in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7504969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0099" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0099 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, GLN890TER
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs79633941 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs79633941;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs79633941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs79633941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007625 OR RCV000505859 OR RCV001831549 OR RCV003473044 OR RCV005042007" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007625, RCV000505859, RCV001831549, RCV003473044, RCV005042007" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007625...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 related Portuguese patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#103" class="mim-tip-reference" title="Ghanem, N., Costes, B., Girodon, E., Martin, J., Fanen, P., Goossens, M. <strong>Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Genomics 21: 434-436, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7522211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7522211</a>] [<a href="https://doi.org/10.1006/geno.1994.1290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7522211">Ghanem et al. (1994)</a> identified a C-to-T substitution at nucleotide 2880 in exon 15, resulting in a stop codon at position 890. This mutation was found in a 13-year-old girl and her 15-year-old uncle, who have a classic form of the disease and nasal polyposis. Both patients had F508del on the other CF chromosome, and the uncle had a positive sweat test (140 mmol per liter). The mutation changed the restriction sites MseI(+) and MboII(-). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7522211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<div>
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<div>
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<a id="0100" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0100 CFTR POLYMORPHISM</strong>
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</span>
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</h4>
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</div>
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<div>
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CFTR, SER912LEU
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909034 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909034;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909034?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007626 OR RCV000007661 OR RCV000506704 OR RCV000586236 OR RCV001158768 OR RCV002255257" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007626, RCV000007661, RCV000506704, RCV000586236, RCV001158768, RCV002255257" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007626...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a study of 224 non-F508del CF chromosomes, <a href="#103" class="mim-tip-reference" title="Ghanem, N., Costes, B., Girodon, E., Martin, J., Fanen, P., Goossens, M. <strong>Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Genomics 21: 434-436, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7522211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7522211</a>] [<a href="https://doi.org/10.1006/geno.1994.1290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7522211">Ghanem et al. (1994)</a> identified a 2867C-T transition in exon 15 of the CFTR gene, resulting in a ser912-to-leu (S912L) substitution, in a CF carrier of French and Spanish extraction. It was difficult to predict whether this substitution would be deleterious. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7522211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By in vitro functional expression studies, <a href="#53" class="mim-tip-reference" title="Clain, J., Lehmann-Che,J., Girodon, E., Lipecka, J., Edelman, A., Goossens, M., Fanen, P. <strong>A neutral variant involved in a complex CFTR allele contributes to a severe cystic fibrosis phenotype.</strong> Hum. Genet. 116: 454-460, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15744523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15744523</a>] [<a href="https://doi.org/10.1007/s00439-004-1246-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15744523">Clain et al. (2005)</a> demonstrated that the S912L substitution was not disease-causing in isolation, but significantly impaired CFTR function when inherited in cis with another CFTR mutation (see <a href="#0135">602421.0135</a>). <a href="#53" class="mim-tip-reference" title="Clain, J., Lehmann-Che,J., Girodon, E., Lipecka, J., Edelman, A., Goossens, M., Fanen, P. <strong>A neutral variant involved in a complex CFTR allele contributes to a severe cystic fibrosis phenotype.</strong> Hum. Genet. 116: 454-460, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15744523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15744523</a>] [<a href="https://doi.org/10.1007/s00439-004-1246-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15744523">Clain et al. (2005)</a> identified a healthy father of a CF fetus carrying the S912L mutation. A different CF-producing mutation was identified on the father's other allele. <a href="#53" class="mim-tip-reference" title="Clain, J., Lehmann-Che,J., Girodon, E., Lipecka, J., Edelman, A., Goossens, M., Fanen, P. <strong>A neutral variant involved in a complex CFTR allele contributes to a severe cystic fibrosis phenotype.</strong> Hum. Genet. 116: 454-460, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15744523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15744523</a>] [<a href="https://doi.org/10.1007/s00439-004-1246-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15744523">Clain et al. (2005)</a> concluded that the S912L substitution is a neutral variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15744523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0101 CYSTIC FIBROSIS</strong>
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CFTR, 2-BP DEL, 936TA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908773 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908773;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908773" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908773" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007627" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007627" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007627</a>
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<p>In 2 Spanish patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#46" class="mim-tip-reference" title="Chillon, M., Casals, T., Gimenez, J., Nunes, V., Estivill, X. <strong>A cystic fibrosis patient homozygous for the new frameshift mutation 936delTA: description and clinical data.</strong> J. Med. Genet. 31: 369-370, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8064813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8064813</a>] [<a href="https://doi.org/10.1136/jmg.31.5.369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8064813">Chillon et al. (1994)</a> identified a 2-bp deletion (TA) in exon 6b of the CFTR gene at position 936 of the coding sequence. This frameshift mutation leads to a premature termination codon 272 nucleotides downstream and a truncated protein. One patient was homozygous and the other compound heterozygous. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8064813" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0102 CYSTIC FIBROSIS</strong>
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CFTR, HIS949TYR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909035 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909035;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909035?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007628 OR RCV003330386" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007628, RCV003330386" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007628...</a>
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<p>In a study of 224 non-F508del cystic fibrosis (CF; <a href="/entry/219700">219700</a>) chromosomes, <a href="#103" class="mim-tip-reference" title="Ghanem, N., Costes, B., Girodon, E., Martin, J., Fanen, P., Goossens, M. <strong>Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Genomics 21: 434-436, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7522211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7522211</a>] [<a href="https://doi.org/10.1006/geno.1994.1290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7522211">Ghanem et al. (1994)</a> identified a C-to-T substitution at nucleotide 2977 in exon 15, changing histidine to tyrosine at position 949, in a 60-year-old woman with a 10-year history of chronic lung disease. The sweat chloride value was 42 mmol per liter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7522211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0103 CYSTIC FIBROSIS</strong>
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CFTR, LEU1065PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909036 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909036;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909036" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909036" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007629 OR RCV000311326 OR RCV001004297 OR RCV001831550" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007629, RCV000311326, RCV001004297, RCV001831550" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007629...</a>
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<p>In a 10-year-old girl with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#103" class="mim-tip-reference" title="Ghanem, N., Costes, B., Girodon, E., Martin, J., Fanen, P., Goossens, M. <strong>Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Genomics 21: 434-436, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7522211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7522211</a>] [<a href="https://doi.org/10.1006/geno.1994.1290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7522211">Ghanem et al. (1994)</a> identified a T-to-C substitution at nucleotide 3326 in exon 17b, changing leucine to proline at position 1065 (L1065P). The L1065P mutation was found on the maternal chromosome of the patient, who bore a F508del mutation (<a href="#0001">602421.0001</a>) on the paternal allele. The leucine at this position is conserved in the mouse CFTR protein. This mutation changes the MnlI(+) restriction site. The patient had gastrointestinal and pulmonary manifestations of cystic fibrosis, as well as high sweat chloride values (66 mmol per liter). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7522211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4>
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<span class="mim-font">
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<strong>.0104 CYSTIC FIBROSIS</strong>
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CFTR, GLN1071PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909037 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909037;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909037?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007630" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007630" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007630</a>
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<p>In a 21-year-old woman with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#103" class="mim-tip-reference" title="Ghanem, N., Costes, B., Girodon, E., Martin, J., Fanen, P., Goossens, M. <strong>Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Genomics 21: 434-436, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7522211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7522211</a>] [<a href="https://doi.org/10.1006/geno.1994.1290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7522211">Ghanem et al. (1994)</a> identified an A-to-C substitution at nucleotide 3344 in exon 17b, changing glutamine to proline at position 1071 (Q1071P). Since the age of 5 years the patient had suffered from chronic gastrointestinal disorders, pancreatic insufficiency, diarrhea, steatorrhea, and very high sweat chloride values (160 mmol per liter). This missense mutation occurs on an amino acid conserved in mouse CFTR. The patient carried the F508del mutation on the other CF chromosome. The mutation changes the restriction site HaeIII(+). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7522211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0105" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0105 CYSTIC FIBROSIS</strong>
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</h4>
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CFTR, HIS1085ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs79635528 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs79635528;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs79635528?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs79635528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs79635528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007631" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007631" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007631</a>
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<p>In a systematic study of 133 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in northern Italy, <a href="#100" class="mim-tip-reference" title="Gasparini, P., Marigo, C., Bisceglia, G., Nicolis, E., Zelante, L., Bombieri, C., Borgo, G., Pignatti, P. F., Cabrini, G. <strong>Screening of 62 mutations in the cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes.</strong> Hum. Mutat. 2: 389-394, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7504969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7504969</a>] [<a href="https://doi.org/10.1002/humu.1380020511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7504969">Gasparini et al. (1993)</a> identified a his1085-to-arg mutation in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7504969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0106" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0106 CYSTIC FIBROSIS</strong>
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CFTR, TYR1092TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908761 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908761;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908761?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908761" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908761" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000056379 OR RCV000056380 OR RCV000119251 OR RCV000522700 OR RCV000763157 OR RCV000780122 OR RCV000781257 OR RCV001004305 OR RCV001009514 OR RCV001831551 OR RCV001831621 OR RCV003473243" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056379, RCV000056380, RCV000119251, RCV000522700, RCV000763157, RCV000780122, RCV000781257, RCV001004305, RCV001009514, RCV001831551, RCV001831621, RCV003473243" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056379...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a systematic study of 133 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in northern Italy, <a href="#100" class="mim-tip-reference" title="Gasparini, P., Marigo, C., Bisceglia, G., Nicolis, E., Zelante, L., Bombieri, C., Borgo, G., Pignatti, P. F., Cabrini, G. <strong>Screening of 62 mutations in the cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes.</strong> Hum. Mutat. 2: 389-394, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7504969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7504969</a>] [<a href="https://doi.org/10.1002/humu.1380020511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7504969">Gasparini et al. (1993)</a> found a point mutation creating a stop codon in place of tyrosine-1092 in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7504969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="0107" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0107 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, TRP1204TER
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908764 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908764;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908764" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908764" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908765 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908765;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908765?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007633 OR RCV001831552" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007633, RCV001831552" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007633...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#103" class="mim-tip-reference" title="Ghanem, N., Costes, B., Girodon, E., Martin, J., Fanen, P., Goossens, M. <strong>Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Genomics 21: 434-436, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7522211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7522211</a>] [<a href="https://doi.org/10.1006/geno.1994.1290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7522211">Ghanem et al. (1994)</a> identified a G-to-A substitution at nucleotide 3743 in exon 19, resulting in a stop codon at position 1204. This mutation was found on the paternal chromosome of a 4-year-old child with pancreatic insufficiency and a sweat chloride level of 120 mmol per liter but no pulmonary infection. The maternal chromosome bears the F508 deletion. The mutation changes the restriction sites MaeI(+). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7522211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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</div>
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<div>
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<a id="0108" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0108 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, 1-BP DEL, 1215G
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906375 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906375;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007634 OR RCV000727368 OR RCV003466831" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007634, RCV000727368, RCV003466831" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007634...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#201" class="mim-tip-reference" title="Romey, M.-C., Desgeorges, M., Laussel, M., Durand, M.-F., Demaille, J., Claustres, M. <strong>Two novel rare frameshift mutations (2423 del G in exon 13 and 1215 del G in exon 7) and one novel rare sequence variation (3271 + 18 C or T) identified in a patient with cystic fibrosis.</strong> Hum. Molec. Genet. 3: 1003-1004, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7524910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7524910</a>] [<a href="https://doi.org/10.1093/hmg/3.6.1003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7524910">Romey et al. (1994)</a> identified a 1-bp deletion (G) at nucleotide 2423 in exon 7 of the CFTR gene. This frameshift mutation leads to a premature termination (UAA) 7 codons downstream. The deletion creates an AflIII restriction site and was inherited from the patient's father. The patient, a 7-year-old boy of French and Spanish origin, carries a second mutation 2423delG (<a href="#0116">602421.0116</a>). Despite the 2 frameshift mutations, this patient does not present a severe form of cystic fibrosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7524910" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0109" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0109 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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CFTR, THR1220ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1800123 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800123;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1800123?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1800123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1800123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007635 OR RCV000589624 OR RCV003230350 OR RCV004528090" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007635, RCV000589624, RCV003230350, RCV004528090" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007635...</a>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#103" class="mim-tip-reference" title="Ghanem, N., Costes, B., Girodon, E., Martin, J., Fanen, P., Goossens, M. <strong>Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Genomics 21: 434-436, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7522211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7522211</a>] [<a href="https://doi.org/10.1006/geno.1994.1290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7522211">Ghanem et al. (1994)</a> identified a C-to-T substitution at nucleotide 3791 in exon 19 of the CFTR gene, changing threonine to isoleucine at position 1220. No other variation in CFTR was found, but the authors could not determine if the variants were found on the same or different alleles. No other family members were available for testing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7522211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0110" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0110 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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CFTR, ILE1234VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs75389940 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs75389940;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs75389940?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs75389940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs75389940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007636 OR RCV001269696 OR RCV001831553 OR RCV004566693" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007636, RCV001269696, RCV001831553, RCV004566693" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007636...</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a systematic study of 133 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in northern Italy, <a href="#100" class="mim-tip-reference" title="Gasparini, P., Marigo, C., Bisceglia, G., Nicolis, E., Zelante, L., Bombieri, C., Borgo, G., Pignatti, P. F., Cabrini, G. <strong>Screening of 62 mutations in the cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes.</strong> Hum. Mutat. 2: 389-394, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7504969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7504969</a>] [<a href="https://doi.org/10.1002/humu.1380020511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7504969">Gasparini et al. (1993)</a> identified an ile1234-to-val mutation in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7504969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0111" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0111 CYSTIC FIBROSIS</strong>
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</h4>
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CFTR, GLY1249GLU
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909040 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909040;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909040?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007637" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007637" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007637</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#114" class="mim-tip-reference" title="Greil, I., Wagner, K., Rosenkranz, W. <strong>A new missense mutation G1249E in exon 20 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Hum. Hered. 44: 238-240, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7520022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7520022</a>] [<a href="https://doi.org/10.1159/000154223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7520022">Greil et al. (1994)</a> identified a G-to-A substitution at nucleotide 3878 in exon 20 of the CFTR gene, changing a glycine (GGG) to glutamic acid (GAG) at amino acid 1249. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7520022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0112" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0112 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, SER1251ASN
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74503330 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74503330;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs74503330?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74503330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs74503330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007638 OR RCV000211301 OR RCV000506301 OR RCV000780175 OR RCV001731144 OR RCV001826447 OR RCV003466832" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007638, RCV000211301, RCV000506301, RCV000780175, RCV001731144, RCV001826447, RCV003466832" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007638...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a systematic study of 133 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in northern Italy, <a href="#100" class="mim-tip-reference" title="Gasparini, P., Marigo, C., Bisceglia, G., Nicolis, E., Zelante, L., Bombieri, C., Borgo, G., Pignatti, P. F., Cabrini, G. <strong>Screening of 62 mutations in the cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes.</strong> Hum. Mutat. 2: 389-394, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7504969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7504969</a>] [<a href="https://doi.org/10.1002/humu.1380020511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7504969">Gasparini et al. (1993)</a> identified a ser1251-to-asn mutation in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7504969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0113" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0113 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, SER1255PRO
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909041 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909041;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909041?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007613 OR RCV001787320 OR RCV002247264" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007613, RCV001787320, RCV002247264" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007613...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a systematic study of 133 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in northern Italy, <a href="#100" class="mim-tip-reference" title="Gasparini, P., Marigo, C., Bisceglia, G., Nicolis, E., Zelante, L., Bombieri, C., Borgo, G., Pignatti, P. F., Cabrini, G. <strong>Screening of 62 mutations in the cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes.</strong> Hum. Mutat. 2: 389-394, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7504969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7504969</a>] [<a href="https://doi.org/10.1002/humu.1380020511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7504969">Gasparini et al. (1993)</a> identified a ser1255-to-pro mutation in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7504969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0114" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0114 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, ASN1303HIS
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909042 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909042;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909042?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007639" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007639" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007639</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a systematic study of 133 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in northern Italy, <a href="#100" class="mim-tip-reference" title="Gasparini, P., Marigo, C., Bisceglia, G., Nicolis, E., Zelante, L., Bombieri, C., Borgo, G., Pignatti, P. F., Cabrini, G. <strong>Screening of 62 mutations in the cohort of cystic fibrosis patients from north eastern Italy: their incidence and clinical features of defined genotypes.</strong> Hum. Mutat. 2: 389-394, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7504969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7504969</a>] [<a href="https://doi.org/10.1002/humu.1380020511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7504969">Gasparini et al. (1993)</a> identified an asp1303-to-his mutation in the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7504969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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</div>
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</div>
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<div>
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<div>
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<a id="0115" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0115 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, 2-BP DEL, 1609CA
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908775 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908775;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007640 OR RCV001826448 OR RCV002496301" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007640, RCV001826448, RCV002496301" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007640...</a>
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</span>
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</div>
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<div>
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<p>In a systematic study of 133 patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) in northern Italy, <a href="#99" class="mim-tip-reference" title="Gasparini, P., Borgo, G., Mastella, G., Bonizzato, A., Dognini, M., Pignatti, P. F. <strong>Nine cystic fibrosis patients homozygous for the CFTR nonsense mutation R1162X have mild or moderate lung disease.</strong> J. Med. Genet. 29: 558-562, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1381442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1381442</a>] [<a href="https://doi.org/10.1136/jmg.29.8.558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1381442">Gasparini et al. (1992)</a> identified a 2-bp deletion (CA) in exon 10 of the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1381442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0116 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906376 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906376;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906376?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007641" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007641" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007641</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#201" class="mim-tip-reference" title="Romey, M.-C., Desgeorges, M., Laussel, M., Durand, M.-F., Demaille, J., Claustres, M. <strong>Two novel rare frameshift mutations (2423 del G in exon 13 and 1215 del G in exon 7) and one novel rare sequence variation (3271 + 18 C or T) identified in a patient with cystic fibrosis.</strong> Hum. Molec. Genet. 3: 1003-1004, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7524910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7524910</a>] [<a href="https://doi.org/10.1093/hmg/3.6.1003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7524910">Romey et al. (1994)</a> identified a 1-bp (G) deletion at position 2423 of the coding sequence in exon 13 of the CFTR gene. This frameshift mutation leads to a premature termination (UGA) 6 codons downstream. The patient, a 7-year-old boy of French and Spanish origin, carried a second mutation, 1215delG (<a href="#0108">602421.0108</a>). Despite the 2 frameshift mutations, this patient did not present a severe form of cystic fibrosis. The mutation 2423delG is also associated with sequence variation in intron 17a 3271+18C or T. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7524910" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0117 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906377 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906377;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906377?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007642 OR RCV000506268" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007642, RCV000506268" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007642...</a>
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#103" class="mim-tip-reference" title="Ghanem, N., Costes, B., Girodon, E., Martin, J., Fanen, P., Goossens, M. <strong>Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong> Genomics 21: 434-436, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7522211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7522211</a>] [<a href="https://doi.org/10.1006/geno.1994.1290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7522211">Ghanem et al. (1994)</a> identified a 1-bp deletion (A) at position 3293 of the coding sequence in exon 10 of the CFTR gene. This frameshift mutation leads to a premature termination codon 15 nucleotides downstream and a truncated protein. The patient, a 15-year-old F508del heterozygous girl of French origin, has a positive sweat test (80 mmol per liter) and pancreatic insufficiency but no chronic lung infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7522211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0118 CYSTIC FIBROSIS</strong>
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CFTR, 4-BP INS, NT3667
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906378 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906378;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007643 OR RCV001826449" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007643, RCV001826449" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007643...</a>
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<p>In a 20-year-old cystic fibrosis (CF; <a href="/entry/219700">219700</a>) patient of north-central Italian origin with pancreatic insufficiency and severe pulmonary involvement, <a href="#214" class="mim-tip-reference" title="Sangiuolo, F., Cicero, S. L., Maceratesi, P., Quattrucci, S., Novelli, G., Dallapiccola, B. <strong>Molecular characterization of a frameshift mutation in exon 19 of the CFTR gene.</strong> Hum. Mutat. 2: 422-424, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7504970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7504970</a>] [<a href="https://doi.org/10.1002/humu.1380020517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7504970">Sangiuolo et al. (1993)</a> identified a 4-bp insertion (TCAA) at position 3667 of the coding sequence in exon 19 of the CFTR gene. This frameshift mutation leads to a premature termination codon (TGA) at amino acid position 1195 and destroys a HincII restriction enzyme site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7504970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0119 SWEAT CHLORIDE ELEVATION WITHOUT CYSTIC FIBROSIS</strong>
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CFTR, SER1455TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909043 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909043;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909043?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909043" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909043" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007644 OR RCV000590108 OR RCV001004310 OR RCV001781201 OR RCV001826450 OR RCV003473045 OR RCV005031414" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007644, RCV000590108, RCV001004310, RCV001781201, RCV001826450, RCV003473045, RCV005031414" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007644...</a>
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<p><a href="#162" class="mim-tip-reference" title="Mickle, J. E., Macek, M., Jr., Fulmer-Smentek, S. B., Egan, M. M., Schwiebert, E., Guggino, W., Moss, R., Cutting, G. R. <strong>A mutation in the cystic fibrosis transmembrane conductance regulator gene associated with elevated sweat chloride concentrations in the absence of cystic fibrosis.</strong> Hum. Molec. Genet. 7: 729-735, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499426</a>] [<a href="https://doi.org/10.1093/hmg/7.4.729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499426">Mickle et al. (1998)</a> identified a 6.8-kb deletion and a nonsense mutation (ser1455 to ter; S1455X) in the CFTR gene of a mother and her youngest daughter with isolated elevated sweat chloride concentrations. Detailed clinical evaluation of both individuals found no evidence of pulmonary or pancreatic disease characteristic of CF. A second child in this family had classic CF and was homozygous for the 6.8-kb deletion, indicating that this mutation caused severe CFTR dysfunction. CFTR mRNA transcripts bearing the S1455X mutation were stable in vivo, implying that this allele encoded a truncated version of CFTR missing the last 26 amino acids. Loss of this region did not affect processing of transiently expressed S1455X-CFTR compared with wildtype CFTR. When expressed in CF airway cells, this mutant generated cAMP-activated whole-cell chloride currents similar to wildtype CFTR. Preservation of chloride channel function of the S1455X-CFTR mutation was consistent with normal lung and pancreatic function in the mother and her daughter. The study indicated that mutations in CFTR can be associated with elevated sweat chloride concentrations in the absence of the CF phenotype, and suggested a previously unrecognized functional role in the sweat gland for the C-terminus of CFTR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9499426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#213" class="mim-tip-reference" title="Salvatore, D., Tomaiuolo, R., Vanacore, B., Elce, A., Castaldo, G., Salvatore, F. <strong>Isolated elevated sweat chloride concentrations in the presence of the rare mutation S1455X: an extremely mild form of CFTR dysfunction.</strong> Am. J. Med. Genet. 133A: 207-208, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15666307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15666307</a>] [<a href="https://doi.org/10.1002/ajmg.a.30518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15666307">Salvatore et al. (2005)</a> reported 2 asymptomatic sisters with isolated increased sweat chloride concentrations in whom systematic scanning of the whole coding region of the CFTR gene revealed compound heterozygosity for S1455X and delF508 (<a href="#0001">602421.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15666307" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs75096551 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs75096551;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs75096551?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs75096551" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs75096551" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007645 OR RCV000759761 OR RCV000763580 OR RCV001004285 OR RCV001027899 OR RCV003473046" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007645, RCV000759761, RCV000763580, RCV001004285, RCV001027899, RCV003473046" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007645...</a>
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<p><a href="#81" class="mim-tip-reference" title="Dork, T., El-Harith, E.-H. A., Stuhrmann, M., Macek, M., Jr., Egan, M., Cutting, G. R., Tzetis, M., Kanavakis, E., Carles, S., Claustres, M., Padoa, C., Ramsay, M., Schmidtke, J. <strong>Evidence for a common ethnic origin of cystic fibrosis mutation 3120+1G-to-A in diverse populations. (Letter)</strong> Am. J. Hum. Genet. 63: 656-662, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683582</a>] [<a href="https://doi.org/10.1086/301950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683582">Dork et al. (1998)</a> concluded that the 3120+1G-A mutation, which is present in African, Arab, and a few Greek families with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), probably was derived from a common ancestor because the haplotypes are very similar or identical. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9683582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909044 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909044;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909044?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007646 OR RCV004799734" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007646, RCV004799734" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007646...</a>
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<p>In a pancreatic-insufficient patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#83" class="mim-tip-reference" title="Dork, T., Wulbrand, U., Richter, T., Neumann, T., Wolfes, H., Wulf, B., Maass, G., Tummler, B. <strong>Cystic fibrosis with three mutations in the cystic fibrosis transmembrane conductance regulator gene.</strong> Hum. Genet. 87: 441-446, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1715308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1715308</a>] [<a href="https://doi.org/10.1007/BF00197165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1715308">Dork et al. (1991)</a> identified a G-to-A transition at nucleotide 1790 of the CFTR gene, resulting in an arg553-to-gln substitution. See also <a href="#237" class="mim-tip-reference" title="Stern, R. C. <strong>The diagnosis of cystic fibrosis.</strong> New Eng. J. Med. 336: 487-491, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9017943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9017943</a>] [<a href="https://doi.org/10.1056/NEJM199702133360707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9017943">Stern (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1715308+9017943" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1797973431 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1797973431;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1797973431" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1797973431" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007647" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007647" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007647</a>
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<p>For discussion of the T-to-A transversion at position -102 in the minimal CFTR promoter that was found in compound heterozygous state in patients with cystic fibrosis by <a href="#202" class="mim-tip-reference" title="Romey, M.-C., Guittard, C., Carles, S., Demaille, J., Claustres, M., Ramsay, M. <strong>First putative sequence alterations in the minimal CFTR promoter region. (Letter)</strong> J. Med. Genet. 36: 263-264, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10204861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10204861</a>]" pmid="10204861">Romey et al. (1999)</a>, see <a href="#0012">602421.0012</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10204861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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CFTR, 21-KB DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007648" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007648" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007648</a>
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<p><a href="#82" class="mim-tip-reference" title="Dork, T., Macek, M., Jr., Mekus, F., Tummler, B., Tzountzouris, J., Casals, T., Krebsova, A., Koudova, M., Sakmaryova, I., Macek, M., Sr., Vavrova, V., Zemkova, D., and 64 others. <strong>Characterization of a novel 21-kb deletion, CFTRdele2,3(21 kb), in the CFTR gene: a cystic fibrosis mutation of Slavic origin common in Central and East Europe.</strong> Hum. Genet. 106: 259-268, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10798353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10798353</a>] [<a href="https://doi.org/10.1007/s004390000246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10798353">Dork et al. (2000)</a> described a large genomic deletion of the CFTR gene that is frequently observed in Central and Eastern Europe. The mutation deletes 21,080 bp spanning from intron 1 to intron 3 of the CFTR gene. Transcript analyses demonstrated that the deletion results in the loss of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature termination signal within exon 4. A simple PCR assay for the allele was devised and used to screen for the mutation in European and European-derived populations. Some 197 cystic fibrosis (CF; <a href="/entry/219700">219700</a>) patients, including 7 homozygotes, were identified. Clinical evaluation of the homozygotes and a comparison of compound heterozygotes for delF508 (<a href="#0001">602421.0001</a>) with pairwise-matched delF508 homozygotes indicated that the 21-kb deletion represents a severe mutation associated with pancreatic insufficiency and early age at diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10798353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0124 PANCREATITIS, IDIOPATHIC, SUSCEPTIBILITY TO</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1800111 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800111;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1800111?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1800111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1800111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007650 OR RCV000007651 OR RCV000046745 OR RCV000078991 OR RCV000243402 OR RCV000583195 OR RCV001009470 OR RCV001327946 OR RCV001642202 OR RCV005031415" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007650, RCV000007651, RCV000046745, RCV000078991, RCV000243402, RCV000583195, RCV001009470, RCV001327946, RCV001642202, RCV005031415" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007650...</a>
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<p><a href="#107" class="mim-tip-reference" title="Gomez Lira, M., Benetazzo, M. G., Marzari, M. G., Bombieri, C., Belpinati, F., Castellani, C., Cavallini, G. C., Mastella, G., Pignatti, P. F. <strong>High frequency of cystic fibrosis transmembrane regulator mutation L997F in patients with recurrent idiopathic pancreatitis and in newborns with hypertrypsinemia. (Letter)</strong> Am. J. Hum. Genet. 66: 2013-2014, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10801389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10801389</a>] [<a href="https://doi.org/10.1086/302928" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10801389">Gomez Lira et al. (2000)</a> postulated that there might be particular CFTR gene mutations involved in pancreatic ductular obstruction, as manifested in idiopathic pancreatitis or in neonatal hypertrypsinemia. Following up on this hypothesis, they performed a complete screening of the CFTR gene in a group of 32 patients with idiopathic pancreatitis (14 of whom carried the 5T variant CF mutation (<a href="#0086">602421.0086</a>) or had a borderline sweat chloride level, and 18 of whom were without common CF mutations or any other CF characteristic) and in 49 newborns with hypertrypsinemia and normal sweat chloride (32 of whom had a common CF mutation, and 17 of whom did not have a common CF mutation). Rare mutations were found in 9 of 32 patients with idiopathic pancreatitis and in 21 of 49 newborns with hypertrypsinemia. Of these rare mutations, leu997 to phe (L997F) was identified in 4 (12.5%) of 32 patients with idiopathic pancreatitis and in 4 (8%) of 39 newborns with hypertrypsinemia. L997 is a highly conserved residue in transmembrane domain 9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10801389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Since most neonatal screening programs for cystic fibrosis combine the assay of immunoreactive trypsinogen (IRT) with analysis for the most common mutations of the CFTR gene, the identification of heterozygotes among neonates because of increased IRT is considered a drawback. <a href="#222" class="mim-tip-reference" title="Scotet, V., De Braekeleer, M., Audrezet, M.-P., Lode, L., Verlingue, C., Quere, I., Mercier, B., Dugueperoux, I., Codet, J.-P., Moineau, M.-P., Parent, P., Ferec, C. <strong>Prevalence of CFTR mutations in hypertrypsinaemia detected through neonatal screening for cystic fibrosis.</strong> Clin. Genet. 59: 42-47, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11168024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11168024</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2001.590107.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11168024">Scotet et al. (2001)</a> assessed the heterozygosity frequency among children with hypertrypsinemia detected during a CF screening program in Brittany (France) 10 years previously. A total of 160,019 babies were screened for CF between 1992 and 1998. Of the 1,964 newborns with increased IRT (1.2%), 60 had CF and 213 were carriers. Heterozygosity frequency was 12.8%, or 3 times greater than in the general population (3.9%). A high proportion of mild mutations or variants was observed in carriers. The allelic frequency of the 5T variant (5.6%) was not increased. The study was consistent with previous ones in finding a significantly higher rate of heterozygotes than expected among neonates with hypertrypsinemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11168024" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#135" class="mim-tip-reference" title="Kabra, M, Kabra, S. K., Ghosh, M., Khanna, A., Arora, S., Menon, P. S. N., Verma, I. C. <strong>Is the spectrum of mutations in Indian patients with cystic fibrosis different? (Letter)</strong> Am. J. Med. Genet. 93: 161-163, 2000. Note: Erratum: Am. J. Med. Genet. 95: 410 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10869121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10869121</a>] [<a href="https://doi.org/10.1002/1096-8628(20000717)93:2<161::aid-ajmg15>3.0.co;2-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10869121">Kabra et al. (2000)</a> identified the L997F mutation in a Pakistani patient with cystic fibrosis (<a href="/entry/219700">219700</a>), but did not identify the second mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10869121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#75" class="mim-tip-reference" title="Derichs, N., Schuster, A., Grund, I., Ernsting, A., Stolpe, C., Kortge-Jung, S., Gallati, S., Stuhrmann, M., Kozlowski, P., Ballmann, M. <strong>Homozygosity for L997F in a child with normal clinical and chloride secretory phenotype provides evidence that this cystic fibrosis transmembrane conductance regulator mutation does not cause cystic fibrosis. (Letter)</strong> Clin. Genet. 67: 529-531, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15857421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15857421</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00437.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15857421">Derichs et al. (2005)</a> reported a child, born of consanguineous Turkish parents, who was homozygous for the L997F substitution. The child showed normal development with no evidence of pancreatic insufficiency or cystic fibrosis. Sweat chloride tests and intestinal chloride secretion were normal. <a href="#75" class="mim-tip-reference" title="Derichs, N., Schuster, A., Grund, I., Ernsting, A., Stolpe, C., Kortge-Jung, S., Gallati, S., Stuhrmann, M., Kozlowski, P., Ballmann, M. <strong>Homozygosity for L997F in a child with normal clinical and chloride secretory phenotype provides evidence that this cystic fibrosis transmembrane conductance regulator mutation does not cause cystic fibrosis. (Letter)</strong> Clin. Genet. 67: 529-531, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15857421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15857421</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00437.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15857421">Derichs et al. (2005)</a> concluded that the L997F mutation does not cause cystic fibrosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15857421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906379 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906379;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007652 OR RCV003473047" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007652, RCV003473047" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007652...</a>
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<p>In an Indian child with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#135" class="mim-tip-reference" title="Kabra, M, Kabra, S. K., Ghosh, M., Khanna, A., Arora, S., Menon, P. S. N., Verma, I. C. <strong>Is the spectrum of mutations in Indian patients with cystic fibrosis different? (Letter)</strong> Am. J. Med. Genet. 93: 161-163, 2000. Note: Erratum: Am. J. Med. Genet. 95: 410 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10869121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10869121</a>] [<a href="https://doi.org/10.1002/1096-8628(20000717)93:2<161::aid-ajmg15>3.0.co;2-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10869121">Kabra et al. (2000)</a> identified a 1-bp insertion (T) at nucleotide 3622 of the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10869121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0126 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs373002889 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs373002889;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs373002889?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs373002889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs373002889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007649 OR RCV000595140 OR RCV001810837 OR RCV002255258 OR RCV004734503" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007649, RCV000595140, RCV001810837, RCV002255258, RCV004734503" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007649...</a>
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<p>In 2 Indian patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#135" class="mim-tip-reference" title="Kabra, M, Kabra, S. K., Ghosh, M., Khanna, A., Arora, S., Menon, P. S. N., Verma, I. C. <strong>Is the spectrum of mutations in Indian patients with cystic fibrosis different? (Letter)</strong> Am. J. Med. Genet. 93: 161-163, 2000. Note: Erratum: Am. J. Med. Genet. 95: 410 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10869121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10869121</a>] [<a href="https://doi.org/10.1002/1096-8628(20000717)93:2<161::aid-ajmg15>3.0.co;2-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10869121">Kabra et al. (2000)</a> identified a T-to-C change at position -20 from nucleotide 3601 of the CFTR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10869121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908784 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908784;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908784?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007653 OR RCV000755920 OR RCV001004505 OR RCV001831554 OR RCV003473048 OR RCV005031416" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007653, RCV000755920, RCV001004505, RCV001831554, RCV003473048, RCV005031416" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007653...</a>
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<p><a href="#261" class="mim-tip-reference" title="Wang, J., Bowman, M. C., Hsu, E., Wertz, K., Wong, L.-J. C. <strong>A novel mutation in the CFTR gene correlates with severe clinical phenotype in seven Hispanic patients.</strong> J. Med. Genet. 37: 215-218, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10777364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10777364</a>] [<a href="https://doi.org/10.1136/jmg.37.3.215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10777364">Wang et al. (2000)</a> found that 7 of 29 Hispanic patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) were heterozygous for a single-basepair deletion at nucleotide 3876 (3876delA) resulting in a frameshift and termination at residue 1258 (L1258X). This mutation accounted for 10.3% of mutant alleles in this group. The patients with this mutation had a severe phenotype as determined by early age of diagnosis, high sweat chloride, presence of allergic bronchopulmonary aspergillosis, pancreatic insufficiency, liver disease, cor pulmonale, and early death. <a href="#261" class="mim-tip-reference" title="Wang, J., Bowman, M. C., Hsu, E., Wertz, K., Wong, L.-J. C. <strong>A novel mutation in the CFTR gene correlates with severe clinical phenotype in seven Hispanic patients.</strong> J. Med. Genet. 37: 215-218, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10777364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10777364</a>] [<a href="https://doi.org/10.1136/jmg.37.3.215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10777364">Wang et al. (2000)</a> noted that this mutation had not been reported in any other ethnic group. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10777364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908769 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908769;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007654 OR RCV000506648 OR RCV001004235 OR RCV001269534 OR RCV001835625 OR RCV002496302 OR RCV003473049" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007654, RCV000506648, RCV001004235, RCV001269534, RCV001835625, RCV002496302, RCV003473049" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007654...</a>
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<p>The 394delTT mutation in CFTR causing cystic fibrosis (CF; <a href="/entry/219700">219700</a>), referred to as the 'Nordic mutation,' is found at a high frequency in the countries bordering the Baltic Sea and associated waterways (Sweden, Norway, Denmark, Finland, Estonia, Russia, etc.). This mutation is associated almost exclusively with a single chromosomal haplotype, which suggests a single origin, centered in this region (<a href="#220" class="mim-tip-reference" title="Schwartz, M., Anvret, M., Claustres, M., Eiken, H. G., Eiklid, K., Schaedel, C., Stolpe, L., Tranebjaerg, L. <strong>394delTT: a Nordic cystic fibrosis mutation.</strong> Hum. Genet. 93: 157-161, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7509310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7509310</a>] [<a href="https://doi.org/10.1007/BF00210602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7509310">Schwartz et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7509310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0129 MOVED TO <a href="/entry/602421#0022">602421.0022</a></strong>
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<strong>.0130 CYSTIC FIBROSIS</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007656" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007656" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007656</a>
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<p>For discussion of the ala445-to-glu mutation in the CFTR gene that was found in compound heterozygous state in a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) by <a href="#147" class="mim-tip-reference" title="Kulczycki, L. L., Kostuch, M., Bellanti, J. A. <strong>A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype-phenotype manifestations.</strong> Am. J. Med. Genet. 116A: 262-267, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12503104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12503104</a>] [<a href="https://doi.org/10.1002/ajmg.a.10886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12503104">Kulczycki et al. (2003)</a>, see <a href="#0022">602421.0022</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12503104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0131" class="mim-anchor"></a>
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<strong>.0131 CYSTIC FIBROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909045 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909045;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909045?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007657 OR RCV000278439" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007657, RCV000278439" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007657...</a>
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<span class="mim-text-font">
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<p>In a 1.5-year-old Taiwanese boy with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#276" class="mim-tip-reference" title="Wong, L.-J. C., Alper, O. M., Wang, B.-T., Lee, M.-H., Lo, S.-Y. <strong>Two novel null mutations in a Taiwanese cystic fibrosis patient and a survey of East Asian CFTR mutations. (Letter)</strong> Am. J. Med. Genet. 120A: 296-298, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12833420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12833420</a>] [<a href="https://doi.org/10.1002/ajmg.a.20039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12833420">Wong et al. (2003)</a> found compound heterozygosity for 2 novel mutations in the CFTR gene, a G-to-T transversion at nucleotide 151 in exon 1 that resulted in a glu7-to-ter (E7X) substitution in the first transmembrane domain of the protein, and a 1-bp insertion in exon 6b (989_992insA). The insertion caused a frameshift and a truncated CFTR protein of 306 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12833420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0132" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0132 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, 1-BP INS, 989A
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906380 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906380;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007658" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007658" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007658</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the 1-bp insertion (989_992insA) in the CFTR gene that was found in compound heterozygous state in a Taiwanese boy with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) by <a href="#276" class="mim-tip-reference" title="Wong, L.-J. C., Alper, O. M., Wang, B.-T., Lee, M.-H., Lo, S.-Y. <strong>Two novel null mutations in a Taiwanese cystic fibrosis patient and a survey of East Asian CFTR mutations. (Letter)</strong> Am. J. Med. Genet. 120A: 296-298, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12833420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12833420</a>] [<a href="https://doi.org/10.1002/ajmg.a.20039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12833420">Wong et al. (2003)</a>, see <a href="#0131">602421.0131</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12833420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<a id="0133" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0133 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, GLN1352HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs113857788 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113857788;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs113857788?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs113857788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs113857788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007659 OR RCV000586028 OR RCV001009487 OR RCV001375489 OR RCV005031417" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007659, RCV000586028, RCV001009487, RCV001375489, RCV005031417" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007659...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#151" class="mim-tip-reference" title="Lee, J. H., Choi, J. H., Namkung, W., Hanrahan, J. W., Chang, J., Song, S. Y., Park, S. W., Kim, D. S., Yoon, J.-H., Suh, Y., Jang, I.-J., Nam, J. H., Kim, S. J., Cho, M.-O., Lee, J.-E., Kim, K. H., Lee, M. G. <strong>A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases.</strong> Hum. Molec. Genet. 12: 2321-2332, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12952861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12952861</a>] [<a href="https://doi.org/10.1093/hmg/ddg243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12952861">Lee et al. (2003)</a> identified a G-to-C transversion at nucleotide 4188 in exon 22 of the CFTR gene that resulted in a gln1352-to-his (Q1352H) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12952861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0134" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0134 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, GLU217GLY
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909046 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909046;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909046?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909046" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007660 OR RCV000506350 OR RCV000586415 OR RCV001095295" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007660, RCV000506350, RCV000586415, RCV001095295" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007660...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#151" class="mim-tip-reference" title="Lee, J. H., Choi, J. H., Namkung, W., Hanrahan, J. W., Chang, J., Song, S. Y., Park, S. W., Kim, D. S., Yoon, J.-H., Suh, Y., Jang, I.-J., Nam, J. H., Kim, S. J., Cho, M.-O., Lee, J.-E., Kim, K. H., Lee, M. G. <strong>A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases.</strong> Hum. Molec. Genet. 12: 2321-2332, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12952861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12952861</a>] [<a href="https://doi.org/10.1093/hmg/ddg243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12952861">Lee et al. (2003)</a> identified a 782A-G transition in exon 6a of the CFTR gene that resulted in a glu217-to-gly (E217G) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12952861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0135" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0135 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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CFTR, GLY1244VAL AND SER912LEU
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267606723 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606723;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267606723?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267606723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267606723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007626 OR RCV000007661 OR RCV000506704 OR RCV000577733 OR RCV000586236 OR RCV001158768 OR RCV002255257" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007626, RCV000007661, RCV000506704, RCV000577733, RCV000586236, RCV001158768, RCV002255257" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007626...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with a severe form of cystic fibrosis (CF; <a href="/entry/219700">219700</a>), <a href="#218" class="mim-tip-reference" title="Savov, A., Angelicheva, D., Balassopoulou, A., Jordanova, A., Noussia-Arvanitakis, S., Kalaydjieva, L. <strong>Double mutant alleles: are they rare?</strong> Hum. Molec. Genet. 4: 1169-1171, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528204</a>] [<a href="https://doi.org/10.1093/hmg/4.7.1169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528204">Savov et al. (1995)</a> identified compound heterozygosity for mutations in the CFTR gene. One allele carried a G542X substitution (<a href="#0009">602421.0009</a>). The other allele carried 2 mutations: S912L (see <a href="#0100">602421.0100</a>) and a 3863G-T transversion in exon 20, resulting in a gly1244-to-val (G1244V) substitution in the second nucleotide binding domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By in vitro functional expression studies, <a href="#53" class="mim-tip-reference" title="Clain, J., Lehmann-Che,J., Girodon, E., Lipecka, J., Edelman, A., Goossens, M., Fanen, P. <strong>A neutral variant involved in a complex CFTR allele contributes to a severe cystic fibrosis phenotype.</strong> Hum. Genet. 116: 454-460, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15744523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15744523</a>] [<a href="https://doi.org/10.1007/s00439-004-1246-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15744523">Clain et al. (2005)</a> demonstrated that the S912L substitution was not disease-causing in isolation, but significantly impaired CFTR function when inherited in cis with the G1244V mutation. Although the G1244V substitution alone resulted in decreased cAMP-dependent chloride conductance (43% of control values), the G1244V/S912L complex allele had an almost 20-fold reduction in chloride conduction (2.4% of control values) compared with the G1244V mutant alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15744523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121909047 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909047;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121909047?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121909047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121909047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007662 OR RCV000759032 OR RCV001004265 OR RCV001826451 OR RCV003473050" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007662, RCV000759032, RCV001004265, RCV001826451, RCV003473050" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007662...</a>
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<p><a href="#161" class="mim-tip-reference" title="Mendes, F., Roxo Rosa, M., Dragomir, A., Farinha, C. M., Roomans, G. M., Amaral, M. D., Penque, D. <strong>Unusually common cystic fibrosis mutation in Portugal encodes a misprocessed protein.</strong> Biochem. Biophys. Res. Commun. 311: 665-671, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14623323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14623323</a>] [<a href="https://doi.org/10.1016/j.bbrc.2003.10.048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14623323">Mendes et al. (2003)</a> stated that an ala561-to-glu (A561E) substitution in exon 12 of the CFTR gene is the second most common mutation among Portuguese patients with cystic fibrosis (CF; <a href="/entry/219700">219700</a>), accounting for 3% of mutant alleles. Overexpression of the A561E mutant protein in baby hamster kidney cells showed that it was misprocessed and retained in the endoplasmic reticulum, thus belonging to the class II type of CFTR mutation. Low temperature treatment partially rescued a functional A561E-CFTR channel, similar to findings with the common F508del mutation (<a href="#0001">602421.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14623323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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CFTR, MET1101LYS (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs36210737;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs36210737</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs36210737 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs36210737;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs36210737?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs36210737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs36210737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000032712 OR RCV000757078 OR RCV000781258 OR RCV001004494 OR RCV001831623 OR RCV002496491 OR RCV003466886" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032712, RCV000757078, RCV000781258, RCV001004494, RCV001831623, RCV002496491, RCV003466886" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032712...</a>
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<p><a href="#240" class="mim-tip-reference" title="Stuhrmann, M., Dork, T., Fruhwirth, M., Golla, A., Skawran, B., Antonin, W., Ebhardt, M., Loos, A., Ellemunter, H., Schmidtke, J. <strong>Detection of 100% of the CFTR mutations in 63 CF families from Tyrol.</strong> Clin. Genet. 52: 240-246, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9383031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9383031</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1997.tb02555.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9383031">Stuhrmann et al. (1997)</a> identified a T-to-A transversion at nucleotide 3302 of the CFTR gene, resulting in met-to-lys substitution at codon 1101 (M1101K) in a single individual with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) from the South Tyrol. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9383031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, <a href="#49" class="mim-tip-reference" title="Chong, J. X., Ouwenga, R., Anderson, R. L., Waggoner, D. J., Ober, C. <strong>A population-based study of autosomal-recessive disease-causing mutations in a founder population.</strong> Am. J. Hum. Genet. 91: 608-620, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22981120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22981120</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.08.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22981120">Chong et al. (2012)</a> identified this mutation in heterozygous state in 108 individuals among 1,473 screened and in homozygous state in 6, for a carrier frequency of 0.073 (1 in 13.5). <a href="#49" class="mim-tip-reference" title="Chong, J. X., Ouwenga, R., Anderson, R. L., Waggoner, D. J., Ober, C. <strong>A population-based study of autosomal-recessive disease-causing mutations in a founder population.</strong> Am. J. Hum. Genet. 91: 608-620, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22981120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22981120</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.08.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22981120">Chong et al. (2012)</a> noted that the South Tyrol was the home of some of the Hutterite founders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22981120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000851288" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000851288" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000851288</a>
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<p><a href="#105" class="mim-tip-reference" title="Girardet, A., Guittard, C., Altieri, J.-P., Templin, C., Stremler, N., Beroud, C., des Georges, M., Claustres, M. <strong>Negative genetic neonatal screening for cystic fibrosis caused by compound heterozygosity for two large CFTR rearrangements.</strong> Clin. Genet. 72: 374-377, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17850636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17850636</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00850.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17850636">Girardet et al. (2007)</a> reported a male neonate with cystic fibrosis (CF; <a href="/entry/219700">219700</a>) who was compound heterozygous for 2 large CFTR rearrangements, one a deletion involving exon 2 inherited from his Sicilian father, and the other a deletion removing exons 16, 17a, and 17b (c.2908+1085_c.3367+260del7201, NM_000492.2) inherited from his South Korean mother. The deletion extended from intron 15 to intron 17b of the gene. Numbering of this mutation uses A of the ATG start codon as the +1 position. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17850636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Japanese boy diagnosed with CF on the basis of chronic respiratory infection and elevated sweat chloride levels, in whom no mutation had been identified by conventional analysis, <a href="#168" class="mim-tip-reference" title="Nakakuki, M., Fujiki, K., Yamamoto, A., Ko, S. B. H., Yi, L., Ishiguro, M., Yamaguchi, M., Kondo, S., Maruyama, S., Yanagimoto, K., Naruse, S., Ishiguro, H. <strong>Detection of a large heterozygous deletion and a splicing defect in the CFTR transcripts from nasal swab of a Japanese case of cystic fibrosis.</strong> J. Hum. Genet. 57: 427-433, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22572733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22572733</a>] [<a href="https://doi.org/10.1038/jhg.2012.46" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22572733">Nakakuki et al. (2012)</a> detected the 7.2-kb deletion identified by <a href="#105" class="mim-tip-reference" title="Girardet, A., Guittard, C., Altieri, J.-P., Templin, C., Stremler, N., Beroud, C., des Georges, M., Claustres, M. <strong>Negative genetic neonatal screening for cystic fibrosis caused by compound heterozygosity for two large CFTR rearrangements.</strong> Clin. Genet. 72: 374-377, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17850636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17850636</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00850.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17850636">Girardet et al. (2007)</a> using direct sequencing. A splicing defect was found on the other allele. <a href="#168" class="mim-tip-reference" title="Nakakuki, M., Fujiki, K., Yamamoto, A., Ko, S. B. H., Yi, L., Ishiguro, M., Yamaguchi, M., Kondo, S., Maruyama, S., Yanagimoto, K., Naruse, S., Ishiguro, H. <strong>Detection of a large heterozygous deletion and a splicing defect in the CFTR transcripts from nasal swab of a Japanese case of cystic fibrosis.</strong> J. Hum. Genet. 57: 427-433, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22572733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22572733</a>] [<a href="https://doi.org/10.1038/jhg.2012.46" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22572733">Nakakuki et al. (2012)</a> predicted that the mutated protein would lack amino acids 970 through 1122, which correspond to transmembrane regions 9, 10, and 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17850636+22572733" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#236" class="mim-tip-reference" title="Sohn, Y. B., Ko, J. M., Jang, J. Y., Seong, M.-W., Park, S. S., Suh, D. I., Ko, J. S., Shin, C.-H. <strong>Deletion of exons 16-17b of CFTR is frequently identified in Korean patients with cystic fibrosis.</strong> Europ. J. Med. Genet. 62: 103681, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31136843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31136843</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.103681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31136843">Sohn et al. (2019)</a> performed a clinical characterization and genetic analysis of CFTR in 6 Korean patients from 5 families with cystic fibrosis. Six of the 12 alleles (50%) showed the 16-17b multiexon deletion. All 6 patients had a classical cystic fibrosis phenotype and 5 of the 6 presented with meconium ileus. All patients were alive with supportive care at ages ranging from 8 to 19 years. <a href="#236" class="mim-tip-reference" title="Sohn, Y. B., Ko, J. M., Jang, J. Y., Seong, M.-W., Park, S. S., Suh, D. I., Ko, J. S., Shin, C.-H. <strong>Deletion of exons 16-17b of CFTR is frequently identified in Korean patients with cystic fibrosis.</strong> Europ. J. Med. Genet. 62: 103681, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31136843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31136843</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.103681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31136843">Sohn et al. (2019)</a> suggested molecular investigation for this deletion mutation in Asian populations including Korea and Japan. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31136843" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#259" class="mim-tip-reference" title="Wakabayashi-Nakao, K., Yu, Y., Nakakuki, M., Hwang, T.-C., Ishiguro, H., Sohma, Y. <strong>Characterization of delta-(G970-T1122)-CFTR, the most frequent CFTR mutant identified in Japanese cystic fibrosis patients.</strong> J. Physiol. Sci. 69: 103-112, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29951967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29951967</a>] [<a href="https://doi.org/10.1007/s12576-018-0626-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29951967">Wakabayashi-Nakao et al. (2019)</a> reported identification of a deletion of exons 16-17b in CFTR as the most common Japanese cystic fibrosis variant, with frequency of about 70% among Japanese CF patients definitely diagnosed. The pathogenic mutation results in a deletion of 153 amino acids, from glycine at position 970 (G970) to threonine at 1122 (T1122) in the CFTR protein without a frameshift; the authors referred to the mutation as delta-(G970-T1122). The authors characterized this variant in CFTR carrying this deletion in CHO cells using immunoblots and super-resolution microscopy. The protein is synthesized and core-glycosylated but not complex-glycosylated. Lumacaftor (VX-809) could not rescue the maturation defect of the delta-(G970-T1122) protein. <a href="#259" class="mim-tip-reference" title="Wakabayashi-Nakao, K., Yu, Y., Nakakuki, M., Hwang, T.-C., Ishiguro, H., Sohma, Y. <strong>Characterization of delta-(G970-T1122)-CFTR, the most frequent CFTR mutant identified in Japanese cystic fibrosis patients.</strong> J. Physiol. Sci. 69: 103-112, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29951967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29951967</a>] [<a href="https://doi.org/10.1007/s12576-018-0626-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29951967">Wakabayashi-Nakao et al. (2019)</a> suggested that this mutation should be characterized as a class II variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29951967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Baylin1980" class="mim-tip-reference" title="Baylin, S. B., Rosenstein, B. J., Marton, L. J., Lockwood, D. H. <strong>Age-related abnormalities of circulating polyamines and diamine oxidase activity in cystic fibrosis heterozygotes and homozygotes.</strong> Pediat. Res. 14: 921-925, 1980.">Baylin et al. (1980)</a>; <a href="#Chalkley1991" class="mim-tip-reference" title="Chalkley, G., Harris, A. <strong>Lymphocyte mRNA as a resource for detection of mutations and polymorphism in the CF gene.</strong> J. Med. Genet. 28: 777-780, 1991.">Chalkley and Harris (1991)</a>; <a href="#Chillon1995" class="mim-tip-reference" title="Chillon, M., Casals, T., Mercier, B., Bassas, L., Lissens, W., Silber, S., Romey, M.-C., Ruiz-Romero, J., Verlingue, C., Claustres, M., Nunes, V., Ferec, C., Estivill, X. <strong>Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens.</strong> New Eng. J. Med. 332: 1475-1480, 1995.">Chillon et al.
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(1995)</a>; <a href="#Cutting1992" class="mim-tip-reference" title="Cutting, G. R., Curristin, S. M., Nash, E., Rosenstein, B. J., Lerer, I., Abeliovich, D., Hill, A., Graham, C. <strong>Analysis of four diverse population groups indicates that a subset of cystic fibrosis mutations occur in common among Caucasians.</strong> Am. J. Hum. Genet. 50: 1185-1194, 1992.">Cutting et al. (1992)</a>; <a href="#de1997" class="mim-tip-reference" title="de Vries, H. G., Collee, J. M., de Walle, H. E. K., van Veldhuizen, M. H. R., Smit Sibinga, C. T., Scheffer, H., ten Kate, L. P. <strong>Prevalence of delta-F508 cystic fibrosis carriers in The Netherlands: logistic regression on sex, age, region of residence and number of offspring.</strong> Hum. Genet. 99: 74-79, 1997.">de Vries et al. (1997)</a>; <a href="#Devoto1991" class="mim-tip-reference" title="Devoto, M., Ronchetto, P., Fanen, P., Orriols, J. J. T., Romeo, G., Goossens, M., Ferrari, M., Magnani, C., Seia, M., Cremonesi, L. <strong>Screening for non-delta-F508 mutations in five exons of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in Italy.</strong> Am. J. Hum. Genet. 48: 1127-1132, 1991.">Devoto et al.
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(1991)</a>; <a href="#Dumur1996" class="mim-tip-reference" title="Dumur, V., Gervais, R., Rigot, J.-M., Delomel-Vinner, E., Decaestecker, B., Lafitte, J.-J., Roussel, P. <strong>Congenital bilateral absence of the vas deferens (CBAVD) and cystic fibrosis transmembrane regulator (CFTR): correlation between genotype and phenotype.</strong> Hum. Genet. 97: 7-10, 1996.">Dumur et al. (1996)</a>; <a href="#Dumur1990" class="mim-tip-reference" title="Dumur, V., Lafitte, J. J., Gervais, R., Debaecker, D., Kesteloot, M., Lalau, G., Roussel, P. <strong>Abnormal distribution of cystic fibrosis delta-F508 allele in adults with chronic bronchial hypersecretion.</strong> Lancet 335: 1340, 1990.">Dumur et al. (1990)</a>; <a href="#Fanen1992" class="mim-tip-reference" title="Fanen, P., Ghanem, N., Vidaud, M., Besmond, C., Martin, J., Costes, B., Plassa, F., Goossens, M. <strong>Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions.</strong> Genomics 13: 770-776, 1992.">Fanen et al.
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(1992)</a>; <a href="#Kerem1990" class="mim-tip-reference" title="Kerem, E., Corey, M., Kerem, B., Rommens, J., Markiewicz, D., Levison, H., Tsui, L.-C., Durie, P. <strong>The relation between genotype and phenotype in cystic fibrosis--analysis of the most common mutation (delta-F508).</strong> New Eng. J. Med. 323: 1517-1522, 1990.">Kerem et al. (1990)</a>; <a href="#Kerem1995" class="mim-tip-reference" title="Kerem, E., Kalman, Y. M., Yahav, Y., Shoshani, T., Abeliovich, D., Szeinberg, A., Rivlin, J., Blau, H., Tal, A., Ben-Tur, L., Springer, C., Augarten, A., Godfrey, S., Lerer, I., Branski, D., Friedman, M., Kerem, B. <strong>Highly variable incidence of cystic fibrosis and different mutation distribution among different Jewish ethnic groups in Israel.</strong> Hum. Genet. 96: 193-197, 1995.">Kerem et al. (1995)</a>; <a href="#Klinger1990" class="mim-tip-reference" title="Klinger, K., Horn, G. T., Stanislovitis, P., Schwartz, R. H., Fujiwara, T. M., Morgan, K. <strong>Cystic fibrosis mutations in the Hutterite brethren.</strong> Am. J. Hum. Genet. 46: 983-987, 1990.">Klinger et al.
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(1990)</a>; <a href="#Laroche1991" class="mim-tip-reference" title="Laroche, D., Travert, G. <strong>Abnormal frequency of delta-F(508) mutation in neonatal transitory hypertrypsinaemia. (Letter)</strong> Lancet 337: 55 only, 1991.">Laroche and Travert (1991)</a>; <a href="#Marino1991" class="mim-tip-reference" title="Marino, C. R., Matovcik, L. M., Gorelick, F. S., Cohn, J. A. <strong>Localization of the cystic fibrosis transmembrane conductance regulator in pancreas.</strong> J. Clin. Invest. 88: 712-716, 1991. Note: Erratum: J. Clin. Invest. 88: 1433 only, 1991.">Marino et al. (1991)</a>; <a href="#Nunes1991" class="mim-tip-reference" title="Nunes, V., Gasparini, P., Novelli, G., Gaona, A., Bonizzato, A., Sangiuolo, F., Balassopoulou, A., Gimenez, F. J., Dognini, M., Ravnik-Glavac, M., Cikuli, M., Mokini, V., Komel, R., Dallapiccola, B., Pignatti, P. F., Loukopoulos, D., Casals, T., Estivill, X. <strong>Analysis of 14 cystic fibrosis mutations in five south European populations.</strong> Hum. Genet. 87: 737-738, 1991.">Nunes et
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al. (1991)</a>; <a href="#Orita1989" class="mim-tip-reference" title="Orita, M., Suzuki, Y., Sekiya, T., Hayashi, K. <strong>Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction.</strong> Genomics 5: 874-879, 1989.">Orita et al. (1989)</a>; <a href="#Pier1996" class="mim-tip-reference" title="Pier, G. B., Grout, M., Zaldi, T. S., Olsen, J. C., Johnson, L. G., Yankaskas, J. R., Goldberg, J. B. <strong>Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections.</strong> Science 271: 64-67, 1996.">Pier et al. (1996)</a>; <a href="#Rich1990" class="mim-tip-reference" title="Rich, D. P., Anderson, M. P., Gregory, R. J., Cheng, S. H., Paul, S., Jefferson, D. M., McCann, J. D., Klinger, K. W., Smith, A. E., Welsh, M. J. <strong>Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells.</strong> Nature 347: 358-363, 1990.">Rich et al.
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(1990)</a>; <a href="#Rosenfeld1992" class="mim-tip-reference" title="Rosenfeld, M. A., Yoshimura, K., Trapnell, B. C., Yoneyama, K., Rosenthal, E. R., Dalemans, W., Fukayama, M., Bargon, J., Stier, L. E., Stratford-Perricaudet, L., Perricaudet, M., Guggino, W. B., Pavirani, A., Lecocq, J.-P., Crystal, R. G. <strong>In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium.</strong> Cell 68: 143-155, 1992.">Rosenfeld et al. (1992)</a>; <a href="#Sheppard1993" class="mim-tip-reference" title="Sheppard, D. N., Rich, D. P., Ostedgaard, L. S., Gregory, R. J., Smith, A. E., Welsh, M. J. <strong>Mutations in CFTR associated with mild-disease form CI- channels with altered pore properties.</strong> Nature 362: 160-164, 1993.">Sheppard et al. (1993)</a>; <a href="#Shoshani1994" class="mim-tip-reference" title="Shoshani, T., Kerem, E., Szeinberg, A., Augarten, A., Yahav, Y., Cohen, D., Rivlin, J., Tal, A., Kerem, B. S. <strong>Similar levels of mRNA from the W1282X and the delta-F508 cystic fibrosis alleles, in nasal epithelial cells.</strong> J. Clin. Invest. 93: 1502-1507, 1994.">Shoshani et
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al. (1994)</a>; <a href="#The1993">The Cystic Fibrosis Genotype-Phenotype Consortium (1993)</a>; <a href="#Varon1995" class="mim-tip-reference" title="Varon, R., Stuhrmann, M., Macek, M., Jr., Kufardjieva, A., Angelicheva, D., Magdorf, K., Jordanova, A., Savov, A., Wahn, U., Macek, M., Lalov, V., Ivanova, T., Ellemunter, H., Vavrova, V., Ferak, V., Kayserova, H., Reis, A., Kalaydjieva, L. <strong>Pancreatic insufficiency and pulmonary disease in German and Slavic cystic fibrosis patients with the R347P mutation.</strong> Hum. Mutat. 6: 219-225, 1995.">Varon et al. (1995)</a>; <a href="#Yang1993" class="mim-tip-reference" title="Yang, Y., Raper, S. E., Cohn, J. A., Engelhardt, J. F., Wilson, J. M. <strong>An approach for treating the hepatobiliary disease of cystic fibrosis by somatic gene transfer.</strong> Proc. Nat. Acad. Sci. 90: 4601-4605, 1993.">Yang et al. (1993)</a>
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Accurso, F. J., Rowe, S. M., Clancy, J. P., Boyle, M. P., Dunitz, J. M., Durie, P. R., Sagel, S. D., Hornick, D. B., Konstan, K. W., Donaldson, S. H., Moss, R. B., Pilewski, J. M., and 14 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21083385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21083385</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21083385[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21083385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa0909825" target="_blank">Full Text</a>]
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Alonso, M. J., Heine-Suner, D., Calvo, M., Rosell, J., Gimenez, J., Ramos, M. D., Telleria, J. J., Palacio, A., Estivill, X., Casals, T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17331079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17331079</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17331079" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1469-1809.2006.00310.x" target="_blank">Full Text</a>]
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Alper, O. M., Wong, L.-J. C., Hostetter, G., Cook, J., Tenenholz, B., Hsu, E., Woo, M. S.
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<strong>1154insTC is not a rare CFTR mutation. (Letter)</strong>
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Am. J. Med. Genet. 120A: 294-295, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12833419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12833419</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12833419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20038" target="_blank">Full Text</a>]
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Anand, R., Ogilvie, D. J., Butler, R., Riley, J. H., Finniear, R. S., Powell, S. J., Smith, J. C., Markham, A. F.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1706309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1706309</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1706309" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(91)90229-8" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1545465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1545465</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1545465" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039981</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9039981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.34.2.89" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/2.1.51" target="_blank">Full Text</a>]
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<strong>Determination of the relative contribution of three genes--the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene--to the etiology of idiopathic chronic pancreatitis.</strong>
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[<a href="https://doi.org/10.1038/sj.ejhg.5200786" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20009" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0140-6736(93)91885-p" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg215" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2006.045880" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.28.10.715" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/343220a0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1203/00006450-198008000-00005" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nm1197-1280" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41598-017-10910-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.30.9.797" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.10041" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/11.2.125" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI12108" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/420978" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0140-6736(91)91603-r" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/nar/13.17.6265" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1067/mpd.2000.109198" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004390050643" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19970317)69:2<155::aid-ajmg7>3.0.co;2-o" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.28.12.875" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.28.11.777" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s1097-2765(00)80196-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI5645" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.29.8.597" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF02428304" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0308393100" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00219336" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0092-8674(92)90213-v" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.1380050103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-003-0963-z" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/3.4.657" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1993.1046" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI117128" target="_blank">Full Text</a>]
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Yang, H., Shelat, A. A., Guy, R. K., Gopinath, V. S., Ma, T., Du, K., Lukacs, G. L., Taddei, A., Folli, C., Pedemonte, N., Galietta, L. J. V., Verkman, A. S.
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[<a href="https://doi.org/10.1074/jbc.M303098200" target="_blank">Full Text</a>]
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Yang, Y., Devor, D. C., Engelhardt, J. F., Ernst, S. A., Strong, T. V., Collins, F. S., Cohn, J. A., Frizzell, R. A., Wilson, J. M.
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[<a href="https://doi.org/10.1093/hmg/2.8.1253" target="_blank">Full Text</a>]
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Yang, Y., Janich, S., Cohn, J. A., Wilson, J. M.
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[<a href="https://doi.org/10.1073/pnas.90.20.9480" target="_blank">Full Text</a>]
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Yang, Y., Raper, S. E., Cohn, J. A., Engelhardt, J. F., Wilson, J. M.
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[<a href="https://doi.org/10.1073/pnas.90.10.4601" target="_blank">Full Text</a>]
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Youil, R., Kemper, B. W., Cotton, R. G. H.
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<strong>Screening for mutations by enzyme mismatch cleavage with T4 endonuclease VII.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7816853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7816853</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7816853" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.92.1.87" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.cell.2006.06.041" target="_blank">Full Text</a>]
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Zeiher, B. G., Eichwald, E., Zabner, J., Smith, J. J., Puga, A. P., McCray, P. B., Jr., Capecchi, M. R., Welsh, M. J., Thomas, K. R.
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[<a href="https://doi.org/10.1172/JCI118253" target="_blank">Full Text</a>]
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Zeitlin, P. L., Crawford, I., Lu, L., Woel, S., Cohen, M. E., Donowitz, M., Montrose, M. H., Hamosh, A., Cutting, G. R., Gruenert, D., Huganir, R., Maloney, P., Guggino, W. B.
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Proc. Nat. Acad. Sci. 89: 344-347, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1370353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1370353</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1370353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.89.1.344" target="_blank">Full Text</a>]
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Zhang, F., Kartner, N., Lukacs, G. L.
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<strong>Limited proteolysis as a probe for arrested conformational maturation of deltaF508 CFTR.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9501909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9501909</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9501909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nsb0398-180" target="_blank">Full Text</a>]
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Zielenski, J., Bozon, D., Kerem, B., Markiewicz, D., Durie, P., Rommens, J. M., Tsui, L.-C.
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<strong>Identification of mutations in exons 1 through 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1710599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1710599</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1710599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(91)90504-8" target="_blank">Full Text</a>]
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Zielenski, J., Markiewicz, D., Rininsland, F., Rommens, J., Tsui, L.-C.
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<strong>A cluster of highly polymorphic dinucleotide repeats in intron 17b of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.</strong>
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Am. J. Hum. Genet. 49: 1256-1262, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1720926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1720926</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1720926" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Zielenski, J., Patrizio, P., Corey, M., Handelin, B., Markiewicz, D., Asch, R., Tsui, L.-C.
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<strong>CFTR gene variant for patients with congenital absence of vas deferens. (Letter)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7573058/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7573058</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7573058" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bao Lige - updated : 10/21/2022
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Bao Lige - updated : 10/07/2022<br>Ada Hamosh - updated : 09/20/2019<br>Ada Hamosh - updated : 08/27/2019<br>Ada Hamosh - updated : 09/21/2018<br>Ada Hamosh - updated : 12/08/2016<br>Ada Hamosh - updated : 10/21/2015<br>Patricia A. Hartz - updated : 7/16/2013<br>Ada Hamosh - updated : 2/7/2013<br>Ada Hamosh - updated : 9/6/2012<br>Ada Hamosh - updated : 6/20/2012<br>Ada Hamosh - updated : 3/7/2012<br>Patricia A. Hartz - updated : 12/16/2011<br>Ada Hamosh - updated : 1/3/2011<br>Ada Hamosh - updated : 8/31/2010<br>Nara Sobreira - updated : 3/11/2010<br>Marla J. F. O'Neill - updated : 10/29/2009<br>Matthew B. Gross - updated : 5/7/2009<br>Ada Hamosh - updated : 7/17/2008<br>Patricia A. Hartz - updated : 5/19/2008<br>Ada Hamosh - updated : 7/25/2007<br>Cassandra L. Kniffin - updated : 7/10/2007<br>Cassandra L. Kniffin - updated : 6/22/2007<br>Cassandra L. Kniffin - updated : 5/4/2007<br>Marla J. F. O'Neill - updated : 3/15/2007<br>Patricia A. Hartz - updated : 2/8/2007<br>Patricia A. Hartz - updated : 11/29/2006<br>Victor A. McKusick - updated : 6/27/2006<br>Patricia A. Hartz - updated : 6/12/2006<br>Cassandra L. Kniffin - updated : 5/25/2006<br>Cassandra L. Kniffin - updated : 2/20/2006<br>Ada Hamosh - updated : 2/10/2006<br>Paul J. Converse - updated : 2/8/2006<br>Cassandra L. Kniffin - updated : 12/8/2005<br>Marla J. F. O'Neill - updated : 11/11/2005<br>Victor A. McKusick - updated : 10/14/2005<br>George E. Tiller - updated : 9/9/2005<br>George E. Tiller - updated : 6/3/2005<br>Cassandra L. Kniffin - updated : 5/18/2005<br>Marla J. F. O'Neill - updated : 5/16/2005<br>Victor A. McKusick - updated : 4/28/2005<br>Victor A. McKusick - updated : 3/23/2005<br>George E. Tiller - updated : 2/25/2005<br>George E. Tiller - updated : 2/17/2005<br>Marla J. F. O'Neill - updated : 1/28/2005<br>Victor A. McKusick - updated : 1/12/2005<br>Patricia A. Hartz - updated : 12/2/2004<br>Victor A. McKusick - updated : 11/9/2004<br>Victor A. McKusick - updated : 5/21/2004<br>Victor A. McKusick - updated : 5/5/2004<br>Ada Hamosh - updated : 4/30/2004<br>Victor A. McKusick - updated : 4/27/2004<br>Victor A. McKusick - updated : 1/8/2004<br>Victor A. McKusick - updated : 11/6/2003<br>Ada Hamosh - updated : 9/26/2003<br>Victor A. McKusick - updated : 8/13/2003<br>Ada Hamosh - updated : 7/8/2003<br>Victor A. McKusick - updated : 2/4/2003<br>George E. Tiller - updated : 12/16/2002<br>Michael B. Petersen - updated : 10/8/2002<br>George E. Tiller - updated : 9/17/2002<br>George E. Tiller - updated : 9/17/2002<br>Victor A. McKusick - updated : 8/16/2002<br>Victor A. McKusick - updated : 6/14/2002<br>Sonja A. Rasmussen - updated : 4/18/2002<br>Deborah L. Stone - updated : 4/10/2002<br>George E. Tiller - updated : 12/6/2001<br>Ada Hamosh - updated : 2/28/2001<br>Victor A. McKusick - updated : 2/5/2001<br>Michael J. Wright - updated : 1/8/2001<br>Ada Hamosh - updated : 11/17/2000<br>Stylianos E. Antonarakis - updated : 10/19/2000<br>Carol A. Bocchini - updated : 9/22/2000<br>Victor A. McKusick - updated : 7/26/2000<br>Victor A. McKusick - updated : 7/20/2000<br>Victor A. McKusick - updated : 5/18/2000<br>Victor A. McKusick - updated : 2/22/2000<br>Ada Hamosh - updated : 2/11/2000<br>Ada Hamosh - updated : 2/9/2000<br>Victor A. McKusick - updated : 10/21/1999<br>Wilson H. Y. Lo - updated : 9/9/1999<br>Victor A. McKusick - updated : 8/23/1999<br>Stylianos E. Antonarakis - updated : 8/3/1999<br>Victor A. McKusick - updated : 7/6/1999<br>Ada Hamosh - updated : 3/17/1999<br>Ada Hamosh - updated : 3/15/1999<br>Michael J. Wright - updated : 3/1/1999<br>Victor A. McKusick - updated : 11/6/1998<br>Victor A. McKusick - updated : 9/18/1998<br>Victor A. McKusick - updated : 9/17/1998<br>Victor A. McKusick - updated : 9/14/1998<br>Victor A. McKusick - updated : 5/7/1998<br>Victor A. McKusick - updated : 5/6/1998<br>Victor A. McKusick - updated : 4/30/1998<br>Victor A. McKusick - updated : 4/20/1998<br>Victor A. McKusick - updated : 3/19/1998<br>John F. Jackson - reorganized : 3/7/1998
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Victor A. McKusick : 3/7/1998
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<span class="mim-text-font">
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mgross : 10/21/2022
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mgross : 10/07/2022<br>carol : 07/18/2022<br>alopez : 07/13/2022<br>carol : 08/06/2021<br>carol : 08/05/2021<br>carol : 09/30/2019<br>alopez : 09/20/2019<br>alopez : 08/27/2019<br>carol : 06/11/2019<br>alopez : 09/21/2018<br>alopez : 07/13/2018<br>carol : 05/11/2018<br>carol : 04/10/2018<br>carol : 04/09/2018<br>alopez : 12/08/2016<br>alopez : 11/01/2016<br>carol : 09/22/2016<br>joanna : 07/13/2016<br>carol : 7/6/2016<br>carol : 2/5/2016<br>alopez : 10/21/2015<br>joanna : 10/21/2015<br>carol : 5/27/2014<br>carol : 2/21/2014<br>mgross : 7/16/2013<br>alopez : 2/13/2013<br>alopez : 2/13/2013<br>alopez : 2/13/2013<br>alopez : 2/11/2013<br>terry : 2/7/2013<br>carol : 10/4/2012<br>alopez : 9/12/2012<br>alopez : 9/10/2012<br>terry : 9/6/2012<br>terry : 8/8/2012<br>alopez : 6/25/2012<br>alopez : 6/22/2012<br>terry : 6/20/2012<br>carol : 5/10/2012<br>alopez : 3/9/2012<br>terry : 3/7/2012<br>mgross : 3/6/2012<br>terry : 12/16/2011<br>terry : 10/26/2011<br>carol : 4/7/2011<br>terry : 3/18/2011<br>mgross : 3/17/2011<br>terry : 3/15/2011<br>alopez : 1/5/2011<br>terry : 1/3/2011<br>carol : 10/27/2010<br>alopez : 9/3/2010<br>alopez : 9/3/2010<br>alopez : 9/3/2010<br>alopez : 9/3/2010<br>terry : 8/31/2010<br>carol : 4/29/2010<br>carol : 3/23/2010<br>terry : 3/11/2010<br>terry : 1/20/2010<br>wwang : 10/29/2009<br>alopez : 9/30/2009<br>carol : 8/11/2009<br>terry : 6/3/2009<br>wwang : 5/11/2009<br>mgross : 5/7/2009<br>wwang : 4/29/2009<br>terry : 4/3/2009<br>joanna : 2/2/2009<br>alopez : 10/22/2008<br>terry : 10/20/2008<br>alopez : 7/17/2008<br>terry : 7/17/2008<br>mgross : 5/19/2008<br>terry : 12/17/2007<br>wwang : 9/6/2007<br>alopez : 8/2/2007<br>terry : 7/25/2007<br>wwang : 7/18/2007<br>ckniffin : 7/10/2007<br>wwang : 7/2/2007<br>ckniffin : 6/22/2007<br>wwang : 5/23/2007<br>ckniffin : 5/4/2007<br>wwang : 3/16/2007<br>terry : 3/15/2007<br>alopez : 2/27/2007<br>terry : 2/19/2007<br>mgross : 2/8/2007<br>wwang : 11/29/2006<br>terry : 11/16/2006<br>carol : 6/29/2006<br>terry : 6/27/2006<br>mgross : 6/12/2006<br>wwang : 6/12/2006<br>ckniffin : 5/25/2006<br>wwang : 3/14/2006<br>ckniffin : 2/20/2006<br>alopez : 2/17/2006<br>terry : 2/10/2006<br>carol : 2/8/2006<br>carol : 12/23/2005<br>ckniffin : 12/8/2005<br>wwang : 11/11/2005<br>terry : 11/11/2005<br>carol : 10/21/2005<br>terry : 10/14/2005<br>wwang : 10/12/2005<br>alopez : 10/4/2005<br>terry : 9/9/2005<br>alopez : 6/3/2005<br>ckniffin : 5/18/2005<br>wwang : 5/16/2005<br>tkritzer : 5/11/2005<br>terry : 4/28/2005<br>tkritzer : 3/24/2005<br>terry : 3/23/2005<br>tkritzer : 3/3/2005<br>terry : 2/25/2005<br>wwang : 2/25/2005<br>wwang : 2/22/2005<br>terry : 2/17/2005<br>tkritzer : 1/31/2005<br>terry : 1/28/2005<br>wwang : 1/21/2005<br>wwang : 1/21/2005<br>wwang : 1/20/2005<br>wwang : 1/18/2005<br>terry : 1/12/2005<br>mgross : 12/2/2004<br>tkritzer : 11/10/2004<br>terry : 11/9/2004<br>alopez : 5/28/2004<br>terry : 5/21/2004<br>tkritzer : 5/7/2004<br>terry : 5/5/2004<br>alopez : 5/5/2004<br>terry : 4/30/2004<br>terry : 4/27/2004<br>carol : 2/19/2004<br>cwells : 1/12/2004<br>terry : 1/8/2004<br>cwells : 11/7/2003<br>carol : 11/6/2003<br>alopez : 11/6/2003<br>terry : 11/6/2003<br>carol : 11/3/2003<br>alopez : 10/16/2003<br>tkritzer : 10/2/2003<br>alopez : 9/29/2003<br>terry : 9/26/2003<br>tkritzer : 8/20/2003<br>tkritzer : 8/19/2003<br>terry : 8/13/2003<br>mgross : 7/14/2003<br>terry : 7/8/2003<br>terry : 3/19/2003<br>carol : 2/28/2003<br>tkritzer : 2/19/2003<br>terry : 2/4/2003<br>cwells : 12/16/2002<br>tkritzer : 11/19/2002<br>cwells : 10/8/2002<br>cwells : 9/17/2002<br>cwells : 9/17/2002<br>tkritzer : 8/23/2002<br>tkritzer : 8/21/2002<br>terry : 8/16/2002<br>cwells : 6/19/2002<br>cwells : 6/18/2002<br>terry : 6/14/2002<br>ckniffin : 6/5/2002<br>carol : 4/19/2002<br>terry : 4/18/2002<br>carol : 4/10/2002<br>carol : 4/10/2002<br>alopez : 3/14/2002<br>alopez : 3/13/2002<br>joanna : 2/14/2002<br>joanna : 2/14/2002<br>cwells : 12/18/2001<br>cwells : 12/6/2001<br>carol : 9/10/2001<br>alopez : 2/28/2001<br>terry : 2/28/2001<br>carol : 2/26/2001<br>cwells : 2/8/2001<br>terry : 2/5/2001<br>alopez : 1/8/2001<br>mgross : 11/17/2000<br>terry : 11/17/2000<br>mcapotos : 10/20/2000<br>mcapotos : 10/20/2000<br>terry : 10/19/2000<br>carol : 9/22/2000<br>mcapotos : 9/22/2000<br>carol : 8/3/2000<br>terry : 7/26/2000<br>mcapotos : 7/20/2000<br>mcapotos : 7/5/2000<br>carol : 6/12/2000<br>mcapotos : 6/7/2000<br>mcapotos : 5/30/2000<br>terry : 5/18/2000<br>mcapotos : 3/22/2000<br>mcapotos : 3/15/2000<br>mcapotos : 3/13/2000<br>terry : 2/22/2000<br>alopez : 2/15/2000<br>terry : 2/11/2000<br>alopez : 2/9/2000<br>carol : 12/13/1999<br>mcapotos : 12/7/1999<br>alopez : 11/24/1999<br>carol : 11/9/1999<br>carol : 11/9/1999<br>carol : 10/21/1999<br>carol : 9/9/1999<br>carol : 9/9/1999<br>jlewis : 9/8/1999<br>terry : 8/23/1999<br>carol : 8/18/1999<br>carol : 8/18/1999<br>mgross : 8/3/1999<br>mgross : 8/3/1999<br>mgross : 7/14/1999<br>jlewis : 7/14/1999<br>terry : 7/6/1999<br>terry : 5/20/1999<br>alopez : 3/24/1999<br>alopez : 3/17/1999<br>alopez : 3/15/1999<br>carol : 3/1/1999<br>terry : 11/18/1998<br>carol : 11/16/1998<br>terry : 11/6/1998<br>carol : 9/28/1998<br>terry : 9/18/1998<br>terry : 9/17/1998<br>carol : 9/17/1998<br>carol : 9/17/1998<br>terry : 9/14/1998<br>carol : 8/11/1998<br>carol : 8/10/1998<br>dkim : 7/24/1998<br>alopez : 5/21/1998<br>alopez : 5/18/1998<br>alopez : 5/7/1998<br>alopez : 5/7/1998<br>alopez : 5/6/1998<br>terry : 5/6/1998<br>carol : 5/2/1998<br>terry : 4/30/1998<br>alopez : 4/23/1998<br>alopez : 4/23/1998<br>alopez : 4/23/1998<br>terry : 4/20/1998<br>carol : 4/17/1998<br>carol : 3/28/1998<br>carol : 3/7/1998
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<span class="mim-font">
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<strong>*</strong> 602421
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<h3>
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CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; CFTR
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 7; ABCC7
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CFTR</em></strong>
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<p>
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<strong>SNOMEDCT:</strong> 190905008;
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<strong>ICD10CM:</strong> E84, E84.9;
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<strong>ICD9CM:</strong> 277.0;
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</p>
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<p>
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<strong>
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<em>
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Cytogenetic location: 7q31.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:117,480,025-117,668,665 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<td rowspan="6">
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<span class="mim-font">
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7q31.2
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<span class="mim-font">
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{Bronchiectasis with or without elevated sweat chloride 1, modifier of}
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<td>
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<span class="mim-font">
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211400
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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{Hypertrypsinemia, neonatal}
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<span class="mim-font">
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</td>
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<td>
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<span class="mim-font">
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<span class="mim-font">
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3
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{Pancreatitis, hereditary}
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<span class="mim-font">
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167800
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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Congenital bilateral absence of vas deferens
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<span class="mim-font">
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277180
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Autosomal recessive
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3
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Cystic fibrosis
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<span class="mim-font">
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219700
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<span class="mim-font">
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Autosomal recessive
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3
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Sweat chloride elevation without CF
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<span class="mim-font">
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The CFTR gene encodes an ATP-binding cassette (ABC) transporter that functions as a low conductance Cl(-)-selective channel gated by cycles of ATP binding and hydrolysis at its nucleotide-binding domains (NBDs) and regulated tightly by an intrinsically disordered protein segment distinguished by multiple consensus phosphorylation sites termed the regulatory domain (summary by Wang et al., 2014). </p>
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<div>
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<br />
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</div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Riordan et al. (1989) isolated overlapping cDNA clones from epithelial cell libraries with a genomic DNA segment containing a portion of the putative gene causing cystic fibrosis (CF; 219700). Transcripts approximately 6,500 nucleotides in size were detectable in the tissues affected in patients with CF. The predicted protein consists of 2 similar motifs, each with a domain having properties consistent with membrane-association, and a domain believed to be involved in ATP binding. In CF patients, a deleted phenylalanine residue occurs at the center of the putative first nucleotide-binding fold (NBF). The predicted protein has 1,480 amino acids with a molecular mass of 168,138 Da. The characteristics are remarkably similar to those of the mammalian multidrug resistant P-glycoprotein (171050), which also maps to 7q, and to a number of other membrane-associated proteins. To avoid confusion with the previously named CF antigen (123885), Riordan et al. (1989) referred to the protein as cystic fibrosis transmembrane conductance regulator (CFTR). </p><p>Cystic fibrosis represents the first genetic disorder elucidated strictly by the process of reverse genetics (later called positional cloning), i.e., on the basis of map location but without the availability of chromosomal rearrangements or deletions such as those that have greatly facilitated previous success in the cloning of human disease genes in Duchenne muscular dystrophy (310200), retinoblastoma (180200), and chronic granulomatous disease (306400), for example. By use of a combination of chromosome walking and jumping, Rommens et al. (1989) succeeded in covering the CF region on 7q. The jumping technique was particularly useful in bypassing 'unclonable' regions, which are estimated to constitute 5% of the human genome. (Yeast artificial chromosome (YAC) vectors represent an alternative strategy.) The identification of undermethylated CpG islands was 1 tip-off; another was screening of a cDNA library constructed from cultured sweat gland cells of a non-CF individual. The CF gene proved to be about 250,000 bp long, a surprising finding since the absence of apparent genomic rearrangements in CF chromosomes and the evidence of a limited number of CF mutations predicted a small mutational target. </p><p>Green and Olson (1990) described a general strategy for cloning and mapping large regions of human DNA with yeast artificial chromosomes (YACs). By analyzing 30 YAC clones from the region of chromosome 7 containing the CFTR gene, a contig map spanning more than 1.5 Mbp was assembled. Individual YACs as large as 790 kb and containing the entire CF gene were constructed in vivo by meiotic recombination in yeast between pairs of overlapping YACs. Anand et al. (1991) described the physical mapping of a 1.5-Mbp region encompassing 2 genetic loci flanking the CF locus and contained within a series of YAC clones. The entire CFTR gene was included within 1 of these YACs, a 310-kb clone also containing flanking sequence in both the 5-prime and 3-prime directions from the gene. </p>
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<strong>Gene Structure</strong>
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<p>Riordan et al. (1989) identified 24 exons in the CFTR gene. </p><p>With the hope of identifying conserved regions of biologic interest by sequence comparison, Ellsworth et al. (2000) sought to establish the sequence of the chromosomal segments encompassing the human CFTR and mouse Cftr genes. Bacterial clone-based physical maps of the relevant human and mouse genomic regions were constructed, and minimally overlapping sets of clones were selected and sequenced. Analyses of the resulting data provided insights about the organization of the CFTR/Cftr genes and potential sequence elements regulating their expression. </p>
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<strong>Mapping</strong>
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<p>Riordan et al. (1989) mapped the CFTR gene to chromosome 7q. For additional information on the mapping of the gene for cystic fibrosis, see 219700. </p><p>The mapping of the murine equivalent of the WNT2 and MET (164860) genes to mouse chromosome 6 (Chan et al., 1989) strongly indicated that the mouse equivalent of the cystic fibrosis gene is also located on chromosome 6. By Southern analysis of mouse/Chinese hamster somatic cell hybrid DNAs, Kelley et al. (1992) mapped the Cftr gene to chromosome 6. Using restriction fragment length variants (RFLVs) in the study of interspecific backcrosses, Siegel et al. (1992) demonstrated that the Cftr gene in the mouse is close to Met and Cola-2. Trezise et al. (1992) demonstrated that the Cftr locus is on rat chromosome 4. Study of other loci suggested that an ancestral mammalian chromosome is represented by the present-day rat chromosome 4: 5 genes are syntenic on rat chromosome 4 and mouse chromosome 6 but are divided between human chromosomes 7 and 12. Another 5 genes that are syntenic on rat chromosome 4 and human chromosome 7 are divided between chromosomes 5 and 6 in the mouse. </p>
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<p>In addition to functioning as a chloride channel, CFTR controls the regulation of other transport pathways. For example, patients with CF and the homozygous CFTR-deficient mouse have enhanced sodium ion absorption; this enhanced sodium ion absorption is corrected by addition of a wildtype copy of CFTR. CFTR and outwardly rectifying chloride channels (ORCCs) are distinct channels but are linked functionally via an unknown regulatory mechanism. Schwiebert et al. (1995) presented results from whole-cell and single-channel patch-clamp recordings, short-circuit current recordings, and ATP-release assays of normal, CF, and wildtype or mutant CFTR-transfected CF airway cultured epithelial cells indicating that CFTR regulates ORCCs by triggering the transport of the potent agonist, ATP, out of the cell. The results suggested that CFTR functions to regulate other chloride ion secretory pathways in addition to conducting chloride ion itself. </p><p>A quality control system that rapidly degrades abnormal membrane and secretory protein is stringently applied to the CFTR protein; approximately 75% of the wildtype precursor and 100% of the delF508 variant (602421.0001) are rapidly degraded before exiting from the endoplasmic reticulum (ER). Jensen et al. (1995) demonstrated that CFTR and presumably other intrinsic membrane proteins are substrates for proteasomal degradation during their maturation within the endoplasmic reticulum. Chang et al. (1999) showed that export-incompetent CFTR proteins display multiple arginine-framed tripeptide sequences. Inactivation of 4 of these motifs by replacement of arginine residues at positions R29, R516, R555, and R766 with lysine residues simultaneously caused mutant delF508 CFTR protein to escape ER quality control and function at the cell surface. Chang et al. (1999) suggested that interference with recognition of these signals may be helpful in the management of CF. </p><p>Younger et al. (2006) identified an ER membrane-associated ubiquitin ligase complex containing the E3 RMA1 (RNF5; 602677), the E2 UBC6E (UBE2J1), and derlin-1 (DERL1; 608813) that cooperated with the cytosolic HSC70 (HSPA8; 600816)/CHIP (STUB1; 607207) E3 complex to triage CFTR and delFl508. Derlin-1 retained CFTR in the ER membrane and interacted with RMA1 and UBC6E to promote proteasomal degradation of CFTR. RMA1 could recognize folding defects in delF508 coincident with translation, whereas CHIP appeared to act posttranslationally. A folding defect in delF508 detected by RMA1 involved the inability of the second membrane-spanning domain of CFTR to productively interact with N-terminal domains. Younger et al. (2006) concluded that the RMA1 and CHIP E3 ubiquitin ligases act sequentially in ER membrane and cytosol to monitor the folding status of CFTR and delF508. </p><p>Randak et al. (1997) expressed NBF2 of CFTR as a soluble protein fused to maltose-binding protein in E. coli and found that it catalyzed hydrolysis of ATP to form ADP and Pi. The ADP product inhibited ATPase activity. NBF2 also hydrolyzed GTP to GDP and Pi. In the presence of AMP, however, the ATPase reaction was superseded by adenylate kinase activity, resulting in formation of 2 ADP molecules from ATP and AMP. Randak et al. (1997) identified a typical adenylate kinase-like AMP-binding site in NBF2. </p><p>To determine the structural basis for the ATPase activity of CFTR, Ramjeesingh et al. (1999) studied the effect of mutations in the Walker A consensus motifs on ATP hydrolysis by the purified, intact protein. Mutation of the lysine residue in the Walker A motif of either NBF inhibited the ATPase activity of purified, intact CFTR protein by greater than 50%, suggesting that the 2 NBFs function cooperatively in catalysis. Surprisingly, the rate of channel gating was significantly inhibited only when the mutation was in the second NBF, suggesting that ATPase activity may not be tightly coupled to channel gating. </p><p>Randak and Welsh (2003) demonstrated that full-length CFTR and the isolated nucleotide-binding domain-2 (NBD2) had ATPase and adenylate kinase activities following expression in HeLa cells. The adenylate kinase inhibitor Ap5A inhibited CFTR Cl- currents, and it inhibited channel activity by binding an ATP site and an AMP site. Adding AMP switched enzymatic activity of the NBD2 polypeptide from ATPase to adenylate kinase. ATP and AMP appeared to induce dimerization between NBD1 and NBD2, causing the channel to open. Randak and Welsh (2003) hypothesized that at physiologic AMP concentrations, the predominant reaction regulating channel activity is likely adenylate kinase. </p><p>Jiang and Engelhardt (1998) reviewed the cellular heterogeneity of CFTR expression and function in the lung and the important implications for gene therapy of cystic fibrosis. </p><p>Cystic fibrosis is characterized by persistent Pseudomonas aeruginosa colonization of the conducting airways leading to the migration of inflammatory cells, including polymorphonuclear leukocytes (PMNs), into the airways of CF patients. PMNs release a potent chemokinetic and chemoattractant, leukotriene B, during an inflammatory response, resulting in the further migration of inflammatory cells. Cromwell et al. (1981) demonstrated the existence of leukotrienes in the sputum of CF patients. The oxidative metabolites of arachidonic acid and the inflammatory cell-derived proteases have been implicated in the destruction and shedding of the airway epithelia observed in CF. Based on these observations, it has been proposed that antiinflammatory drugs might be useful in CF therapy. The nonsteroidal antiinflammatory drug (NSAID) ibuprofen inhibits 5-lipoxygenase and hence leukotriene formation, suggesting that ibuprofen may be useful in the treatment of CF. Its possible benefit in CF, with no apparent adverse effects, was reported by Konstan et al. (1995). However, other effects of ibuprofen may counteract therapeutic strategies designed to increase CFTR expression and/or function in secretory epithelia. Devor and Schultz (1998) evaluated the acute effects of ibuprofen and salicylic acid on cAMP-mediated Cl- secretion in both colonic and airway epithelia and found that at a pharmacologically relevant concentration the drugs inhibited chloride ion secretion across these epithelia and that this inhibition was due at least in part to the blocking of the CFTR Cl- channels. </p><p>Wei et al. (1998) studied CFTR channel activity of mature R-domain mutants with point mutations at sites other than the predicted phosphorylation sites. Whole-cell chloride conduction was increased in Xenopus oocytes injected with H620Q-CFTR mRNA, but decreased in the E822K and E826K mutants compared to wildtype CFTR. Anion permeability and single-channel conductances did not differ from wildtype for any of the mutants. Cell-attached single channel studies in COS cells revealed that both open channel probability and/or the number of functional channels were either higher (H260Q) or lower (E822K and E826K) than in wildtype CFTR. These results suggested that sites other than the phosphorylation sites in the R-domain influence gating. </p><p>Chanson et al. (1999) compared gap junctional coupling in a human pancreatic cell line harboring the delF508 mutation in CFTR and in the same cell line in which the defect was corrected by transfection with wildtype CFTR. Exposure to agents that elevate intracellular cAMP or specifically activate protein kinase A evoked chloride ion currents and markedly increased junctional conductance of CFTR-expressing cell pairs, but not in the parental cells. Thus, the expression of functional CFTR restored the cAMP-dependent regulation of junctional conductance as well as the chloride ion channel in CF cells. Consequently, defective regulation of gap junction channels may contribute to the altered functions of tissues affected in CF. </p><p>Reddy et al. (1999) demonstrated that in freshly isolated normal sweat ducts, epithelial sodium channel (ENaC; see 600228) activity is dependent on, and increases with, CFTR activity. Reddy et al. (1999) also found that the primary defect in chloride permeability in cystic fibrosis is accompanied secondarily by a sodium conductance in this tissue that cannot be activated. Thus, reduced salt absorption in cystic fibrosis is due not only to poor chloride conductance but also to poor sodium conductance. </p><p>Weixel and Bradbury (2000) used in vivo cross-linking and in vitro pull-down assays to show that full-length CFTR binds to the endocytic adaptor complex AP2 (see 601024). Substitution of an alanine residue for tyrosine at position 1424 significantly reduced the ability of AP2 to bind the C terminus of CFTR. However, mutation to a phenylalanine residue, which is normally found in dogfish CFTR at this position, did not perturb AP2 binding. Taken together, these data suggest that the C terminus of CFTR contains a tyrosine-based internalization signal that interacts with the endocytic adaptor complex AP2 to facilitate efficient entry of CFTR into clathrin-coated vesicles. </p><p>Wang et al. (2000) identified a hydrophilic CFTR-binding protein, CAP70, which is concentrated on the apical surfaces. CAP70 had previously been identified by Kocher et al. (1998) as PDZK1 (603831). The protein contains 4 PDZ domains, 3 of which are capable of binding to the CFTR C terminus. Linking at least 2 CFTR molecules via cytoplasmic C-terminal binding by either multivalent CAP70 or a bivalent monoclonal antibody potentiates the CFTR chloride channel activity. Thus, the CFTR channel can be switched to a more active conducting state via a modification of intermolecular CFTR-CFTR contact that is enhanced by an accessory protein. </p><p>Moyer et al. (2000) reported that the C terminus of CFTR constitutes a PDZ-interacting domain that is required for CFTR polarization to the apical plasma membrane and interaction with the PDZ domain-containing protein EBP50 (604990). PDZ-interacting domains are typically composed of the C-terminal 3 to 5 amino acids, which in CFTR are gln-asp-thr-arg-leu. Point substitution of the leucine at position 0 with alanine abrogated apical polarization of CFTR, interaction between CFTR and EBP50, efficient expression of CFTR in the apical membrane, and chloride secretion. Point substitution of the threonine at position -2 with alanine or valine had no effect on the apical polarization of CFTR, but reduced interaction between CFTR and EBP50, efficient expression of CFTR in the apical membrane, and chloride secretion. By contrast, individual point substitution of any of the other amino acids in the PDZ domain had no effect on measured parameters. Moyer et al. (2000) concluded that mutations that delete the C terminus of CFTR may cause cystic fibrosis because CFTR is not polarized, complexed with EBP50, or efficiently expressed in the apical membrane of epithelial cells. </p><p>CFTR regulates other transporters, including chloride-coupled bicarbonate transport. Alkaline fluids are secreted by normal tissues, whereas acidic fluids are secreted by mutant CFTR-expressing tissues, indicating the importance of this activity. Bicarbonate and pH affect mucin viscosity and bacterial binding. Choi et al. (2001) examined chloride-coupled bicarbonate transport by CFTR mutants that retain substantial or normal chloride channel activity. Choi et al. (2001) demonstrated that mutants reported to be associated with cystic fibrosis with pancreatic insufficiency do not support bicarbonate transport, and those associated with pancreatic sufficiency show reduced bicarbonate transport. Choi et al. (2001) concluded that their findings demonstrate the importance of bicarbonate transport in the function of secretory epithelia and in CF. </p><p>Rowntree et al. (2001) showed that removal of a DNase I hypersensitive site (DHS) in intron 1 (185+10 kb) of CFTR abolished the activity of this DHS in transient transfection assays of reporter/enhancer gene constructs. Stable transfections of a human colon carcinoma cell line with CFTR-containing YACs showed that transcription from the DHS element-deleted YAC was reduced by 60% compared to the intact construct. In transgenic mice, deletion of the intron 1 DHS had no effect on expression in the lung, but reduced expression in the intestine by 60%. The authors concluded that the regulatory element associated with the intron 1 DHS is tissue-specific and is required for normal CFTR expression levels in the intestinal epithelium in vivo. </p><p>Callen et al. (2000) developed a cAMP-mediated sweat rate test that allows the quantitative discrimination of CFTR function, thereby indicating CF genotype: CF, CF carrier, and non-CF. Callen et al. (2000) remarked that this test may be helpful in the diagnosis of ambiguous cases and in studies of new agents to increase the function of CFTR. </p><p>In CFTR, an abbreviated polypyrimidine tract between the branch point A and the 3-prime splice site is associated with increased exon skipping and disease. However, many exons, both in CFTR and in other genes, have short polypyrimidine tracts in their 3-prime splice sites, yet they are not skipped. Hefferon et al. (2002) examined the molecular basis of the skipping of constitutive exons in mRNAs and the skipping of exon 9 in the CFTR gene. They reported observations in human, mouse, and sheep that placed renewed emphasis on deviations at 3-prime splice sites in nucleotides other than the invariant GT, particularly when such changes are found in conjunction with other altered splicing sequences, such as a shortened polypyrimidine tract. Hefferon et al. (2002) suggested that careful inspection of entire 5-prime splice sites may identify constitutive exons that are vulnerable to skipping. </p><p>Using a quantitative mRNA assay at 14 time points through ovine gestation, Broackes-Carter et al. (2002) determined that CFTR expression was highest at the start of the second trimester followed by a gradual decline through to term. In contrast, epithelial sodium channel (SCNN1A; 600228) expression increased from the start of the third trimester. The authors proposed a role for CFTR in differentiation of the respiratory epithelium and suggested that its expression levels are not merely reflecting major changes in the sodium/chloride bulk flow close to term. </p><p>Eidelman et al. (2002) found that NBF1 of CFTR interacted selectively with phosphatidylserine rather than phosphatidylcholine. In contrast, NBF1 with the delta-F508 mutation lost the ability to discriminate between these phospholipids. In mouse L cells expressing delta-F508 CFTR, replacement of phosphatidylcholine by noncharged analogs led to increased CFTR protein expression, suggesting that aberrant interaction between the delta-F508 NFB1 domain and phospholipid chaperones may contribute to the processing defect of the delta-F508 CFTR mutant. </p><p>Plasma membrane expression of delta-F508 CFTR can be rescued in epithelial cells by culturing them at 27 degrees Celsius for 24 hours. By screening 100,000 diverse small molecules, Yang et al. (2003) found that tetrahydrobenzothiophenes could activate cold-induced membrane-associated delta-F508 CFTR, resulting in reversible Cl- conductance in transfected rat thyroid epithelial cells. Single-cell voltage clamp analysis showed characteristic CFTR currents. Activation required low concentrations of a cAMP agonist, mimicking the normal physiologic response. </p><p>Reddy and Quinton (2003) reported phosphorylation- and ATP-independent activation of CFTR by cytoplasmic glutamate that exclusively elicits chloride but not bicarbonate conductance in the human sweat duct. They also showed that the anion selectivity of glutamate-activated CFTR is not intrinsically fixed, but can undergo a dynamic shift to conduct bicarbonate by a process involving ATP hydrolysis. Duct cells from patients with the delta-F508 CFTR mutation showed no glutamate/ATP-activated chloride or bicarbonate conductance. In contrast, duct cells from heterozygous patients with R117H (602421.0005)/delta-F508 mutations also lost most of the chloride conductance, yet retained significant bicarbonate conductance. Reddy and Quinton (2003) concluded that not only does glutamate control neuronal ion channels, but it can also regulate anion conductance and selectivity of CFTR in native epithelial cells. They proposed that the loss of this uniquely regulated bicarbonate conductance is most likely responsible for the more severe forms of cystic fibrosis pathology. </p><p>Wang et al. (2003) demonstrated that endometrial epithelial cells possess a CFTR-mediated bicarbonate transport mechanism. Coculture of sperm with endometrial cells treated with antisense oligonucleotide against CFTR, or with bicarbonate secretion-defective CF epithelial cells, resulted in lower sperm capacitation and egg-fertilizing ability. These results were considered consistent with a critical role of CFTR in controlling uterine bicarbonate secretion and the fertilizing capacity of sperm, providing a link between defective CFTR and lower female fertility in CF. </p><p>Sheep and human CFTR genes show a gradual decline in expression during lung development, from the early midtrimester through to term. Mouchel et al. (2003) identified a novel 5-prime exon of the sheep CFTR gene (ov1a) that occurs in 2 splice forms (ov1aL and ov1aS), which are both mutually exclusive with exon 1. CFTR transcripts, including ov1aL and ov1aS, were present at low levels in many sheep tissues; however, ov1aS showed temporal and spatial regulation during fetal lung development, being most abundant when CFTR expression starts to decline. Alternative 5-prime exons -1a and 1a in the human CFTR gene also showed changes in expression levels through lung development. Structural evaluation of ov1aL and ov1aS revealed the potential to form extremely stable secondary structures which would cause ribosomal subunit detachment. Further, the loss of exon 1 from the CFTR transcript removed motifs that are thought crucial for normal trafficking of the CFTR protein. Mouchel et al. (2003) hypothesized that recruitment of these alternative upstream exons may represent a novel mechanism of developmental regulation of CFTR expression. </p><p>Fischer et al. (2004) found that vitamin C induced the opening of CFTR chloride channels by increasing the average open probability in the absence of detectable increased cAMP levels. Exposure of the apical airway surface to physiologic concentrations of vitamin C stimulated transepithelial chloride secretion. When instilled into the nasal epithelium of human subjects, vitamin C activated chloride transport. Fischer et al. (2004) concluded that cellular vitamin C, via its apical vitamin C transporter, is a biologic regulator of CFTR-mediated chloride secretion in epithelia. </p><p>Vergani et al. (2005) used single-channel recording methods on intact CFTR molecules to directly follow opening and closing of the channel gates, and related these occurrences to ATP-mediated events in the nucleotide binding domains (NBDs). They found that energetic coupling between 2 CFTR residues, expected to lie on opposite sides of its predicted NBD1-NBD2 dimer interface, changes in concert with channel gating status. The 2 monitored side chains are independent of each other in closed channels but become coupled as the channels open. Vergani et al. (2005) concluded that their results directly link ATP-driven tight dimerization of CFTR's cytoplasmic nucleotide binding domains to opening of the ion channel in the transmembrane domains. This establishes a molecular mechanism, involving dynamic restructuring of the NBD dimer interface, that is probably common to all members of the ABC protein superfamily. </p><p>Using proteomics to assess global CFTR protein interactions, Wang et al. (2006) showed that HSP90 (see 140571) cochaperones modulated HSP90-dependent stability of CFTR protein folding in the ER. Small interfering RNA-mediated partial silencing of the HSP90 cochaperone ATPase regulator AHA1 (AHSA1; 608466) in human embryonic kidney and lung cell lines rescued delivery of CFTR delta-F508 to the cell surface. Wang et al. (2006) proposed that failure of CFTR delta-F508 to achieve an energetically favorable fold in response to steady-state dynamics of the chaperone folding environment is responsible for the pathophysiology of CF. </p><p>Using proteomic approaches, Thelin et al. (2007) showed that filamin (FLNA; 300017) associates with the extreme CFTR N terminus, and found that the disease-causing S13F mutation disrupts this interaction. Cell studies revealed that FLNA tethers plasma membrane CFTR to the underlying actin network, stabilizing CFTR at the cell surface and regulating the plasma membrane dynamics and confinement of the channel. In the absence of filamin binding, CFTR is rapidly internalized from the cell surface, where it accumulates prematurely in lysosomes and is ultimately degraded. Thelin et al. (2007) concluded that the CFTR N terminus plays a role in the regulation of the plasma membrane stability and metabolic stability of CFTR, and stated that S13F is the first missense mutation in CFTR found to disrupt a protein-protein interaction. </p><p>Coimmunoprecipitation analysis and immunofluorescence microscopy by Cheng et al. (2002) showed that CAL (GOPC; 606845) interacted with the C terminus of CFTR in the Golgi. Functional analysis indicated that the CAL-CFTR interaction resulted in a reduction of the CFTR chloride current by a selective inhibition of cell surface CFTR expression; this could be reversed by competition from NHERF (604990). </p><p>Cheng et al. (2010) showed that both syntaxin-6 (STX6; 603944) and CAL were involved in downregulation of CFTR via lysosome-mediated degradation. STX6 bound the N terminus of CFTR, and CAL independently bound the C terminus of CFTR. Overexpression of STX6 reduced cell surface expression of CFTR and caused its instability, but not in the absence of CAL and not in the presence of a lysosome inhibitor. Conversely, overexpression of a dominant-negative STX6 mutant or knockdown of STX6 resulted in CFTR stability. STX6 and CAL had no effect on the stability of delta-F508 CFTR, which is retained in the ER and undergoes ER-associated degradation. Cheng et al. (2010) concluded that STX6 and CAL function in the trans-Golgi network and direct trafficking of CFTR to the lysosome. </p><p>By coimmunoprecipitation of transfected COS-7 and CHO-K1 cells, Rode et al. (2012) found that human testis anion transporter-1 (TAT1, or SLC26A8; 608480) interacted with the Cl- and HCO3- conductor CFTR. The 2 proteins colocalized at the equatorial segment of the human sperm head, with partial colocalization at the annulus. Similar colocalization was observed in mouse sperm. Voltage clamp experiments showed that TAT1 enhanced PKA (see 188830)-stimulated currents in CFTR-expressing Xenopus oocytes and stimulated cAMP-dependent CFTR-mediated iodide efflux in transfected CHO-K1 cells. TAT1 alone did not mediate iodide efflux in CHO-K1 cells and did not affect whole-cell conductance in Xenopus oocytes, suggesting that TAT1 is an electroneutral anion exchanger. Rode et al. (2012) concluded that TAT1 and CFTR cooperate in the regulation of Cl-/HCO3- fluxes required for sperm motility and capacitation. </p><p>By overexpression and knockdown analyses, Ousingsawat et al. (2011) showed that TMEM16A (610108) formed Ca(2+)-activated Cl- channels (CaCCs) in human airway epithelial cells and that TMEM16A was inhibited by CFTR (602421). However, knockdown analysis in HEK293 cells revealed that CFTR currents were largely independent of other TMEM16 isoforms. CFTR and TMEM16A had an inverse relationship, as CFTR currents were attenuated by additional expression of TMEM16A in HEK293 cells. CFTR and TMEM16A localized to the membrane and appeared to interact physically. </p><p>El Khouri et al. (2013) found that the RING-dependent E3 ligase RNF185 (620096) was transcriptionally induced during the unfolded protein response (UPR) and was associated with ER-associated degradation (ERAD). RNF185 targeted CFTR to ERAD to regulate CFTR turnover by inducing ubiquitin-proteasome-dependent degradation of CFTR proteins during translation. Further analysis indicated that RNF5 and RNF185 had redundant function in the control of CFTR stability. </p><p>Benedetto et al. (2017) found that Ca(2+)-activated and cAMP-stimulated Cftr-dependent chloride secretion depended on Tmem16a expression, as knockout of Tmem16a eliminated Cftr currents in mouse intestinal epithelial cells and mouse respiratory epithelial cells. Analysis with human airway epithelial cells further established that Cl- currents by CFTR and TMEM16A were functionally linked and interdependent. Mechanistically, TMEM16A enhanced Ca(2+) store release to provide Ca(2+) for activation of CFTR in the presence of cAMP through Ca(2+)-dependent adenylate cyclases. TMEM16A also regulated membrane expression of CFTR. Further analysis revealed that CFTR and TMEM16A interacted, likely with the help of adaptor proteins. </p><p>Using single-cell RNA sequencing and in vivo lineage tracing to study the composition and hierarchy of the mouse tracheal epithelium, Montoro et al. (2018) identified a rare cell type, the Foxi1 (601093)-positive pulmonary ionocyte; functional variations in club cells based on their location; a distinct cell type in high turnover squamous epithelial structures that they termed 'hillocks'; and disease-relevant subsets of tuft and goblet cells. Montoro et al. (2018) developed 'pulse-seq,' combining single-cell RNA-seq and lineage tracing, to show that tuft, neuroendocrine, and ionocyte cells are continually and directly replenished by basal progenitor cells. Ionocytes are the major source of transcripts of the CFTR in both mouse and human. Knockout of Foxi1 in mouse ionocytes caused loss of Cftr expression and disrupted airway fluid and mucus physiology, phenotypes that are characteristic of cystic fibrosis. Montoro et al. (2018) concluded that by associating cell type-specific expression programs with key disease genes, they had established a new cellular narrative for airway disease. </p><p>Plasschaert et al. (2018) performed single-cell profiling of human bronchial epithelial cells and mouse tracheal epithelial cells to obtain a comprehensive census of cell types in the conducting airway and their behavior in homeostasis and regeneration. The analysis revealed cell states that represent known and novel cell populations, delineated their heterogeneity, and identified distinct differentiation trajectories during homeostasis and tissue repair. In addition, Plasschaert et al. (2018) identified a novel, rare cell type that they called the 'pulmonary ionocyte,' which coexpresses FOXI1, multiple subunits of the vacuolar-type H(+)-ATPase (V-ATPase), and CFTR. Using immunofluorescence, modulation of signaling pathways, and electrophysiology, Plasschaert et al. (2018) showed that Notch signaling (see 190198) is necessary and FOXI1 expression is sufficient to drive the production of the pulmonary ionocyte, and that the pulmonary ionocyte is a major source of CFTR activity in the conducting airway epithelium. </p>
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<p>Serohijos et al. (2008) presented a 3-dimensional structure of CFTR, constructed by molecular modeling and supported biochemically, in which phe508 mediates a tertiary interaction between the surface of the N-terminal nucleotide-binding domain and cytoplasmic loop-4 in the C-terminal membrane-spanning domain. This crucial cytoplasmic membrane interface is involved in regulation of channel gating and explains the sensitivity of CFTR assembly to disease-associated mutations in cytoplasmic loop-4, as well as in the N-terminal nucleotide-binding domain. </p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Liu et al. (2019) reported 2 cryoelectron microscopy structures of human CFTR in complex with potentiators: one with ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These 2 drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggested that in both cases, hydrogen bonds provided by the protein are important for drug recognition. </p>
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<p>Kerem et al. (1989) found that approximately 70% of the mutations in CF patients correspond to a specific deletion of 3 basepairs, which results in the loss of a phenylalanine residue at amino acid position 508 of the putative product of the CF gene (F508del; 602421.0001). Haplotype data based on DNA markers closely linked to the putative disease gene locus suggested that the remainder of the CF mutant gene pool consists of multiple, different mutations. A small set of these latter mutant alleles (about 8%) may confer residual pancreatic exocrine function in a subgroup of patients who are pancreatic sufficient. The discovery that the most common CF abnormality gives rise to the loss of a single amino acid residue in a functional domain suggests that the phenotype of CF is not due to complete loss of function of the gene product. The situation may be comparable to that in sickling disorders, in which a specific subset of mutations in the beta-globin gene gives rise to an altered protein with unusual behavior. Complete absence of function of the beta-globin gene gives rise to a different phenotype, namely, beta-0-thalassemia; similarly, homozygous loss of function of the CF gene may lead to a distinctive phenotype. </p><p>Trapnell et al. (1991) studied CFTR mRNA transcripts in respiratory tract epithelial cells recovered by fiberoptic bronchoscopy with a cytology brush. They found that the transcripts reflected the normal and the delta-F508 alleles in appropriate proportions. CFTR mRNA transcripts were expressed in nasal, tracheal, and bronchial epithelial cells in about 1 to 2 copies per cell, more than 100-fold greater than in pharyngeal epithelium. Zeitlin et al. (1992) identified a polyclonal antibody that was used to detect the CFTR glycoprotein in biopsied human nasal and bronchial tissues and in the apical membrane fraction of ileal villus tissue. Levels of the protein were modulated pharmacologically. </p><p>Zielenski et al. (1991) found a cluster of highly polymorphic dinucleotide repeats in intron 17b of the CFTR gene, 200 bp downstream from the preceding exon. At least 24 alleles, with sizes ranging from 7 to 56 units of a TA repeat, were identified in a panel of 92 unrelated carriers of CF. The common alleles had 7, 30, and 31 dinucleotide units, with frequencies of 0.22, 0.19, and 0.12, respectively, among the non-CF chromosomes. A less polymorphic dinucleotide cluster, a CA repeat, was also detected in a region 167 bp downstream from the TA repeat. This varied from 11 to 17 dinucleotide units and appeared to bear an inverse relationship to that of the TA repeats. These repeats were considered to be useful in genetic linkage studies, in counseling CF families with unknown mutations, and in tracing the origins of various mutant CF alleles. Morral et al. (1991) and Chehab et al. (1991) also described repeats within introns of the CFTR gene. The significance of the inverse correlation between the lengths of the 2 repeat regions was not investigated; length compensation may be involved and may have functional importance. </p><p>Chalkley and Harris (1991) made use of 'ectopic' or 'illegitimate' transcription of CF mRNA in leukocytes in the detection of CF mutations. By use of PCR, it was possible to detect such ectopic transcription as in the case of other genes such as those for dystrophin (300377) and factor VIII (300841). Fonknechten et al. (1992) extended these observations, using the PCR reaction for detecting CFTR mutations in the study of lymphocytes and lymphoblasts. Ferrie et al. (1992) applied the amplification refractory mutation system (ARMS) to the detection of mutations in the CFTR gene. </p><p>Cutting et al. (1990) sought mutations in the 2 NBFs of CFTR by nucleotide sequencing of exons 9, 10, 11, and 12 (encoding the first NBF) and exons 20, 21, and 22 (encoding most of the second NBF) from 20 Caucasian and 18 American black CF patients. They found a cluster of 4 mutations in a 30-bp region of exon 11. Three of the mutations caused amino acid substitutions at residues that are highly conserved among the CFTR protein, the multiple-drug-resistance proteins, and ATP-binding membrane-associated transport proteins. The fourth mutation created a premature termination signal. </p><p>To explore the molecular mechanisms responsible for defective chloride transport in patients with CF, Yang et al. (1993) studied the processing, localization, and function of wildtype, delF508 (602421.0001) and G551D (602421.0013) CFTR in retrovirus transduced L cells. They concluded that the molecular pathology of G551D is explained by an abnormality in channel activity, while the defect in delF508 is a combination of mislocalization and instability of the protein in addition to partial defects in channel function. Some of their observations suggested the possibility of pharmacologic therapies for CF based on activating latent CFTR. </p><p>Not only is there heterogeneity in the mutations causing cystic fibrosis, but the pathogenetic mechanisms also vary. Deletion of phenylalanine-508 appears to cause disease by abrogating normal biosynthetic processing and thereby resulting in retention and degradation of the mutant protein within the endoplasmic reticulum. Other mutations, such as the relatively common gly551-to-asp mutation, appear to be normally processed and, therefore, must cause disease through some other mechanism. Because both delta-F508 and G551D occur within a predicted nucleotide-binding domain (NBD) of CFTR, Logan et al. (1994) tested the influence of these mutations on nucleotide binding by the protein. They found that G551D and the corresponding mutation in the CFTR second nucleotide binding domain, gly1349-to-asp (G1349D), led to decreased nucleotide binding by CFTR NBDs, while the delta-F508 mutation did not alter nucleotide binding. These results implicated defective ATP-binding as the pathogenic mechanism of a relatively common mutation leading to CF and suggested that structural integrity of a highly conserved region present in over 30 prokaryotic and eukaryotic nucleotide-binding domains may be critical for normal nucleotide binding. </p><p>There is a polymorphic string of thymidines at the end of intron 8 of the CFTR gene; 3 different alleles can be found depending on the number of thymidines (5, 7, or 9) present at this site (Chu et al., 1991). The number of thymidines determines the efficiency by which the intron 8 splice acceptor site is used. The efficiency decreases when a shorter stretch of thymidine residues is found. A higher proportion of CFTR transcripts that lack exon 9 sequences, which encode part of the functionally important first nucleotide-binding domain, will therefore be found when a shorter stretch of thymidine residues is present (Chu et al., 1993). If a CFTR gene with the arg117-to-his (R117H) mutation (602421.0005) harbors a T5 allele, the mutant gene will be responsible for CF. An R117H mutant CFTR gene that harbors a T7 allele can either result in CF or CBAVD (Kiesewetter et al., 1993). Teng et al. (1997) noted that the T5 allele results in the most inefficient use of this splice acceptor site. Most CFTR transcripts from a T5 allele will therefore lack exon 9 sequencing. Such exon 9-deficient CFTR transcripts are known to be translated into CFTR proteins that will not mature, and will therefore not function as chloride channels in the apical membrane of epithelial cells. Among CBAVD patients, the frequency of this T5 allele is 4- to 6-fold higher than in the control population (see 602421.0005). Teng et al. (1997) analyzed CFTR transcripts qualitatively and quantitatively in nasal epithelial and vas deferens cells. Alternative splicing of exon 9, which had been known to occur in nasal epithelial cells, also occurred in vas deferens cells. The extent of this alternative splicing was determined by the allele present at the Tn locus at the end of intron 8 of the CFTR gene. However, the proportion of transcripts lacking exon 9 sequences was increased in vas deferens cells compared with nasal epithelial cells, independent of the Tn genotype. Thus, Teng et al. (1997) postulated that tissue-specific differences in the proportion of CFTR transcripts lacking exon 9 sequences may contribute to the tissue-specific disease phenotype observed in individuals with CBAVD. </p><p>Besides the polymorphic Tn locus, more than 120 polymorphisms have been described in the CFTR gene. Cuppens et al. (1998) hypothesized that the combination of particular alleles at several polymorphic loci might result in less functional or even insufficient CFTR protein. Analysis of 3 polymorphic loci with frequent alleles in the general population showed that, in addition to the known effect of the Tn locus, the quantity and quality of CFTR transcripts and/or proteins were affected by 2 other polymorphic loci: M470V (602421.0023) and a dinucleotide repeat polymorphism (TG)m. On a T7 background, the (TG)11 allele gave a 2.8-fold increase in the proportion of CFTR transcripts that lacked exon 9, and (TG)12 gave a 6-fold increase, compared with the (TG)10 allele. T5 CFTR genes derived from patients were found to carry a high number of TG repeats, while T5 CFTR genes derived from healthy CF fathers harbored a low number of TG repeats. Moreover, it was found that M470 CFTR proteins matured more slowly, and that they had a 1.7-fold increased intrinsic chloride channel activity compared with V470 CFTR proteins, suggesting that the M470V locus might also play a role in the partial penetrance of T5 as a disease mutation. Such polyvalent mutant genes could explain why apparently normal CFTR genes cause disease. Moreover, they might be responsible for variation in the phenotypic expression of CFTR mutations. This study suggested that genetic and functional studies of polymorphisms in relation to genetic diseases will become of major interest, in relation both to monogenic disorders and complex traits. </p><p>In 9 of 16 cases of disseminated bronchiectasis (56%), Pignatti et al. (1996) found the 5T allele in intron 8 (IVS8-5T) and/or a CFTR gene mutation. The results confirmed, at the molecular genetic level, a clinical connection between CF and one obstructive pulmonary disease, disseminated bronchiectasis of unknown origin. Similarly, Girodon et al. (1997) studied 32 patients with disseminated bronchiectasis and a clinically isolated respiratory syndrome. Analysis of all CFTR gene exons and their flanking regions demonstrated 13 CFTR gene mutations in 16 different alleles. Six of these mutations, which had previously been reported as CF defects, were found in 9 alleles. Four patients were compound heterozygotes; 6 were heterozygous for a mutation. Girodon et al. (1997) concluded that CFTR gene mutations may play a role in bronchiectatic lung disease, possibly in a multifactorial context. </p><p>It has been proposed that in heterozygous state mutations of the CFTR gene provide increased resistance to infectious diseases, thereby maintaining mutant CFTR alleles at high levels in selected populations. Pier et al. (1998) investigated whether typhoid fever could be one such disease. This disease is initiated when Salmonella typhi enters gastrointestinal epithelial cells for submucosal translocation. They found that S. typhi, but not the related murine pathogen S. typhimurium, uses CFTR for entry into epithelial cells. Cells expressing wildtype CFTR internalized more S. typhi than isogenic cells expressing the most common CFTR mutation, delta-F508 (602421.0001). Monoclonal antibodies and synthetic peptides containing a sequence corresponding to the first predicted extracellular domain of CFTR inhibited uptake of S. typhi. Heterozygous delta-F508 Cftr mice translocated 86% fewer S. typhi into the gastrointestinal submucosa than did wildtype Cftr mice; no translocation occurred in delta-F508 Cftr homozygous mice. The Cftr genotype had no effect on the translocation of S. typhimurium. Immunoelectron microscopy revealed that more CFTR bound S. typhi in the submucosa of Cftr wildtype mice than in delta-F508 heterozygous mice. Pier et al. (1998) concluded that diminished levels of CFTR in heterozygotes decreases susceptibility to typhoid fever. </p><p>Van de Vosse et al. (2005) tested the hypothesis that CFTR heterozygotes have a selective advantage against typhoid, which may be conferred through reduced attachment of S. typhi to the intestinal mucosa. They genotyped patients and controls in a typhoid endemic area in Indonesia for 2 highly polymorphic markers in CFTR and the most common CF mutation, F508del. Consistent with the apparently very low incidence of CF in Indonesia, the F508del mutation was not present in any patients or controls. However, they found significant association between a common polymorphism in intron 8 (16 or 17 CA repeats) and selective advantage against typhoid. </p><p>Sharer et al. (1998) studied 134 consecutive patients with chronic pancreatitis (167800) (alcohol-related disease in 71, hyperparathyroidism in 2, hypertriglyceridemia in 1, and idiopathic disease in 60). DNA was examined for 22 mutations of the CFTR gene that together account for 95% of all mutations in patients with cystic fibrosis in the northwest of England where the study was performed. They also determined the length of the noncoding sequence of thymidines in intron 8, since the shorter the sequence, the lower the proportion of normal CFTR mRNA. None of the patients had a mutation on both copies of the CFTR gene. Eighteen patients (13.4%), including 12 without alcoholism, had a CFTR mutation on 1 chromosome, as compared with a frequency of 5.3% among 600 local unrelated partners of persons with a family history of cystic fibrosis (P less than 0.001). A total of 10.4% of the patients had the 5T allele in intron 8 (14 of 134), which is twice the expected frequency (P = 0.008). Four patients were heterozygous for both a CFTR mutation and the 5T allele. Patients with a CFTR mutation were younger than those with no mutations (P = 0.03). None had the combination of sinopulmonary disease, high sweat electrolyte concentrations, and low nasal potential-difference values that is diagnostic of cystic fibrosis. </p><p>Similarly, Cohn et al. (1998) studied 27 patients (mean age at diagnosis, 36 years), 22 of whom were female, who had been referred for an evaluation of idiopathic pancreatitis. DNA was tested for 17 CFTR mutations and for the 5T allele in intron 8. The 5T allele reduces the level of functional CFTR and is associated with an inherited form of infertility in males, CBAVD. Cohn et al. (1998) found that 10 patients with idiopathic chronic pancreatitis (37%) had at least 1 abnormal CFTR allele. Eight CFTR mutations were detected. In 3 patients both alleles were affected. These 3 patients did not have lung disease typical of cystic fibrosis on the basis of sweat testing, spirometry, or base-line nasal potential-difference measurements. Nonetheless, each had abnormal nasal cyclic AMP-mediated chloride transport. The genotypes of the 3 patients were delF508/wildtype (602421.0001), 9T/5T in 2, and delF508/R117H (602421.0005), 9T/7T in 1. These are the 2 most common genotypes in patients with CBAVD. These genotypes do not typically cause lung disease. In contrast, lung disease is present in patients with a genotype of delF508/R117H, 9T/5T. </p><p>An abbreviated tract of 5T in intron 8 of the CFTR gene is found in approximately 10% of individuals. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, Groman et al. (2004) determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens (277180), 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P less than 0.00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1-103.7.7, P less than 0.00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles. </p><p>Lee et al. (2003) haplotyped 117 Korean controls and 75 CF patients having bronchiectasis or chronic pancreatitis using 11 polymorphisms in CFTR. Several haplotypes, especially those with Q1352H (602421.0133), IVS8 T5 (602421.0086), and E217G (602421.0134), were found to have disease associations in a case-control study. The common M470V polymorphism (602421.0023) appeared to affect the intensity of the disease association. The T5-V470 haplotype showed higher disease association than T5-M470, but the Q1352H mutation in a V470 background showed the strongest disease association. Nonsynonymous E217G and Q1352H mutations in the M470 background caused a 60 to 80% reduction in CFTR-dependent chloride currents and bicarbonate transport activities. The M470V polymorphic variant in combination with the Q1352H mutation completely abolished CFTR-dependent anion transport activities. The results revealed that interactions between multiple genetic variants in cis affected the final function of the gene products. </p><p>Buratti et al. (2001) showed that nuclear factor TDP43 (605078) binds specifically to the UG repeat sequence of CFTR pre-mRNA and, in this way, promotes skipping of CFTR exon 9. Wang et al. (2004) found that the mouse homolog of human TDP43 also inhibits human CFTR exon 9 splicing in a minigene system. Buratti et al. (2004) described experiments consistent with the model in which the TG repeats in the CFTR intron 8 bind to TDP43, and this protein, in turn, inhibits splicing of exon 9. They suggested that their results provide a mechanistic explanation for the association data of Groman et al. (2004) and also an explanation for the variable phenotypic penetrance of the TG repeats. Individual and tissue-specific variability in the concentration of this inhibitory splicing factor may even determine whether an individual will develop multisystemic (non-classic CF) or monosymptomatic (CBAVD) disease. </p><p>Audrezet et al. (2002) analyzed the entire coding sequence and exon/intron junctions of the CFTR gene by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing in 39 white French patients with idiopathic chronic pancreatitis. A total of 18 mutant alleles were identified in 14 patients (35.9%), among whom 4 were compound heterozygotes. None of the 4 compound heterozygotes were found to have unrecognized CF-related pulmonary symptoms following reevaluation. However, a sweat test done retrospectively was positive in 2 of them. The 5T allele of the polymorphic string of thymidines at the end of intron 8 of the CFTR gene was present in 7 of the 36 patients tested, an allele frequency (9.7%) nearly 2 times greater than the rate of 5% in the general population (P = 0.09). </p><p>The molecular pathogenesis of cystic fibrosis has been investigated by analysis of delF508 CFTR in different heterologous systems, revealing an abrogation of CFTR expression by defective protein maturation. Mutant CFTR was found arrested in an early wildtype intermediate, unable to adopt a protease-resistant mature conformation (Cheng et al., 1990; Gregory et al., 1991; Zhang et al., 1998) that enables exit from the endoplasmic reticulum and processing in the Golgi compartment. Prolonged interaction of immature delF508 CFTR with the chaperones calnexin (CANX; 114217) and Hsp70 (see 140550) in experiments by Pind et al. (1994) and Yang et al. (1993), respectively, indicated that the aberrant protein is recognized by the cell's quality control and that premature degradation by the ubiquitin-proteasome pathway occurs in a pre-Golgi compartment (Jensen et al., 1995; Sato et al., 1998). Reduction of temperature (Denning et al., 1992) and addition of chemical chaperones such as glycerol (Sato et al., 1996) and trimethylamine-N-oxide (Brown et al., 1996) overcame impediments in the folding pathway of delF508 CFTR and allowed proper targeting, thus demonstrating that the mutant protein is still capable of assuming a mature conformation. However, at the cell surface, the chloride channel formed therefrom showed a decreased half-life and reduced open probability and sensitivity to stimulation with cAMP agonists. </p><p>Kalin et al. (1999) investigated endogenous CFTR expression in skin biopsies and respiratory and intestinal tissue specimens from delF508 homozygous patients and non-CF persons, using immunohistochemical and immunoblot analyses with a panel of CFTR antibodies. CFTR expression was detected at the luminal surface of reabsorptive sweat ducts and airway submucosal glands, at the apex of ciliated cells in pseudostratified respiratory epithelia and of isolated cells of the villi of duodenum and jejunum, and within intracellular compartments of intestinal goblet cells. In delF508 homozygous patients, expression of the mutant protein proved to be tissue specific. Whereas delF508 CFTR was undetectable in sweat glands, the expression in the respiratory and intestinal tracts could not be distinguished from the wildtype by signal intensity or localization. The tissue-specific variation of delF508 CFTR expression from null to apparently normal amounts indicated that delF508 CFTR maturation can be modulated and suggested that determinants other than CFTR mislocalization should play a role in delF508 CF respiratory and intestinal disease. </p><p>Welsh and Smith (1993) provided a classification of the mechanisms by which mutations in CFTR cause cystic fibrosis. The grouping of mutations into 5 classes was based on their functional effect: (I) defective protein production; (II) defective protein processing; (III) defective protein regulation; (IV) defective protein conductance; and (V) reduced amounts of functional CFTR protein. Class I, II, and III mutations have been associated with typical severe multiorgan disease on the basis of clinical studies. In contrast, class IV and V mutations appeared to confer sufficient functional CFTR to result in a mild phenotype. </p><p>Haardt et al. (1999) reviewed the various classes of CF-associated mutations and added a tentative additional class VI. They suggested that the mutations can be grouped into 2 major categories. The first group includes those mutants that are unable to accumulate at the cell surface, either because of impaired biosynthesis (class I and class V), or because of defective folding at the endoplasmic reticulum (class II). Mutants that belong to the second category are expressed at the cell surface but fail to translocate chloride ions because of a defect in activation (class IV) or channel conductance (class III). Because the biosynthetic processing and macroscopic chloride channel function of some of the truncated CFTR constructs appear to be normal but the biologic stability of their mature, complex-glycosylated form is dramatically reduced, Haardt et al. (1999) proposed a class VI, which would include stability mutants such as those characterized by their experiments. </p><p>To study the consequences that disease-causing mutations have on the regulatory function of CFTR, Mickle et al. (2000) transiently expressed CFTR-bearing mutations associated with CF or its milder phenotype, congenital bilateral absence of the vas deferens (277180), and determined whether mutant CFTR could regulate outwardly rectifying chloride channels (ORCCs). CFTR bearing a CF-associated mutation in the first nucleotide-binding domain, delta-F508del (602421.0001), functioned as a chloride channel but did not regulate ORCCs. However, CFTR that had disease-associated mutations in other domains retained both functions, regardless of the associated phenotype. Thus, a relationship between loss of CFTR regulatory function and disease severity is evident for NBD1, a region of CFTR that appears important for regulation of separate channels. </p><p>Bronsveld et al. (2001) determined chloride transport properties of the respiratory and intestinal tracts in delta-F508 twins and sibs. In respiratory tissue, the expression of basal CFTR-mediated chloride conductance, demonstrated by 30% of delta-F508 homozygotes, was identified as a positive predictor of milder CF. In intestinal tissue, 4,4-prime-diisothiocyanatostilbene-2,2-prime-disulfonic acid (DIDS)-insensitive chloride secretion, which is indicative of functional CFTR channels, correlated with a milder phenotype, whereas DIDS-sensitive chloride secretion was observed mainly in more severely affected patients. Bronsveld et al. (2001) concluded that in delta-F508 patients, the ability to secrete chloride in the organs that are primarily involved in the course of CF is predictive of the CF phenotype. </p><p>Bobadilla et al. (2002) determined the distribution of CFTR mutations in as many regions throughout the world as possible in an effort to understand the evolution of the disease in each region and gain insight for decisions regarding screening programs. Although wide mutational heterogeneity was found throughout the world, characterization of the most common mutations in most populations was possible. A significant positive correlation was found between delta-F508 frequency and the CF incidence of regional populations. </p><p>Primary sclerosing cholangitis (PSC; see 109720), a slowly progressive cholestatic liver disease characterized by fibroobliterative inflammation of the biliary tract, leads to cirrhosis and portal hypertension and is a major indication for liver transplantation. Sheth et al. (2003) stated that 75 to 80% of cases were associated with inflammatory bowel disease (IBD; 266600) and that 2.5 to 7.5% of patients with IBD develop PSC (Lee and Kaplan, 1995). Sheth et al. (2003) hypothesized that dysfunction of CFTR may explain why a subset of patients with IBD develop PSC. They prospectively evaluated CFTR genotype and phenotype in 19 patients with PSC compared with 18 patients with IBD and no liver disease, 17 with primary biliary cirrhosis (PBC; 109720), 81 with CF, and 51 healthy controls. They found an increased prevalence of CFTR abnormalities in heterozygous state in PSC as demonstrated by molecular and functional analyses, and concluded that these abnormalities may contribute to the development of PSC in a subset of patients with IBD. Eighty-nine percent of PSC patients carried genotypes containing the 1540G variant (602421.0023) resulting in decreased functional CFTR compared with 57% of disease controls (P = 0.03). Only 1 of 19 PSC patients had neither a CFTR mutation nor the 1540G variant. CFTR chloride channel function assessed by nasal potential difference testing demonstrated a reduced median isoproterenol response in PSC patients compared with disease controls and healthy controls. </p><p>Pagani et al. (2003) showed that several nucleotide changes in exon 12 of the CFTR gene induced a variable extent of exon skipping, leading to reduced levels of normal transcripts. This was the case in 2 natural mutations--1 of which was gly576 to ala (G576A; 602421.0061), which had previously been considered a neutral polymorphism--and several site-directed silent substitutions. This phenomenon was due to the interference with a regulatory element, which the authors named composite exonic regulatory element of splicing (CERES). The effect of single-nucleotide substitutions at CERES could not be predicted by either serine-arginine-rich (SR) matrices or enhancer identification. Pagani et al. (2003) suggested that appropriate functional splicing assays should be included in genotype screenings to distinguish between polymorphisms and pathogenic mutations. </p><p>By testing 19 synonymous changes in nucleotides 13 to 52 of the human CFTR exon 12, Pagani et al. (2005) found that the probability of inducing exon skipping with a single synonymous substitution was approximately 30%, demonstrating that synonymous substitutions can affect splicing and are not neutral in evolution as they can be constrained by splicing requirements. Pagani et al. (2005) suggested that evolutionary selection of genomic variation takes place at 2 sequential levels: splicing control and protein function optimization. </p><p>Aznarez et al. (2003) investigated the consequence of 2 CF disease-causing mutations on the function of a putative exonic splicing enhancer (ESE) in exon 13 of the CFTR gene. Both mutations caused aberrant splicing in a predicted manner, supporting a role for the putative ESE sequence in pre-mRNA splicing. In addition, 3 mutations, including D648V (602421.0097), caused aberrant splicing of exon 13 by improving the polypyrimidine tracts of 2 cryptic 3-prime splice sites. The relative levels of 2 splicing factors, Tra2-alpha (TRA2A; 602718) and SF2/ASF (SFRS1; 600812), altered the effect on splicing of some of the exon 13 disease mutations. The authors suggested that the severity of CF may be modulated by changes in the fidelity of CFTR pre-mRNA splicing. </p><p>Audrezet et al. (2004) reported the first systematic screening of the 27 exons of the CFTR gene for large genomic rearrangements, by means of the quantitative multiplex PCR of short fluorescent fragments (QMPSF). Although many disease alleles of CFTR had previously been identified, up to 30% of disease alleles still remained to be identified in some populations, and it had been suggested that gross genomic rearrangements could account for these unidentified alleles. Audrezet et al. (2004) studied a well-characterized cohort of 39 patients with classic CF carrying at least 1 unidentified allele. Using QMPSF, approximately 16% of the previously unidentified CF mutant alleles were identified and characterized, including 5 novel mutations (1 large deletion and 4 insertions/deletions). The breakpoints of these 5 mutations were precisely determined. Although nonhomologous recombination may be invoked to explain all 5 complex lesions, each mutation appeared to have arisen through a different mechanism. One of the insertions/deletions was highly unusual in that it involved the insertion of a short 41-bp sequence with partial homology to a retrotranspositionally-competent LINE-1 element. Audrezet et al. (2004) suggested that the insertion of this ultra-short LINE-1 element (dubbed a 'hyphen element') may constitute a novel type of mutation associated with human genetic disease. </p><p>Dinucleotide repeats are ubiquitous features of eukaryotic genomes. The highly variable nature of dinucleotide repeats makes them particularly interesting candidates for modifiers of RNA splicing when they are found near splicing signals. An example of a variable dinucleotide repeat that affects splicing is a TG repeat located in the splice acceptor of exon 9 of the CFTR gene. Higher repeat numbers result in reduced exon 9 splicing efficiency and, in some instances, the reduction in full-length transcript is sufficient to cause male infertility due to congenital bilateral absence of the vas deferens (277180) or nonclassic cystic fibrosis. Using a CFTR minigene system, Hefferon et al. (2004) studied TG tract variation and observed the same correlation between dinucleotide repeat number and exon 9 splicing efficiency seen in vivo. Placement of the TG dinucleotide tract in the minigene with random sequence abolished splicing of exon 9. Replacement of the TG tract with sequences that can self-basepair suggested that the formation of an RNA secondary structure was associated with efficient splicing; however, splicing efficiency was inversely correlated with the predicted thermodynamic stability of such structures, demonstrating that intermediate stability was optimal. Finally, substitution with TA repeats of differing length confirmed that stability of the RNA secondary structure, not sequence content, correlated with splicing efficiency. Hefferon et al. (2004) concluded that dinucleotide repeats can form secondary structures that have variable effects on RNA splicing efficiency and clinical phenotype. </p><p>Wong et al. (2003) described pancreatic-insufficient CF in a child whose father was from Taiwan and mother from Vietnam. The child had 2 different null mutations, glu7 to ter (602421.0131) in exon 1 and a 1-bp insertion, 989A (602421.0132), which caused frameshift and a truncated CFTR protein of 306 amino acids. Wong et al. (2003) commented on the fact that East Asian CF patients did not share mutations with patients of other ethnic backgrounds. Even within East Asians, the CFTR mutation spectrum in Chinese patients is distinct from that of Japanese patients. </p><p>Chang et al. (2007) identified mutations in the CFTR gene in 14.1% of total alleles and 24.4% of 78 Chinese/Taiwanese patients with idiopathic chronic pancreatitis (ICP; 167800) compared to 4.8% of total alleles and 9.5% of 200 matched controls. The findings indicated that heterozygous carriers of CFTR mutations have an increased risk of developing ICP. The mutations identified were different from those usually observed in Western countries. The T5 allele with 12 or 13 TG repeats was significantly associated with earlier age at onset in patients with ICP, although the frequency of this allele did not differ between patients and controls. </p><p>Sun et al. (2006) analyzed the polymorphic TG dinucleotide repeat adjacent to the 5T variant in intron 8 and the codon 470 in exon 10. Patients selected for this study were positive for both the 5T variant and the major cystic fibrosis mutation, delta-F508. Almost all delta-F508 mutations occur in a 10TG-9T-470M haplotype. Therefore, it is possible to determine the haplotype of the 5T variant in trans. Of the 74 samples analyzed, 41 (55%) were 11TG-5T-470M, 31 (42%) were 12TG-5T-470V, and 2 (3%) were 13TG-5T-470M. Of the 49 cases for which they had clinical information, Sun et al. (2006) reported that 17.6% of females (6 of 34) and 66.7% of males (10 of 15) showed symptoms resembling atypical cystic fibrosis. The haplotype with the highest penetrance in females (42%, or 5 of 12) and more than 80% (5 of 6) in males was 12TG-5T-470V. The authors also evaluated 12 males affected with congenital bilateral absence of vas deferens and positive for the 5T variant; 10 of 12 had the 12TG-5T-470V haplotype. Sun et al. (2006) concluded that overall, the 5T variant has a milder clinical consequence than previously estimated in females. The clinical presentations of the 5T variant are associated with the 5T-12TG-470M haplotype. </p><p>Alonso et al. (2007) analyzed 1,954 Spanish cystic fibrosis alleles to define the molecular spectrum of mutations. Commercial panels showed a limited detection power, leading to the identification of only 76% of alleles. More sensitive assays identified 12 mutations with frequencies above 1%, the F508del mutation being the most frequent, present on 51% of alleles. In the Spanish population, 18 mutations were needed to achieve a detection rate of 80%. Fifty-one mutations (42%) were observed once. Alonso et al. (2007) identified a total of 121 disease-causing mutations that accounted for 96% of CF alleles. </p><p><strong><em>Effect of Aminoglycoside Antibiotics</em></strong></p><p>
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In addition to their antimicrobial activity, aminoglycoside antibiotics can suppress premature termination codons by allowing an amino acid to be incorporated in place of the stop codon, thus permitting translation to continue to the normal end of the transcript. The mechanism translation termination is highly conserved among most organisms and is almost always signaled by an amber (UAG), ochre (UAA), or opal (UGA) termination codon. The nucleotide sequence surrounding the termination codon has an important role in determining the efficiency of translation termination. Aminoglycoside antibiotics can reduce the fidelity of translation, predominantly by inhibiting ribosomal 'proofreading,' a mechanism to exclude poorly matched aminoacyl-tRNA from becoming incorporated into the polypeptide chain. In this way aminoglycosides increase the frequency of erroneous insertions at the nonsense codon and permit translation to continue to the end of the gene, as has been shown in eukaryotic cells (Burke and Mogg, 1985), including human fibroblasts (Buchanan et al., 1987). </p><p>Howard et al. (1996) demonstrated that 2 CFTR-associated stop mutations could be suppressed by treating cells with low doses of an aminoglycoside antibiotic. Others demonstrated this effect in cultured cells bearing CFTR nonsense mutations and in connection with stop mutations in muscular dystrophy in mice and in vitro in Hurler syndrome (607014), cystinosis (219800), and other disorders. </p><p>In a CF bronchial cell line carrying the CFTR W1282X (602421.0022) mutation, Bedwell et al. (1997) demonstrated that treatment with the aminoglycosides G418 and gentamicin restored CFTR expression, as shown by the reappearance of cAMP-activated chloride currents, the restoration of CFTR protein at the apical plasma membrane, and an increase in the abundance of CFTR mRNA levels from the W1282X allele. </p><p>Wilschanski et al. (2003) performed a double-blind placebo-controlled crossover trial of intranasal gentamicin in patients with stop mutations in CFTR, in comparison with patients homozygous for the delta-F508 mutation. Nasal potential difference was measured at baseline and after each treatment. Gentamicin treatment caused a significant reduction in basal potential difference in 19 patients carrying stop mutations and a significant response to chloride-free isoproterenol solution. This effect of gentamicin on nasal potential difference occurred both in patients who were homozygous for stop mutations and in those who were heterozygous, but not in patients who were homozygous for delta-F508. After gentamicin treatment, a significant increase in peripheral and surface staining for CFTR was observed in the nasal epithelial cells of patients carrying stop mutations. </p>
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<strong>Animal Model</strong>
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<p>Tata et al. (1991) cloned the mouse homolog of the human CFTR gene. </p><p>McCombie et al. (1992) used expressed sequence tags to identify homologs of human genes, including CFTR and the LDL receptor gene (606945), in Caenorhabditis elegans. They suggested that C. elegans, because of the extensive information on the physical and genetic map of the organism, might have unique advantages for the study of the function of normal and mutant genes. The same approach was applied even more extensively by Waterston et al. (1992) who, by study of a cDNA library, identified about 1,200 of the estimated 15,000 genes of C. elegans. More than 30% of the inferred protein sequences had significant similarity to existing sequences in databases. </p><p>Zeiher et al. (1995) noted that the F508del (602421.0001) mutation disrupts the biosynthetic processing of CFTR so that the protein is retained in the endoplasmic reticulum and is then degraded. As a result, affected epithelia lack CFTR in the apical membrane and lack cAMP-stimulated chloride ion permeability. Dorin et al. (1992) and Snouwaert et al. (1992), as well as others, disrupted the mouse CFTR gene to create null mutant mice that lack CFTR or express greatly reduced amounts of wildtype protein. To understand the pathophysiology of the disease and to evaluate new therapies, Zeiher et al. (1995) used a targeting strategy to introduce the F508del mutation into the mouse CFTR gene. Murine CFTR is 78% identical to human CFTR, and it contains a phenylalanine at residue 508 flanked by 28 amino acids identical to those in human CFTR. They could show that affected epithelia from homozygous F508del mice lacked CFTR in the apical membrane and were chloride ion-impermeable. Forty percent of homozygous animals survived into adulthood and displayed several abnormalities found in human disease and in CFTR null mice. </p><p>Van Doorninck et al. (1995) generated a mouse model of CF with the phe508del mutation using the 'hit-and-run' mutagenesis procedure. In this model, the intron structure was not disturbed, in contrast to similar models (Zeiher et al., 1995; Colledge et al., 1995). French et al. (1996) demonstrated that in this model of CF the mutant CFTR was not processed efficiently to the fully glycosylated form in vivo. However, the mutant protein was expressed as functional chloride channels in the plasma membrane of cells cultured at reduced temperature. Furthermore, they could show that the electrophysiologic characteristics of the mouse phe508del-CFTR channels were indistinguishable from normal. In homozygous mutant mice they did not observe a significant effect of genetic background on the level of residual chloride channel activity. The data showed that like its human homolog, the mouse mutant CFTR is a temperature-sensitive processing mutant, and therefore an authentic model for study of pathophysiology and therapy. </p><p>Dickinson et al. (2002) replicated the G480C mutation (602421.0083) in the murine Cftr gene using the 'hit-and-run' double recombination procedure. The G480C cystic fibrosis mouse model expressed the G480C mutant transcript at a level comparable to that of wildtype Cftr. The homozygous mutant mice were fertile and had normal survival, weight, tooth color, and no evidence of cecal blockage, despite mild goblet cell hypertrophy in the intestine. Analysis of the mutant protein revealed that the majority of G480C CFTR was abnormally processed and no G480C CFTR-specific immunostaining in the apical membranes of intestinal cells was detected. The bioelectric phenotype of these mice revealed organ-specific electrophysiological effects. In contrast to delta-F508 'hit-and-run' homozygotes, the classic defect of forskolin-induced chloride ion transport was not replicated in the cecum, but the response to low chloride in the nose was clearly defective in the G480C mutant animals. </p><p>Of importance to any gene-replacement strategy for treatment of CF is the identification of the cell type(s) within the lung milieu that need to be corrected and an indication whether this is sufficient to restore a normal inflammatory response and bacterial clearance. Oceandy et al. (2002) generated G551D CF mice transgenically expressing the human CFTR gene in 2 tissue compartments previously demonstrated to mediate a CFTR-dependent inflammatory response: lung epithelium and alveolar macrophages. Following chronic pulmonary infection with Pseudomonas aeruginosa, CF mice with epithelial-expressed (but not macrophage-specific) CFTR showed an improvement in pathogen clearance and inflammatory markers compared with control CF animals. The authors concluded that there may be a role for CFTR-mediated events in epithelial cells in response of the lung to bacterial pathogens. </p><p>Di et al. (2006) found that alveolar macrophages from Cftr -/- mice retained the ability to phagocytose and generate an oxidative burst, but exhibited defective killing of internalized bacteria. Lysosomes from Cftr -/- macrophages failed to acidify, although they retained normal fusogenic capacity with nascent phagosomes. Di et al. (2006) proposed that CFTR contributes to lysosome acidification and that in its absence phagolysosomes acidify poorly, thus providing an environment conducive to bacterial replication. </p><p>The delta-F508 CFTR mutation results in the production of a misfolded CFTR protein that is retained in the endoplasmic reticulum and targeted for degradation. Curcumin, a major component of the curry spice turmeric, is a nontoxic calcium-adenosine triphosphatase pump inhibitor that can be administered to humans safely. Egan et al. (2004) found that oral administration of curcumin to homozygous delta-F508 Cftr mice in doses comparable, on a weight-per-weight basis, to those well tolerated by humans corrected these animals' characteristic nasal potential difference defect. These effects were not observed in mice homozygous for a complete knockout of the CFTR gene. Curcumin also induced the functional appearance of delta-F508 CFTR protein in the plasma membranes of transfected baby hamster kidney cells. Egan et al. (2004) concluded that curcumin treatment may be able to correct defects associated with the homozygous expression of the delta-F508 CFTR gene, as it allows for dissociation from ER chaperone proteins and transfer to the cell membrane. </p><p>Delayed puberty is common among individuals with cystic fibrosis and is usually attributed to chronic disease and/or poor nutrition. However, delayed puberty has been reported as a feature of CF even in the setting of good nutritional and clinical status (Johannesson et al., 1997). This finding, along with evidence that Cftr is expressed in rat brain, human hypothalamus, and a gonadotropin-releasing hormone secreting line, raised the possibility that some of the pubertal delay in cystic fibrosis could stem directly from alterations in Cftr function that affects the hypothalamic-pituitary-gonadal axis. To examine this hypothesis, Jin et al. (2006) studied pubertal timing in a mouse model of CF engineered to produce a truncated Cftr mRNA and referred to as S489X. Homozygous knockout mice, which have chronic inflammation and gastrointestinal disease, grew more slowly and had later onset of puberty than wildtype animals. Jin et al. (2006) anticipated that the knockout heterozygotes, which have no clinical CF phenotype, might display an intermediate timing of puberty. They found, however, that these mice had earlier onset of puberty, as assessed by vaginal opening (VO), than wildtype. These findings were confirmed in a second independent model of CF engineered to generate the delta-F508 mutation in mice. Again the homozygotes displayed later pubertal timing, and the heterozygotes displayed earlier VO than the wildtype animals. These data provided further evidence that Cftr can directly modulate the reproductive endocrine axis and raised the possibility that heterozygote mutation carriers may have a reproductive advantage. </p><p>For further information on animal models for CF, see 219700.</p><p>To investigate the abnormalities that impair elimination when a bacterium lands on the pristine surface of a newborn CF airway, Pezzulo et al. (2012) interrogated the viability of individual bacteria immobilized on solid grids and placed onto the airway surface. As a model, they studied CF pigs, which spontaneously develop hallmark features of CF lung disease. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. Pezzulo et al. (2012) showed that in newborn wildtype pigs, the thin layer of airway surface liquid (ASL) rapidly kills bacteria in vivo, when removed from the lung, and in primary epithelial cultures. Lack of CFTR reduces bacterial killing. Pezzulo et al. (2012) found that the ASL pH was more acidic in CF pigs, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wildtype pigs, and, conversely, increasing ASL pH rescued killing in CF pigs. Pezzulo et al. (2012) concluded that their results directly linked the initial host defense defect to the loss of CFTR, an anion channel that facilitates bicarbonate transport. Without CFTR, airway epithelial bicarbonate secretion is defective; the ASL pH falls and inhibits antimicrobial function, and thereby impairs the killing of bacteria that enter the newborn lung. Pezzulo et al. (2012) also concluded that increasing ASL pH might prevent the initial infection in patients with CF, and that assaying bacterial killing could report on the benefit of therapeutic interventions. </p>
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<strong>History</strong>
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<p>CFTR was one of the genes used by Mashal et al. (1995) to test their method of mutation detection using bacteriophage resolvases, whose function in vivo is to cleave branched DNA and which have the property of recognizing mismatched bases in double-stranded DNA and cutting the DNA at the mismatch. The new method, termed enzyme mismatch cleavage (EMC) by Youil et al. (1995), who independently developed the method, takes advantage of this characteristic of resolvases to detect individuals who are heterozygous at a given site. Radiolabeled DNA is cleaved by the resolvase at the site of mismatch in heteroduplex DNA and digestion is monitored on a gel. Thus, both the presence and the estimated position of an alteration is revealed. One may think of the resolvase as a restriction enzyme that only recognizes mutations. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>138 Selected Examples):</strong>
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<strong>.0001 CYSTIC FIBROSIS</strong>
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BRONCHIECTASIS WITH OR WITHOUT ELEVATED SWEAT CHLORIDE 1, MODIFIER OF, INCLUDED
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CFTR, PHE508DEL ({dbSNP rs113993960})
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SNP: rs113993960,
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ClinVar: RCV000007523, RCV000007524, RCV000058929, RCV000119038, RCV000626692, RCV000626693, RCV000785641, RCV001004459, RCV001642198, RCV001787370, RCV001787371, RCV001831519, RCV002243627, RCV002251888, RCV002490332, RCV003227599, RCV003444054
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<p>In individuals with cystic fibrosis (CF; 219700), Kerem et al. (1989) identified deletion of 3 basepairs in exon 10 of the CFTR gene, leading to deletion of phenylalanine at codon 508 (delta-F508). The exon in which the delta-F508 mutation occurs has been corrected to exon 11; see, e.g., Sharma et al. (2014). </p><p>The European Working Group on CF Genetics (1990) published information on the distribution of the delta-F508 mutation in Europe. The data, illustrated with a useful map, indicated a striking cline across Europe from low values of 30% in the southeast (in Turkey) to high values in the northwest (e.g., 88% in Denmark). The group suggested that the spread of the CF gene might have accompanied the migrations of early farmers starting from the Middle East and slowly progressing toward the northwest of Europe. The diffusion of the gene may have been favored by the selective advantage conferred by the gene. Strong association with the so-called haplotype B was demonstrated. The possibility of 'hitchhiking,' i.e., the influence of neighboring genes was discussed. Rozen et al. (1990) found the delta-F508 mutation in 71% of CF chromosomes from urban Quebec province French Canadian families, 55% of those from Saguenay-Lac-Saint-Jean region families and in 70% of those from Louisiana Acadian families. De Braekeleer (1991) estimated that the frequency at birth of cystic fibrosis is 1/926 in the Saguenay-Lac-Saint-Jean region, giving a carrier rate of 1/15. For the same region, Daigneault et al. (1991) reported a prevalence of CF at birth of 1/902 liveborns, and a carrier rate of 1/15. Rozen et al. (1992) found that the delta-F508 mutation was present in 58% of Saguenay-Lac-Saint-Jean CF families, with the G-to-T donor splice site mutation after codon 621 being found in 23%, and the A455E mutation (602421.0007) in 8%. The latter 2 mutations were not found in urban Quebec families. This provided further evidence of the role of founder effect. Among 293 patients, Kerem et al. (1990) found that those who were homozygous for the F508 deletion had received a diagnosis of cystic fibrosis at an earlier age and had a greater frequency of pancreatic insufficiency. Pancreatic insufficiency was present in 99% of the homozygous patients, 72% of those heterozygous for the deletion, and only 36% of patients with other mutations. Wauters et al. (1991) studied the frequency of the delta-F508 mutation among Belgian patients with CF. The mutation was present in 80% of CF chromosomes from 36 unrelated families. Ninety-three percent of the CF chromosomes carrying the delta-F508 mutation also carried haplotype B in this population. Gille et al. (1991) described a strategy for efficient heterozygote screening for the delta-F508 mutation. They showed that PCR could detect a heterozygote in a pool of up to 49 unrelated DNA samples. Lerer et al. (1992) reported that the delta-F508 mutation accounts for 33.8% of Jewish CF alleles. </p><p>The Basque population is thought to be one of the oldest in Europe, having been established in western Europe during the late Paleolithic Age. Euskera, the Basque language, is thought to be pre-Indo-European, originating from the first settlers of Europe. The variable distribution of the delF508 mutation in Europe, with higher frequencies in northern Europe and lower frequencies in southern Europe, has been attributed to a spread of the mutation by early farmers migrating from the Middle East during the Neolithic period. However, a very high frequency of this mutation was found in the Basque Provinces, where the incidence of CF is approximately 1 in 4,500. In a study of 45 CF families from the Basque Provinces, Casals et al. (1992) found that the frequency of the delF508 mutation was 87% in the chromosomes of individuals of pure Basque extraction and 58% in those of mixed Basque origin. Casals et al. (1992) proposed that the delF508 mutation was present in Europe more than 10,000 years ago, preceding the agricultural migrations which diluted the mutation rather than introducing it. Ballabio et al. (1990) described an allele-specific amplification method for diagnosing the phenylalanine-508 deletion. Among Pueblo and Navajo Native Americans of the U.S. Southwest, Grebe et al. (1992) found no instance of the delF508 mutation in 12 affected individuals. Clinically, 6 of the affected individuals had growth deficiency and 5 (all from the Zuni Pueblo) had a severe CF phenotype. Four of the 6 Zunis with CF were also microcephalic, a finding not previously noted in CF patients. In an analysis of 640 Spanish cystic fibrosis families, Casals et al. (1997) found that 75 mutations accounted for 90.2% of CF chromosomes - an extraordinarily high heterozygosity. The frequency of the delta-F508 mutation was 53.2%. The next most frequent mutation was gly542 to ter (602421.0009) with a frequency of 8.43%. </p><p>Using 3 intragenic microsatellites of the CFTR gene located in introns, Russo et al. (1995) evaluated linkage disequilibrium between each marker and various CF mutations on a total of 377 CF and 358 normal chromosomes from Italian subjects. Results were considered consistent with the hypothesis that all del508 chromosomes derived from a single mutational event. The same hypothesis was valid for 3 other mutations which might have originated more recently than del508. </p><p>Grebe et al. (1994) performed molecular genetic analyses on 129 Hispanic individuals with cystic fibrosis in the southwestern United States. Only 46% (59 of 129) carried mutation F508del (frequency in the general population 67.1%). </p><p>In 69 Italian patients with CF due to homozygosity for the delF508 mutation, De Rose et al. (2005) found that those who also carried the R131 allele of the immunoglobulin Fc-gamma receptor II gene (FCGR2A; see 146790.0001) had a 4-fold increased risk of acquiring chronic Pseudomonas aeruginosa infection (p = 0.042). De Rose et al. (2005) suggested that FCGR2A locus variability contributes to this infection susceptibility in CF patients. </p><p>In a 62-year-old woman with idiopathic bronchiectasis (BESC1; 211400) and elevated sweat chloride but normal nasal potential difference, who carried a heterozygous F508del CFTR mutation, Fajac et al. (2008) also identified heterozygosity for a missense mutation in the SCNN1B gene (600760.0015). The patient had a forced expiratory volume in 1 second (FEV1) that was 89% of predicted. Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene. </p><p>Okiyoneda et al. (2010) identified the components of the peripheral protein quality control network that removes unfolded CFTR containing the F508del mutation from the plasma membrane. Based on their results and proteostatic mechanisms at different subcellular locations, Okiyoneda et al. (2010) proposed a model in which the recognition of unfolded cytoplasmic regions of CFTR is mediated by HSC70 (600816) in concert with DNAJA1 (602837) and possibly by the HSP90 machinery (140571). Prolonged interaction with the chaperone-cochaperone complex recruits CHIP (607207)-UBCH5C (602963) and leads to ubiquitination of conformationally damaged CFTR. This ubiquitination is probably influenced by other E3 ligases and deubiquitinating enzyme activities, culminating in accelerated endocytosis and lysosomal delivery mediated by Ub-binding clathrin adaptors and the endosomal sorting complex required for transport (ESCRT) machinery, respectively. In an accompanying perspective, Hutt and Balch (2010) commented that the 'yin-yang' balance maintained by the proteostasis network is critical for normal cellular, tissue, and organismal physiology. </p><p>Among 1,482 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 32 heterozygotes and no homozygotes for the phe508del mutation in the CFTR gene, for a frequency of 0.022, or 1 in 45.5. This frequency is lower than that for the general population for this mutation, which is 1 in 30. </p><p>Pankow et al. (2015) reported the first comprehensive analysis of the CFTR and delta-F508 CFTR interactome and its dynamics during temperature shift and inhibition of histone deacetylases. By using a novel deep proteomic analysis method, they identified 638 individual high-confidence CFTR interactors and discovered a delta-F508 deletion-specific interactome, which is extensively remodeled upon rescue. Detailed analysis of the interactome remodeling identified key novel interactors, whose loss promote delta-F508i CFTR channel function in primary cystic fibrosis epithelia or which are critical for CFTR biogenesis. The results of Pankow et al. (2015) demonstrated that global remodeling of delta-F508 CFTR interactions is crucial for rescue, and provided comprehensive insight into the molecular disease mechanisms of cystic fibrosis caused by deletion of F508. </p><p><strong><em>Clinical Trials</em></strong></p><p>
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Wainwright et al. (2015) conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator. A total of 1,108 patients 12 years of age or older who were homozygous for the Phe508del CFTR mutation were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary endpoint was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24. In both studies, there were significant improvements in the primary endpoint. The difference between active and placebo with respect to mean absolute improvement in the percentage FEV1 ranged from 2.6 to 4.0 percentage points (p less than 0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (p less than 0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the treated groups than in the placebo group. In addition, the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the treated groups. The incidence of adverse events was similar in the treated and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo. Wainwright et al. (2015) concluded that the combination of a CFTR corrector and potentiator, designed to address the underlying cause of cystic fibrosis by targeting CFTR, can benefit the 45% of patients who are homozygous for the Phe508del mutation. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 CYSTIC FIBROSIS</strong>
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<span class="mim-text-font">
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CFTR, ILE507DEL
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SNP: rs121908745,
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ClinVar: RCV000007525, RCV000224705, RCV000780118, RCV001004458, RCV001826426, RCV002496293, RCV003472998
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected deletion of 3 bp in the CFTR gene, resulting in deletion of isoleucine at either position 506 or 507 (delta-I507). Nelson et al. (1991) found the same mutation in homozygous state in 2 sibs with severe pancreatic insufficiency. Orozco et al. (1994) commented on the difficulties in recognizing the ile507-to-del mutation in a compound heterozygote with F508del. </p>
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<span class="mim-font">
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<strong>.0003 CYSTIC FIBROSIS</strong>
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<span class="mim-text-font">
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CFTR, GLN493TER
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SNP: rs77101217,
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gnomAD: rs77101217,
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ClinVar: RCV000007526, RCV000727628, RCV001004456, RCV001835623, RCV002288473, RCV002496294, RCV003472999
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected a C-to-T change in nucleotide 1609 in exon 10 of the CFTR gene that caused a premature stop position 493 (Q493X). </p>
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<span class="mim-font">
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<strong>.0004 CYSTIC FIBROSIS</strong>
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CFTR, ASP110HIS
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SNP: rs113993958,
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gnomAD: rs113993958,
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ClinVar: RCV000007527, RCV000058930, RCV000660769, RCV000780153, RCV001004427, RCV001009392, RCV001835624, RCV002247259, RCV003473000, RCV005042001
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<div>
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<span class="mim-text-font">
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<p>Using the method for identifying single-strand conformation polymorphisms (SSCPs) developed by Orita et al. (1989), Dean et al. (1990) identified 3 different mutations associated with mild cystic fibrosis (CF; 219700). All 3 mutations replaced charged amino acids with less polar residues and resulted in changes in the putative transmembrane sections of the molecule. The mutated amino acids were found to be ones conserved in both rodents and amphibians and to lie in a region of CFTR that is believed to form a channel in the membrane. In a family identified as BOS-7, a C-to-G transversion in exon 4 replaced an aspartic acid residue with histidine (D110H). (The Orita method for identifying SSCPs involves amplification of 100-400 bp segments of radiolabeled DNA, which are subsequently denatured and electrophoresed on high resolution, nondenaturing acrylamide gels. Under these conditions each strand of the DNA fragment can fold back on itself in a unique conformation. Mutations within a DNA segment will often alter the secondary structure of the molecule and affect its electrophoretic mobility.) </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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VAS DEFERENS, CONGENITAL BILATERAL ABSENCE OF, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, ARG117HIS
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<br />
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SNP: rs78655421,
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gnomAD: rs78655421,
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ClinVar: RCV000007528, RCV000007529, RCV000078997, RCV000190992, RCV000417156, RCV000763151, RCV000826137, RCV001009478, RCV001642199, RCV003473001, RCV004018585
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 presumably unrelated families with mild cystic fibrosis (CF; 219700), Dean et al. (1990) found a 482G-A transition in exon 4 of the CFTR gene, resulting in an arg117-to-his (R117H) substitution. </p><p>Gervais et al. (1993) reported that the R117H mutation was present in 4 of 23 patients with congenital absence of the vas deferens (CBAVD; 277180). Three patients had compound heterozygosity for R117H and delF508 (602421.0001), whereas a fourth was a compound heterozygote for R117H and 2322delG. None of the 23 patients had pulmonary evidence of cystic fibrosis. Five patients without the delF508 mutation had unilateral renal agenesis in addition to absence of the vas deferens; these patients may represent a different distinct subset. Bienvenu et al. (1993) described for the first time homozygosity for the R117H mutation in a 30-year-old French male with sterility owing to congenital bilateral absence of the vas deferens. The subject had no respiratory or pancreatic involvement and had a normal sweat electrolyte value. His parents were not consanguineous, and there were no other cases of CBAVD or CF in the family. </p><p>Kiesewetter et al. (1993) presented evidence that the chromosome background of the R117H mutation has a profound effect on the phenotype produced. Three length variants of CFTR have been observed with varying degrees of exon 9 splicing depending on variation in the length of the polypyrimidine tract in the splice acceptor site in intron 8 (Chu et al. (1991, 1993)). Varied lengths of a thymidine (T)-tract (5, 7, or 9Ts) were noted in front of the splice acceptor site of intron 8. The 5T variant is present in 5% of the CFTR alleles among Caucasian populations producing almost exclusively (95%) exon 9-minus RNA. The effect of this T-tract polymorphism in CFTR gene expression was also documented by its relationship with the R117H mutation: R117H (5T) is found in typical CF patients with pancreatic sufficiency; R117H (7T) is associated with CBAVD. The R117H mutation has been reported in CF patients, males with congenital bilateral absence of the vas deferens, and in an asymptomatic woman. Furthermore, population screening discovered a 19-fold higher than expected number of carriers of this CF mutation. The situation was compared to that in Gaucher disease in which the severity of neuronopathic disease associated with a missense mutation appears to be altered by additional missense mutations in the same allele (Latham et al., 1990). </p><p>White et al. (2001) reported a healthy 29-year-old female who was found to be an R117H/delF508 heterozygote. The patient had atopic asthma and infertility, but normal height and weight and no pulmonary symptoms of CF. Analysis of the polythymidine tract showed that the R117H mutation was in cis with a 7T tract and the delta-F508 mutation in cis with a 9T tract. The authors concluded that poly-T studies are important in any patient found to have the R117H mutation, and recommended caution in the genetic counseling of such families. </p><p>Thauvin-Robinet et al. (2009) reported the results of a national collaborative study in France to establish the overall phenotype associated with R117H and to evaluate the disease penetrance of the R117H+F508del genotype. In 184 R117H+F508del individuals of the French population, including 72 newborns, the disease phenotype was predominantly mild; 1 child had classic cystic fibrosis, and 3 adults had severe pulmonary symptoms. In 5,245 healthy adults with no family history of CF, the allelic prevalence of F508del was 1.06%, R117H;T7 0.27%, and R117H;T5 less than 0.01%. The theoretical number of R117H;T7+F508del individuals in the French populations was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classic CF for R117H;T7+F508del was estimated at 0.03% and that of severe CF in adulthood at 0.06%. Thauvin-Robinet et al. (2009) suggested that R117H should be withdrawn from CF mutation panels used for screening programs. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, ARG347PRO
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<br />
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SNP: rs77932196,
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gnomAD: rs77932196,
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ClinVar: RCV000007530, RCV001004251, RCV001530124, RCV001831520, RCV002504761, RCV003473002
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 sibs with cystic fibrosis (CF; 219700) from a family identified as UT 1446, Dean et al. (1990) found a C-to-G transversion at position 1172 in the CFTR gene, resulting in substitution of proline for aspartic acid (R347P). The mutation destroyed a HhaI restriction site and created a NcoI site. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, ALA455GLU
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<br />
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SNP: rs74551128,
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gnomAD: rs74551128,
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ClinVar: RCV000007531, RCV000660853, RCV000763569, RCV001004446, RCV001530091, RCV001826427, RCV003473003
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 chromosomes from patients with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected a C-to-A change at nucleotide 1496 in exon 9 of the CFTR gene that caused substitution of glutamic acid for alanine at position 455 (A455E). The exon in which the A455E mutation occurs has been corrected to exon 10; see, e.g., Vecchio-Pagan et al. (2016). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0008 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, IVS10, G-A, -1
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<br />
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SNP: rs76713772,
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gnomAD: rs76713772,
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ClinVar: RCV000007532, RCV000224919, RCV001004462, RCV001027893, RCV002496295, RCV003473004
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis, Kerem et al. (1990) identified a splice mutation in the CFTR gene, a G-to-A change of nucleotide -1 in the acceptor site of intron 10. In a French patient with cystic fibrosis, Guillermit et al. (1990) detected the same mutation: a G-to-A change in the last nucleotide at the 3-prime end of intron 10 nucleotide 1717 minus one. The mutation destroyed a splice site. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0009 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, GLY542TER
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<br />
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SNP: rs113993959,
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gnomAD: rs113993959,
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ClinVar: RCV000007535, RCV000058931, RCV000119041, RCV000763572, RCV001004463, RCV001826428, RCV003473006
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) found a G-to-T change at nucleotide 1756 in exon 11 of the CFTR gene that was responsible for a stop mutation in codon 542 (G542X). Cuppens et al. (1990) found the same mutation in a Belgian patient. The G542X mutation accounted for 7.3% of the CF chromosomes in Belgium, being probably the second most frequent mutation. (In a sample of Belgian CF patients, 68.1% of all CF chromosomes carried the delta-F508 mutation.) The clinical manifestations were mild in a homozygote but were severe in a first cousin who was a genetic compound for G542X and gly458-to-val (602421.0028). Lerer et al. (1992) reported that the gly542-to-ter mutation accounts for 13% of Ashkenazi CF mutations. </p><p>Castaldo et al. (1997) described severe liver involvement associated with pancreatic insufficiency and moderate pulmonary expression of CF in a girl, homozygous for the G542X mutation, who died at the age of 10 years. </p><p>Loirat et al. (1997) suggested that G542X is probably the Phoenician cystic fibrosis mutation. They showed that the frequency of G542X varies among different towns at regions of origin, being lower in northeastern Europeans than in southwestern Europeans. G542X mutation mapping that they defined by multiple regression of G542X frequencies covered 28 countries (53 geographic points) and was based on data from 50 laboratories. More elevated values of G542X frequency corresponded to ancient sites of occupation by occidental Phoenicians. </p><p>In a patient with a severe form of cystic fibrosis, Savov et al. (1995) identified compound heterozygosity for the G542X mutation and an allele with a double mutation (S912L and G1244V; 602421.0135). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0010 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, SER549ASN
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<br />
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SNP: rs121908755,
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gnomAD: rs121908755,
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ClinVar: RCV000007536, RCV000211264, RCV000727629, RCV001004465, RCV001831522, RCV002247260, RCV002496296, RCV003473007
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Cutting et al. (1990) detected compound heterozygosity for a G-to-A change at nucleotide 1778 in exon 11 of the CFTR gene, responsible for substitution of asparagine for serine at position 549 (S549N), and a premature termination mutation, also in exon 11 (R553X; 602421.0014). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CYSTIC FIBROSIS</strong>
|
|
</span>
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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CFTR, SER549ILE
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<br />
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SNP: rs121908755,
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gnomAD: rs121908755,
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ClinVar: RCV000007537
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected a G-to-T change at nucleotide 1778 in exon 11 of the CFTR gene, responsible for substitution of isoleucine for serine at amino acid 549 (S549I). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 CYSTIC FIBROSIS</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, SER549ARG
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<br />
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SNP: rs121908757, rs121909005,
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gnomAD: rs121908757, rs121909005,
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ClinVar: RCV000007538, RCV000043664, RCV000056350, RCV000211129, RCV000211346, RCV000508411, RCV000763573, RCV000781222, RCV001004464, RCV001004466, RCV001826533, RCV001826538, RCV002247407, RCV003466883, RCV003473249, RCV003476914
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected a T-to-G change at nucleotide 1779 in exon 11 of the CFTR gene, resulting in substitution of arginine for serine at amino acid 549 (S549R). Sangiuolo et al. (1991) found the same ser549-to-arg substitution in an Italian patient with severe cystic fibrosis; however, the substitution was caused by an A-to-C change at nucleotide 1777. Thus, the 2 mutations are AGT-to-AGG and AGT-to-CGT. A T-to-C change at nucleotide 1779 would also change serine to arginine. </p><p>Romey et al. (1999) reported a novel complex allele in the CFTR gene, combining the S549R mutation due to a T-to-G transversion in exon 11 with the first described sequence change in the minimal CFTR promoter, a T-to-A transversion at position -102 (602421.0122). In a separate publication, Romey et al. (1999) compared the main clinical features of 6 CF patients carrying the complex allele with those of 16 CF patients homozygous for the S549R mutation alone. Age at diagnosis was higher, and current age was significantly higher (P = 0.0032), in the group with the complex allele, compared with the S549R/S549R group. Although the proportion of patients with lung colonization was similar in the 2 groups, the age at onset was significantly higher in the group with the complex allele (P = 0.0022). Patients with the complex allele also had significantly lower sweat test chloride values (P = 0.0028) and better overall clinical scores (P = 0.004). None of the 22 patients involved in this study had meconium ileus. All 16 patients homozygous for S549R, however, were pancreatic insufficient, as compared with 50% of patients carrying the complex allele (P = 0.013). Moreover, the single patient homozygous for the complex allele presented with mild disease at 34 years of age. These observations strongly suggested that the sequence change in the CFTR minimal promoter attenuates the severe clinical phenotype associated with the S549R mutation. </p><p>Romey et al. (2000) postulated that the -102T-A sequence change may attenuate the effects of the severe S549R mutation through regulation of CFTR expression. Analysis of transiently transfected cell lines with wildtype and -102A variant human CFTR-directed luciferase reporter genes demonstrated that constructs containing the -102A variant, which creates a Yin Yang 1 (YY1) core element, increases CFTR expression significantly. Electrophoretic mobility shift assays indicated that the -102 site is located within a region of multiple DNA-protein interactions and that the -102A allele recruits specifically an additional nuclear protein related to YY1. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0013 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, GLY551ASP
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<br />
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SNP: rs75527207,
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gnomAD: rs75527207,
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ClinVar: RCV000007540, RCV000119040, RCV000211289, RCV000301838, RCV000763574, RCV001004467, RCV001831524, RCV003473009
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 7 patients, including 2 sibs, with cystic fibrosis (CF; 219700), Cutting et al. (1990) detected a G-to-A change at nucleotide 1784 in exon 11 of the CFTR gene that was responsible for substitution of aspartic acid for glycine at amino acid 551 (G551D). In 6 of these patients the delta-F508 mutation (602421.0001) was present on the other allele; 3 of these patients, aged 11 to 13 years, had mild lung disease with normal pulmonary function test results. In the seventh patient, with mild lung disease, the mutation on the other allele was unknown. </p><p>Curtis et al. (1991) described this mutation in 2 sibs in homozygous state and in an unrelated adult who was a compound heterozygote for G551D and delta-I507 (602421.0002). All 3 showed clinically mild disease. The G551D mutation creates an MboI recognition site at codon 551 in the CFTR gene. Burger et al. (1991) suggested that heterozygosity for the G551D mutation is a causative factor in recurrent polyposis nasi (nasal polyps). Hamosh et al. (1992) stated that the gly551-to-asp mutation, which is within the first nucleotide-binding fold of the CFTR, is the third most common CF mutation, with a worldwide frequency of 3.1% among CF chromosomes. Regions with a high frequency correspond to areas with large populations of Celtic descent. To determine whether G551D confers a different phenotype than does delta-F508, Hamosh et al. (1992) studied 79 compound heterozygotes for the 2 mutations in comparison with age- and sex-matched delta-F508 homozygotes from 9 CF centers in Europe and North America. There was less meconium ileus among the compound heterozygotes but otherwise no statistically significant difference was found between the 2 groups. Clinical outcome (after survival of meconium ileus) was indistinguishable. </p><p>Delaney et al. (1996) showed that mice carrying the human G551D mutation in the Cftr gene show cystic fibrosis pathology but have a reduced risk of fatal intestinal blockage compared with 'null' mutants, in keeping with the reduced incidence of meconium ileus in G551D patients. The G551D mutant mice showed greatly reduced CFTR-related chloride transport, displaying activity (equivalent to approximately 4% of wildtype Cftr) intermediate between that of 'null' mice and Cftr insertional mutants with residual activity. The authors stated that long-term survival of these animals should provide an excellent model for the study of cystic fibrosis. </p><p>The G551D allele is associated characteristically with populations of Celtic descent and is seen at its highest prevalence in regions such as Ireland and Brittany. It is seen in diminishing frequencies as one moves to the southern and eastern portions of Europe. An initially puzzling phenomenon was the relatively high incidence of this mutation in the Czech Republic (3.8%). As pointed out by Bobadilla et al. (2002), however, population movements of the past provide an explanation. </p><p>Accurso et al. (2010) reported the results of a 2-phase clinical trial using VX-770, a CFTR potentiator, in 39 adults with cystic fibrosis and at least 1 G551D allele. Subjects received 150 mg of VX-770 every 12 hours for 28 days in phase 2 of the study. All showed a change in the nasal potential difference from baseline of -3.5 mV (range, -8.3 to 0.5; P = 0.02 for the within-subject comparison; P = 0.13 vs placebo), and the median change in the level of sweat chloride was -59.5 mmol per liter (range, -66.0 to -19.0; P = 0.008 within-subject, P = 0.02 vs placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P = 0.008 within-subject, P = 0.56 vs placebo). The VX-770 was well tolerated. None of the subjects withdrew from the study. All severe adverse events resolved without the discontinuation of VX-770. </p><p>Ramsey et al. (2011) conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770) in subjects 12 years of age or older with cystic fibrosis and at least 1 G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of the drug every 12 hours (84 subjects, of whom 83 received at least 1 dose) or placebo (83, of whom 78 received at least 1 dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of forced expiratory volume in 1 second (FEV1). The change from baseline through week 24 in the percent of predicted FEV1 was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (p less than 0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have pulmonary exacerbation than were patients receiving placebo, through week 48 (p less than 0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory symptoms domain of the Cystic Fibrosis Questionnaire revised instrument (p less than 0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (p less than 0.001). The change from baseline through week 48 in the concentration of sweat chloride with ivacaftor as compared with placebo was -48.1 mmol per liter (p less than 0.001). The incidence of adverse events was similar with treatment and controls, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs 42%). </p><p>On January 31, 2012, the FDA approved Kalydeco, formerly VX-770 (ivacaftor), for use in cystic fibrosis patients with the G551D mutation, as reported by Ledford (2012). </p>
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</span>
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</div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0014 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, ARG553TER
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<br />
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SNP: rs74597325,
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gnomAD: rs74597325,
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ClinVar: RCV000007542, RCV000506601, RCV000763575, RCV000781237, RCV001004260, RCV001831525, RCV003137499
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; 219700), Cutting et al. (1990) detected a C-to-T change at nucleotide 1789 in exon 11 of the CFTR gene that was responsible for a stop mutation at amino acid 553 (R553X). </p><p>Bal et al. (1991) described a patient homozygous for the arg553-to-ter mutation in exon 11. The patient was moderately severely affected. Hamosh et al. (1991) studied a CF patient who was a compound heterozygote for 2 nonsense mutations, R553X and W1316X (602421.0029). The patient had undetectable CFTR mRNA in bronchial and nasal epithelial cells associated with severe pancreatic disease but unexpectedly mild pulmonary disease. The R553X mutation has the fourth highest frequency worldwide, 1.5%, according to the CF Consortium (Hamosh et al., 1991). The patient was a 22-year-old African American female, 1 of 2 patients with mild pulmonary disease reported by Cutting et al. (1990). Cheadle et al. (1992) described a child who despite being homozygous for the R553X mutation had only mild pulmonary disease. They raised the possibility that the lack of CFTR protein in airway cells may be less damaging than the presence of an altered protein, a suggestion advanced by Cutting et al. (1990). </p><p>Chen et al. (2005) reported a Taiwanese CF patient who was homozygous for the R553X mutation. He had a severe clinical course, with early onset of chronic diarrhea, failure to thrive, and frequent respiratory infections. The parents, who were not related, were both heterozygous for the mutation. Both of their families were native to Taiwan, having been on the island for at least 3 generations. Chen et al. (2005) noted that cystic fibrosis is rare among Asians and that homozygosity for R553X had only been reported previously in Caucasian patients. </p><p>Aznarez et al. (2007) performed transcript analysis of 5 CF patients who were compound heterozygous for the R553X and delta-F508 (602421.0001) mutations. RT-PCR of patient lymphoblastoid cells showed variable levels of an aberrantly spliced CFTR isoform that corresponded to the skipping of exon 11. Use of a splice reporter construct indicated that the R553X substitution creates a putative exonic splicing silencer (ESS) that may result in exon skipping by preventing selection of the proximal 5-prime splice site. Exon 11 skipping did not result from a nonsense-associated altered splicing mechanism. Aznarez et al. (2007) concluded that aminoglycoside treatment would not be effective for CF patients with this mutation owing to its effect of skipping exon 11. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0015 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, ALA559THR
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<br />
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SNP: rs75549581,
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gnomAD: rs75549581,
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ClinVar: RCV000007543, RCV000521321, RCV001004261, RCV001826429, RCV002476941, RCV003473010
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; 219700), Cutting et al. (1990) detected a G-to-A change at nucleotide 1807 in exon 11 of the CFTR gene that caused a substitution of threonine for alanine at amino acid 559 (A559T). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0016 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, ARG560THR
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<br />
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SNP: rs80055610,
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gnomAD: rs80055610,
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ClinVar: RCV000007533, RCV000224789, RCV000780134, RCV001004262, RCV001831521, RCV002504762, RCV003473005
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) found a G-to-C change at nucleotide 1811 in exon 11 of the CFTR gene responsible for substitution of threonine for arginine at amino acid 560 (R560T). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0017 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, TYR563ASN
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<br />
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SNP: rs121909006,
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gnomAD: rs121909006,
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ClinVar: RCV000007534, RCV001004266, RCV001009533, RCV002254258, RCV004566688, RCV004734501, RCV005042002
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) found a T-to-A change at nucleotide 1819 in exon 12 of the CFTR gene responsible for substitution of asparagine for tyrosine at amino acid 563 (Y563N). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0018 CYSTIC FIBROSIS</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, PRO574HIS
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<br />
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SNP: rs121908758,
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gnomAD: rs121908758,
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ClinVar: RCV000007539, RCV001004269, RCV001009367, RCV001831523, RCV002254259, RCV002490333, RCV003473008
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected a C-to-A change at nucleotide 1853 in exon 12 of the CFTR gene responsible for substitution of histidine for proline at amino acid 574 (P574H). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0019 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, 2-BP INS, 2566AT
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<br />
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SNP: rs387906359,
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ClinVar: RCV000190991
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), White et al. (1990) detected insertion of 2 nucleotides, AT, after nucleotide 2566 (2566insAT) in exon 13 of the CFTR gene, responsible for a frameshift. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0020 CYSTIC FIBROSIS</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, 1-BP DEL, 3659C
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<br />
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SNP: rs121908811,
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gnomAD: rs121908811,
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|
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ClinVar: RCV000007544, RCV001004502, RCV001831526, RCV003473011, RCV004558238, RCV005031406
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected deletion of a C at nucleotide 3659 in exon 19 of the (3659delC) CFTR gene resulting in a frameshift. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, SER1255TER
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|
|
|
|
|
<br />
|
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|
|
SNP: rs76649725,
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|
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|
|
gnomAD: rs76649725,
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|
|
|
|
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ClinVar: RCV000007545, RCV000781247, RCV001810834, RCV001831527, RCV003473012
|
|
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|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 11-year-old black boy with cystic fibrosis (CF; 219700), Cutting et al. (1990) detected a C-to-A change at nucleotide 3896 in exon 20 of the CFTR gene responsible for a stop mutation at amino acid 1255 (S1255X). The boy inherited this mutation from his father. The chromosome inherited from his mother carried another nonsense mutation, gly542-to-ter (602421.0009). The patient had serious pancreatic disease but only mild pulmonary involvement. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, TRP1282TER
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|
<br />
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|
|
SNP: rs77010898,
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gnomAD: rs77010898,
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|
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ClinVar: RCV000007549, RCV000271658, RCV000763161, RCV000780159, RCV001004509, RCV001731145, RCV002228015, RCV002255994, RCV003473013
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|
|
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</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French patient with cystic fibrosis (CF; 219700), Vidaud et al. (1990) identified the substitution of tryptophan-1282 by a termination codon in the CFTR gene. The other chromosome carried the delta-F508 mutation (602421.0001). In another French patient with cystic fibrosis, Vidaud et al. (1990) found precisely the same mutation on one chromosome but the mutation on the other chromosome was unknown. A G-to-A substitution at nucleotide 3978 was responsible for the trp1282-to-ter change. </p><p>Hamosh et al. (1991) cited evidence that the W1282X mutation, located in exon 20, is the most common CF mutation in the Ashkenazi Jewish population where it is present on 50% of CF chromosomes. In Israel, Shoshani et al. (1992) found the W1282X mutation in 63 chromosomes from 97 CF families. Sixteen patients homozygous for the W1282X mutation and 22 patients heterozygous for the delta-F508 and W1282X mutations had similarly severe disease, reflected by pancreatic insufficiency, high incidence of meconium ileus (37% and 27%, respectively), early age at diagnosis, poor nutritional status, and variable pulmonary function. Again, the W1282X mutation was the most common form in Ashkenazi Jewish patients in Israel. In the Jewish Ashkenazi patient population, 60% of the CF chromosomes carry the W1282X nonsense mutation. Patients homozygous for this mutation have severe disease with variable pulmonary complications. Studies by Shoshani et al. (1994) demonstrated that CFTR mRNA levels in patients homozygous for the W1282X mutation are not significantly decreased by the mutation. In patients heterozygous for the mutation, the relative levels of mRNA with the W1282X allele and either the delta-F508 or the normal allele were similar in each patient. These results indicated that the severe clinical phenotype of patients carrying the W1282X mutation is not due to a severe deficiency of mRNA. The severity, progression, and variability of the pulmonary disease appear to be affected by other, as yet unknown factors. </p><p>Kulczycki et al. (2003) described their oldest patient with cystic fibrosis, a 71-year-old white male who had been diagnosed at the age of 27 years because of recurrent nasal polyposis, elevated sweat sodium and chloride, and a history of CF in his sister. Urologic examination demonstrated congenital bilateral absence of the vas deferens (277180). At the age of 60 years, genetic testing indicated compound heterozygosity for a severe W1282X mutation and a mild ala445-to-glu (602421.0130) mutation in the CFTR gene. (In the article by Kulczycki et al. (2003), the W1282X mutation was erroneously cited as H1282X.) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 CFTR POLYMORPHISM</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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CFTR, MET470VAL
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<br />
|
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|
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SNP: rs213950,
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gnomAD: rs213950,
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|
|
ClinVar: RCV000007550, RCV000036517, RCV001095216, RCV001810835
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Kerem et al. (1990) found 'normal' A or G variation at nucleotide 1540 resulting in methionine or valine, respectively, at position 470. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
|
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</div>
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|
|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 CFTR POLYMORPHISM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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|
|
CFTR, ILE506VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1800091,
|
|
|
|
|
|
gnomAD: rs1800091,
|
|
|
|
|
|
ClinVar: RCV000007551, RCV000245320, RCV000759754, RCV001282755
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant in the CFTR gene was found by Kobayashi et al. (1990) in a compound heterozygote with delta-F508 (602421.0001). Clinical and epithelial physiologic studies yielded normal results, indicating that the I506V mutation is benign. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 CFTR POLYMORPHISM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, PHE508CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74571530,
|
|
|
|
|
|
gnomAD: rs74571530,
|
|
|
|
|
|
ClinVar: RCV000007546, RCV000078978, RCV001009496, RCV001281707, RCV001327947, RCV001642200, RCV001731144, RCV002255993
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This mutation was found by Kobayashi et al. (1990) in a compound heterozygote with delta-F508 (602421.0001). Clinical and epithelial physiologic studies yielded normal results, indicating that the F508C mutation is benign. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, TRP846TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606722,
|
|
|
|
|
|
gnomAD: rs267606722,
|
|
|
|
|
|
ClinVar: RCV000007547, RCV001004480, RCV001826430, RCV004566689, RCV005042003
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French patient with cystic fibrosis (CF; 219700), Vidaud et al. (1990) found a replacement of tryptophan-846 by a stop codon on one chromosome; the nature of the mutation on the other chromosome was unidentified. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, TYR913CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909008,
|
|
|
|
|
|
gnomAD: rs121909008,
|
|
|
|
|
|
ClinVar: RCV000007548, RCV001004485, RCV004566690, RCV005031407
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French patient with cystic fibrosis (CF; 219700), Vidaud et al. (1990) identified substitution of tyrosine-913 by cysteine. The other chromosome carried the delta-F508 mutation. An A-to-G substitution at position 2870 was responsible for the tyr913-to-cys change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, GLY458VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909009,
|
|
|
|
|
|
|
|
ClinVar: RCV000007552
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Cuppens et al. (1990) described compound heterozygosity for the G542X mutation (602421.0009) and a change of glycine-458 to valine (G458V). The patient died at the age of 12 years of respiratory insufficiency and right heart failure. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, TRP1316TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909010,
|
|
|
|
|
|
|
|
ClinVar: RCV000007553
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 21-year-old black woman with cystic fibrosis (CF; 219700) with substantial pancreatic disease but only mild pulmonary involvement, Cutting et al. (1990) found an A-to-G substitution at nucleotide 4079 in exon 21, leading to replacement of tryptophan at codon 1316 by a termination signal. The mutation appeared to have been inherited from the father; from the mother the patient had inherited the arg553-to-ter mutation (602421.0014). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 2-BP INS, 1154TC
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906360,
|
|
|
|
|
|
|
|
ClinVar: RCV000007554, RCV000723429, RCV000780169, RCV001004249, RCV001831528, RCV003473014, RCV005031408
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 37-year-old woman with cystic fibrosis (CF; 219700) who had a high sweat chloride level, pancreatic insufficiency since infancy, and mild lung disease, Iannuzzi et al. (1991) identified insertion of 2 nucleotides, T and C, at position 1154 of the CFTR gene, predicting a shift in the reading frame of the protein and the introduction of a UAA(ochre) termination codon at residue 369. The patient carried delta-F508 (602421.0001) on the other allele. Alper et al. (2003) described the truncated protein as lacking ATP binding domains, the regulatory domain, and the second transmembrane domain and as thought to be nonfunctional. </p><p>Screening 80 CFTR patients, Alper et al. (2003) found two 1154insTC mutations, both in Caucasians, accounting for 1.25% of the CF chromosomes. They also reported compound heterozygosity with delF508 (602421.0001) in CF with pancreatic insufficiency and meconium ileus in a Caucasian male. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 1-BP DEL, 1213T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906361,
|
|
|
|
|
|
gnomAD: rs387906361,
|
|
|
|
|
|
ClinVar: RCV000007555, RCV001009522, RCV001831529, RCV003466826
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with cystic fibrosis (CF; 219700), Iannuzzi et al. (1991) identified deletion of thymine at position 1213, which was predicted to shift the reading frame of the protein and to introduce a UAA(ochre) termination codon at residue 368. The patients had mildly impaired lung function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ASN1303LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80034486,
|
|
|
|
|
|
gnomAD: rs80034486,
|
|
|
|
|
|
ClinVar: RCV000007556, RCV000224445, RCV001004513, RCV001831530, RCV002255995, RCV002287325, RCV003473015, RCV005042004
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>On 4 of 52 chromosomes from patients with cystic fibrosis (CF; 219700), including 2 sibs, Osborne et al. (1991) identified a C-to-G change at nucleotide 4041 of the CFTR gene resulting in a change from asparagine to lysine at amino acid position 1303 (N1303K). This mutation was found exclusively in heterozygous state and no correlation could be made between clinical phenotype and the presence of the gene. Pooling laboratories throughout Europe and the United States, Osborne et al. (1992) identified 216 examples of N1303K among nearly 15,000 CF chromosomes tested, a frequency of 1.5%. The frequency was greater in southern than in northern Europe; it was not found in U.K. Asians, American blacks, or Australians. Ten patients were homozygous, whereas 106 of the remainder carried 1 of 12 known CF mutations in the other allele. Osborne et al. (1992) concluded that N1303K is a 'severe' mutation with respect to the pancreas, but could find no correlation between this mutation in either the homozygous or heterozygous state and the severity of lung disease. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ARG1162TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74767530,
|
|
|
|
|
|
gnomAD: rs74767530,
|
|
|
|
|
|
ClinVar: RCV000007557, RCV000508142, RCV000780138, RCV001004500, RCV001831531, RCV002504763, RCV003473016, RCV004720229
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of cystic fibrosis (CF; 219700) mutations in south European cases, Gasparini et al. (1991) found a nonsense mutation in exon 19 due to a C-to-T substitution at nucleotide 3616. The normal codon CGA, which codes for arginine at position 1162, was changed to a stop codon UGA (R1162X). It was detected in 2 of 16 non-delta-F508 chromosomes. In 9 patients homozygous for this mutation, Gasparini et al. (1992) found mild lung disease. They had expected that the interruption in the synthesis of the CFTR protein would result in a severe clinical course. The findings of mild to moderate involvement of the lungs (although pancreatic insufficiency was present in all) suggested to them that this form of truncated CFTR protein, still containing the regulatory region, the first ATP binding domain, and both transmembrane domains, could be partially working in lung tissues. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ARG334TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909011,
|
|
|
|
|
|
gnomAD: rs121909011,
|
|
|
|
|
|
ClinVar: RCV000007559, RCV000224060, RCV000763567, RCV001000033, RCV001004246, RCV001826431, RCV003473017
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the course of a study of cystic fibrosis (CF; 219700) mutations in south European cases, Gasparini et al. (1991) found a C-to-T substitution at nucleotide 1132 in exon 7. This point mutation changed an arginine codon to a tryptophan at position 334 of the putative first transmembrane domain of the protein (R334W). The patient was a compound heterozygote for mutations R334X and N1303K (602421.0032). </p><p>Antinolo et al. (1997) compared the phenotype of 12 patients with cystic fibrosis caused by the R334W mutation with those of homozygous delF508 patients. Current age and age at diagnosis were significantly higher in the R334W mutation group. They found a lower rate of Pseudomonas aeruginosa colonization in patients carrying the R334W mutation, although the difference was not statistically significant. However, they found a statistically significant higher age of onset of Pseudomonas aeruginosa colonization in the group of patients with the R334W mutation. Pancreatic insufficiency was found in a lower percentage of R334W patients (33%). The body weight expressed as a percentage of ideal weight for height was significantly higher in patients with the R334W mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 2-BP DEL, 1677TA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908776,
|
|
|
|
|
|
|
|
ClinVar: RCV000007560, RCV001528991, RCV001813963, RCV001826432, RCV003473018
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In both parents of a sibship in which 3 children with cystic fibrosis (CF; 219700) had died within months of birth (2 with pneumonia and 1 with presumed meconium ileus), Ivaschenko et al. (1991) found the same mutation, namely, deletion of 2 nucleotides (TA) at position 1677. As a result of the deletion, the protein reading frame was shifted, introducing a termination codon (TAG) at amino acid position 515 in the resulting transcript. The family was from a small Soviet ethnic group called the Megrals in western Georgia. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0036 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ARG851TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909012,
|
|
|
|
|
|
|
|
ClinVar: RCV000007561, RCV001004481, RCV001831532, RCV002476942, RCV003473019
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a compound heterozygote with cystic fibrosis (CF; 219700), White et al. (1991) found a de novo mutation which converted codon 851 (CGA;ARG) to a stop codon (TGA). The mother lacked any CFTR mutation and the father was heterozygous for the common delta-F508 mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0037 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, GLY551SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909013,
|
|
|
|
|
|
gnomAD: rs121909013,
|
|
|
|
|
|
ClinVar: RCV000007562, RCV000211256, RCV000224595, RCV001831533, RCV002247261, RCV003473020
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters with mild cystic fibrosis (CF; 219700), the offspring of second-cousin parents, Strong et al. (1991) found a G-to-A substitution at basepair 1783 resulting in substitution of a serine for a glycine residue at the highly conserved position of amino acid 551. The proposita was a 50-year-old woman with a chronic productive cough. She had frequent pulmonary infections. Her sweat electrolyte concentrations were borderline normal. The patient had 2 normal pregnancies and deliveries and raised these children while working as a truck inspector. The patient had a sister who died of respiratory failure at the age of 48. She had delivered 4 healthy children without difficulty, had no evidence of malabsorption, and was in good health until the age of 23 when she had an episode of hemoptysis. At that time she was reported to have digital clubbing and bronchiectasis on chest roentgenography. Several sweat tests were normal. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0038 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, GLY85GLU
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|
|
<br />
|
|
|
|
SNP: rs75961395,
|
|
|
|
|
|
gnomAD: rs75961395,
|
|
|
|
|
|
ClinVar: RCV000007563, RCV000224170, RCV001004234, RCV001831534, RCV002490334, RCV003473021
|
|
|
|
|
|
</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 11-year-old boy of Iranian extraction with cystic fibrosis (CF; 219700), Chalkley and Harris (1991) found homozygosity for a G-to-A mutation at nucleotide 386 in exon 3 of the CFTR gene, resulting in substitution of glutamic acid for glycine-85. The diagnosis of CF was made when the patient presented with a nasal polyp. He had sweat sodium values of 90 mmol per liter and mild lung disease and was pancreatic sufficient. The G85E mutation was first defined by Zielenski et al. (1991) in a French Canadian patient who was a compound heterozygote. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0039 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
|
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|
<div>
|
|
<span class="mim-text-font">
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CFTR, ARG1158TER
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<br />
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|
|
|
SNP: rs79850223,
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gnomAD: rs79850223,
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ClinVar: RCV000007564, RCV000579152, RCV000763158, RCV001004499, RCV001831535, RCV003473022
|
|
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|
|
|
</span>
|
|
</div>
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|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian patient with cystic fibrosis (CF; 219700) known to be a genetic compound, Ronchetto et al. (1992) found a C-to-T transition at nucleotide 3604 of the CFTR gene, which changed an arginine residue at position 1158 to a stop codon (R1158X). The patient carried an unknown mutation on the other chromosome and was pancreatic sufficient. </p>
|
|
</span>
|
|
</div>
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0040 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
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CFTR, IVS19, A-G, +4
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<br />
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|
|
SNP: rs387906362,
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|
|
ClinVar: RCV000007558
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|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian patient with cystic fibrosis (CF; 219700) with pancreatic insufficiency but mild pulmonary disease, Ronchetto et al. (1992) found an A-to-G transition located at the 5-prime end of intron 19 of the CFTR gene, which changed the consensus sequence of the donor site from GTGAGA to GTGGGA (3849+4A-G). </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0041 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
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|
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|
CFTR, 22-BP DEL
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<br />
|
|
|
|
SNP: rs121908804,
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|
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|
|
ClinVar: RCV000007565, RCV001826433
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>As part of a search for additional mutations causing cystic fibrosis (CF; 219700), Dean et al. (1992) used flanking primers for exon 6A to amplify DNA from over 150 CF patients who lacked the delta-F508 mutation on at least 1 chromosome. In 1 individual, a 22-bp deletion, beginning at nucleotide 852 and stopping 2 bp before the end of the exon, was found. The deletion was predicted to alter the reading frame of the protein, causing the introduction of an in-frame termination codon, TGA, at amino acid 253. Dean et al. (1992) stated that were no documented cases of large deletions and only 1 report of a de novo mutation in the CFTR gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0042 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 1-BP DEL, 556A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906363,
|
|
|
|
|
|
|
|
ClinVar: RCV000007566, RCV001826434
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700) with pancreatic insufficiency, Zielenski et al. (1991) identified an exon 4 mutation in CFTR that created a new BglI site, a frameshift due to deletion of nucleotide 556, an A. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0043 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 1-BP DEL, 557T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906364,
|
|
|
|
|
|
|
|
ClinVar: RCV000007567, RCV001831536, RCV005031409
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700) with relatively mild symptoms, Graham et al. (1992) identified deletion of a single nucleotide, a T, in the T tract from base 557 to 561 in exon 4 of the CFTR gene. Like the 556A deletion (602421.0042), the mutation created a new BglI site. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0044 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 84-BP DEL, NT1949
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908777,
|
|
|
|
|
|
|
|
ClinVar: RCV000046486, RCV004558294, RCV005042130
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Granell et al. (1992) identified an 84-bp deletion in exon 13 of the CFTR gene by DNA amplification and direct sequencing of 500 bp of the 5-prime end of exon 13. The deletion was in the maternal allele, and the patient's paternal allele bore the delta-F508 deletion (602421.0001). The deletion spanned from a 4-A cluster in positions 1949-1952 to another 4-A cluster in positions 2032-2035. The mutation resulted in the loss of 28 amino acid residues in the R domain of the CFTR protein. Since this in-frame mutation, the largest identified to that time, began after nucleotide 1949, it was referred to as 1949del84. Out of 340 Spanish CF patients, Nunes et al. (1992) found 3 patients who were compound heterozygotes for the 1949del84 and delF508 mutations and 1 for 1949del84 and an unknown mutation. The patients had a similar severity of disease to that in delF508 homozygous patients. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0045 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 1-BP INS, 2869G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908788,
|
|
|
|
|
|
|
|
ClinVar: RCV000007569, RCV001826435, RCV002490335
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 patients with cystic fibrosis (CF; 219700), Nunes et al. (1992) identified a frameshift mutation resulting from insertion of a guanine (G) after nucleotide 2869 in exon 15. One patient was homozygous for the mutation and the other 4 were compound heterozygous. Direct sequencing of the person homozygous for this mutation showed that the mutation resulted in a TGA stop codon at the site of insertion, followed by another stop signal at the beginning of exon 16. The mutation created a new restriction site for the MboI endonuclease. Nunes et al. (1992) demonstrated that the mutation was present in 6 of 191 non-delF508 chromosomes in the Spanish population and in none of 86 Italian non-delF508 chromosomes. All chromosomes carrying the mutation had the same haplotype. A homozygous patient had a moderately severe clinical course. (This mutation is also referred to as 2869insG.) </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0046 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, VAL520PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs77646904,
|
|
|
|
|
|
gnomAD: rs77646904,
|
|
|
|
|
|
ClinVar: RCV000007570, RCV000781233, RCV001004460, RCV001528232, RCV001826436, RCV003473023
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Jones et al. (1992) used the chemical cleavage mismatch technique to demonstrate a V520F mutation which resulted from a G-to-T transversion. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0047 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, CYS524TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908754,
|
|
|
|
|
|
gnomAD: rs121908754,
|
|
|
|
|
|
ClinVar: RCV000007571, RCV001831537, RCV003466827
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Using the chemical cleavage mismatch technique for the study of DNA from a patient with cystic fibrosis (CF; 219700), Jones et al. (1992) discovered a nonsense C524X mutation resulting from a C-to-A transversion. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0048 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, GLN1291HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909015,
|
|
|
|
|
|
gnomAD: rs121909015,
|
|
|
|
|
|
ClinVar: RCV000007572, RCV000780123, RCV002228016, RCV003473024
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Jones et al. (1992) demonstrated a Q1291H mutation caused by a G-to-C transversion at the last nucleotide of exon 20 using the chemical cleavage mismatch technique. Further study, involving RNA-based PCR, demonstrated that the Q1291H is also a splice mutation. Both correctly and aberrantly spliced mRNAs were produced by the Q1291H allele. The incorrectly spliced product resulted from the use of a nearby cryptic splice site 29 bases into the adjacent intron. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0049 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, PHE311LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909016,
|
|
|
|
|
|
|
|
ClinVar: RCV000007573, RCV001642201, RCV003473025
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Using DGGE in a systematic study of cystic fibrosis (CF; 219700) mutations in a Celtic population in Brittany, Ferec et al. (1992) identified a C-to-G mutation at nucleotide 1065 of the CFTR gene changing codon 311 from phenylalanine to leucine. The mutation was found in a compound heterozygous child who was classified as pancreatic insufficient; the other allele was gly551-to-asp (602421.0013). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0050 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 2-BP DEL, NT1221
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906365,
|
|
|
|
|
|
|
|
ClinVar: RCV000007574, RCV003473026
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 365 cystic fibrosis (CF; 219700) chromosomes in the Celtic population in Brittany, Ferec et al. (1992) detected a frameshift mutation in exon 7. The patient, who was severely pancreatic insufficient, was a compound heterozygote for a deletion of 2 nucleotides at position 1221. The other allele had a deletion of T at 1078. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0051 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, SER492PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909017,
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|
|
|
|
|
gnomAD: rs121909017,
|
|
|
|
|
|
ClinVar: RCV000007575, RCV000763571, RCV001004455, RCV001810836, RCV003473027, RCV004734502
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 365 cystic fibrosis (CF; 219700) chromosomes in the Celtic population in Brittany, Ferec et al. (1992) identified a ser492-to-phe mutation, due to a change at nucleotide 1607 from C to T, in a child classified as pancreatic sufficient. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0052 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ARG560LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80055610,
|
|
|
|
|
|
gnomAD: rs80055610,
|
|
|
|
|
|
ClinVar: RCV000007576, RCV003466828
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 365 cystic fibrosis (CF; 219700) chromosomes in the Celtic population in Brittany, Ferec et al. (1992) identified an arg560-to-lys mutation at the 3-prime end of exon 11, resulting from a G-to-A transition at nucleotide 1811. As well as resulting in an amino acid change in the protein product, the substitution in the last residue of the exon may represent a splice mutation; a similar change in exon 1 of the human beta-globin gene diminishes RNA splicing (Vidaud et al., 1989; see hemoglobin Kairouan; HBB, ARG30THR; 141900.0144). The patient was pancreatic insufficient. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0053 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, GLU827TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909018,
|
|
|
|
|
|
|
|
ClinVar: RCV000007577
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a child with pancreatic-insufficient cystic fibrosis (CF; 219700) in the Celtic population of Brittany, Ferec et al. (1992) identified a G-to-T change at position 2611 in exon 13 leading to change of glutamic acid-827 to a stop codon. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0054 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ARG1066HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909019,
|
|
|
|
|
|
gnomAD: rs121909019,
|
|
|
|
|
|
ClinVar: RCV000007578, RCV000506781, RCV000592350, RCV001004299, RCV001831538, RCV002496297, RCV003473028
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a pancreatic-insufficient cystic fibrosis (CF; 219700) patient in the Celtic population of Brittany, Ferec et al. (1992) found an arg1066-to-his mutation resulting from a G-to-A transition at nucleotide 3329. This CpG dinucleotide is a known hotspot for mutations. Ferec et al. (1992) quoted unpublished results indicating that another mutation, C3328 to T leading to arg1066-to-cys, had been discovered (602421.0058). The child with the arg1066-to-his mutation was a compound heterozygote, the other allele having a deletion of T at nucleotide 1078. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0055 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ALA1067THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909020,
|
|
|
|
|
|
gnomAD: rs121909020,
|
|
|
|
|
|
ClinVar: RCV000007579, RCV000078995, RCV000660774, RCV000723610, RCV001831539
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a pancreatic-insufficient child with cystic fibrosis (CF; 219700) in the Celtic population in Brittany, Ferec et al. (1992) found a G-to-A transition at position 3331 resulting in an ala1067-to-thr substitution. The modification replaced a nonpolar residue with a polar residue. The other chromosome carried the delta-F508 mutation (602421.0001). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0056 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, IVS20, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs143570767,
|
|
|
|
|
|
|
|
ClinVar: RCV000007580, RCV001004510, RCV001831540, RCV002496298, RCV003736536
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a pancreatic-insufficient patient with cystic fibrosis (CF; 219700) in the Celtic population of Brittany, Ferec et al. (1992) identified a G-to-A mutation in the first nucleotide of the splice donor site of intron 20. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0057 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 5-BP DUP, NT3320
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906366,
|
|
|
|
|
|
|
|
ClinVar: RCV000007581
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a pancreatic-insufficient patient with cystic fibrosis (CF; 219700) in the Celtic population of Brittany, Ferec et al. (1992) found duplication of 5 nucleotides (CTATG) after nucleotide 3320, creating a frameshift. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0058 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ARG1066CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs78194216,
|
|
|
|
|
|
gnomAD: rs78194216,
|
|
|
|
|
|
ClinVar: RCV000007582, RCV000723839, RCV001001063, RCV001004298, RCV001831541, RCV002496299, RCV003473029
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ferec et al. (1992) cited unpublished results of P. Fanen: a C-to-T transition at nucleotide 3328 led to an arg1066-to-cys substitution. This CpG dinucleotide is a hotspot for mutations; see 602421.0054. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0059 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 1-BP DEL, 1078T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908744, rs75528968,
|
|
|
|
|
|
gnomAD: rs121908744,
|
|
|
|
|
|
ClinVar: RCV000007583, RCV000079016, RCV001826437, RCV003473030
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 602421.0050. Claustres et al. (1992) found this mutation in exon 7 in a CF patient with cystic fibrosis (CF; 219700) from southern France. Romey et al. (1993) described an improved procedure that allows the detection of single basepair deletions on nondenaturing polyacrylamide gels and demonstrated its applicability for identifying this mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0060 VAS DEFERENS, CONGENITAL BILATERAL ABSENCE OF</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ASP1270ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs11971167,
|
|
|
|
|
|
gnomAD: rs11971167,
|
|
|
|
|
|
ClinVar: RCV000007584, RCV000046985, RCV000176372, RCV000480239, RCV000587433, RCV001158873, RCV001255580, RCV005031410
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of 25 unrelated, unselected white azoospermic men with clinically diagnosed congenital bilateral absence of the vas deferens (CBAVD; 277180), aged 24 to 43 years, Anguiano et al. (1992) found 2 in whom there was heterozygosity for the phe508-to-del mutation (602421.0001) with another rare mutation on the other chromosome. In 1 patient, of English/Italian extraction, the second mutation was a G-to-A transition resulting in substitution of asparagine for aspartic acid at amino acid 1270 (D1270N). The patient had a normal chest x-ray and sweat electrolytes well within the normal range. There were no signs of pulmonary or gastrointestinal disease and no signs of overt malabsorption. Thus, the patient had a primarily genital form of cystic fibrosis. Both this mutation and the G576A mutation (602421.0061) occur within the adenosine triphosphate-binding domains of the CFTR protein. These domains are believed to play a role in the regulation of chloride transport. It is possible that the cells of the developing wolffian duct have regulatory pathways functionally associated to CFTR that are different from the lung, pancreas, or sweat duct. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0061 VAS DEFERENS, CONGENITAL BILATERAL ABSENCE OF</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, GLY576ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1800098,
|
|
|
|
|
|
gnomAD: rs1800098,
|
|
|
|
|
|
ClinVar: RCV000007585, RCV000029486, RCV000078981, RCV000155472, RCV000582695, RCV000584175, RCV001009484, RCV001089864, RCV001172493, RCV005031411
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a man with isolated congenital bilateral absence of the vas deferens (277180), Anguiano et al. (1992) found compound heterozygosity for the phe508-to-del (602421.0001) mutation and another rare mutation: a GGA-to-GCA transversion in codon 576 in exon 12, predicted to cause a substitution of alanine for glycine. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0062 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 3849+10KB, C-T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs75039782,
|
|
|
|
|
|
gnomAD: rs75039782,
|
|
|
|
|
|
ClinVar: RCV000007586, RCV000507372, RCV000727872, RCV000763159, RCV001009390, RCV001826438, RCV002257359
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Abeliovich et al. (1992) found that among 94 Ashkenazi Jewish patients with cystic fibrosis (CF; 219700) in Israel, 5 mutations accounted for 97% of mutant CFTR alleles. Four of these were delF508 (602421.0001), G542X (602421.0009), W1282X (602421.0022), and N1303K (602421.0032). The fifth, which accounted for 4% of alleles, was an unusual mutation found by Highsmith (1991). Referred to as 3849+10kbC-T, it was detected by cleavage of a PCR product by HphI. Highsmith et al. (1991) detected the 3849+10kbC-T mutation in a 19-year-old Pakistani woman with mild manifestations of CF and normal sweat chloride values. To explain the milder course of the disease in patients with this mutation, Highsmith et al. (1991) hypothesized that the C-to-T base substitution created an alternative splice site, which resulted in insertion of 84 basepairs into the CFTR coding region. This change may cause synthesis of a protein with normal CFTR function together with a nonfunctional protein. Alternatively, this mutation might lead to production of a protein that is only partly functional and causes milder disease. In Israel, Augarten et al. (1993) investigated 15 patients with CF and this mutation, all Ashkenazi Jews. Their clinical features were compared with those of CF patients with mutations known to be associated with severe disease. Patients with the 3849+10kbC-T mutation were older, had been diagnosed as having CF at a more advanced age, and were in a better nutritional state. Sweat chloride values were normal in 5 of the 15 patients; 4 of these patients and 6 others had normal pancreatic function. However, age-adjusted pulmonary function did not differ between these patients and those with mutations known to cause severe disease. None of the patients with the 3849+10kbC-T mutation had had meconium ileus and none had liver disease or diabetes mellitus. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0063 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ARG1283MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs77902683,
|
|
|
|
|
|
gnomAD: rs77902683,
|
|
|
|
|
|
ClinVar: RCV000007587, RCV001731145, RCV001831542
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 pancreatic-insufficient patients with cystic fibrosis (CF; 219700), Cheadle et al. (1992) identified a novel CFTR mutation which, like the trp1282-to-ter mutation (602421.0022), abolishes an MnlII restriction site. The new mutation was found to be a G-to-T transversion at position 3980 resulting in replacement of arginine by methionine at residue 1283 (R1283M). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0064 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
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|
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|
CFTR, IVS12, G-A, +1
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|
<br />
|
|
|
|
SNP: rs121908748,
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|
|
|
|
|
gnomAD: rs121908748,
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|
|
|
|
ClinVar: RCV000007588, RCV000985681, RCV001002343, RCV001004273, RCV001027908, RCV002496300, RCV003473031
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
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<span class="mim-text-font">
|
|
<p>In 2 patients with cystic fibrosis (CF; 219700), Strong et al. (1992) used chemical mismatch cleavage and subsequent DNA sequencing to identify a splice mutation at the 5-prime end of intron 12 of the CFTR gene. A G-to-A transition at position 1 of the donor-splice site resulted in skipping of exon 12. The mutation was found in compound heterozygous state with the delF508 mutation (602421.0001) in a 39-year-old white male and a 9-year-old female with typical pulmonary and gastrointestinal changes of CF. Both were pancreatic insufficient. The male had a history of liver disease requiring splenorenal shunt for portal hypertension at age 14 years. </p>
|
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</span>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
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|
</div>
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|
<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0065 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
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|
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|
CFTR, GLN359LYS AND THR360LYS
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|
<br />
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|
|
SNP: rs75053309, rs76879328,
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|
gnomAD: rs75053309,
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|
|
|
ClinVar: RCV000007589, RCV001293471, RCV001293472, RCV002247262, RCV002415404, RCV002420286
|
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|
|
|
</span>
|
|
</div>
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|
<div>
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|
<span class="mim-text-font">
|
|
<p>Shoshani et al. (1993) found that 88% of identified cystic fibrosis (CF; 219700) chromosomes among CF patients who were Jews from Soviet Georgia had a double mutation in adjacent codons: one alteration was a C-to-A transversion at nucleotide position 1207, changing the glutamine codon to lysine (Q359K); the second alteration was a C-to-A transversion at nucleotide position 1211, changing the threonine codon to lysine (T360K). </p>
|
|
</span>
|
|
</div>
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|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0066 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
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|
|
CFTR, IVS6, 12-BP DEL
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|
<br />
|
|
|
|
SNP: rs387906367,
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|
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|
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|
|
ClinVar: RCV000007590
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a pancreatic-insufficient cystic fibrosis (CF; 219700) patient, Audrezet et al. (1993) found compound heterozygosity for a delta-F508 mutation and a novel mutation which they designated 876--14 del 12 NT: a large deletion which began at position -14 of exon 6b corresponded to a loss of 12 nucleotides. Because the mutation involved a 4-bp repeat (GATT), the deletion could involve 8 nucleotides depending on the allele in which it occurred. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0067 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ARG347LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs77932196,
|
|
|
|
|
|
gnomAD: rs77932196,
|
|
|
|
|
|
ClinVar: RCV000007591, RCV001004252, RCV003466829, RCV005031412
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 2-year-old girl with cystic fibrosis (CF; 219700) detected during a systematic neonatal screening who was up to that time symptom free and pancreatic sufficient, Audrezet et al. (1993) found a G-to-T transversion at bp 1172 changing arginine (an amino acid with a basic side chain) to leucine (bearing a nonpolar side chain) at residue 347. Audrezet et al. (1993) pointed out that 2 other mutations involving nucleotide 1172 have been observed, one leading to R347P (602421.0006) and the other to R347H (602421.0078). Both are associated with pancreatic sufficiency. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0068 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ALA349VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909021,
|
|
|
|
|
|
gnomAD: rs121909021,
|
|
|
|
|
|
ClinVar: RCV000007592, RCV000728852, RCV000780115, RCV001004253, RCV002247263, RCV003466830
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the course of screening the normal husband of a heterozygous woman, Audrezet et al. (1993) found a C-to-T transition at nucleotide 1178 predicting substitution of valine for alanine at residue 349. Since both of these amino acids carry a nonpolar side chain, it was not obvious that the variation would lead to a CF allele. However, this nucleotide change was not observed on more than 300 normal chromosomes screened, and alanine at position 349 is conserved in the CFTR gene of human, Xenopus, and cow. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0069 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ALA534GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909022, rs387906368,
|
|
|
|
|
|
gnomAD: rs387906368,
|
|
|
|
|
|
ClinVar: RCV000007593, RCV000755924, RCV001831543, RCV002482841, RCV003234896
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a screening of 48 patients with cystic fibrosis (CF; 219700) and 12 obligate carriers, Audrezet et al. (1993) observed a C-to-T transition at nucleotide 1733 leading to substitution of glutamic acid for alanine-534 (A534E). The change is a drastic one since it replaces an acidic residue with one that is nonpolar. Observed in heterozygotes, the mutation is probably of functional significance. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0070 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, LYS716TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909023,
|
|
|
|
|
|
|
|
ClinVar: RCV000007594
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a screening of 48 patients with cystic fibrosis (CF; 219700) and 12 obligate carriers, Audrezet et al. (1993) found an A-to-T transversion at nucleotide 2278 resulting in a stop codon at lysine-716. The mutation was detected in the heterozygous father of a deceased child; no clinical data were available. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0071 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, IVS13, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs141158996,
|
|
|
|
|
|
gnomAD: rs141158996,
|
|
|
|
|
|
ClinVar: RCV000007595, RCV001509317, RCV001826439, RCV005031413
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 2-year-old child with cystic fibrosis (CF; 219700) who carried the delta-F508 mutation (602421.0001) and manifested classic symptoms of CF, namely, pancreatic insufficiency and pulmonary disease, Audrezet et al. (1993) detected on the other chromosome a G-to-A transition in the first nucleotide in the 5-prime splice site of intron 13. Audrezet et al. (1993) referred to this mutation as 2622 +1 G-to-A. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0072 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, GLN1238TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908766,
|
|
|
|
|
|
gnomAD: rs121908766,
|
|
|
|
|
|
ClinVar: RCV000007596
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with classic pancreatic-insufficient CF (CF; 219700), Audrezet et al. (1993) found a C-to-T transition at nucleotide 3844 creating a stop codon (TAG) in place of glutamine (CAG). The other chromosome carried the G542X mutation (602421.0009). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0073 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, IVS19, G-A, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906369,
|
|
|
|
|
|
|
|
ClinVar: RCV000007597, RCV001831544, RCV003996079
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 children with classic cystic fibrosis (CF; 219700), all with pancreatic insufficiency, Audrezet et al. (1993) observed a G-to-A transition at nucleotide -1 of intron 19, involving the splice acceptor site (3850, -1, G-to-A). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0074 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 1-BP INS, 3898C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906370,
|
|
|
|
|
|
gnomAD: rs387906370,
|
|
|
|
|
|
ClinVar: RCV000007598
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a severely affected, pancreatic-insufficient, 20-year-old patient with cystic fibrosis (CF; 219700), Audrezet et al. (1993) found insertion of a C after nucleotide 3898 resulting in frameshift. The other chromosome carried the R1162X mutation (602421.0033). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0075 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, TRP57TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909025,
|
|
|
|
|
|
|
|
ClinVar: RCV000007599, RCV001826440
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with pancreatic-insufficient cystic fibrosis (CF; 219700), Audrezet et al. (1993) found compound heterozygosity for a G-to-A transition at nucleotide 302 in exon 3 converting codon 57 from TGG (trp) to TGA (stop). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0076 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, GLN1313TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909026,
|
|
|
|
|
|
gnomAD: rs121909026,
|
|
|
|
|
|
ClinVar: RCV000007600, RCV001826441, RCV003473032
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a severely affected, pancreatic-insufficient patient with cystic fibrosis (CF; 219700), Audrezet et al. (1993) found homozygosity for a C-to-T transition at nucleotide 4069 in exon 21 converting gln1313 to a stop codon. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0077 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, GLU92LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908751,
|
|
|
|
|
|
gnomAD: rs121908751,
|
|
|
|
|
|
ClinVar: RCV000007601, RCV001009395, RCV001093484, RCV001831545, RCV003473033
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Spanish patient with mild cystic fibrosis (CF; 219700), Nunes et al. (1993) found a G-to-A transition at nucleotide 406 resulting in a change of codon 92 in exon 4 from glutamic acid to lysine. The same mutation was found in homozygous state in a Turkish patient with consanguineous parents living in Germany. Both patients were pancreatic sufficient and had normal fat excretion. In both cases physical activity led rapidly to excessive sweating and fatigue; the mother of the Turkish boy reported that after 1 hour of sports the boy's skin and hair became covered with a white salty crust which required 2 or 3 showers to remove. </p>
|
|
</span>
|
|
</div>
|
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0078 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, ARG347HIS
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<br />
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SNP: rs77932196,
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gnomAD: rs77932196,
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ClinVar: RCV000007602, RCV000224726, RCV000508504, RCV001004250, RCV001009366, RCV001027909, RCV003473034, RCV005042005
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Audrezet et al. (1993) referred to an R347H mutation causing pancreatic-sufficient cystic fibrosis (CF; 219700). This is 1 of 3 mutations that involve nucleotide 1172, the others being R347P (602421.0006) and R347L (602421.0067). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0079 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, GLY91ARG
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<br />
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SNP: rs121908750,
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gnomAD: rs121908750,
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ClinVar: RCV000007603, RCV001831546, RCV004566691
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a study of 87 non-delF508 chromosomes of Breton origin, Guillermit et al. (1993) found a G91R mutation in 3 pancreatic-sufficient cystic fibrosis patients (CF; 219700). The 3 patients were compound heterozygous for the G91R mutation and delF508 (602421.0001). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0080 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, PHE1286SER
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<br />
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SNP: rs121909028,
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ClinVar: RCV000007604
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an analysis of 160 cystic fibrosis (CF; 219700) chromosomes, Dorval et al. (1993) detected an F1286S mutation in exon 20 of the CFTR gene using denaturing gel electrophoresis followed by direct sequencing of the PCR products. A T-to-C transition at nucleotide 3989 was responsible for the change from phenylalanine to serine. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0081 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, 1-BP INS, 2307A
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<br />
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SNP: rs121908787, rs746418935,
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gnomAD: rs746418935,
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ClinVar: RCV000007605, RCV000727574, RCV000781235, RCV001004471, RCV001826442, RCV003473035
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>By chemical mismatch cleavage in an African American patient with cystic fibrosis (CF; 219700), Smit et al. (1993) found homozygosity for insertion of an adenine after nucleotide 2307 in exon 13. The resulting shift of the reading frame at codon 726 introduced 2 consecutive stop codons at amino acid positions 729 and 730. To examine the mRNA level associated with the 2307insA mutation, RNA from nasal epithelial cells of the patient and a normal subject were reverse transcribed. Subsequent amplification of the cDNA demonstrated that the CFTR message level associated with 2307insA was markedly reduced compared to the normal control, while both the patient and the normal subject showed similar levels of expression. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0082 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, GLU92TER
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<br />
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SNP: rs121908751,
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gnomAD: rs121908751,
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ClinVar: RCV000007606, RCV001004423, RCV001009515, RCV001826443, RCV003473036
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In each of 4 German patients with cystic fibrosis (CF; 219700), Will et al. (1994) found a G-to-T transversion that affected the first base of exon 4 and created a termination codon glu92-to-ter. Lymphocyte RNA of patients heterozygous for the E92X mutation were found to contain the wildtype sequence and a differentially spliced isoform lacking exon 4. On the other hand, RNA derived from nasal epithelial cells of these patients showed a third fragment of longer length. Sequencing revealed the presence of E92X and an additional 183-bp fragment, inserted between exons 3 and 4. The 183-bp sequence was mapped to intron 3 of the CFTR gene. It was flanked by acceptor and donor splice sites. Will et al. (1994) concluded that the 183-bp fragment in intron 3 is a cryptic CFTR exon that can be activated in epithelial cells by the presence of the E92X mutation. E92X abolishes correctly spliced CFTR mRNA and leads to severe cystic fibrosis. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0083 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, GLY480CYS
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<br />
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SNP: rs79282516,
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gnomAD: rs79282516,
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ClinVar: RCV000007607, RCV000790782, RCV001004453, RCV004566692
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a pancreatic-insufficient African American CF (CF; 219700) patient, Smit et al. (1995) found a novel CFTR missense mutation associated with a protein trafficking defect in mammalian cells but normal chloride channel properties in a Xenopus oocyte assay. The mutation resulted in substitution of a cysteine for glycine at residue 480. In mammalian cells, the encoded mutant protein was not fully glycosylated and failed to reach the plasma membrane, suggesting that the G480C protein was subject to defective intracellular processing. However, in Xenopus oocytes, a system in which mutant CFTR proteins are less likely to experience an intracellular processing/trafficking deficit, expression of G480C CFTR was associated with a chloride conductance that exhibited a sensitivity to activation by forskolin and 3-isobutyl-1-methylxanthine (IBMX) that was similar to that of wildtype CFTR. This appeared to be the first identification of a CFTR mutant in which the sole basis for disease was mislocation of the protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0084 CYSTIC FIBROSIS</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, LEU206TRP
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<br />
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SNP: rs121908752,
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gnomAD: rs121908752,
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ClinVar: RCV000007611, RCV000079011, RCV000660772, RCV000763156, RCV001004443, RCV001009388, RCV001831547, RCV003473037
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>The leu206-to-trp (L206W) mutation of the CFTR gene was first identified in 3 cystic fibrosis (CF; 219700) patients from South France (Claustres et al., 1993). Rozen et al. (1995) reported that it is relatively frequent in French Canadians from Quebec. On the basis of findings in 7 French Canadian probands, they suggested that this mutation is likely to be present in patients with atypical forms of CF and may be present in otherwise healthy men and women with infertility. Their group contained 47-year-old and 48-year-old sisters and their 30-year-old brother. The women were thought to have reduced fertility and the man had absence of the vas deferentia. The man and 1 sister had normal pulmonary function and high-resolution CT scan of the chest. The 47-year-old sister had had left upper lobectomy for presumed bronchiectasis at the age of 20 years and had had frequent pulmonary infections but had surprisingly well-preserved lung function. </p><p>Clain et al. (2005) noted that the L206W mutation can result in variable disease phenotypes. Individuals bearing this mutation in trans with the severe CF-causing mutation F508del (602421.0001) may have CF or isolated congenital bilateral absence of the vas deferens (277180). Clain et al. (2005) studied the effect of the L206W mutation on CFTR protein production and function and examined the genotype-phenotype correlation of L206W/F508del compound heterozygote patients. They showed that L206W is a processing (class II) mutation, as the CFTR biosynthetic pathway was severely impaired, whereas single-channel measurements indicated ion conductance similar to the wildtype protein. These data raised the larger question of the phenotypic variability of class II mutants, including F508del. Clain et al. (2005) concluded that since multiple potential properties could modify the processing of the CFTR protein during its course to the cell surface, environmental and other genetic factors might contribute to this variability. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0085 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, 18-BP DEL, NT591
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<br />
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SNP: rs387906371,
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ClinVar: RCV000007608
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Varon et al. (1995) described recurrent nasal polyps as a monosymptomatic form of cystic fibrosis (CF; 219700) in association with a novel in-frame mutation, deletion of 18 bp in exon 4 of the CFTR gene. Since the deletion started with nucleotide 591 of their cDNA clone, the mutation was symbolized 591del18. It was found in male twins of Turkish origin. The twins inherited the 591del18 mutation from their mother. On the paternal allele, they carried the nonsense mutation glu831-to-ter (Verlingue et al., 1994). The patients had been diagnosed as having CF at the age of 10 years due to persistent nasal polyps and elevated sweat electrolytes. Nasal polyps had been surgically removed on 4 occasions. The neonatal period and early infancy were completely uneventful. They were pancreatic sufficient and had no lung disease or other CF-related problems. </p><p>Burger et al. (1991) suggested that heterozygosity for the G551D mutation (602421.0013) is a causative factor in recurrent nasal polyps. Presentation with a nasal polyp was the basis of the diagnosis of cystic fibrosis in an 11-year-old boy of Iranian extraction in whom Chalkley and Harris (1991) found homozygosity for a gly85-to-glu mutation (602421.0038). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0086 VAS DEFERENS, CONGENITAL BILATERAL ABSENCE OF</strong>
|
|
</span>
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
BRONCHIECTASIS WITH OR WITHOUT ELEVATED SWEAT CHLORIDE 1, MODIFIER OF
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, IVS8AS, 5T VARIANT
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<br />
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SNP: rs1805177,
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ClinVar: RCV000007609, RCV000007610, RCV000155619, RCV000173692, RCV000190992, RCV000405075, RCV001009378, RCV001010359, RCV001706280, RCV002243923, RCV003330602, RCV003483594
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>Zielenski et al. (1995) estimated that CBAVD (277180) is associated with the 5T variant at the 3-prime end of intron 8 of the CFTR gene with a penetrance of 0.60 in males. Chu et al. (1993) noted varied lengths of a thymidine (T)-tract (5, 7, or 9T) in front of the splice-acceptor site of intron 8. The length appeared to correlate with the efficiency of exon 9 splicing, with the 5T variant that is present in 5% of the CFTR alleles among the Caucasian population producing almost exclusively (95%) exon 9-minus mRNA. The effect of this T-tract polymorphism in CFTR gene expression was also documented by its relationship with the CF mutation R117H (602421.0005): while R117H (5T) is found in typical CF patients with pancreatic sufficiency, R117H (7T) is associated with CBAVD (Kiesewetter et al., 1993). </p><p>Costes et al. (1995) studied the CFTR gene in 45 azoospermic individuals with isolated CBAVD. They detected a CFTR gene defect in 86% of chromosomes from these subjects. In addition to identifying 9 novel CFTR gene mutations, they found that 84% of men with CBAVD who were heterozygous for a CF mutation carried the intron 8 polypyrimidine 5T CFTR allele on 1 chromosome. </p><p>De Meeus et al. (1998) found linkage disequilibrium between the 5T allele and the val allele of the met470-to-val polymorphism (602421.0023). </p><p>Groman et al. (2004) demonstrated that the number of TG repeats adjacent to 5T influences disease penetrance. They determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. They found that those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats. Thus, determination of TG repeat number will allows for more accurate prediction of benign versus pathogenic 5T alleles. </p><p>The TG repeat located at the splice acceptor site of exon 9 of the CFTR gene is an example of a variable dinucleotide repeat that affects splicing. Higher repeat numbers result in reduced exon 9 splicing efficiency and, in some instances, the reduction in full-length transcript is sufficient to cause male infertility due to congenital bilateral absence of the vas deferens or nonclassic cystic fibrosis. Using a CFTR minigene system, Hefferon et al. (2004) studied TG tract variation and observed the same correlation between dinucleotide repeat number and exon 9 splicing efficiency seen in vivo. Replacement of the TG dinucleotide tract in the minigene with random sequence abolished splicing of exon 9. Replacements of the TG tract with sequences that can self-basepair suggested that the formation of an RNA secondary structure was associated with efficient splicing. However, splicing efficiency was inversely correlated with the predicted thermodynamic stability of such structures, demonstrating that intermediate stability was optimal. Finally, substitution of TA repeats of differing lengths confirmed that stability of the RNA secondary structure, not sequence content, correlated with splicing efficiency. Taken together, these data indicated that dinucleotide repeats can form secondary structures that have variable effects on RNA splicing efficiency and clinical phenotype. </p><p>In a 66-year-old woman and an unrelated 67-year-old man with idiopathic bronchiectasis (BESC1; 211400), who were heterozygous for the 5T CFTR variant, Fajac et al. (2008) also identified heterozygosity for a missense mutation in the SCNN1B gene (600760.0015). The woman had a borderline elevated sweat chloride, normal nasal potential difference (PD), and FEV1 that was 77% of predicted. The man had normal sweat chloride and nasal PD, and FEV1 that was 80% of predicted. Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0087 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, THR338ILE
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<br />
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SNP: rs77409459,
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gnomAD: rs77409459,
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ClinVar: RCV000007614, RCV000506655, RCV001009472, RCV001269654, RCV003473038, RCV005042006
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In all 8 children of Sardinian descent seen because of hypotonic dehydration associated with hyponatremia, hypochloremia, hypokalemia, and metabolic alkalosis, Leoni et al. (1995) found a T338I mutation either in homozygosity or compound heterozygosity with another CF mutation. None had pulmonary or pancreatic involvement. The T338I mutation was not detected in patients with CF who had classic symptoms or in healthy persons of the same descent. Their data suggested that the T338I mutation is associated with a specific mild cystic fibrosis (CF; 219700) phenotype. The patients were seen at ages varying between 2 months and 7 years of age. Three of the patients had failed to thrive. The sweat chloride concentration was high in all patients but 1, who at 3 months of age had borderline values. All the patients had normal steatocrit values for their age, and none of them required pancreatic enzyme supplements. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0088 CYSTIC FIBROSIS</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, TRP1089TER
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<br />
|
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SNP: rs78802634,
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gnomAD: rs78802634,
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ClinVar: RCV000007615, RCV000507617, RCV000763581, RCV001004304, RCV001027902, RCV003473039
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In 2 of 138 alleles in Jewish patients with cystic fibrosis (CF; 219700), Shoshani et al. (1994) identified a G-to-A transition at nucleotide 3398 of exon 17b of the CFTR gene. This substitution results in a termination codon (TAG) instead of tryptophan at residue 1089. Both mutant chromosomes carry the same extra- and intragenic haplotype, A112. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0089 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, 4-BP DEL, NT4010
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<br />
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SNP: rs387906373,
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ClinVar: RCV000047015, RCV001831781, RCV003474594, RCV004998162, RCV005031516
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient of Arab origin with cystic fibrosis (CF; 219700), Shoshani et al. (1994) detected a 4-bp deletion in the CFTR gene, TATT, at position 4010 of the coding sequence using direct sequencing of exon 21. This frameshift mutation is expected to create a termination codon (TAG) 34 amino acids downstream of the mutation. This alteration is likely to be a disease-causing mutation since it is predicted to create a truncated polypeptide that lacks the second ATP binding domain. The patient inherited this deletion from her father. The CFTR chromosome carries the D121 haplotype. Her other CFTR chromosome has the asn1303-to-lys mutation (602421.0032). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0090 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, ILE556VAL
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<br />
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SNP: rs75789129,
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gnomAD: rs75789129,
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ClinVar: RCV000007617, RCV000046398, RCV000174251, RCV001009505
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant, formerly titled CYSTIC FIBROSIS, has been reclassified based on a review of the gnomAD database by Hamosh (2018).</p><p>In a study of 224 non-F508del cystic fibrosis (CF; 219700) chromosomes, Ghanem et al. (1994) identified a C-to-T substitution at nucleotide 223, changing arginine to cysteine at position 31, in a French couple with cystic fibrosis and one affected child. Since their apparently unaffected 6-year-old child was found to be homozygous for this mutation, it is probably a polymorphism. The father and the affected child had another substitution changing an isoleucine-556 to valine in exon 11. This mutation can be detected by restriction analysis since it abolishes a HhaI recognition sequence. </p><p>Hamosh (2018) found that the I556V variant was present in heterozygous state in 914 of 276,478 alleles and in 28 homozygotes in the gnomAD database, with an allelic frequency of 0.0033 (May 3, 2018).</p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>.0091 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, TYR109CYS
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<br />
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SNP: rs121909031,
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ClinVar: RCV000007618, RCV003473040
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 16-year-old girl with cystic fibrosis (CF; 219700) diagnosed at age 9 months who has remained pancreatic-sufficient, Schaedel et al. (1994) identified an A-to-G substitution at nucleotide 458 in exon 4 of the CFTR gene, converting tyrosine-109 to cysteine (Y109C). Her second mutation was 3659delC (602421.0020) in exon 19. The 3659delC mutation is associated with the pancreatic insufficiency phenotype. The authors concluded that tyr109-to-cys is the mutation conferring pancreatic sufficiency. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0092 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, ARG352GLN
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<br />
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SNP: rs121908753,
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gnomAD: rs121908753,
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ClinVar: RCV000007619, RCV000660773, RCV000763568, RCV000985669, RCV001004254, RCV001826444, RCV003473041
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a systematic study of 133 cystic fibrosis (CF; 219700) patients in northern Italy, Gasparini et al. (1993) identified an arg352-to-glu mutation in the CFTR gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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|
<span class="mim-font">
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|
<strong>.0093 CYSTIC FIBROSIS</strong>
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|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, IVS3, A-G, +4
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<br />
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SNP: rs387906374,
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gnomAD: rs387906374,
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ClinVar: RCV000007620, RCV001753408, RCV001831548, RCV002281699
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</span>
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|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Ghanem et al. (1994) identified an A-to-G substitution at the fourth nucleotide of the donor splice site of intron 3. It is not known if this mutation is drastic enough to cause aberrant splicing. It could simply be sufficient for a cryptic splice site to be used. This mutation was found on the maternal cystic fibrosis (CF; 219700) chromosome in an African family originating from Cameroon. The CF-affected child, a 9-year-old girl, had no pancreatic insufficiency and no serious lung disease, but suffered from asthma. The sweat chloride was elevated (90 to 110 mmol per liter). </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0094 CYSTIC FIBROSIS</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, GLN524HIS
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<br />
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ClinVar: RCV000007612
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 133 cystic fibrosis (CF; 219700) individuals in northern Italy, Gasparini et al. (1993) identified a gln524-to-his (Q524H) mutation in the CFTR gene. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0095 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
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|
|
CFTR, GLY542TER
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<br />
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ClinVar: RCV000007535, RCV000058931, RCV000119041, RCV000763572, RCV001004463, RCV001826428, RCV003473006
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|
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|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) found a point mutation creating a stop codon in place of glycine-542. In molecular genetic analyses on 129 Hispanic individuals with cystic fibrosis in the southwestern United States, Grebe et al. (1994) found that 5.4% (7 of 129) individuals carried this mutation. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0096 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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CFTR, GLN552TER
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|
<br />
|
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|
|
SNP: rs76554633,
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ClinVar: RCV000007622, RCV001826445, RCV003473042
|
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|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a cystic fibrosis (CF; 219700) patient with severe pancreatic insufficiency, Gasparini et al. (1993) found a mutation in the CFTR gene that created a stop codon in place of glutamine-552. This mutation was found in 3 of 225 cases. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0097 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ASP648VAL
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|
<br />
|
|
|
|
SNP: rs121909033,
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|
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ClinVar: RCV000007623
|
|
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|
|
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</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified an asp648-to-val mutation in the CFTR gene. </p>
|
|
</span>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
|
|
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|
<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0098 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, LYS710TER
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<br />
|
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|
|
SNP: rs75115087,
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ClinVar: RCV000007624, RCV000759034, RCV001004470, RCV001826446, RCV003473043
|
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|
|
|
</span>
|
|
</div>
|
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|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) found a point mutation creating a stop codon in place of lysine-710 in the CFTR gene. </p>
|
|
</span>
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</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
|
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|
<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0099 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
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</div>
|
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<div>
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<span class="mim-text-font">
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|
|
|
CFTR, GLN890TER
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|
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<br />
|
|
|
|
SNP: rs79633941,
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ClinVar: RCV000007625, RCV000505859, RCV001831549, RCV003473044, RCV005042007
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|
|
|
</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 related Portuguese patients with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified a C-to-T substitution at nucleotide 2880 in exon 15, resulting in a stop codon at position 890. This mutation was found in a 13-year-old girl and her 15-year-old uncle, who have a classic form of the disease and nasal polyposis. Both patients had F508del on the other CF chromosome, and the uncle had a positive sweat test (140 mmol per liter). The mutation changed the restriction sites MseI(+) and MboII(-). </p>
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</span>
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</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0100 CFTR POLYMORPHISM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, SER912LEU
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<br />
|
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|
|
SNP: rs121909034,
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gnomAD: rs121909034,
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|
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ClinVar: RCV000007626, RCV000007661, RCV000506704, RCV000586236, RCV001158768, RCV002255257
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a study of 224 non-F508del CF chromosomes, Ghanem et al. (1994) identified a 2867C-T transition in exon 15 of the CFTR gene, resulting in a ser912-to-leu (S912L) substitution, in a CF carrier of French and Spanish extraction. It was difficult to predict whether this substitution would be deleterious. </p><p>By in vitro functional expression studies, Clain et al. (2005) demonstrated that the S912L substitution was not disease-causing in isolation, but significantly impaired CFTR function when inherited in cis with another CFTR mutation (see 602421.0135). Clain et al. (2005) identified a healthy father of a CF fetus carrying the S912L mutation. A different CF-producing mutation was identified on the father's other allele. Clain et al. (2005) concluded that the S912L substitution is a neutral variant. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0101 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 2-BP DEL, 936TA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908773,
|
|
|
|
|
|
|
|
ClinVar: RCV000007627
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Spanish patients with cystic fibrosis (CF; 219700), Chillon et al. (1994) identified a 2-bp deletion (TA) in exon 6b of the CFTR gene at position 936 of the coding sequence. This frameshift mutation leads to a premature termination codon 272 nucleotides downstream and a truncated protein. One patient was homozygous and the other compound heterozygous. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0102 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, HIS949TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909035,
|
|
|
|
|
|
gnomAD: rs121909035,
|
|
|
|
|
|
ClinVar: RCV000007628, RCV003330386
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of 224 non-F508del cystic fibrosis (CF; 219700) chromosomes, Ghanem et al. (1994) identified a C-to-T substitution at nucleotide 2977 in exon 15, changing histidine to tyrosine at position 949, in a 60-year-old woman with a 10-year history of chronic lung disease. The sweat chloride value was 42 mmol per liter. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0103 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, LEU1065PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909036,
|
|
|
|
|
|
|
|
ClinVar: RCV000007629, RCV000311326, RCV001004297, RCV001831550
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 10-year-old girl with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified a T-to-C substitution at nucleotide 3326 in exon 17b, changing leucine to proline at position 1065 (L1065P). The L1065P mutation was found on the maternal chromosome of the patient, who bore a F508del mutation (602421.0001) on the paternal allele. The leucine at this position is conserved in the mouse CFTR protein. This mutation changes the MnlI(+) restriction site. The patient had gastrointestinal and pulmonary manifestations of cystic fibrosis, as well as high sweat chloride values (66 mmol per liter). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0104 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, GLN1071PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909037,
|
|
|
|
|
|
gnomAD: rs121909037,
|
|
|
|
|
|
ClinVar: RCV000007630
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 21-year-old woman with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified an A-to-C substitution at nucleotide 3344 in exon 17b, changing glutamine to proline at position 1071 (Q1071P). Since the age of 5 years the patient had suffered from chronic gastrointestinal disorders, pancreatic insufficiency, diarrhea, steatorrhea, and very high sweat chloride values (160 mmol per liter). This missense mutation occurs on an amino acid conserved in mouse CFTR. The patient carried the F508del mutation on the other CF chromosome. The mutation changes the restriction site HaeIII(+). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0105 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, HIS1085ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs79635528,
|
|
|
|
|
|
gnomAD: rs79635528,
|
|
|
|
|
|
ClinVar: RCV000007631
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified a his1085-to-arg mutation in the CFTR gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0106 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, TYR1092TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908761,
|
|
|
|
|
|
gnomAD: rs121908761,
|
|
|
|
|
|
ClinVar: RCV000056379, RCV000056380, RCV000119251, RCV000522700, RCV000763157, RCV000780122, RCV000781257, RCV001004305, RCV001009514, RCV001831551, RCV001831621, RCV003473243
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) found a point mutation creating a stop codon in place of tyrosine-1092 in the CFTR gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0107 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, TRP1204TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908764, rs121908765,
|
|
|
|
|
|
gnomAD: rs121908765,
|
|
|
|
|
|
ClinVar: RCV000007633, RCV001831552
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified a G-to-A substitution at nucleotide 3743 in exon 19, resulting in a stop codon at position 1204. This mutation was found on the paternal chromosome of a 4-year-old child with pancreatic insufficiency and a sweat chloride level of 120 mmol per liter but no pulmonary infection. The maternal chromosome bears the F508 deletion. The mutation changes the restriction sites MaeI(+). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0108 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 1-BP DEL, 1215G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906375,
|
|
|
|
|
|
|
|
ClinVar: RCV000007634, RCV000727368, RCV003466831
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Romey et al. (1994) identified a 1-bp deletion (G) at nucleotide 2423 in exon 7 of the CFTR gene. This frameshift mutation leads to a premature termination (UAA) 7 codons downstream. The deletion creates an AflIII restriction site and was inherited from the patient's father. The patient, a 7-year-old boy of French and Spanish origin, carries a second mutation 2423delG (602421.0116). Despite the 2 frameshift mutations, this patient does not present a severe form of cystic fibrosis. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0109 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, THR1220ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1800123,
|
|
|
|
|
|
gnomAD: rs1800123,
|
|
|
|
|
|
ClinVar: RCV000007635, RCV000589624, RCV003230350, RCV004528090
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified a C-to-T substitution at nucleotide 3791 in exon 19 of the CFTR gene, changing threonine to isoleucine at position 1220. No other variation in CFTR was found, but the authors could not determine if the variants were found on the same or different alleles. No other family members were available for testing. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0110 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ILE1234VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs75389940,
|
|
|
|
|
|
gnomAD: rs75389940,
|
|
|
|
|
|
ClinVar: RCV000007636, RCV001269696, RCV001831553, RCV004566693
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified an ile1234-to-val mutation in the CFTR gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0111 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, GLY1249GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909040,
|
|
|
|
|
|
gnomAD: rs121909040,
|
|
|
|
|
|
ClinVar: RCV000007637
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Greil et al. (1994) identified a G-to-A substitution at nucleotide 3878 in exon 20 of the CFTR gene, changing a glycine (GGG) to glutamic acid (GAG) at amino acid 1249. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0112 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, SER1251ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs74503330,
|
|
|
|
|
|
gnomAD: rs74503330,
|
|
|
|
|
|
ClinVar: RCV000007638, RCV000211301, RCV000506301, RCV000780175, RCV001731144, RCV001826447, RCV003466832
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified a ser1251-to-asn mutation in the CFTR gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0113 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, SER1255PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909041,
|
|
|
|
|
|
gnomAD: rs121909041,
|
|
|
|
|
|
ClinVar: RCV000007613, RCV001787320, RCV002247264
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified a ser1255-to-pro mutation in the CFTR gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0114 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ASN1303HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909042,
|
|
|
|
|
|
gnomAD: rs121909042,
|
|
|
|
|
|
ClinVar: RCV000007639
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified an asp1303-to-his mutation in the CFTR gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0115 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 2-BP DEL, 1609CA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908775,
|
|
|
|
|
|
|
|
ClinVar: RCV000007640, RCV001826448, RCV002496301
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1992) identified a 2-bp deletion (CA) in exon 10 of the CFTR gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0116 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 1-BP DEL, 2423G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906376,
|
|
|
|
|
|
gnomAD: rs387906376,
|
|
|
|
|
|
ClinVar: RCV000007641
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Romey et al. (1994) identified a 1-bp (G) deletion at position 2423 of the coding sequence in exon 13 of the CFTR gene. This frameshift mutation leads to a premature termination (UGA) 6 codons downstream. The patient, a 7-year-old boy of French and Spanish origin, carried a second mutation, 1215delG (602421.0108). Despite the 2 frameshift mutations, this patient did not present a severe form of cystic fibrosis. The mutation 2423delG is also associated with sequence variation in intron 17a 3271+18C or T. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0117 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, 1-BP DEL, 3293A
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<br />
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|
|
SNP: rs387906377,
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|
|
gnomAD: rs387906377,
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|
|
|
ClinVar: RCV000007642, RCV000506268
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|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified a 1-bp deletion (A) at position 3293 of the coding sequence in exon 10 of the CFTR gene. This frameshift mutation leads to a premature termination codon 15 nucleotides downstream and a truncated protein. The patient, a 15-year-old F508del heterozygous girl of French origin, has a positive sweat test (80 mmol per liter) and pancreatic insufficiency but no chronic lung infection. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0118 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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CFTR, 4-BP INS, NT3667
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<br />
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SNP: rs387906378,
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ClinVar: RCV000007643, RCV001826449
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 20-year-old cystic fibrosis (CF; 219700) patient of north-central Italian origin with pancreatic insufficiency and severe pulmonary involvement, Sangiuolo et al. (1993) identified a 4-bp insertion (TCAA) at position 3667 of the coding sequence in exon 19 of the CFTR gene. This frameshift mutation leads to a premature termination codon (TGA) at amino acid position 1195 and destroys a HincII restriction enzyme site. </p>
|
|
</span>
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|
</div>
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<div>
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<br />
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|
</div>
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</div>
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|
<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0119 SWEAT CHLORIDE ELEVATION WITHOUT CYSTIC FIBROSIS</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
CFTR, SER1455TER
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<br />
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|
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SNP: rs121909043,
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gnomAD: rs121909043,
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|
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ClinVar: RCV000007644, RCV000590108, RCV001004310, RCV001781201, RCV001826450, RCV003473045, RCV005031414
|
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|
|
</span>
|
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</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>Mickle et al. (1998) identified a 6.8-kb deletion and a nonsense mutation (ser1455 to ter; S1455X) in the CFTR gene of a mother and her youngest daughter with isolated elevated sweat chloride concentrations. Detailed clinical evaluation of both individuals found no evidence of pulmonary or pancreatic disease characteristic of CF. A second child in this family had classic CF and was homozygous for the 6.8-kb deletion, indicating that this mutation caused severe CFTR dysfunction. CFTR mRNA transcripts bearing the S1455X mutation were stable in vivo, implying that this allele encoded a truncated version of CFTR missing the last 26 amino acids. Loss of this region did not affect processing of transiently expressed S1455X-CFTR compared with wildtype CFTR. When expressed in CF airway cells, this mutant generated cAMP-activated whole-cell chloride currents similar to wildtype CFTR. Preservation of chloride channel function of the S1455X-CFTR mutation was consistent with normal lung and pancreatic function in the mother and her daughter. The study indicated that mutations in CFTR can be associated with elevated sweat chloride concentrations in the absence of the CF phenotype, and suggested a previously unrecognized functional role in the sweat gland for the C-terminus of CFTR. </p><p>Salvatore et al. (2005) reported 2 asymptomatic sisters with isolated increased sweat chloride concentrations in whom systematic scanning of the whole coding region of the CFTR gene revealed compound heterozygosity for S1455X and delF508 (602421.0001). </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
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<span class="mim-font">
|
|
<strong>.0120 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
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|
|
CFTR, IVS16, G-A, +1
|
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|
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<br />
|
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|
|
SNP: rs75096551,
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|
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|
|
gnomAD: rs75096551,
|
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|
|
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ClinVar: RCV000007645, RCV000759761, RCV000763580, RCV001004285, RCV001027899, RCV003473046
|
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|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Dork et al. (1998) concluded that the 3120+1G-A mutation, which is present in African, Arab, and a few Greek families with cystic fibrosis (CF; 219700), probably was derived from a common ancestor because the haplotypes are very similar or identical. </p>
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|
</span>
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</div>
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<div>
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<br />
|
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</div>
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</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0121 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ARG553GLN
|
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|
|
<br />
|
|
|
|
SNP: rs121909044,
|
|
|
|
|
|
gnomAD: rs121909044,
|
|
|
|
|
|
ClinVar: RCV000007646, RCV004799734
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a pancreatic-insufficient patient with cystic fibrosis (CF; 219700), Dork et al. (1991) identified a G-to-A transition at nucleotide 1790 of the CFTR gene, resulting in an arg553-to-gln substitution. See also Stern (1997). </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
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</div>
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|
|
</div>
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|
<div>
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0122 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, -102T-A, PROMOTER
|
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|
|
|
<br />
|
|
|
|
SNP: rs1797973431,
|
|
|
|
|
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|
|
ClinVar: RCV000007647
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the T-to-A transversion at position -102 in the minimal CFTR promoter that was found in compound heterozygous state in patients with cystic fibrosis by Romey et al. (1999), see 602421.0012. </p>
|
|
</span>
|
|
</div>
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|
|
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|
<div>
|
|
<br />
|
|
</div>
|
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|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0123 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 21-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000007648
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Dork et al. (2000) described a large genomic deletion of the CFTR gene that is frequently observed in Central and Eastern Europe. The mutation deletes 21,080 bp spanning from intron 1 to intron 3 of the CFTR gene. Transcript analyses demonstrated that the deletion results in the loss of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature termination signal within exon 4. A simple PCR assay for the allele was devised and used to screen for the mutation in European and European-derived populations. Some 197 cystic fibrosis (CF; 219700) patients, including 7 homozygotes, were identified. Clinical evaluation of the homozygotes and a comparison of compound heterozygotes for delF508 (602421.0001) with pairwise-matched delF508 homozygotes indicated that the 21-kb deletion represents a severe mutation associated with pancreatic insufficiency and early age at diagnosis. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0124 PANCREATITIS, IDIOPATHIC, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
HYPERTRYPSINEMIA, NEONATAL, SUSCEPTIBILITY TO, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, LEU997PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1800111,
|
|
|
|
|
|
gnomAD: rs1800111,
|
|
|
|
|
|
ClinVar: RCV000007650, RCV000007651, RCV000046745, RCV000078991, RCV000243402, RCV000583195, RCV001009470, RCV001327946, RCV001642202, RCV005031415
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Gomez Lira et al. (2000) postulated that there might be particular CFTR gene mutations involved in pancreatic ductular obstruction, as manifested in idiopathic pancreatitis or in neonatal hypertrypsinemia. Following up on this hypothesis, they performed a complete screening of the CFTR gene in a group of 32 patients with idiopathic pancreatitis (14 of whom carried the 5T variant CF mutation (602421.0086) or had a borderline sweat chloride level, and 18 of whom were without common CF mutations or any other CF characteristic) and in 49 newborns with hypertrypsinemia and normal sweat chloride (32 of whom had a common CF mutation, and 17 of whom did not have a common CF mutation). Rare mutations were found in 9 of 32 patients with idiopathic pancreatitis and in 21 of 49 newborns with hypertrypsinemia. Of these rare mutations, leu997 to phe (L997F) was identified in 4 (12.5%) of 32 patients with idiopathic pancreatitis and in 4 (8%) of 39 newborns with hypertrypsinemia. L997 is a highly conserved residue in transmembrane domain 9. </p><p>Since most neonatal screening programs for cystic fibrosis combine the assay of immunoreactive trypsinogen (IRT) with analysis for the most common mutations of the CFTR gene, the identification of heterozygotes among neonates because of increased IRT is considered a drawback. Scotet et al. (2001) assessed the heterozygosity frequency among children with hypertrypsinemia detected during a CF screening program in Brittany (France) 10 years previously. A total of 160,019 babies were screened for CF between 1992 and 1998. Of the 1,964 newborns with increased IRT (1.2%), 60 had CF and 213 were carriers. Heterozygosity frequency was 12.8%, or 3 times greater than in the general population (3.9%). A high proportion of mild mutations or variants was observed in carriers. The allelic frequency of the 5T variant (5.6%) was not increased. The study was consistent with previous ones in finding a significantly higher rate of heterozygotes than expected among neonates with hypertrypsinemia. </p><p>Kabra et al. (2000) identified the L997F mutation in a Pakistani patient with cystic fibrosis (219700), but did not identify the second mutation. </p><p>Derichs et al. (2005) reported a child, born of consanguineous Turkish parents, who was homozygous for the L997F substitution. The child showed normal development with no evidence of pancreatic insufficiency or cystic fibrosis. Sweat chloride tests and intestinal chloride secretion were normal. Derichs et al. (2005) concluded that the L997F mutation does not cause cystic fibrosis. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0125 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 1-BP INS, 3622T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906379,
|
|
|
|
|
|
|
|
ClinVar: RCV000007652, RCV003473047
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Indian child with cystic fibrosis (CF; 219700), Kabra et al. (2000) identified a 1-bp insertion (T) at nucleotide 3622 of the CFTR gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0126 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 3601, T-C, -20
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs373002889,
|
|
|
|
|
|
gnomAD: rs373002889,
|
|
|
|
|
|
ClinVar: RCV000007649, RCV000595140, RCV001810837, RCV002255258, RCV004734503
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Indian patients with cystic fibrosis (CF; 219700), Kabra et al. (2000) identified a T-to-C change at position -20 from nucleotide 3601 of the CFTR gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0127 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 1-BP DEL, 3876A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908784,
|
|
|
|
|
|
gnomAD: rs121908784,
|
|
|
|
|
|
ClinVar: RCV000007653, RCV000755920, RCV001004505, RCV001831554, RCV003473048, RCV005031416
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Wang et al. (2000) found that 7 of 29 Hispanic patients with cystic fibrosis (CF; 219700) were heterozygous for a single-basepair deletion at nucleotide 3876 (3876delA) resulting in a frameshift and termination at residue 1258 (L1258X). This mutation accounted for 10.3% of mutant alleles in this group. The patients with this mutation had a severe phenotype as determined by early age of diagnosis, high sweat chloride, presence of allergic bronchopulmonary aspergillosis, pancreatic insufficiency, liver disease, cor pulmonale, and early death. Wang et al. (2000) noted that this mutation had not been reported in any other ethnic group. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0128 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, 2-BP DEL, 394TT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908769,
|
|
|
|
|
|
|
|
ClinVar: RCV000007654, RCV000506648, RCV001004235, RCV001269534, RCV001835625, RCV002496302, RCV003473049
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>The 394delTT mutation in CFTR causing cystic fibrosis (CF; 219700), referred to as the 'Nordic mutation,' is found at a high frequency in the countries bordering the Baltic Sea and associated waterways (Sweden, Norway, Denmark, Finland, Estonia, Russia, etc.). This mutation is associated almost exclusively with a single chromosomal haplotype, which suggests a single origin, centered in this region (Schwartz et al., 1994). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0129 MOVED TO 602421.0022</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0130 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, ALA445GLU
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<br />
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ClinVar: RCV000007656
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the ala445-to-glu mutation in the CFTR gene that was found in compound heterozygous state in a patient with cystic fibrosis (CF; 219700) by Kulczycki et al. (2003), see 602421.0022. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0131 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, GLU7TER
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<br />
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SNP: rs121909045,
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gnomAD: rs121909045,
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ClinVar: RCV000007657, RCV000278439
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 1.5-year-old Taiwanese boy with cystic fibrosis (CF; 219700), Wong et al. (2003) found compound heterozygosity for 2 novel mutations in the CFTR gene, a G-to-T transversion at nucleotide 151 in exon 1 that resulted in a glu7-to-ter (E7X) substitution in the first transmembrane domain of the protein, and a 1-bp insertion in exon 6b (989_992insA). The insertion caused a frameshift and a truncated CFTR protein of 306 amino acids. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0132 CYSTIC FIBROSIS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CFTR, 1-BP INS, 989A
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<br />
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SNP: rs387906380,
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ClinVar: RCV000007658
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the 1-bp insertion (989_992insA) in the CFTR gene that was found in compound heterozygous state in a Taiwanese boy with cystic fibrosis (CF; 219700) by Wong et al. (2003), see 602421.0131. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0133 CYSTIC FIBROSIS</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
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CFTR, GLN1352HIS
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<br />
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SNP: rs113857788,
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gnomAD: rs113857788,
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ClinVar: RCV000007659, RCV000586028, RCV001009487, RCV001375489, RCV005031417
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</span>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Lee et al. (2003) identified a G-to-C transversion at nucleotide 4188 in exon 22 of the CFTR gene that resulted in a gln1352-to-his (Q1352H) amino acid change. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0134 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
|
CFTR, GLU217GLY
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<br />
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|
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SNP: rs121909046,
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|
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gnomAD: rs121909046,
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|
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ClinVar: RCV000007660, RCV000506350, RCV000586415, RCV001095295
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cystic fibrosis (CF; 219700), Lee et al. (2003) identified a 782A-G transition in exon 6a of the CFTR gene that resulted in a glu217-to-gly (E217G) amino acid substitution. </p>
|
|
</span>
|
|
</div>
|
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<div>
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|
<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0135 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
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|
|
CFTR, GLY1244VAL AND SER912LEU
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<br />
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SNP: rs267606723,
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|
|
gnomAD: rs267606723,
|
|
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|
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ClinVar: RCV000007626, RCV000007661, RCV000506704, RCV000577733, RCV000586236, RCV001158768, RCV002255257
|
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|
|
</span>
|
|
</div>
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with a severe form of cystic fibrosis (CF; 219700), Savov et al. (1995) identified compound heterozygosity for mutations in the CFTR gene. One allele carried a G542X substitution (602421.0009). The other allele carried 2 mutations: S912L (see 602421.0100) and a 3863G-T transversion in exon 20, resulting in a gly1244-to-val (G1244V) substitution in the second nucleotide binding domain. </p><p>By in vitro functional expression studies, Clain et al. (2005) demonstrated that the S912L substitution was not disease-causing in isolation, but significantly impaired CFTR function when inherited in cis with the G1244V mutation. Although the G1244V substitution alone resulted in decreased cAMP-dependent chloride conductance (43% of control values), the G1244V/S912L complex allele had an almost 20-fold reduction in chloride conduction (2.4% of control values) compared with the G1244V mutant alone. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0136 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, ALA561GLU
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|
<br />
|
|
|
|
SNP: rs121909047,
|
|
|
|
|
|
gnomAD: rs121909047,
|
|
|
|
|
|
ClinVar: RCV000007662, RCV000759032, RCV001004265, RCV001826451, RCV003473050
|
|
|
|
|
|
</span>
|
|
</div>
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Mendes et al. (2003) stated that an ala561-to-glu (A561E) substitution in exon 12 of the CFTR gene is the second most common mutation among Portuguese patients with cystic fibrosis (CF; 219700), accounting for 3% of mutant alleles. Overexpression of the A561E mutant protein in baby hamster kidney cells showed that it was misprocessed and retained in the endoplasmic reticulum, thus belonging to the class II type of CFTR mutation. Low temperature treatment partially rescued a functional A561E-CFTR channel, similar to findings with the common F508del mutation (602421.0001). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0137 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, MET1101LYS ({dbSNP rs36210737})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs36210737,
|
|
|
|
|
|
gnomAD: rs36210737,
|
|
|
|
|
|
ClinVar: RCV000032712, RCV000757078, RCV000781258, RCV001004494, RCV001831623, RCV002496491, RCV003466886
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Stuhrmann et al. (1997) identified a T-to-A transversion at nucleotide 3302 of the CFTR gene, resulting in met-to-lys substitution at codon 1101 (M1101K) in a single individual with cystic fibrosis (CF; 219700) from the South Tyrol. </p><p>In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, Chong et al. (2012) identified this mutation in heterozygous state in 108 individuals among 1,473 screened and in homozygous state in 6, for a carrier frequency of 0.073 (1 in 13.5). Chong et al. (2012) noted that the South Tyrol was the home of some of the Hutterite founders. </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
|
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|
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|
<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0138 CYSTIC FIBROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CFTR, EX16-17b DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000851288
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Girardet et al. (2007) reported a male neonate with cystic fibrosis (CF; 219700) who was compound heterozygous for 2 large CFTR rearrangements, one a deletion involving exon 2 inherited from his Sicilian father, and the other a deletion removing exons 16, 17a, and 17b (c.2908+1085_c.3367+260del7201, NM_000492.2) inherited from his South Korean mother. The deletion extended from intron 15 to intron 17b of the gene. Numbering of this mutation uses A of the ATG start codon as the +1 position. </p><p>In a Japanese boy diagnosed with CF on the basis of chronic respiratory infection and elevated sweat chloride levels, in whom no mutation had been identified by conventional analysis, Nakakuki et al. (2012) detected the 7.2-kb deletion identified by Girardet et al. (2007) using direct sequencing. A splicing defect was found on the other allele. Nakakuki et al. (2012) predicted that the mutated protein would lack amino acids 970 through 1122, which correspond to transmembrane regions 9, 10, and 11. </p><p>Sohn et al. (2019) performed a clinical characterization and genetic analysis of CFTR in 6 Korean patients from 5 families with cystic fibrosis. Six of the 12 alleles (50%) showed the 16-17b multiexon deletion. All 6 patients had a classical cystic fibrosis phenotype and 5 of the 6 presented with meconium ileus. All patients were alive with supportive care at ages ranging from 8 to 19 years. Sohn et al. (2019) suggested molecular investigation for this deletion mutation in Asian populations including Korea and Japan. </p><p>Wakabayashi-Nakao et al. (2019) reported identification of a deletion of exons 16-17b in CFTR as the most common Japanese cystic fibrosis variant, with frequency of about 70% among Japanese CF patients definitely diagnosed. The pathogenic mutation results in a deletion of 153 amino acids, from glycine at position 970 (G970) to threonine at 1122 (T1122) in the CFTR protein without a frameshift; the authors referred to the mutation as delta-(G970-T1122). The authors characterized this variant in CFTR carrying this deletion in CHO cells using immunoblots and super-resolution microscopy. The protein is synthesized and core-glycosylated but not complex-glycosylated. Lumacaftor (VX-809) could not rescue the maturation defect of the delta-(G970-T1122) protein. Wakabayashi-Nakao et al. (2019) suggested that this mutation should be characterized as a class II variant. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
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</div>
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</div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Baylin et al. (1980); Chalkley and Harris (1991); Chillon et al.
|
|
(1995); Cutting et al. (1992); de Vries et al. (1997); Devoto et al.
|
|
(1991); Dumur et al. (1996); Dumur et al. (1990); Fanen et al.
|
|
(1992); Kerem et al. (1990); Kerem et al. (1995); Klinger et al.
|
|
(1990); Laroche and Travert (1991); Marino et al. (1991); Nunes et
|
|
al. (1991); Orita et al. (1989); Pier et al. (1996); Rich et al.
|
|
(1990); Rosenfeld et al. (1992); Sheppard et al. (1993); Shoshani et
|
|
al. (1994); The Cystic Fibrosis Genotype-Phenotype Consortium (1993);
|
|
Varon et al. (1995); Yang et al. (1993)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
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<ol>
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<li>
|
|
<p class="mim-text-font">
|
|
Abeliovich, D., Lavon, I. P., Lerer, I., Cohen, T., Springer, C., Avital, A., Cutting, G. R.
|
|
<strong>Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population.</strong>
|
|
Am. J. Hum. Genet. 51: 951-956, 1992.
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|
|
[PubMed: 1384328]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Accurso, F. J., Rowe, S. M., Clancy, J. P., Boyle, M. P., Dunitz, J. M., Durie, P. R., Sagel, S. D., Hornick, D. B., Konstan, K. W., Donaldson, S. H., Moss, R. B., Pilewski, J. M., and 14 others.
|
|
<strong>Effect of VX-770 in persons with cystic fibrosis and the G155D-CFTR mutation.</strong>
|
|
New Eng. J. Med. 363: 1991-2003, 2010.
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[PubMed: 21083385]
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[Full Text: https://doi.org/10.1056/NEJMoa0909825]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Alonso, M. J., Heine-Suner, D., Calvo, M., Rosell, J., Gimenez, J., Ramos, M. D., Telleria, J. J., Palacio, A., Estivill, X., Casals, T.
|
|
<strong>Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry.</strong>
|
|
Ann. Hum. Genet. 71: 194-201, 2007.
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|
|
[PubMed: 17331079]
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[Full Text: https://doi.org/10.1111/j.1469-1809.2006.00310.x]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Alper, O. M., Wong, L.-J. C., Hostetter, G., Cook, J., Tenenholz, B., Hsu, E., Woo, M. S.
|
|
<strong>1154insTC is not a rare CFTR mutation. (Letter)</strong>
|
|
Am. J. Med. Genet. 120A: 294-295, 2003.
|
|
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|
|
[PubMed: 12833419]
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[Full Text: https://doi.org/10.1002/ajmg.a.20038]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Anand, R., Ogilvie, D. J., Butler, R., Riley, J. H., Finniear, R. S., Powell, S. J., Smith, J. C., Markham, A. F.
|
|
<strong>A yeast artificial chromosome contig encompassing the cystic fibrosis locus.</strong>
|
|
Genomics 9: 124-130, 1991.
|
|
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|
|
[PubMed: 1706309]
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[Full Text: https://doi.org/10.1016/0888-7543(91)90229-8]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Anguiano, A., Oates, R. D., Amos, J. A., Dean, M., Gerrard, B., Stewart, C., Maher, T. A., White, M. B., Milunsky, A.
|
|
<strong>Congenital bilateral absence of the vas deferens: a primarily genital form of cystic fibrosis.</strong>
|
|
JAMA 267: 1794-1797, 1992.
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|
[PubMed: 1545465]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Antinolo, G., Borrego, S., Gili, M., Dapena, J., Alfageme, I., Reina, F.
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Contributors:
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<span class="mim-text-font">
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Bao Lige - updated : 10/21/2022<br>Bao Lige - updated : 10/07/2022<br>Ada Hamosh - updated : 09/20/2019<br>Ada Hamosh - updated : 08/27/2019<br>Ada Hamosh - updated : 09/21/2018<br>Ada Hamosh - updated : 12/08/2016<br>Ada Hamosh - updated : 10/21/2015<br>Patricia A. Hartz - updated : 7/16/2013<br>Ada Hamosh - updated : 2/7/2013<br>Ada Hamosh - updated : 9/6/2012<br>Ada Hamosh - updated : 6/20/2012<br>Ada Hamosh - updated : 3/7/2012<br>Patricia A. Hartz - updated : 12/16/2011<br>Ada Hamosh - updated : 1/3/2011<br>Ada Hamosh - updated : 8/31/2010<br>Nara Sobreira - updated : 3/11/2010<br>Marla J. F. O'Neill - updated : 10/29/2009<br>Matthew B. Gross - updated : 5/7/2009<br>Ada Hamosh - updated : 7/17/2008<br>Patricia A. Hartz - updated : 5/19/2008<br>Ada Hamosh - updated : 7/25/2007<br>Cassandra L. Kniffin - updated : 7/10/2007<br>Cassandra L. Kniffin - updated : 6/22/2007<br>Cassandra L. Kniffin - updated : 5/4/2007<br>Marla J. F. O'Neill - updated : 3/15/2007<br>Patricia A. Hartz - updated : 2/8/2007<br>Patricia A. Hartz - updated : 11/29/2006<br>Victor A. McKusick - updated : 6/27/2006<br>Patricia A. Hartz - updated : 6/12/2006<br>Cassandra L. Kniffin - updated : 5/25/2006<br>Cassandra L. Kniffin - updated : 2/20/2006<br>Ada Hamosh - updated : 2/10/2006<br>Paul J. Converse - updated : 2/8/2006<br>Cassandra L. Kniffin - updated : 12/8/2005<br>Marla J. F. O'Neill - updated : 11/11/2005<br>Victor A. McKusick - updated : 10/14/2005<br>George E. Tiller - updated : 9/9/2005<br>George E. Tiller - updated : 6/3/2005<br>Cassandra L. Kniffin - updated : 5/18/2005<br>Marla J. F. O'Neill - updated : 5/16/2005<br>Victor A. McKusick - updated : 4/28/2005<br>Victor A. McKusick - updated : 3/23/2005<br>George E. Tiller - updated : 2/25/2005<br>George E. Tiller - updated : 2/17/2005<br>Marla J. F. O'Neill - updated : 1/28/2005<br>Victor A. McKusick - updated : 1/12/2005<br>Patricia A. Hartz - updated : 12/2/2004<br>Victor A. McKusick - updated : 11/9/2004<br>Victor A. McKusick - updated : 5/21/2004<br>Victor A. McKusick - updated : 5/5/2004<br>Ada Hamosh - updated : 4/30/2004<br>Victor A. McKusick - updated : 4/27/2004<br>Victor A. McKusick - updated : 1/8/2004<br>Victor A. McKusick - updated : 11/6/2003<br>Ada Hamosh - updated : 9/26/2003<br>Victor A. McKusick - updated : 8/13/2003<br>Ada Hamosh - updated : 7/8/2003<br>Victor A. McKusick - updated : 2/4/2003<br>George E. Tiller - updated : 12/16/2002<br>Michael B. Petersen - updated : 10/8/2002<br>George E. Tiller - updated : 9/17/2002<br>George E. Tiller - updated : 9/17/2002<br>Victor A. McKusick - updated : 8/16/2002<br>Victor A. McKusick - updated : 6/14/2002<br>Sonja A. Rasmussen - updated : 4/18/2002<br>Deborah L. Stone - updated : 4/10/2002<br>George E. Tiller - updated : 12/6/2001<br>Ada Hamosh - updated : 2/28/2001<br>Victor A. McKusick - updated : 2/5/2001<br>Michael J. Wright - updated : 1/8/2001<br>Ada Hamosh - updated : 11/17/2000<br>Stylianos E. Antonarakis - updated : 10/19/2000<br>Carol A. Bocchini - updated : 9/22/2000<br>Victor A. McKusick - updated : 7/26/2000<br>Victor A. McKusick - updated : 7/20/2000<br>Victor A. McKusick - updated : 5/18/2000<br>Victor A. McKusick - updated : 2/22/2000<br>Ada Hamosh - updated : 2/11/2000<br>Ada Hamosh - updated : 2/9/2000<br>Victor A. McKusick - updated : 10/21/1999<br>Wilson H. Y. Lo - updated : 9/9/1999<br>Victor A. McKusick - updated : 8/23/1999<br>Stylianos E. Antonarakis - updated : 8/3/1999<br>Victor A. McKusick - updated : 7/6/1999<br>Ada Hamosh - updated : 3/17/1999<br>Ada Hamosh - updated : 3/15/1999<br>Michael J. Wright - updated : 3/1/1999<br>Victor A. McKusick - updated : 11/6/1998<br>Victor A. McKusick - updated : 9/18/1998<br>Victor A. McKusick - updated : 9/17/1998<br>Victor A. McKusick - updated : 9/14/1998<br>Victor A. McKusick - updated : 5/7/1998<br>Victor A. McKusick - updated : 5/6/1998<br>Victor A. McKusick - updated : 4/30/1998<br>Victor A. McKusick - updated : 4/20/1998<br>Victor A. McKusick - updated : 3/19/1998<br>John F. Jackson - reorganized : 3/7/1998
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Victor A. McKusick : 3/7/1998
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4/7/2011<br>terry : 3/18/2011<br>mgross : 3/17/2011<br>terry : 3/15/2011<br>alopez : 1/5/2011<br>terry : 1/3/2011<br>carol : 10/27/2010<br>alopez : 9/3/2010<br>alopez : 9/3/2010<br>alopez : 9/3/2010<br>alopez : 9/3/2010<br>terry : 8/31/2010<br>carol : 4/29/2010<br>carol : 3/23/2010<br>terry : 3/11/2010<br>terry : 1/20/2010<br>wwang : 10/29/2009<br>alopez : 9/30/2009<br>carol : 8/11/2009<br>terry : 6/3/2009<br>wwang : 5/11/2009<br>mgross : 5/7/2009<br>wwang : 4/29/2009<br>terry : 4/3/2009<br>joanna : 2/2/2009<br>alopez : 10/22/2008<br>terry : 10/20/2008<br>alopez : 7/17/2008<br>terry : 7/17/2008<br>mgross : 5/19/2008<br>terry : 12/17/2007<br>wwang : 9/6/2007<br>alopez : 8/2/2007<br>terry : 7/25/2007<br>wwang : 7/18/2007<br>ckniffin : 7/10/2007<br>wwang : 7/2/2007<br>ckniffin : 6/22/2007<br>wwang : 5/23/2007<br>ckniffin : 5/4/2007<br>wwang : 3/16/2007<br>terry : 3/15/2007<br>alopez : 2/27/2007<br>terry : 2/19/2007<br>mgross : 2/8/2007<br>wwang : 11/29/2006<br>terry : 11/16/2006<br>carol 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7/14/1999<br>terry : 7/6/1999<br>terry : 5/20/1999<br>alopez : 3/24/1999<br>alopez : 3/17/1999<br>alopez : 3/15/1999<br>carol : 3/1/1999<br>terry : 11/18/1998<br>carol : 11/16/1998<br>terry : 11/6/1998<br>carol : 9/28/1998<br>terry : 9/18/1998<br>terry : 9/17/1998<br>carol : 9/17/1998<br>carol : 9/17/1998<br>terry : 9/14/1998<br>carol : 8/11/1998<br>carol : 8/10/1998<br>dkim : 7/24/1998<br>alopez : 5/21/1998<br>alopez : 5/18/1998<br>alopez : 5/7/1998<br>alopez : 5/7/1998<br>alopez : 5/6/1998<br>terry : 5/6/1998<br>carol : 5/2/1998<br>terry : 4/30/1998<br>alopez : 4/23/1998<br>alopez : 4/23/1998<br>alopez : 4/23/1998<br>terry : 4/20/1998<br>carol : 4/17/1998<br>carol : 3/28/1998<br>carol : 3/7/1998
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