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Entry
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- *613113 - NEUROFIBROMIN 1; NF1
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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">*613113</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="#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>
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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/613113">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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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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</li>
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</ul>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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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=ENSG00000196712;t=ENST00000358273" 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=4763" 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=613113" 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=ENSG00000196712;t=ENST00000358273" 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_000267,NM_001042492,NM_001128147" 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_001042492" 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=613113" 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=01203&isoform_id=01203_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/NF1" 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/189158,189160,189161,189163,189165,189170,189172,219938,219940,262288,292354,300450,300452,416524,494225,548350,736764,736765,1060901,1084090,1084091,1084092,1084093,1084094,1084095,1772563,4261590,4262774,4557793,31873836,45510875,55375983,62088252,66730939,66730941,109826564,119600673,119600674,119600675,119600676,119600677,119600678,119600679,119600680,119600681,158260895,189458804,194378040,194378576,1102131887,1102131893,1102131895,1102131897,1102131899,1102131901,1102131903,1102131905" 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/P21359" 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=4763" 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=ENSG00000196712;t=ENST00000358273" 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=NF1" 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=NF1" 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+4763" 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/NF1" 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:4763" 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/4763" 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=chr17&hgg_gene=ENST00000358273.9&hgg_start=31094927&hgg_end=31377677&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:7765" 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://search.clinicalgenome.org/kb/genes/HGNC:7765" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/nf1" 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=613113[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=613113[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/NF1/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/ENSG00000196712" 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=NF1" 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=NF1" 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=NF1" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=NF1&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/PA31572" 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:7765" 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://flybase.org/reports/FBgn0015269.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:97306" 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/NF1#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:97306" 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/4763/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/OMIA002241/" 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=4763" 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://zfin.org/ZDB-GENE-030131-4907" 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="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:4763" 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=NF1&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> 1003465006, 128832006, 277587001, 403820003, 445227008, 715344006, 92824003<br />
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<strong>ICD10CM:</strong> C93.3, C93.30, Q85.01<br />
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<strong>ICD9CM:</strong> 237.71<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>
|
|
613113
|
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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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NEUROFIBROMIN 1; NF1
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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>
|
|
</span>
|
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
NEUROFIBROMIN
|
|
</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=NF1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NF1</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/17/380?start=-3&limit=10&highlight=380">17q11.2</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr17:31094927-31377677&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'})">17:31,094,927-31,377,677</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=607785,601321,162210,162200,193520" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="5">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/17/380?start=-3&limit=10&highlight=380">
|
|
17q11.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Leukemia, juvenile myelomonocytic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/607785"> 607785 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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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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<p>The NF1 gene encodes neurofibromin, a cytoplasmic protein that is predominantly expressed in neurons, Schwann cells, oligodendrocytes, and leukocytes. It is a multidomain molecule with the capacity to regulate several intracellular processes, including the RAS (see <a href="/entry/190020">190020</a>)-cyclic AMP pathway, the ERK (<a href="/entry/600997">600997</a>)/MAP (see <a href="/entry/600178">600178</a>) kinase cascade, adenylyl cyclase, and cytoskeletal assembly (summary by <a href="#95" class="mim-tip-reference" title="Trovo-Marqui, A. B., Tajara, E. H. <strong>Neurofibromin: a general outlook.</strong> Clin. Genet. 70: 1-13, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16813595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16813595</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00639.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16813595">Trovo-Marqui and Tajara, 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16813595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#12" class="mim-tip-reference" title="Buchberg, A. M., Cleveland, L. S., Jenkins, N. A., Copeland, N. G. <strong>Sequence homology shared by neurofibromatosis type-1 gene and IRA-1 and IRA-2 negative regulators of the RAS cyclic AMP pathway.</strong> Nature 347: 291-294, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2169593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2169593</a>] [<a href="https://doi.org/10.1038/347291a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2169593">Buchberg et al. (1990)</a> sequenced a portion of the murine NF1 gene and showed that the predicted amino acid sequence is nearly the same as the corresponding region of the human NF1 gene product. Computer searches identified homology between the mouse NF1 gene and the Ira1 and Ira2 genes identified in Saccharomyces cerevisiae, which negatively regulate the RAS-cyclic AMP pathway. RAS proteins are involved in the control of proliferation and differentiation in mammalian cells. Their activity is modulated by their ability to bind and hydrolyze guanine nucleotides. GTP-binding activates RAS, whereas GTP hydrolysis inactivates RAS. Mutant forms of RAS found in human tumors have greatly decreased GTPase activity, resulting in accumulation of RAS in the GTP-bound active form. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2169593" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Xu, G., O'Connell, P., Viskochil, D., Cawthon, R., Robertson, M., Culver, M., Dunn, D., Stevens, J., Gesteland, R., White, R., Weiss, R. <strong>The neurofibromatosis type 1 gene encodes a protein related to GAP.</strong> Cell 62: 599-608, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2116237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2116237</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90024-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2116237">Xu et al. (1990)</a> extended the known open reading frame of the human NF1 gene by cDNA walking and sequencing. The new sequence predicted 2,485 amino acids of the NF1 peptide. A 360-residue region showed significant similarity to the catalytic domains of both human and bovine GTPase-activating protein (GAP, or RASA1; <a href="/entry/139150">139150</a>). <a href="#112" class="mim-tip-reference" title="Xu, G., O'Connell, P., Viskochil, D., Cawthon, R., Robertson, M., Culver, M., Dunn, D., Stevens, J., Gesteland, R., White, R., Weiss, R. <strong>The neurofibromatosis type 1 gene encodes a protein related to GAP.</strong> Cell 62: 599-608, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2116237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2116237</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90024-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2116237">Xu et al. (1990)</a> suggested that NF1 encodes a cytoplasmic GAP-like protein that may be involved in the control of cell growth by interacting with proteins such as the RAS gene product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2116237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#63" class="mim-tip-reference" title="Marchuk, D. A., Saulino, A. M., Tavakkol, R., Swaroop, M., Wallace, M. R., Andersen, L. B., Mitchell, A. L., Gutmann, D. H., Boguski, M., Collins, F. S. <strong>cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product.</strong> Genomics 11: 931-940, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1783401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1783401</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90017-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1783401">Marchuk et al. (1991)</a> reported an extensive cDNA walk resulting in the cloning of the complete coding region of the NF1 transcript. Analysis of the sequences revealed an open reading frame of 2,818 amino acids, although alternatively spliced products may code for different protein isoforms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1783401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 NF1 gene product, <a href="#36" class="mim-tip-reference" title="Gutmann, D. H., Wood, D. L., Collins, F. S. <strong>Identification of the neurofibromatosis type 1 gene product.</strong> Proc. Nat. Acad. Sci. 88: 9658-9662, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1946382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1946382</a>] [<a href="https://doi.org/10.1073/pnas.88.21.9658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1946382">Gutmann et al. (1991)</a> raised antibodies against both fusion proteins and synthetic peptides. A specific protein of about 250 kD was identified by both immunoprecipitation and immunoblotting. The protein was found in all tissues and cell lines examined and was detected in human, rat, and mouse tissues. Based on the homology between the NF1 gene product and members of the GAP superfamily, the name NF1-GAP-related protein (NF1-GRD) was suggested. <a href="#24" class="mim-tip-reference" title="DeClue, J. E., Cohen, B. D., Lowy, D. R. <strong>Identification and characterization of the neurofibromatosis type 1 protein product.</strong> Proc. Nat. Acad. Sci. 88: 9914-9918, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1946460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1946460</a>] [<a href="https://doi.org/10.1073/pnas.88.22.9914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1946460">DeClue et al. (1991)</a> raised rabbit antisera to a bacterially synthesized peptide corresponding to the GAP-related domain of NF1 (NF1-GRD). The sera specifically detected a 280-kD protein in lysates of HeLa cells. This protein corresponded to the NF1 gene product, as shown by several criteria. NF1 was present in a large molecular mass complex in fibroblast and schwannoma cell lines and appeared to associate with a very large (400-500 kD) protein in both cell lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1946382+1946460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Daston, M. M., Scrable, H., Nordlund, M., Sturbaum, A. K., Nissen, L. M., Ratner, N. <strong>The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes.</strong> Neuron 8: 415-428, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1550670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1550670</a>] [<a href="https://doi.org/10.1016/0896-6273(92)90270-n" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1550670">Daston et al. (1992)</a> raised antibodies against peptides coded by portions of the NF1 cDNA. These antibodies specifically recognized a 220-kD protein, called neurofibromin, in both human and rat spinal cord. Neurofibromin was most abundant in the nervous system. Immunostaining of tissue sections indicated that neurons, oligodendrocytes, and nonmyelinating Schwann cells contained neurofibromin, whereas astrocytes and myelinating Schwann cells did not. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1550670" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#95" class="mim-tip-reference" title="Trovo-Marqui, A. B., Tajara, E. H. <strong>Neurofibromin: a general outlook.</strong> Clin. Genet. 70: 1-13, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16813595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16813595</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00639.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16813595">Trovo-Marqui and Tajara (2006)</a> stated that 4 splicing exons (9a, 10a-2, 23a, and 48a) are responsible for the production of 5 human neurofibromin isoforms (II, 3, 4, 9a, and 10a-2), which exhibit differential expression in distinct tissues. Neurofibromin II, named GRD2 (domain II-related GAP), is the result of the insertion of exon 23a, is expressed in Schwann cells, and has a reduced capacity of acting as GAP. Neurofibromins 3 and 4, which contain exon 48a and both exons 23a and 48a, respectively, are expressed in muscle tissue, mainly in cardiac and skeleton muscles. Neurofibromin 9a (also called 9br) is the result of the inclusion of exon 9a and shows limited neuronal expression. Isoform 10a-2 is the result of insertion of exon 10a-2, which introduces a transmembrane domain. This isoform has been observed in the majority of human tissues analyzed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16813595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#112" class="mim-tip-reference" title="Xu, G., O'Connell, P., Viskochil, D., Cawthon, R., Robertson, M., Culver, M., Dunn, D., Stevens, J., Gesteland, R., White, R., Weiss, R. <strong>The neurofibromatosis type 1 gene encodes a protein related to GAP.</strong> Cell 62: 599-608, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2116237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2116237</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90024-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2116237">Xu et al. (1990)</a> found that 3 active genes, called OMGP (<a href="/entry/164345">164345</a>), EVI2B (<a href="/entry/158381">158381</a>), and EVI2A (<a href="/entry/158380">158380</a>), lie within an intron of NF1 but in opposite orientation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2116237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Xu, G., O'Connell, P., Stevens, J., White, R. <strong>Characterization of human adenylate kinase 3 (AK3) cDNA and mapping of the AK3 pseudogene to an intron of the NF1 gene.</strong> Genomics 13: 537-542, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1639383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1639383</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90122-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1639383">Xu et al. (1992)</a> found a pseudogene of the AK3L1 gene (<a href="/entry/103030">103030</a>) in an intron of the NF1 gene. It appeared to be a processed pseudogene since it lacked introns and contained a polyadenylate tract; it nevertheless retained coding potential because the open reading frame was not impaired by any observed base substitutions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1639383" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#39" class="mim-tip-reference" title="Heim, R. A., Silverman, L. M., Farber, R. A., Kam-Morgan, L. N. W., Luce, M. C. <strong>Screening for truncated NF1 proteins. (Letter)</strong> Nature Genet. 8: 218-219, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874161</a>] [<a href="https://doi.org/10.1038/ng1194-218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874161">Heim et al. (1994)</a> cited evidence that the NF1 gene spans approximately 350 kb of genomic DNA, encodes an mRNA of 11 to 13 kb, and contains at least 56 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Li, Y., O'Connell, P., Huntsman Breidenbach, H., Cawthon, R., Stevens, J., Xu, G., Neil, S., Robertson, M., White, R., Viskochil, D. <strong>Genomic organization of the neurofibromatosis 1 gene (NF1).</strong> Genomics 25: 9-18, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7774960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7774960</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80104-t" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7774960">Li et al. (1995)</a> showed that the 5-prime end of the NF1 gene is embedded in a CpG island containing a NotI restriction site and that the remainder of the gene lies in the adjacent 35-kb NotI fragment. In their efforts to develop a comprehensive screen for NF1 mutations, they isolated genomic DNA clones that together contain the entire NF1 cDNA sequence. They identified all intron-exon boundaries of the coding region and established that it contains at least 59 exons. The 3-prime untranslated region of the NF1 gene was found to span approximately 3.5 kb and to be continuous with the stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7774960" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#95" class="mim-tip-reference" title="Trovo-Marqui, A. B., Tajara, E. H. <strong>Neurofibromin: a general outlook.</strong> Clin. Genet. 70: 1-13, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16813595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16813595</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00639.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16813595">Trovo-Marqui and Tajara (2006)</a> stated that the NF1 gene contains 61 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16813595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#9" class="mim-tip-reference" title="Barker, D., Wright, E., Nguyen, K., Cannon, L., Fain, P., Goldgar, D., Bishop, D. T., Carey, J., Baty, B., Kivlin, J., Willard, H., Waye, J. S., Greig, G., Leinwand, L., Nakamura, Y., O'Connell, P., Leppert, M., Lalouel, J.-M., White, R., Skolnick, M. <strong>Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17.</strong> Science 236: 1100-1102, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3107130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3107130</a>] [<a href="https://doi.org/10.1126/science.3107130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3107130">Barker et al. (1987)</a> demonstrated that the gene responsible for neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>) is located in the pericentromeric region of chromosome 17. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3107130" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#106" class="mim-tip-reference" title="Wallace, M. R., Marchuk, D. A., Andersen, L. B., Letcher, R., Odeh, H. M., Saulino, A. M., Fountain, J. W., Brereton, A., Nicholson, J., Mitchell, A. L., Brownstein, B. H., Collins, F. S. <strong>Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients.</strong> Science 249: 181-186, 1990. Note: Erratum: Science 250: 1749 only, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2134734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2134734</a>] [<a href="https://doi.org/10.1126/science.2134734" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2134734">Wallace et al. (1990)</a> identified a large transcript from the candidate NF1 region on chromosome 17q11.2 that was disrupted in 3 patients with neurofibromatosis type I. The changes disrupted expression of the NF1 transcript in all 3 patients, consistent with the hypothesis that it acts as a tumor suppressor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2134734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Pseudogenes</em></strong></p><p>
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<a href="#56" class="mim-tip-reference" title="Legius, E., Marchuk, D. A., Hall, B. K., Andersen, L. B., Wallace, M. R., Collins, F. S., Glover, T. W. <strong>NF1-related locus on chromosome 15.</strong> Genomics 13: 1316-1318, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1505963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1505963</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90055-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1505963">Legius et al. (1992)</a> characterized an NF1-related locus on chromosome 15. The nonprocessed NF1 pseudogene (NF1P1) can produce additional fragments in Southern blotting, pulsed field gel, and PCR experiments with some NF1 cDNA probes or oligonucleotides. In addition, certain regions of the NF1 gene cross-hybridize with a locus on chromosome 14. These loci can cause confusion in the mutation analysis of patients with NF1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1505963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Numerous NF1 pseudogenes have been identified in the human genome. Those in 2q21, 14q11, and 22q11 form a subset with a similar genomic organization and a high sequence homology. By PCR and fluorescence in situ hybridization, <a href="#62" class="mim-tip-reference" title="Luijten, M., Redeker, S., Minoshima, S., Shimizu, N., Westerveld, A., Hulsebos, T. J. M. <strong>Duplication and transposition of the NF1 pseudogene regions on chromosomes 2, 14, and 22.</strong> Hum. Genet. 109: 109-116, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479742</a>] [<a href="https://doi.org/10.1007/s004390100543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479742">Luijten et al. (2001)</a> studied the extent of the homology of the regions surrounding these NF1 pseudogenes. They found that a fragment of at least 640 kb is homologous between the 3 regions. Based on previous studies and these new findings, they proposed a model for the spreading of the NF1 pseudogene-containing regions. A fragment of approximately 640 kb was first duplicated in chromosome region 2q21 and transposed to 14q11. Subsequently, this fragment was duplicated in 14q11 and transposed to 22q11. A part of the 640-kb fragment in 14q11, with a length of about 430 kb, was further duplicated to a variable extent in 14q11. In addition, <a href="#62" class="mim-tip-reference" title="Luijten, M., Redeker, S., Minoshima, S., Shimizu, N., Westerveld, A., Hulsebos, T. J. M. <strong>Duplication and transposition of the NF1 pseudogene regions on chromosomes 2, 14, and 22.</strong> Hum. Genet. 109: 109-116, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479742</a>] [<a href="https://doi.org/10.1007/s004390100543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479742">Luijten et al. (2001)</a> identified sequences that may facilitate the duplication and transposition of the 640-kb and 430-kb fragments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#25" class="mim-tip-reference" title="DeClue, J. E., Papageorge, A. G., Fletcher, J. A., Diehl, S. R., Ratner, N., Vass, W. C., Lowy, D. R. <strong>Abnormal regulation of mammalian p21(ras) contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis.</strong> Cell 69: 265-273, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1568246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1568246</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90407-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1568246">DeClue et al. (1992)</a> presented evidence implicating the NF1 protein as a tumor suppressor gene product that negatively regulates p21(ras) (see <a href="/entry/190020">190020</a>) and defined a 'positive' growth role for RAS activity in NF1 malignancies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1568246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Basu, T. N., Gutmann, D. H., Fletcher, J. A., Glover, T. W., Collins, F. S., Downward, J. <strong>Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients.</strong> Nature 356: 713-715, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1570015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1570015</a>] [<a href="https://doi.org/10.1038/356713a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1570015">Basu et al. (1992)</a> presented evidence supporting the hypothesis that NF1 is a tumor-suppressor gene whose product acts upstream of the RAS proteins. They showed that the RAS proteins in malignant tumor cell lines from patients with NF1 were in a constitutively activated state as measured by the ratio of the guanine nucleotides bound to them, i.e., the ratio of GTP (active) to GDP (inactive). Transforming mutants of p21(ras) bind large amounts of GTP, whereas wildtype p21(ras) is almost entirely GDP-bound. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1570015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#71" class="mim-tip-reference" title="Nakafuku, M., Nagamine, M., Ohtoshi, A., Tanaka, K., Toh-e, A., Kaziro, Y. <strong>Suppression of oncogenic Ras by mutant neurofibromatosis type 1 genes with single amino acid substitutions.</strong> Proc. Nat. Acad. Sci. 90: 6706-6710, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8341688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8341688</a>] [<a href="https://doi.org/10.1073/pnas.90.14.6706" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8341688">Nakafuku et al. (1993)</a> took advantage of the yeast RAS system to isolate mutants in the RAS GTPase activating protein-related domain of the NF1 gene product (NF1-GRD) that can act as antioncogenes specific for oncogenic RAS. They demonstrated that these mutant NF1-GRDs, when expressed in mammalian cells, were able to induce morphologic reversion of RAS-transformed NIH 3T3 cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8341688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#46" class="mim-tip-reference" title="Johnson, M. R., Look, A. T., DeClue, J. E., Valentine, M. B., Lowy, D. R. <strong>Inactivation of the NF1 gene in human melanoma and neuroblastoma cell lines without impaired regulation of GTP-Ras.</strong> Proc. Nat. Acad. Sci. 90: 5539-5543, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8516298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8516298</a>] [<a href="https://doi.org/10.1073/pnas.90.12.5539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8516298">Johnson et al. (1993)</a> stated that in schwannoma cell lines from patients with neurofibromatosis, loss of neurofibromin is associated with impaired regulation of GTP/RAS. They analyzed other neural crest-derived tumor cell lines and showed that some melanoma and neuroblastoma cell lines established from tumors occurring in patients without neurofibromatosis also contained reduced or undetectable levels of neurofibromin, with concomitant genetic abnormalities of the NF1 locus. In contrast to the schwannoma cell lines, however, GTP/RAS was appropriately regulated in the melanoma and neuroblastoma lines that were deficient in neurofibromin, even when HRAS (<a href="/entry/190020">190020</a>) was overexpressed. These results demonstrated that some neural crest tumors not associated with neurofibromatosis have acquired somatically inactivated NF1 genes and suggested a tumor-suppressor function for neurofibromin that is independent of RAS GTPase activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8516298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#85" class="mim-tip-reference" title="Silva, A. J., Frankland, P. W., Marowitz, Z., Friedman, E., Laszlo, G. S., Cioffi, D., Jacks, T., Bourtchuladze, R. <strong>A mouse model for the learning and memory deficits associated with neurofibromatosis type I.</strong> Nature Genet. 15: 281-284, 1997. Note: Erratum: Nature Genet. 31: 439 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9054942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9054942</a>] [<a href="https://doi.org/10.1038/ng0397-281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9054942">Silva et al. (1997)</a> cited several studies that suggested a role of neurofibromin in brain function. The expression of the NF1 gene is largely restricted to neuronal tissues in the adult. This GTPase-activating protein may act as a negative regulator of neurotrophin (see BDNF; <a href="/entry/113505">113505</a>)-mediated signaling. They also noted immunohistochemical studies that suggested that activation of astrocytes may be common in the brain of NF1 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9054942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 review of the molecular neurobiology of human cognition, <a href="#107" class="mim-tip-reference" title="Weeber, E. J., Sweatt, J. D. <strong>Molecular neurobiology of human cognition.</strong> Neuron 33: 845-848, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11906692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11906692</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00634-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11906692">Weeber and Sweatt (2002)</a> presented an overview of the RAS-ERK-CREB pathway, including the function of NF1. The authors discussed publications that implicated dysfunction of this signal transduction cascade in cognitive defects, including mental retardation caused by mutation in the NF1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11906692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#104" class="mim-tip-reference" title="Vogel, K. S., Brannan, C. I., Jenkins, N. A., Copeland, N. G., Parada, L. F. <strong>Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons.</strong> Cell 82: 733-742, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7671302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7671302</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90470-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7671302">Vogel et al. (1995)</a> used a targeted disruption of the NF1 gene in mice to examine the role of neurofibromin in the acquisition of neurotrophin dependence in embryonic neurons. They showed that both neural crest- and placode-derived sensory neurons isolated from NF1 -/- embryos develop, extend neurites, and survive in the absence of neurotrophins, whereas their wildtype counterparts die rapidly unless nerve growth factor (<a href="/entry/162030">162030</a>) or BDNF is added to the culture medium. Moreover, NF1 -/- sympathetic neurons survive for extended periods and acquire mature morphology in the presence of NGF-blocking antibodies. These results were considered by <a href="#104" class="mim-tip-reference" title="Vogel, K. S., Brannan, C. I., Jenkins, N. A., Copeland, N. G., Parada, L. F. <strong>Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons.</strong> Cell 82: 733-742, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7671302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7671302</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90470-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7671302">Vogel et al. (1995)</a> as consistent with a model wherein neurofibromin acts as a negative regulator of neurotrophin-mediated signaling for survival of embryonic peripheral neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7671302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the most part the NF1 tumor suppressor acts through the interaction of its GRD with the product of the RAS protooncogene. <a href="#86" class="mim-tip-reference" title="Skuse, G. R., Cappione, A. J., Sowden, M., Metheny, L. J., Smith, H. C. <strong>The neurofibromatosis type I messenger RNA undergoes base-modification RNA editing.</strong> Nucleic Acids Res. 24: 478-485, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8602361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8602361</a>] [<a href="https://doi.org/10.1093/nar/24.3.478" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8602361">Skuse et al. (1996)</a> discovered an mRNA editing site within the NF1 mRNA. Editing at this site changes a cytidine at nucleotide 2914 to a uridine, creating an in-frame translation stop codon. The edited transcript, if translated, would produce a protein truncated in the N-terminal region of the GRD, thereby inactivating the NF1 tumor-suppressor function. Analysis of RNA from a variety of cell lines, tumors, and peripheral blood cells revealed that the NF1 mRNA undergoes editing, to different extents, in every cell type studied. Three tumors analyzed as part of their study, an astrocytoma, a neurofibroma, and a neurofibrosarcoma, each had levels of NF1 mRNA editing substantially higher than did peripheral blood leukocytes. To investigate the role played by editing in NF1 tumorigenesis, <a href="#14" class="mim-tip-reference" title="Cappione, A. J., French, B. L., Skuse, G. R. <strong>A potential role for NF1 mRNA editing in the pathogenesis of NF1 tumors.</strong> Am. J. Hum. Genet. 60: 305-312, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9012403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9012403</a>]" pmid="9012403">Cappione et al. (1997)</a> analyzed RNA from 19 NF1 and 4 non-NF1 tumors. (The authors referred to the editing site as nucleotide 3916.) They observed varying levels in NF1 mRNA editing in different tumors, with a higher range of editing in more malignant tumors (e.g., neurofibrosarcomas) compared to benign tumors (cutaneous neurofibromas). Plexiform neurofibromas had an intermediate range of levels of NF1 mRNA editing. The constitutional levels of NF1 mRNA editing varied slightly in NF1 individuals but were consistent with the levels observed in non-NF1 individuals. In every case, there was a greater level of NF1 mRNA editing in the tumor than in the nontumor tissue from the same patient. These results suggested to <a href="#14" class="mim-tip-reference" title="Cappione, A. J., French, B. L., Skuse, G. R. <strong>A potential role for NF1 mRNA editing in the pathogenesis of NF1 tumors.</strong> Am. J. Hum. Genet. 60: 305-312, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9012403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9012403</a>]" pmid="9012403">Cappione et al. (1997)</a> that inappropriately high levels of NF1 mRNA editing indeed plays a role in NF1 tumorigenesis and that editing may result in the functional equivalent of biallelic inactivation of the NF1 tumor suppressor. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9012403+8602361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#70" class="mim-tip-reference" title="Mukhopadhyay, D., Anant, S., Lee, R. M., Kennedy, S., Viskochil, D., Davidson, N. O. <strong>C-U editing of neurofibromatosis 1 mRNA occurs in tumors that express both the type II transcript and apobec-1, the catalytic subunit of the apolipoprotein B mRNA-editing enzyme.</strong> Am. J. Hum. Genet. 70: 38-50, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11727199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11727199</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11727199[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/10.1086/337952" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11727199">Mukhopadhyay et al. (2002)</a> studied C-to-U RNA editing in peripheral nerve sheath tumor samples (PNSTs) from 34 patients with NF1. Whereas most showed low levels of RNA editing, 8 of the 34 tumors demonstrated 3 to 12% C-to-U editing of NF1 RNA. These tumors demonstrated 2 distinguishing characteristics. First, these PNSTs expressed APOBEC1 (<a href="/entry/600130">600130</a>) mRNA, the catalytic deaminase of the holoenzyme that edits APOB (<a href="/entry/107730">107730</a>) RNA. Second, NF1 RNA from these PNSTs contained increased proportions of an alternatively spliced exon, 23A, downstream of the edited base in which editing occurs preferentially. These findings, together with results of both in vivo and in vitro experiments with APOBEC1, strongly suggested an important mechanistic linkage between NF1 RNA splicing and C-to-U editing and provided a basis for understanding the heterogeneity of posttranscriptional regulation of NF1 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11727199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 NF1 tumor suppressor protein is thought to restrict cell proliferation by functioning as a Ras-specific guanosine triphosphatase-activating protein. However, <a href="#93" class="mim-tip-reference" title="The, I., Hannigan, G. E., Cowley, G. S., Reginald, S., Zhong, Y., Gusella, J. F., Hariharan, I. K., Bernards, A. <strong>Rescue of a Drosophila NF1 mutant phenotype by protein kinase A.</strong> Science 276: 791-794, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9115203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9115203</a>] [<a href="https://doi.org/10.1126/science.276.5313.791" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9115203">The et al. (1997)</a> found that Drosophila homozygous for null mutations of an NF1 homolog show no obvious signs of perturbed RAS1-mediated signaling. Loss of NF1 resulted in a reduction in size of larvae, pupae, and adults. This size defect was not modified by manipulating RAS1 signaling but was restored by expression of activated adenosine 3-prime, 5-prime-monophosphate -dependent protein kinase (PKA; see <a href="/entry/176911">176911</a>). Thus, NF1 and PKA appear to interact in a pathway that controls the overall growth of Drosophila. <a href="#34" class="mim-tip-reference" title="Guo, H.-F., The, I., Hannan, F., Bernards, A., Zhong, Y. <strong>Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides.</strong> Science 276: 795-798, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9115204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9115204</a>] [<a href="https://doi.org/10.1126/science.276.5313.795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9115204">Guo et al. (1997)</a> showed, from a study of Drosophila NF1 mutants, that NF1 is essential for the cellular response to the neuropeptide PACAP38 (pituitary adenylyl cyclase-adenosine activating polypeptide) at the neuromuscular junction. The peptide induced a 3-prime, 5-prime-monophosphate (cAMP) pathway. This response was eliminated in NF1 mutants. NF1 appeared to regulate the rutabaga-encoded adenylyl cyclase rather than the RAS-RAF pathway. Moreover, the NF1 defect was rescued by the exposure of cells to pharmacologic treatment that increased concentrations of cAMP. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9115203+9115204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#37" class="mim-tip-reference" title="Gutmann, D. H. <strong>The neurofibromatoses: when less is more.</strong> Hum Molec. Genet. 10: 747-755, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11257108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11257108</a>] [<a href="https://doi.org/10.1093/hmg/10.7.747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11257108">Gutmann (2001)</a> reviewed the functions of neurofibromin and merlin, the product of the NF2 gene (<a href="/entry/607379">607379</a>), in tumor suppression and cell-cell signaling, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11257108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#95" class="mim-tip-reference" title="Trovo-Marqui, A. B., Tajara, E. H. <strong>Neurofibromin: a general outlook.</strong> Clin. Genet. 70: 1-13, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16813595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16813595</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00639.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16813595">Trovo-Marqui and Tajara (2006)</a> provided a detailed review of neurofibromin and its role in neurofibromatosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16813595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 proteomic approach, <a href="#75" class="mim-tip-reference" title="Phan, V. T., Ding, V. W., Li, F., Chalkley, R. J., Burlingame, A., McCormick, F. <strong>The RasGAP proteins Ira2 and neurofibromin are negatively regulated by Gpb1 in yeast and ETEA in humans.</strong> Molec. Cell. Biol. 30: 2264-2279, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20160012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20160012</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20160012[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/10.1128/MCB.01450-08" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20160012">Phan et al. (2010)</a> showed that ETEA (FAF2; <a href="/entry/616935">616935</a>) interacted with NF1. Overexpression of ETEA downregulated NF1 in human cells. ETEA ubiquitinated the GAP-related domain of NF1 in a UBX domain-dependent manner in vitro. Silencing of ETEA increased NF1 levels and downregulated RAS activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20160012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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><strong><em>Neurofibromatosis Type I</em></strong></p><p>
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Using pulsed field gel electrophoresis, <a href="#96" class="mim-tip-reference" title="Upadhyaya, M., Cheryson, A., Broadhead, W., Fryer, A., Shaw, D. J., Huson, S., Wallace, M. R., Andersen, L. B., Marchuk, D. A., Viskochil, D., Black, D., O'Connell, P., Collins, F. S., Harper, P. S. <strong>A 90 kb DNA deletion associated with neurofibromatosis type 1.</strong> J. Med. Genet. 27: 738-741, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2127432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2127432</a>] [<a href="https://doi.org/10.1136/jmg.27.12.738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2127432">Upadhyaya et al. (1990)</a> identified a 90-kb deletion in the proximal portion of 17q in 1 of 90 unrelated patients with neurofibromatosis I. <a href="#103" class="mim-tip-reference" title="Viskochil, D., Buchberg, A. M., Xu, G., Cawthon, R. M., Stevens, J., Wolff, R. K., Culver, M., Carey, J. C., Copeland, N. G., Jenkins, N. A., White, R., O'Connell, P. <strong>Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus.</strong> Cell 62: 187-192, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1694727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1694727</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90252-a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1694727">Viskochil et al. (1990)</a> detected deletions of 190, 40, and 11 kb in the gene located at the 17q translocation breakpoint in 3 patients with NF1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1694727+2127432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 an NF1 patient, <a href="#105" class="mim-tip-reference" title="Wallace, M. R., Andersen, L. B., Saulino, A. M., Gregory, P. E., Glover, T. W., Collins, F. S. <strong>A de novo Alu insertion results in neurofibromatosis type 1.</strong> Nature 353: 864-866, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1719426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1719426</a>] [<a href="https://doi.org/10.1038/353864a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1719426">Wallace et al. (1991)</a> identified an insertion of an Alu sequence in an intron of the NF1 gene, resulting in deletion of the downstream exon during splicing and a frameshift (<a href="#0001">613113.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1719426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Cawthon, R. M., Viskochil, D., O'Connell, P., Buchberg, A., Andersen, L., Wallace, M., Marchuk, D., Stevens, J., Culver, M., Xu, G., Collins, F. S., Jenkins, N., Copeland, N., White, R. <strong>Identification and characterization of several genes between or nearby neurofibromatosis type I translocation breakpoint. (Abstract)</strong> Am. J. Hum. Genet. 47 (suppl.): A109, 1990."None>Cawthon et al. (1990)</a> identified 2 different point mutations in the NF1 gene (L348P; <a href="#0003">613113.0003</a> and R365X; <a href="#0004">613113.0004</a>) in patients with NF1.</p><p><a href="#101" class="mim-tip-reference" title="Upadhyaya, M., Shen, M., Cherryson, A., Farnham, J., Maynard, J., Huson, S. M., Harper, P. S. <strong>Analysis of mutations at the neurofibromatosis 1 (NF1) locus.</strong> Hum. Molec. Genet. 1: 735-740, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302608</a>] [<a href="https://doi.org/10.1093/hmg/1.9.735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302608">Upadhyaya et al. (1992)</a> identified multiple germline NF1 mutations (see, e.g., <a href="#0006">613113.0006</a>-<a href="#0009">613113.0009</a>) in patients with NF1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#108" class="mim-tip-reference" title="Weiming, X., Yu, Q., Lizhi, L., Ponder, M., Wallace, M., Gangfeng, X., Ponder, B. <strong>Molecular analysis of neurofibromatosis type 1 mutations.</strong> Hum. Mutat. 1: 474-477, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301957</a>] [<a href="https://doi.org/10.1002/humu.1380010604" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301957">Weiming et al. (1992)</a> identified mutations in the NF1 gene in at most 3% of NF1 subjects in an analysis that covered 17% of the coding sequence by SSCP and a larger region by Southern blotting. The results suggested that most NF1 mutations lie elsewhere in the coding sequence or outside it. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#21" class="mim-tip-reference" title="Collins, F. S. <strong>Personal Communication.</strong> Bethesda, Md. 11/17/1993."None>Collins (1993)</a> developed FISH techniques to detect large deletions in the NF1 gene.</p><p>By denaturing gradient gel electrophoresis (DGGE), <a href="#102" class="mim-tip-reference" title="Valero, M. C., Velasco, E., Moreno, F., Hernandez-Chico, C. <strong>Characterization of four mutations in the neurofibromatosis type 1 gene by denaturing gradient gel electrophoresis (DGGE).</strong> Hum. Molec. Genet. 3: 639-641, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8069310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8069310</a>] [<a href="https://doi.org/10.1093/hmg/3.4.639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8069310">Valero et al. (1994)</a> screened 70 unrelated NF1 patients for mutations in exons 29 and 31. Of the 4 mutations that were identified, 3 consisted of C-to-T transitions resulting in nonsense mutations: 2 in exon 29 (5242C-T; <a href="#0004">613113.0004</a> and 5260C-T) and 1 in exon 31 (5839C-T). The fourth mutation consisted of a 2-bp deletion in exon 31, 5843delAA, resulting in a premature stop codon. The 5839C-T mutation had previously been reported in 3 independent studies, suggesting that this position is a mutation hotspot within the NF1 gene. It occurs in a CpG residue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8069310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#39" class="mim-tip-reference" title="Heim, R. A., Silverman, L. M., Farber, R. A., Kam-Morgan, L. N. W., Luce, M. C. <strong>Screening for truncated NF1 proteins. (Letter)</strong> Nature Genet. 8: 218-219, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874161</a>] [<a href="https://doi.org/10.1038/ng1194-218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874161">Heim et al. (1994)</a> stated that although mutations had been sought in several hundred NF1 patients, by August 1994, only 70 germline mutations had been reported in a total of 78 individuals; only the R1947X (<a href="#0012">613113.0012</a>) mutation had been seen in as many as 6 unrelated patients. NF1 mutations that had been identified included 14 large (more than 25 bp) deletions, 3 large insertions, 18 small (less than 25 bp) deletions, 8 small insertions, 6 nonsense mutations, 14 missense mutations, and 7 intronic mutations. At least 56 (80%) of the 70 mutations potentially encode a truncated protein because of premature translation termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#1" class="mim-tip-reference" title="Abernathy, C. R., Rasmussen, S. A., Stalker, H. J., Zori, R., Driscoll, D. J., Williams, C. A., Kousseff, B. G., Wallace, M. R. <strong>NF1 mutation analysis using a combined heteroduplex/SSCP approach.</strong> Hum. Mutat. 9: 548-554, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9195229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9195229</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:6<548::AID-HUMU8>3.0.CO;2-Y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9195229">Abernathy et al. (1997)</a> stated that about half of NF1 cases represent new mutations and fewer than 100 constitutional mutations had been reported. They used a combined heteroduplex/SSCP approach to search for mutations in the NF1 gene in a set of 67 unrelated NF1 patients and identified 26 mutations and/or variants in 45 of the 59 exons tested. Disease-causing mutations were found in 19% (13 of 67) of cases studied. The mutations included splice mutations, insertions, deletions, and point changes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9195229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Maynard, J., Krawczak, M., Upadhyaya, M. <strong>Characterization and significance of nine novel mutations in exon 16 of the neurofibromatosis type 1 (NF1) gene.</strong> Hum. Genet. 99: 674-676, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150739</a>] [<a href="https://doi.org/10.1007/s004390050427" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9150739">Maynard et al. (1997)</a> screened exon 16 of the NF1 gene in 465 unrelated NF1 patients. Nine novel mutations were identified: 3 nonsense, 2 single-base deletions, 1 7-bp duplication, 2 missense, and 1 recurrent splice site mutation. No mutations had been reported previously in exon 16, which is the largest exon (441 bp) of NF1. The previous absence of mutation identification in exon 16 suggested to the authors that codons in this region may have a lower propensity to mutate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Stop, or nonsense, mutations can have a number of effects. In the case of several genes, they affect mRNA metabolism and reduce the amount of detectable mRNA. Also, in the NF1 gene, a correlation between a high proportion of stop mutations and unequal expression of the 2 alleles is demonstrable. A second, less common outcome is that mRNA containing a nonsense mutation is translated and results in a truncated protein. A third possible outcome is an abnormally spliced mRNA induced by a premature-termination codon (PTC) in the skipped exon. This was demonstrated in several disease genes, including the CFTR gene (<a href="#43" class="mim-tip-reference" title="Hull, J., Shackleton, S., Harris, A. <strong>The stop mutation R553X in the CFTR gene results in exon skipping.</strong> Genomics 19: 362-364, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7514569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7514569</a>] [<a href="https://doi.org/10.1006/geno.1994.1070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7514569">Hull et al., 1994</a>) and the fibrillin gene (<a href="#26" class="mim-tip-reference" title="Dietz, H. C., Valle, D., Francomano, C. A., Kendzior, R. J., Jr., Pyeritz, R. E., Cutting, G. R. <strong>The skipping of constitutive exons in vivo induced by nonsense mutations.</strong> Science 259: 680-683, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8430317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8430317</a>] [<a href="https://doi.org/10.1126/science.8430317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8430317">Dietz et al., 1993</a>). <a href="#41" class="mim-tip-reference" title="Hoffmeyer, S., Nurnberg, P., Ritter, H., Fahsold, R., Leistner, W., Kaufmann, D., Krone, W. <strong>Nearby stop codons in exons of the neurofibromatos is type 1 gene are disparate splice effectors.</strong> Am. J. Hum. Genet. 62: 269-277, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9463322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9463322</a>] [<a href="https://doi.org/10.1086/301715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9463322">Hoffmeyer et al. (1998)</a> characterized several stop mutations localized within a few basepairs in exons 7 and 37 of the NF1 gene and noticed complete skipping of either exon in some cases. Because skipping of exons 7 and 37 does not lead to a frameshift, premature termination codons are avoided. <a href="#41" class="mim-tip-reference" title="Hoffmeyer, S., Nurnberg, P., Ritter, H., Fahsold, R., Leistner, W., Kaufmann, D., Krone, W. <strong>Nearby stop codons in exons of the neurofibromatos is type 1 gene are disparate splice effectors.</strong> Am. J. Hum. Genet. 62: 269-277, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9463322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9463322</a>] [<a href="https://doi.org/10.1086/301715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9463322">Hoffmeyer et al. (1998)</a> found that some other stop mutations in the same general region did not lead to a skip. Calculations of minimum-free-energy structures of the respective regions suggested that both changes in the secondary structure of mRNA and creation or disruption of exonic sequences relevant for the splicing process may in fact cause these different splice phenomena observed in the NF1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7514569+8430317+9463322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Mutation analysis in NF1 has been hampered by the large size of the gene (350 kb with 60 exons), the high rate of new mutations, lack of mutational clustering, and the presence of numerous homologous loci. Mutation detection methods based on the direct analysis of the RNA transcript of the gene permit the rapid screening of large multiexonic genes. However, detection of frameshift or nonsense mutations can be limited by instability of the mutant mRNA species due to nonsense-mediated decay. To determine the frequency of this allelic exclusion, <a href="#73" class="mim-tip-reference" title="Osborn, M. J., Upadhyaya, M. <strong>Evaluation of the protein truncation test and mutation detection in the NF1 gene: mutational analysis of 15 known and 40 unknown mutations.</strong> Hum. Genet. 105: 327-332, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10543400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10543400</a>] [<a href="https://doi.org/10.1007/s004399900135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10543400">Osborn and Upadhyaya (1999)</a> analyzed total lymphocyte RNA from 15 NF1 patients with known truncation mutations and a panel of 40 NF1 patients with unknown mutations. The level of expression of the mutant message was greatly reduced in 2 of the 15 samples (13%), and in 3 of the 18 informative samples from the panel of 40. A coupled RT-PCR and protein truncation test method was subsequently applied to screen RNA from the panel of 40 unrelated NF1 patients. Aberrant polypeptide bands were identified and characterized in 21 samples (53%); each of these had a different mutation. The mutations were uniformly distributed across the gene, and 14 represented novel changes, providing further information on the germline mutational spectrum of the NF1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10543400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 mutation rate in the NF1 gene is one of the highest known in humans, with approximately 50% of all NF1 patients presenting with novel mutations (review by <a href="#45" class="mim-tip-reference" title="Huson, S. M., Hughes, R. A. C. <strong>The Neurofibromatoses: a Pathogenetic and Clinical Overview.</strong> London: Chapman & Hall Medical (pub.) 1994."None>Huson and Hughes, 1994</a>). Despite the high frequency of this disorder in all populations, relatively few mutations had been identified at the molecular level, with most unique to 1 family. A limited number of mutation 'hotspots' had been identified: R1947X in exon 31 (<a href="#0012">613113.0012</a>), and the 4-bp region between nucleotides 6789 and 6792 in exon 37, both implicated in about 2% of NF1 patients (review by <a href="#97" class="mim-tip-reference" title="Upadhyaya, M., Cooper, D. N. (eds.). <strong>Neurofibromatosis Type 1: from Genotype to Phenotype.</strong> Oxford: BIOS Scientific Publ. (pub.) 1998."None>Upadhyaya and Cooper (1998)</a>). <a href="#67" class="mim-tip-reference" title="Messiaen, L. M., Callens, T., Roux, K. J., Mortier, G. R., De Paepe, A., Abramowicz, M., Pericak-Vance, M. A., Vance, J. M., Wallace, M. R. <strong>Exon 10b of the NF1 gene represents a mutational hotspot and harbors a recurrent missense mutation Y489C associated with aberrant splicing.</strong> Genet. Med. 1: 248-253, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11258625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11258625</a>] [<a href="https://doi.org/10.1097/00125817-199909000-00002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11258625">Messiaen et al. (1999)</a> identified another mutation hotspot in exon 10b. By analyzing 232 unrelated NF1 patients, they identified 9 mutations in exon 10b, indicating that this exon is mutated in almost 4% of NF1 patients. Two mutations, Y489C (<a href="#0023">613113.0023</a>) and L508P (<a href="#0024">613113.0024</a>), were recurrent, whereas the others were unique. The authors suggested that since 10b shows the highest mutation rate of any of the 60 NF1 exons, it should be given priority in mutation analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11258625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Fahsold, R., Hoffmeyer, S., Mischung, C., Gille, C., Ehlers, C., Kucukceylan, N., Abdel-Nour, M., Gewies, A., Peters, H., Kaufmann, D., Buske, A., Tinschert, S., Nurnberg, P. <strong>Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain.</strong> Am. J. Hum. Genet. 66: 790-818, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10712197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10712197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10712197[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/10.1086/302809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10712197">Fahsold et al. (2000)</a> performed a mutation screen of the NF1 gene in more than 500 unrelated patients with NF1. For each patient, the whole coding sequence and all splice sites were studied for aberrations, either by the protein truncation test (PTT), temperature-gradient gel electrophoresis (TGGE) of genomic PCR products, or, most often, by direct genomic sequencing of all individual exons. Of the variants found, they concluded that 161 different ones were novel. Mutation-detection efficiencies of the various screening methods were similar: 47.1% for PTT, 53.7% for TGGE, and 54.9% for direct sequencing. Of all sequence variants found, less than 20% represented C-to-T or G-to-A transitions within a CpG dinucleotide, and only 6 different mutations also occurred in NF1 pseudogenes, with 5 being typical C-to-T transitions in a CpG. Thus, neither frequent deamination of 5-methylcytosines nor interchromosomal gene conversion can account for the high mutation rate of the NF1 gene. As opposed to the truncating mutations, the 28 (10.1%) missense or single-amino-acid-deletion mutations identified clustered in 2 distinct regions, the GAP-related domain and an upstream gene segment comprising exons 11 to 17. The latter forms a so-called cysteine/serine-rich domain with 3 cysteine pairs suggestive of ATP binding, as well as 3 potential cAMP-dependent protein kinase recognition sites obviously phosphorylated by PKA. Coincidence of mutated amino acids and those conserved between human and Drosophila strongly suggested significant functional relevance of this region, with major roles played by exons 12a and 15 and part of exon 16. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10712197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Ars, E., Serra, E., Garcia, J., Kruyer, H., Gaona, A., Lazaro, C., Estivill, X. <strong>Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1.</strong> Hum. Molec. Genet. 9: 237-247, 2000. Note: Erratum: Hum. Molec. Genet. 9: 659 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10607834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10607834</a>] [<a href="https://doi.org/10.1093/hmg/9.2.237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10607834">Ars et al. (2000)</a> applied a whole NF1 cDNA screening methodology to the study of 80 unrelated NF1 patients and identified 44 different mutations, 32 being novel, in 52 of the patients. Mutations were detected in 87% of the familial cases and in 51% of the sporadic ones. At least 15 of the 80 NF1 patients (19%) had recurrence of a previously observed mutation. The study showed that in 50% of the patients in whom the mutations were identified, these resulted in splicing alterations. Most of the splicing mutations did not involve the conserved AG/GT dinucleotides of the donor and acceptor splice sites. One frameshift, 2 nonsense, and 2 missense mutations were also responsible for alterations in mRNA splicing. Location and type of mutation within the NF1 gene and its putative effect at the protein level did not indicate any relationship to any specific clinical feature of NF1. The high proportion of aberrant spliced transcripts detected in NF1 patients stressed the importance of studying mutations at both the genomic and RNA level. <a href="#7" class="mim-tip-reference" title="Ars, E., Serra, E., Garcia, J., Kruyer, H., Gaona, A., Lazaro, C., Estivill, X. <strong>Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1.</strong> Hum. Molec. Genet. 9: 237-247, 2000. Note: Erratum: Hum. Molec. Genet. 9: 659 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10607834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10607834</a>] [<a href="https://doi.org/10.1093/hmg/9.2.237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10607834">Ars et al. (2000)</a> raised the possibility that part of the clinical variability in NF1 is related to mutations affecting mRNA splicing, which is the most common molecular defect in NF1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10607834" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#66" class="mim-tip-reference" title="Messiaen, L. M., Callens, T., Mortier, G., Beysen, D., Vandenbroucke, I., Van Roy, N., Speleman, F., De Paepe, A. <strong>Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.</strong> Hum. Mutat. 15: 541-555, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10862084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10862084</a>] [<a href="https://doi.org/10.1002/1098-1004(200006)15:6<541::AID-HUMU6>3.0.CO;2-N" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10862084">Messiaen et al. (2000)</a> studied 67 unrelated NF1 patients fulfilling the NIH diagnostic criteria (<a href="#91" class="mim-tip-reference" title="Stumpf, D. A., Alksne, J. F., Annegers, J. F., Brown, S. S., Conneally, P. M., Housman, D., Leppert, M. F., Miller, J. P., Moss, M. L., Pileggi, A. J., Rapin, I., Strohman, R. C., Swanson, L. W., Zimmerman, A. <strong>Neurofibromatosis: conference statement.</strong> Arch. Neurol. 45: 575-578, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3128965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3128965</a>]" pmid="3128965">Stumpf et al., 1988</a>; <a href="#35" class="mim-tip-reference" title="Gutmann, D., Aylsworth, A., Carley, J., Korf, B., Marks, J., Pyeritz, R., Rubenstein, A., et al. <strong>The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2.</strong> JAMA 278: 51-57, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9207339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9207339</a>]" pmid="9207339">Gutmann et al., 1997</a>), 29 familial and 38 sporadic cases, using a cascade of complementary techniques. They performed a protein truncation test starting from puromycin-treated EBV cell lines and, if no mutation was found, continued with heteroduplex, FISH, Southern blot, and cytogenetic analysis. The authors identified the germline mutation in 64 of 67 patients, and 32 of the mutations were novel. The mutation spectrum consisted of 25 nonsense, 12 frameshift, 19 splice mutations, 6 missense and/or small in-frame deletions, 1 deletion of the entire NF1 gene, and a translocation t(14;17)(q32;q11.2). Their data suggested that exons 10a-10c and 37 are mutation-rich regions and that together with some recurrent mutations they may account for almost 30% of the mutations in classic NF1 patients. <a href="#66" class="mim-tip-reference" title="Messiaen, L. M., Callens, T., Mortier, G., Beysen, D., Vandenbroucke, I., Van Roy, N., Speleman, F., De Paepe, A. <strong>Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.</strong> Hum. Mutat. 15: 541-555, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10862084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10862084</a>] [<a href="https://doi.org/10.1002/1098-1004(200006)15:6<541::AID-HUMU6>3.0.CO;2-N" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10862084">Messiaen et al. (2000)</a> found a high frequency of unusual splice mutations outside of the AG/GT 5-prime and 3-prime splice sites. As some of these mutations formed stable transcripts, it remained possible that a truncated neurofibromin was formed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10862084+9207339+3128965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#87" class="mim-tip-reference" title="Skuse, G. R., Cappione, A. J. <strong>RNA processing and clinical variability in neurofibromatosis type 1 (NF1).</strong> Hum. Molec. Genet. 6: 1707-1712, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9300663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9300663</a>] [<a href="https://doi.org/10.1093/hmg/6.10.1707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9300663">Skuse and Cappione (1997)</a> reviewed the possible molecular basis of the wide clinical variability in NF1 observed even among affected members of the same family (<a href="#44" class="mim-tip-reference" title="Huson, S. M., Compston, D. A. S., Clark, P., Harper, P. S. <strong>A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity.</strong> J. Med. Genet. 26: 704-711, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2511318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2511318</a>] [<a href="https://doi.org/10.1136/jmg.26.11.704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2511318">Huson et al., 1989</a>). The complexities of alternative splicing and RNA editing may be involved. <a href="#87" class="mim-tip-reference" title="Skuse, G. R., Cappione, A. J. <strong>RNA processing and clinical variability in neurofibromatosis type 1 (NF1).</strong> Hum. Molec. Genet. 6: 1707-1712, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9300663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9300663</a>] [<a href="https://doi.org/10.1093/hmg/6.10.1707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9300663">Skuse and Cappione (1997)</a> suggested that the classical 2-hit model for tumor suppressor inactivation used to explain NF1 tumorigenesis can be expanded to include post-transcriptional mechanisms that regulate NF1 gene expression. Aberrations in these mechanisms may play a role in the observed clinical variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9300663+2511318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Eisenbarth, I., Beyer, K., Krone, W., Assum, G. <strong>Toward a survey of somatic mutation of the NF1 gene in benign neurofibromas of patients with neurofibromatosis type 1.</strong> Am. J. Hum. Genet. 66: 393-401, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677298</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677298[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/10.1086/302747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677298">Eisenbarth et al. (2000)</a> described a systematic approach of searching for somatic inactivation of the NF1 gene in neurofibromas. In the course of these studies, they identified 2 novel intragenic polymorphisms: a tetranucleotide repeat and a 21-bp duplication. Among 7 neurofibromas from 4 different NF1 patients, they detected 3 tumor-specific point mutations and 2 LOH events. The results suggested that small subtle mutations occur with similar frequency to that of LOH in benign neurofibromas and that somatic inactivation of the NF1 gene is a general event in these tumors. <a href="#27" class="mim-tip-reference" title="Eisenbarth, I., Beyer, K., Krone, W., Assum, G. <strong>Toward a survey of somatic mutation of the NF1 gene in benign neurofibromas of patients with neurofibromatosis type 1.</strong> Am. J. Hum. Genet. 66: 393-401, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677298</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677298[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/10.1086/302747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677298">Eisenbarth et al. (2000)</a> concluded that the spectrum of somatic mutations occurring in various tumors from individual NF1 patients may contribute to the understanding of variable expressivity of the NF1 phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10677298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#50" class="mim-tip-reference" title="Klose, A., Ahmadian, M. R., Schuelke, M., Scheffzek, K., Hoffmeyer, S., Gewies, A., Schmitz, F., Kaufmann, D., Peters, H., Wittinghofer, A., Nurnberg, P. <strong>Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1 (NF1).</strong> Hum. Molec. Genet. 7: 1261-1268, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668168</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668168">Klose et al. (1998)</a> identified a novel missense mutation in the NF1 gene (R1276P; <a href="#0022">613113.0022</a>) in a patient with a classic multisymptomatic NF1 phenotype, including a malignant schwannoma. The mutation specifically abolished the Ras-GTPase-activating function of neurofibromin. The authors suggested that therapeutic approaches aimed at the reduction of the Ras-GTP levels in neural crest-derived cells may relieve NF1 symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#51" class="mim-tip-reference" title="Kluwe, L., Friedrich, R. E., Mautner, V. F. <strong>Allelic loss of the NF1 gene in NF1-associated plexiform neurofibromas.</strong> Cancer Genet. Cytogenet. 113: 65-69, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10459349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10459349</a>] [<a href="https://doi.org/10.1016/s0165-4608(99)00006-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10459349">Kluwe et al. (1999)</a> stated that plexiform neurofibroma can be found in about 30% of NF1 patients, often causing severe clinical symptoms. They examined 14 such tumors from 10 NF1 patients for loss of heterozygosity at the NF1 gene using 4 intragenic polymorphic markers. LOH was found in 8 tumors from 5 patients, and was suspected in 1 additional tumor from another patient. They interpreted these findings as suggesting that loss of the second allele, and thus inactivation of both alleles of the NF1 gene, is associated with the development of plexiform neurofibromas. The 14 plexiform neurofibromas were also examined for mutation in the TP53 gene; no mutations were found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10459349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#31" class="mim-tip-reference" title="Faravelli, F., Upadhyaya, M., Osborn, M., Huson, S. M., Hayward, R., Winter, R. <strong>Unusual clustering of brain tumours in a family with NF1 and variable expression of cutaneous features.</strong> J. Med. Genet. 36: 893-896, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10593996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10593996</a>]" pmid="10593996">Faravelli et al. (1999)</a> reported a family in which 7 members developed brain tumors which in 4 were confirmed as gliomas. Three of these individuals had a clinical history strongly suggestive of NF1. Two individuals with very mild features of NF1 insufficient to meet diagnostic criteria carried a splice site mutation in intron 29 of the NF1 gene, creating a frameshift and premature protein termination. <a href="#31" class="mim-tip-reference" title="Faravelli, F., Upadhyaya, M., Osborn, M., Huson, S. M., Hayward, R., Winter, R. <strong>Unusual clustering of brain tumours in a family with NF1 and variable expression of cutaneous features.</strong> J. Med. Genet. 36: 893-896, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10593996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10593996</a>]" pmid="10593996">Faravelli et al. (1999)</a> noted the unusually high incidence of brain tumors in this family with the NF1 phenotype and suggested that some cases of familial glioma may be explained by mutations in the NF1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10593996" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kluwe, L., Tatagiba, M., Funsterer, C., Mautner, V.-F. <strong>NF1 mutations and clinical spectrum in patients with spinal neurofibromas.</strong> J. Med. Genet. 40: 368-371, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12746402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12746402</a>] [<a href="https://doi.org/10.1136/jmg.40.5.368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12746402">Kluwe et al. (2003)</a> examined 20 patients with spinal tumors from 17 families for clinical symptoms associated with NF1 and for NF1 mutations. Typical NF1 features were found in 12 patients from 11 families. Typical NF1 mutations were found in 10 of the 11 index patients in this group, including 8 truncating mutations, 1 missense mutation, and 1 deletion of the entire NF1 gene. Eight patients from 6 families had no or only a few additional NF1-associated symptoms besides multiple spinal tumors, which were distributed symmetrically in all cases and affected all 38 nerve roots in 6 patients. Only mild NF1 mutations were found in 4 of the 6 index patients in the latter group, including 1 splicing mutation, 2 missense mutations, and 1 nonsense mutation in exon 47 at the 3-prime end of the gene. The data indicated that patients with spinal tumors can have various NF1 symptoms and NF1 mutations; however, patients with no or only a few additional NF1 symptoms may be a subgroup or may have a distinct form of NF1, probably associated with milder NF1 mutations or other genetic alterations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12746402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 underestimates of NF1 gene mutations in neurofibromatosis type I have been attributed to the large size of the NF1 gene, the considerable frequency of gross deletions, and the common occurrence of splicing defects that are only detectable by cDNA analysis. A number of splicing errors do not affect the canonical GT splice donor or AG splice acceptor, or create novel splice sites, but may exert their effect by means of an altered interaction between an exonic splice enhancer (ESE) and mRNA splicing factors (<a href="#66" class="mim-tip-reference" title="Messiaen, L. M., Callens, T., Mortier, G., Beysen, D., Vandenbroucke, I., Van Roy, N., Speleman, F., De Paepe, A. <strong>Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.</strong> Hum. Mutat. 15: 541-555, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10862084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10862084</a>] [<a href="https://doi.org/10.1002/1098-1004(200006)15:6<541::AID-HUMU6>3.0.CO;2-N" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10862084">Messiaen et al., 2000</a>; <a href="#60" class="mim-tip-reference" title="Liu, H.-X., Cartegni, L., Zhang, M. Q., Krainer, A. R. <strong>A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes.</strong> Nature Genet. 27: 55-58, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137998</a>] [<a href="https://doi.org/10.1038/83762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137998">Liu et al., 2001</a>). <a href="#19" class="mim-tip-reference" title="Colapietro, P., Gervasini, C., Natacci, F., Rossi, L., Riva, P., Larizza, L. <strong>NF1 exon 7 skipping and sequence alterations in exonic splice enhancers (ESEs) in a neurofibromatosis 1 patient.</strong> Hum. Genet. 113: 551-554, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13680360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13680360</a>] [<a href="https://doi.org/10.1007/s00439-003-1009-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13680360">Colapietro et al. (2003)</a> reported skipping of exon 7 and sequence alterations in ESEs in a patient with severe NF1 (<a href="#0036">613113.0036</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10862084+11137998+13680360" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 analysis of somatic NF1 gene mutations in neurofibromas from NF1 patients shows that each neurofibroma results from an individual second hit mutation; thus, factors that influence somatic mutation rates may be regarded as potential modifiers of NF1. <a href="#109" class="mim-tip-reference" title="Wiest, V., Eisenbarth, I., Schmegner, C., Krone, W., Assum, G. <strong>Somatic NF1 mutation spectra in a family with neurofibromatosis type 1: toward a theory of genetic modifiers.</strong> Hum. Mutat. 22: 423-427, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14635100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14635100</a>] [<a href="https://doi.org/10.1002/humu.10272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14635100">Wiest et al. (2003)</a> performed a mutation screen of numerous neurofibromas from 2 NF1 patients and found a predominance of point mutations, small deletions, and insertions as second hit mutations in both patients. Seven novel mutations were reported. Together with the results of studies that showed LOH as the predominant second hit in neurofibromas of other patients, these results suggest that in different patients different factors may influence the somatic mutation rate and thereby the severity of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14635100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 can mutations in nucleotides at the ends of introns result in abnormalities of splicing, but nonsense, missense, and even translationally silent mutations have been shown to cause exon skipping. The analysis of individual mutations of this kind can shed light on basic pre-mRNA splicing mechanisms. Using cDNA-based mutation detection analysis, <a href="#113" class="mim-tip-reference" title="Zatkova, A., Messiaen, L., Vandenbroucke, I., Wieser, R., Fonatsch, C., Krainer, A. R., Wimmer, K. <strong>Disruption of exonic splicing enhancer elements is the principal cause of exon skipping associated with seven nonsense or missense alleles of NF1.</strong> Hum. Mutat. 24: 491-501, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523642</a>] [<a href="https://doi.org/10.1002/humu.20103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15523642">Zatkova et al. (2004)</a> identified 1 missense and 6 nonsense mutations (e.g., <a href="#0042">613113.0042</a>) that lead to different extents of exon-lacking transcripts in NF1 patients. They confirmed mutation-associated exon skipping in a heterologous hybrid minigene context. Because of evidence that the disruption of functional ESE sequences is frequently the mechanism underlying mutation-associated exon skipping, <a href="#113" class="mim-tip-reference" title="Zatkova, A., Messiaen, L., Vandenbroucke, I., Wieser, R., Fonatsch, C., Krainer, A. R., Wimmer, K. <strong>Disruption of exonic splicing enhancer elements is the principal cause of exon skipping associated with seven nonsense or missense alleles of NF1.</strong> Hum. Mutat. 24: 491-501, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523642</a>] [<a href="https://doi.org/10.1002/humu.20103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15523642">Zatkova et al. (2004)</a> examined the wildtype and mutant NF1 sequences with 2 available ESE prediction programs. Either or both programs predicted the disruption of ESE motifs in 6 of the 7 analyzed mutations. To ascertain the function of the predicted ESEs, <a href="#113" class="mim-tip-reference" title="Zatkova, A., Messiaen, L., Vandenbroucke, I., Wieser, R., Fonatsch, C., Krainer, A. R., Wimmer, K. <strong>Disruption of exonic splicing enhancer elements is the principal cause of exon skipping associated with seven nonsense or missense alleles of NF1.</strong> Hum. Mutat. 24: 491-501, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523642</a>] [<a href="https://doi.org/10.1002/humu.20103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15523642">Zatkova et al. (2004)</a> quantitatively measured their ability to rescue splicing of an enhancer-dependent exon, and found that all 7 mutant ESEs had reduced splicing enhancement activity compared to the wildtype sequences. The results suggested that the wildtype sequences function as ESE elements, whose disruption is responsible for the mutation-associated exon skipping observed in NF1 patients. Furthermore, this study illustrated the utility of ESE prediction programs for delineating candidate sequences that may serve as ESE elements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15523642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 girl with aniridia (<a href="/entry/106210">106210</a>), microphthalmia, microcephaly, and cafe-au-lait macules, <a href="#40" class="mim-tip-reference" title="Henderson, R. A., Williamson, K., Cumming, S., Clarke, M. P., Lynch, S. A., Hanson, I. M., FitzPatrick, D. R., Sisodiya, S., van Heyningen, V. <strong>Inherited PAX6, NF1 and OTX2 mutations in a child with microphthalmia and aniridia.</strong> Europ. J. Hum. Genet. 15: 898-901, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17406642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17406642</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17406642">Henderson et al. (2007)</a> identified heterozygous mutations in the PAX6 (R38W; <a href="/entry/607108#0026">607108.0026</a>), NF1 (R192X; <a href="#0046">613113.0046</a>), and OTX2 (Y179X; <a href="/entry/600037#0004">600037.0004</a>) genes. Her mother, who carried the NF1 and PAX6 mutations, had NF1 with typical eye defects; in addition, although her eyes were of normal size, she had small corneas, and also had cataracts, optic nerve hypoplasia, nystagmus, and mild iris stromal hypoplasia with normal-sized pupils. The proband's father, who had multiple ocular defects (MCOPS5; <a href="/entry/610125">610125</a>), had previously been studied by <a href="#79" class="mim-tip-reference" title="Ragge, N. K., Brown, A. G., Poloschek, C. M., Lorenz, B., Henderson, R. A., Clarke, M. P., Russell-Eggitt, I., Fielder, A., Gerrelli, D., Martinez-Barbera, J. P., Ruddle, P., Hurst, J., and 9 others. <strong>Heterozygous mutations of OTX2 cause severe ocular malformations.</strong> Am. J. Hum. Genet. 76: 1008-1022, 2005. Note: Erratum: Am. J. Hum. Genet. 77: 334 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15846561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15846561</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15846561[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/10.1086/430721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15846561">Ragge et al. (2005)</a> and was heterozygous for the OTX2 nonsense mutation. <a href="#40" class="mim-tip-reference" title="Henderson, R. A., Williamson, K., Cumming, S., Clarke, M. P., Lynch, S. A., Hanson, I. M., FitzPatrick, D. R., Sisodiya, S., van Heyningen, V. <strong>Inherited PAX6, NF1 and OTX2 mutations in a child with microphthalmia and aniridia.</strong> Europ. J. Hum. Genet. 15: 898-901, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17406642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17406642</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17406642">Henderson et al. (2007)</a> noted that the proband's phenotype was surprisingly mild, given that mutations in PAX6, OTX2, or NF1 can cause a variety of severe developmental defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15846561+17406642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#82" class="mim-tip-reference" title="Sabbagh, A., Pasmant, E., Laurendeau, I., Parfait, B., Barbarot, S., Guillot, B., Combemale, P., Ferkal, S., Vidaud, M., Aubourg, P., Vidaud, D., Wolkenstein, P., NF France Network. <strong>Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1.</strong> Hum. Molec. Genet. 18: 2768-2778, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19417008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19417008</a>] [<a href="https://doi.org/10.1093/hmg/ddp212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19417008">Sabbagh et al. (2009)</a> examined the phenotypic correlations between affected relatives in 750 NF1 patients from 275 multiplex families collected through the NF-France Network. Twelve NF1-related clinical features, including 5 quantitative traits (number of cafe-au-lait spots of small size and of large size, and number of cutaneous, subcutaneous, and plexiform neurofibromas) and 7 binary ones, were scored. All clinical features studied, with the exception of neoplasms, showed significant familial aggregation after adjusting for age and sex. For most of them, patterns of familial correlations indicated a strong genetic component with no apparent influence of the constitutional NF1 mutation. Heritability estimates of the 5 quantitative traits ranged from 0.26 to 0.62. Nine tag SNPs in NF1 were genotyped in 1,132 individuals from 313 NF1 families. No significant deviations of transmission of any of the NF1 variants to affected offspring was found for any of the 12 clinical features examined, based on single marker or haplotype analysis. <a href="#82" class="mim-tip-reference" title="Sabbagh, A., Pasmant, E., Laurendeau, I., Parfait, B., Barbarot, S., Guillot, B., Combemale, P., Ferkal, S., Vidaud, M., Aubourg, P., Vidaud, D., Wolkenstein, P., NF France Network. <strong>Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1.</strong> Hum. Molec. Genet. 18: 2768-2778, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19417008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19417008</a>] [<a href="https://doi.org/10.1093/hmg/ddp212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19417008">Sabbagh et al. (2009)</a> concluded that genetic modifiers, unlinked to the NF1 locus, contribute to the variable expressivity of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19417008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Juvenile Myelomonocytic Leukemia</em></strong></p><p>
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Juvenile myelomonocytic leukemia (JMML; <a href="/entry/607785">607785</a>) is a pediatric myelodysplastic syndrome that is associated with neurofibromatosis type I. The NF1 gene regulates the growth of immature myeloid cells by accelerating guanosine triphosphate hydrolysis on RAS proteins. <a href="#83" class="mim-tip-reference" title="Side, L. E., Emanuel, P. D., Taylor, B., Franklin, J., Thompson, P., Castleberry, R. P., Shannon, K. M. <strong>Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1.</strong> Blood 92: 267-272, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9639526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9639526</a>]" pmid="9639526">Side et al. (1998)</a> undertook a study to determine if the NF1 gene is involved in the pathogenesis of JMML in children without a clinical diagnosis of NF1. An in vitro transcription and translation system was used to screen JMML marrows from 20 children for NF1 mutations that resulted in a truncated protein. SSCP analysis was used to detect RAS point mutations in these samples. <a href="#83" class="mim-tip-reference" title="Side, L. E., Emanuel, P. D., Taylor, B., Franklin, J., Thompson, P., Castleberry, R. P., Shannon, K. M. <strong>Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1.</strong> Blood 92: 267-272, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9639526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9639526</a>]" pmid="9639526">Side et al. (1998)</a> confirmed mutations of NF1 in 3 cases of JMML, 1 of which also showed loss of the normal NF1 allele. An NF1 mutation was detected in normal tissue from the only patient tested, suggesting that JMML may be the presenting feature of NF1 in some children. Activating RAS mutations were found in 4 patients; as expected, none of these samples harbored NF1 mutations. Because 10 to 14% of children with JMML had a clinical diagnosis of NF1, these data were consistent with the existence of NF1 mutations in approximately 30% of JMML cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9639526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 risk of malignant myeloid disorders in young children with NF1 is 200 to 500 times the normal risk. Neurofibromin, the protein encoded by the NF1 gene, negatively regulates signals transduced by Ras proteins. Genetic and biochemical data support the hypothesis that NF1 functions as a tumor-suppressor gene in immature myeloid cells. This hypothesis was further supported by the demonstration by <a href="#84" class="mim-tip-reference" title="Side, L., Taylor, B., Cayouette, M., Conner, E., Thompson, P., Luce, M., Shannon, K. <strong>Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders.</strong> New Eng. J. Med. 336: 1713-1720, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9180088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9180088</a>] [<a href="https://doi.org/10.1056/NEJM199706123362404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9180088">Side et al. (1997)</a> that both NF1 alleles were inactivated in bone marrow cells from children with NF1 complicated by malignant myeloid disorders. Using an in vitro transcription and translation system, they screened bone marrow samples from 18 such children for NF1 mutations that cause a truncated protein. Mutations were confirmed by direct sequencing of genomic DNA from the patients, and from the affected parents in cases of familial NF1. <a href="#84" class="mim-tip-reference" title="Side, L., Taylor, B., Cayouette, M., Conner, E., Thompson, P., Luce, M., Shannon, K. <strong>Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders.</strong> New Eng. J. Med. 336: 1713-1720, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9180088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9180088</a>] [<a href="https://doi.org/10.1056/NEJM199706123362404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9180088">Side et al. (1997)</a> found that the normal NF1 allele was absent in bone marrow samples from 5 of 8 children who had truncating mutations of the NF1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9180088" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Neurofibromatosis-Noonan Syndrome</em></strong></p><p>
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The overlap syndrome neurofibromatosis-Noonan syndrome (<a href="/entry/601321">601321</a>) shows features of both disorders, as was first noted by <a href="#4" class="mim-tip-reference" title="Allanson, J. E., Hall, J. G., Van Allen, M. I. <strong>Noonan phenotype associated with neurofibromatosis.</strong> Am. J. Med. Genet. 21: 457-462, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2411134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2411134</a>] [<a href="https://doi.org/10.1002/ajmg.1320210307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2411134">Allanson et al. (1985)</a>. <a href="#20" class="mim-tip-reference" title="Colley, A., Donnai, D., Evans, D. G. R. <strong>Neurofibromatosis/Noonan phenotype: a variable feature of type 1 neurofibromatosis.</strong> Clin. Genet. 49: 59-64, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8740913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8740913</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1996.tb04328.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8740913">Colley et al. (1996)</a> examined 94 sequentially identified patients with NF1 from their genetic register and found Noonan features in 12. <a href="#15" class="mim-tip-reference" title="Carey, J. C., Stevenson, D. A., Ota, M., Neil, S., Viskochil, D. H. <strong>Is there an NF/Noonan syndrome: Part 2: documentation of the clinical and molecular aspects of an important family.</strong> Proc. Greenwood Genet. Center 17: 152-153, 1997."None>Carey et al. (1997)</a> identified a 3-bp deletion of exon 17 of the NF1 gene in a family with NFNS (<a href="#0033">613113.0033</a>). <a href="#90" class="mim-tip-reference" title="Stevenson, D. A., Viskochil, D. H., Rope, A. F., Carey, J. C. <strong>Clinical and molecular aspects of an informative family with neurofibromatosis type 1 and Noonan phenotype.</strong> Clin. Genet. 69: 246-253, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16542390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16542390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16542390[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/10.1111/j.1399-0004.2006.00576.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16542390">Stevenson et al. (2006)</a> provided a follow-up of this family. <a href="#8" class="mim-tip-reference" title="Baralle, D., Mattocks, C., Kalidas, K., Elmslie, F., Whittaker, J., Lees, M., Ragge, N., Patton, M. A., Winter, R. M., ffrench-Constant, C. <strong>Different mutations in the NF1 gene are associated with neurofibromatosis-Noonan syndrome (NFNS).</strong> Am. J. Med. Genet. 119A: 1-8, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707950</a>] [<a href="https://doi.org/10.1002/ajmg.a.20023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707950">Baralle et al. (2003)</a> identified mutations in the NF1 gene in 2 patients with the overlap syndrome (<a href="#0034">613113.0034</a> and <a href="#0035">613113.0035</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8740913+16542390+12707950+2411134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#11" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., Passetti, F., de Oliveira, P. S. L., Messiaen, L., Gelb, B. D., Kim, C. A., Krieger, J. E. <strong>Neurofibromatosis -Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient.</strong> Am. J. Med. Genet. 136A: 242-245, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15948193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15948193</a>] [<a href="https://doi.org/10.1002/ajmg.a.30813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15948193">Bertola et al. (2005)</a> provided molecular evidence of the concurrence of neurofibromatosis and Noonan syndrome in a patient with a de novo missense mutation in the NF1 gene (<a href="#0043">613113.0043</a>) and a mutation in the PTPN11 gene (<a href="/entry/176876#0023">176876.0023</a>) inherited from her father. The proposita was noted to have cafe-au-lait spots at birth. Valvar and infundibular pulmonary stenosis and aortic coarctation were diagnosed at 20 months of age and surgically corrected at 3 years of age. As illustrated, the patient had marked hypertelorism and proptosis as well as freckling and cafe-au-lait spots. Lisch nodules were present. At the age of 8 years, a pilocytic astrocytoma in the suprasellar region involving the optic chiasm (first presenting symptomatically at 2 years of age), was partially resected. The father, who was diagnosed with Noonan syndrome, had downslanting palpebral fissures and prominent nasal labial folds. He was of short stature (159 cm) and had pectus excavatum. Electrocardiogram showed left-anterior hemiblock and complete right bundle branch block. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15948193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 study of 17 unrelated subjects with NFNS, <a href="#23" class="mim-tip-reference" title="De Luca, A., Bottillo, I., Sarkozy, A., Carta, C., Neri, C., Bellacchio, E., Schirinzi, A., Conti, E., Zampino, G., Battaglia, A., Majore, S., Rinaldi, M. M., Carella, M., Marino, B., Pizzuti, A., Digilio, M. C., Tartaglia, M., Dallapiccola, B. <strong>NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome.</strong> Am. J. Hum. Genet. 77: 1092-1101, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16380919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16380919</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16380919[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/10.1086/498454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16380919">De Luca et al. (2005)</a> found NF1 gene defects in 16. Remarkably, there was a high prevalence of in-frame defects affecting exons 24 and 25, which encode a portion of the GAP-related domain. No defect was observed in PTPN11 (<a href="/entry/176876">176876</a>), which is the usual site of mutations causing classic Noonan syndrome. <a href="#23" class="mim-tip-reference" title="De Luca, A., Bottillo, I., Sarkozy, A., Carta, C., Neri, C., Bellacchio, E., Schirinzi, A., Conti, E., Zampino, G., Battaglia, A., Majore, S., Rinaldi, M. M., Carella, M., Marino, B., Pizzuti, A., Digilio, M. C., Tartaglia, M., Dallapiccola, B. <strong>NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome.</strong> Am. J. Hum. Genet. 77: 1092-1101, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16380919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16380919</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16380919[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/10.1086/498454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16380919">De Luca et al. (2005)</a> stated that including their study, 18 distinct NF1 gene mutations had been described in 22 unrelated patients with NFNS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16380919" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Watson Syndrome</em></strong></p><p>
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Watson syndrome (<a href="/entry/193520">193520</a>) is an autosomal dominant disorder characterized by pulmonic stenosis, cafe-au-lait spots, decreased intellectual ability, and short stature. Most affected individuals have relative macrocephaly and Lisch nodules and about one-third of those affected have neurofibromas. Because of clinical similarities between Watson syndrome and neurofibromatosis, <a href="#5" class="mim-tip-reference" title="Allanson, J. E., Upadhyaya, M., Watson, G. H., Partington, M., MacKenzie, A., Lahey, D., MacLeod, H., Sarfarazi, M., Broadhead, W., Harper, P. S., Huson, S. M. <strong>Watson syndrome: is it a subtype of type 1 neurofibromatosis?</strong> J. Med. Genet. 28: 752-756, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1770531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1770531</a>] [<a href="https://doi.org/10.1136/jmg.28.11.752" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1770531">Allanson et al. (1991)</a> performed linkage studies in families with Watson syndrome, using probes known to flank the NF1 gene on chromosome 17, and found tight linkage. In a patient with Watson syndrome, <a href="#101" class="mim-tip-reference" title="Upadhyaya, M., Shen, M., Cherryson, A., Farnham, J., Maynard, J., Huson, S. M., Harper, P. S. <strong>Analysis of mutations at the neurofibromatosis 1 (NF1) locus.</strong> Hum. Molec. Genet. 1: 735-740, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302608</a>] [<a href="https://doi.org/10.1093/hmg/1.9.735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302608">Upadhyaya et al. (1992)</a> identified an 80-kb deletion in the NF1 gene (<a href="#0011">613113.0011</a>). <a href="#92" class="mim-tip-reference" title="Tassabehji, M., Strachan, T., Sharland, M., Colley, A., Donnai, D., Harris, R., Thakker, N. <strong>Tandem duplication within a neurofibromatosis type I (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome.</strong> Am. J. Hum. Genet. 53: 90-95, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8317503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8317503</a>]" pmid="8317503">Tassabehji et al. (1993)</a> demonstrated an almost perfect in-frame tandem duplication of 42 bases in exon 28 of the NF1 gene in 3 members of a family with Watson syndrome (<a href="#0010">613113.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1770531+1302608+8317503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Spinal Neurofibromatosis</em></strong></p><p>
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In all 5 affected members of 3-generation family with spinal neurofibromatosis (<a href="/entry/162210">162210</a>) and cafe-au-lait spots, <a href="#6" class="mim-tip-reference" title="Ars, E., Kruyer, H., Gaona, A., Casquero, P., Rosell, J., Volpini, V., Serra, E., Lazaro, C., Estivill, X. <strong>A clinical variant of neurofibromatosis type 1: familial spinal neurofibromatosis with a frameshift mutation in the NF1 gene.</strong> Am. J. Hum. Genet. 62: 834-841, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529361</a>] [<a href="https://doi.org/10.1086/301803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529361">Ars et al. (1998)</a> identified a frameshift mutation in the NF1 gene (<a href="#0018">613113.0018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9529361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 affected members of 2 families with spinal neurofibromas but no cafe-au-lait macules, <a href="#47" class="mim-tip-reference" title="Kaufmann, D., Muller, R., Bartelt, B., Wolf, M., Kunzi-Rapp, K., Hanemann, C. O., Fahsold, R., Hein, C., Vogel, W., Assum, G. <strong>Spinal neurofibromatosis without cafe-au-lait macules in two families with null mutations of the NF1 gene.</strong> Am. J. Hum. Genet. 69: 1395-1400, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704931</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11704931[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/10.1086/324648" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704931">Kaufmann et al. (2001)</a> identified 2 different mutations in the NF1 gene (<a href="#0028">613113.0028</a> and <a href="#0029">613113.0029</a>, respectively). Both NF1 mutations caused a reduction in neurofibromin of approximately 50%, with no truncated protein present in the cells. The findings demonstrated that typical NF1 null mutations can result in a phenotype that is distinct from classic NF1, showing only a small spectrum of the NF1 symptoms, such as multiple spinal tumors, but not completely fitting the current clinical criteria for spinal NF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704931" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Role in Cancer</em></strong></p><p>
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Desmoplastic neurotropic melanoma (DNM) is an uncommon melanoma subtype that shares morphologic characteristics with nerve sheath tumors. For that reason, <a href="#38" class="mim-tip-reference" title="Gutzmer, R., Herbst, R. A., Mommert, S., Kiehl, P., Matiaske, F., Rutten, A., Kapp, A., Weiss, J. <strong>Allelic loss at the neurofibromatosis type 1 (NF1) gene locus is frequent in desmoplastic neurotropic melanoma.</strong> Hum. Genet. 107: 357-361, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11129335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11129335</a>] [<a href="https://doi.org/10.1007/s004390000374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11129335">Gutzmer et al. (2000)</a> analyzed 15 DNMs and 20 melanomas without morphologic features of desmoplasia or neuroid differentiation (i.e., common melanomas) for LOH at the NF1 locus and flanking regions. Allelic loss was detected in 10 of 15 (67%) DNMs but in only 1 of 20 (5%) common melanomas. LOH was most frequently observed at marker IVS38, located in intron 38 of NF1. These data suggested a role for NF1 in the pathogenesis of DNM and supported the hypothesis that exon 37 may encode a functional domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11129335" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#13" class="mim-tip-reference" title="Cancer Genome Atlas Research Network. <strong>Comprehensive genomic characterization defines human glioblastoma genes and core pathways.</strong> Nature 455: 1061-1068, 2008. Note: Erratum: Nature 494: 506 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18772890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18772890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18772890[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/nature07385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18772890">Cancer Genome Atlas Research Network (2008)</a> reported the interim integrative analysis of DNA copy number, gene expression, and DNA methylation aberrations in 206 glioblastomas and nucleotide sequence alterations in 91 of the 206 glioblastomas. The RTK/RAS/PI3K signaling pathway was altered in 88% of glioblastomas. NF1 was found to be an important gene in glioblastoma, with mutation or homozygous deletion of the NF1 gene present in 18% of tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18772890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>See <a href="/entry/162200">162200</a> for a discussion of animal models of neurofibromatosis type I.</p><p><a href="#81" class="mim-tip-reference" title="Ruiz-Lozano, P., Chien, K. R. <strong>Cre-constructing the heart.</strong> Nature Genet. 33: 8-9, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12509773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12509773</a>] [<a href="https://doi.org/10.1038/ng0103-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12509773">Ruiz-Lozano and Chien (2003)</a> commented on how it is possible to apply Cre-loxP technology to track the cardiac morphogenic signals mediated by neurofibromin. A growing list of mouse lines that express Cre in specific cardiovascular cell lineages was available. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12509773" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Gene transcription may be regulated by remote enhancer or insulator regions through chromosome looping. Using a modification of chromosome conformation capture and fluorescence in situ hybridization, <a href="#59" class="mim-tip-reference" title="Ling, J. Q., Li, T., Hu, J. F., Vu, T. H., Chen, H. L., Qiu, X. W., Cherry, A. M., Hoffman, A. R. <strong>CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1.</strong> Science 312: 269-272, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16614224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16614224</a>] [<a href="https://doi.org/10.1126/science.1123191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16614224">Ling et al. (2006)</a> found that 1 allele of the Igf2 (<a href="/entry/147470">147470</a>)/H19 (<a href="/entry/103280">103280</a>) imprinting control region (ICR) on mouse chromosome 7 colocalized with 1 allele of Wsb1 (<a href="/entry/610091">610091</a>)/Nf1 on chromosome 17. Omission of CCCTC-binding factor (CTCF; <a href="/entry/604167">604167</a>) or deletion of the maternal ICR abrogated this association and altered Wsb1/Nf1 gene expression. <a href="#59" class="mim-tip-reference" title="Ling, J. Q., Li, T., Hu, J. F., Vu, T. H., Chen, H. L., Qiu, X. W., Cherry, A. M., Hoffman, A. R. <strong>CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1.</strong> Science 312: 269-272, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16614224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16614224</a>] [<a href="https://doi.org/10.1126/science.1123191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16614224">Ling et al. (2006)</a> concluded that CTCF mediates an interchromosomal association, perhaps by directing distant DNA segments to a common transcription factory, and the data provided a model for long-range allele-specific associations between gene regions on different chromosomes that suggested a framework for DNA recombination and RNA trans-splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16614224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 investigate the function of NF1 in skeletal development, <a href="#54" class="mim-tip-reference" title="Kolanczyk, M., Kossler, N., Kuhnisch, J., Lavitas, L., Stricker, S., Wilkening, U., Manjubala, I., Fratzl, P., Sporle, R., Herrmann, B. G., Parada, L. F., Kornak, U., Mundlos, S. <strong>Multiple roles for neurofibromin in skeletal development and growth.</strong> Hum. Molec. Genet. 16: 874-886, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17317783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17317783</a>] [<a href="https://doi.org/10.1093/hmg/ddm032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17317783">Kolanczyk et al. (2007)</a> created mice with Nf1 knockout directed to undifferentiated mesenchymal cells of developing limbs. Inactivation of Nf1 in limbs resulted in bowing of the tibia, diminished growth, abnormal vascularization of skeletal tissues, and fusion of the hip joints and other joint abnormalities. Tibial bowing was caused by decreased stability of the cortical bone due to a high degree of porosity, decreased stiffness, and reduction in the mineral content, as well as hyperosteoidosis. Accordingly, cultured osteoblasts showed increased proliferation and decreased ability to differentiate and mineralize. The reduced growth in Nf1-knockout mice was due to reduced proliferation and differentiation of chondrocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17317783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#61" class="mim-tip-reference" title="Lubeck, B. A., Lapinski, P. E., Oliver, J. A., Ksionda, O., Parada, L. F., Zhu, Y., Maillard, I., Chiang, M., Roose, J., King, P. D. <strong>Cutting edge: codeletion of the Ras GTPase-activating proteins (RasGAPs) neurofibromin 1 and p120 RasGAP in T cells results in the development of T cell acute lymphoblastic leukemia.</strong> J. Immun. 195: 31-35, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26002977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26002977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26002977[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/10.4049/jimmunol.1402639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26002977">Lubeck et al. (2015)</a> found that mice lacking both Nf1 and Rasa1 (<a href="/entry/139150">139150</a>) in T cells, but not those lacking either Nf1 or Rasa1 alone, developed T-cell acute lymphoblastic leukemia/lymphoma (see <a href="/entry/613065">613065</a>) that originated at an early point in T-cell development and was dependent on activating mutations in Notch1 (<a href="/entry/190198">190198</a>). <a href="#61" class="mim-tip-reference" title="Lubeck, B. A., Lapinski, P. E., Oliver, J. A., Ksionda, O., Parada, L. F., Zhu, Y., Maillard, I., Chiang, M., Roose, J., King, P. D. <strong>Cutting edge: codeletion of the Ras GTPase-activating proteins (RasGAPs) neurofibromin 1 and p120 RasGAP in T cells results in the development of T cell acute lymphoblastic leukemia.</strong> J. Immun. 195: 31-35, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26002977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26002977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26002977[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/10.4049/jimmunol.1402639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26002977">Lubeck et al. (2015)</a> concluded that RASA1 and NF1 are co-tumor suppressors in the T-cell lineage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26002977" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#33" class="mim-tip-reference" title="Gervasini, C., Bentivegna, A., Venturin, M., Corrado, L., Larizza, L., Riva, P. <strong>Tandem duplication of the NF1 gene detected by high-resolution FISH in the 17q11.2 region.</strong> Hum. Genet. 110: 314-321, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941479</a>] [<a href="https://doi.org/10.1007/s00439-002-0704-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11941479">Gervasini et al. (2002)</a> reported a direct tandem duplication of the NF1 gene identified in 17q11.2 by high-resolution FISH. FISH on stretched chromosomes with locus-specific probes revealed the duplication of the NF1 gene from the promoter to the 3-prime untranslated region (UTR), but with at least the absence of exon 22. Duplication was probably present in the human-chimpanzee-gorilla common ancestor, as demonstrated by the finding of the duplicated NF1 gene at orthologous chromosome loci. The authors suggested that the NF1 intrachromosomal duplication may contribute to the high whole-gene mutation rate by gene conversion. In contrast to the findings of <a href="#33" class="mim-tip-reference" title="Gervasini, C., Bentivegna, A., Venturin, M., Corrado, L., Larizza, L., Riva, P. <strong>Tandem duplication of the NF1 gene detected by high-resolution FISH in the 17q11.2 region.</strong> Hum. Genet. 110: 314-321, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941479</a>] [<a href="https://doi.org/10.1007/s00439-002-0704-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11941479">Gervasini et al. (2002)</a>, however, <a href="#48" class="mim-tip-reference" title="Kehrer-Sawatzki, H., Assum, G., Hameister, H. <strong>Molecular characterisation of t(17;22)(q11.2;q11.2) is not consistent with NF1 gene duplication.</strong> Hum. Genet. 111: 465-467, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12384794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12384794</a>] [<a href="https://doi.org/10.1007/s00439-002-0794-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12384794">Kehrer-Sawatzki et al. (2002)</a> studied a female NF1 patient with reciprocal translocation t(17;22)(q11.2; q11.2) and determined that there is a single NF1 gene in the 17q11.2 region. <a href="#49" class="mim-tip-reference" title="Kehrer-Sawatzki, H., Messiaen, L. <strong>Interphase FISH, the structure of reciprocal translocation chromosomes and physical mapping studies rule out the duplication of the NF1 gene at 17q11.2: a reply. (Letter)</strong> Hum. Genet. 113: 188-190, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12698359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12698359</a>] [<a href="https://doi.org/10.1007/s00439-003-0955-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12698359">Kehrer-Sawatzki and Messiaen (2003)</a> analyzed another reciprocal translocation, a t(14;17)(q32;q11.2), described in a large family with NF1, which disrupted the NF1 gene (<a href="#66" class="mim-tip-reference" title="Messiaen, L. M., Callens, T., Mortier, G., Beysen, D., Vandenbroucke, I., Van Roy, N., Speleman, F., De Paepe, A. <strong>Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.</strong> Hum. Mutat. 15: 541-555, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10862084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10862084</a>] [<a href="https://doi.org/10.1002/1098-1004(200006)15:6<541::AID-HUMU6>3.0.CO;2-N" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10862084">Messiaen et al., 2000</a>) and again reported findings inconsistent with a duplication of the NF1 gene at 17q11.2 as proposed by <a href="#33" class="mim-tip-reference" title="Gervasini, C., Bentivegna, A., Venturin, M., Corrado, L., Larizza, L., Riva, P. <strong>Tandem duplication of the NF1 gene detected by high-resolution FISH in the 17q11.2 region.</strong> Hum. Genet. 110: 314-321, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941479</a>] [<a href="https://doi.org/10.1007/s00439-002-0704-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11941479">Gervasini et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12698359+10862084+12384794+11941479" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0001 NEUROFIBROMATOSIS, TYPE I</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000000360" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000360" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000360</a>
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<p>In a patient with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>), <a href="#105" class="mim-tip-reference" title="Wallace, M. R., Andersen, L. B., Saulino, A. M., Gregory, P. E., Glover, T. W., Collins, F. S. <strong>A de novo Alu insertion results in neurofibromatosis type 1.</strong> Nature 353: 864-866, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1719426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1719426</a>] [<a href="https://doi.org/10.1038/353864a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1719426">Wallace et al. (1991)</a> demonstrated a de novo heterozygous Alu repetitive element insertion into an intron of the NF1 gene, which resulted in deletion of the downstream exon during splicing and consequently shifted the reading frame. The patient was an isolated case in his family. The insertion, 300-500 bp, began 44 bp upstream of exon 6. This previously undescribed mechanism of mutation indicated that Alu retrotransposition is an ongoing process in the human germline. Alu elements had been involved in the generation of disease mutation by recombination (e.g., in familial hypercholesterolemia (<a href="/entry/143890">143890</a>) and ADA deficiency) or point mutation (e.g., in gyrate atrophy of the choroid and retina <a href="/entry/258870">258870</a>; <a href="/entry/613349#0023">613349.0023</a>), but not as a new element. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1719426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs2151538841 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2151538841;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=rs2151538841" 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=rs2151538841" 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=RCV000000361" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000361" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000361</a>
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<p>In 2 patients with neurofibromatosis type I (<a href="/entry/162200">162200</a>), a 35-year-old man and his daughter, <a href="#89" class="mim-tip-reference" title="Stark, M., Assum, G., Krone, W. <strong>A small deletion and an adjacent base exchange in a potential stem-loop region of the neurofibromatosis 1 gene.</strong> Hum. Genet. 87: 685-687, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1937470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1937470</a>] [<a href="https://doi.org/10.1007/BF00201726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1937470">Stark et al. (1991)</a> demonstrated a 5-bp deletion (CCACC or CACCT) and an adjacent transversion, located about 500 bp downstream from the region that codes for a functional domain of the NF1 gene product. The mutation was demonstrable by heteroduplex analysis. The deletion removed the proximal half of a small potential stem-loop and interrupted the reading frame in exon 1. A severely truncated protein with a grossly altered carboxy terminus lacking one-third of its sequence was the predicted consequence. <a href="#88" class="mim-tip-reference" title="Stark, M., Assum, G., Kaufmann, D., Kehrer, H., Krone, W. <strong>Analysis of segregation and expression of an identified mutation at the neurofibromatosis type 1 locus.</strong> Hum. Genet. 90: 356-359, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1483690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1483690</a>] [<a href="https://doi.org/10.1007/BF00220458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1483690">Stark et al. (1992)</a> found that both alleles were expressed in primary cultures of neurofibroma cells and melanocytes from a cafe-au-lait macule of the proband, thus excluding loss of heterozygosity. The authors used the 5-bp deletion for the presymptomatic diagnosis of the 18-month-old third son of the proband. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1483690+1937470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0003 NEUROFIBROMATOSIS, TYPE I</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">rs199474792 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199474792;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=rs199474792" 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=rs199474792" 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=RCV000000362 OR RCV000059211" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000362, RCV000059211" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000362...</a>
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<p><a href="#18" class="mim-tip-reference" title="Cawthon, R. M., Viskochil, D., O'Connell, P., Buchberg, A., Andersen, L., Wallace, M., Marchuk, D., Stevens, J., Culver, M., Xu, G., Collins, F. S., Jenkins, N., Copeland, N., White, R. <strong>Identification and characterization of several genes between or nearby neurofibromatosis type I translocation breakpoint. (Abstract)</strong> Am. J. Hum. Genet. 47 (suppl.): A109, 1990."None>Cawthon et al. (1990)</a> identified point mutations in a 4-kb sequence of the transcript of the NF1 gene at a translocation breakpoint associated with neurofibromatosis type I (<a href="/entry/162200">162200</a>). One mutant allele contained a T-to-C transition that caused a leu348-to-pro (L348P) substitution, and the second harbored a C-to-T insertion that changed an arg365 to a stop codon (R365X; <a href="#0004">613113.0004</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">rs267606595 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606595;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=rs267606595" 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=rs267606595" 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=RCV000000363" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000363" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000363</a>
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<p>Independently, <a href="#18" class="mim-tip-reference" title="Cawthon, R. M., Viskochil, D., O'Connell, P., Buchberg, A., Andersen, L., Wallace, M., Marchuk, D., Stevens, J., Culver, M., Xu, G., Collins, F. S., Jenkins, N., Copeland, N., White, R. <strong>Identification and characterization of several genes between or nearby neurofibromatosis type I translocation breakpoint. (Abstract)</strong> Am. J. Hum. Genet. 47 (suppl.): A109, 1990."None>Cawthon et al. (1990)</a> and <a href="#28" class="mim-tip-reference" title="Estivill, X., Lazaro, C., Casals, T., Ravella, A. <strong>Recurrence of a nonsense mutation in the NF1 gene causing classical neurofibromatosis type 1.</strong> Hum. Genet. 88: 185-188, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1757093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1757093</a>] [<a href="https://doi.org/10.1007/BF00206069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1757093">Estivill et al. (1991)</a> identified a new mutation in exon 4 of the NF1 gene, a 1087C-T transition (numbering of <a href="#18" class="mim-tip-reference" title="Cawthon, R. M., Viskochil, D., O'Connell, P., Buchberg, A., Andersen, L., Wallace, M., Marchuk, D., Stevens, J., Culver, M., Xu, G., Collins, F. S., Jenkins, N., Copeland, N., White, R. <strong>Identification and characterization of several genes between or nearby neurofibromatosis type I translocation breakpoint. (Abstract)</strong> Am. J. Hum. Genet. 47 (suppl.): A109, 1990."None>Cawthon et al., 1990</a>), resulting in an arg365-to-ter (R365X) substitution, in patients with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>). Although a different numbering system was used, this is the same mutation as that found by <a href="#102" class="mim-tip-reference" title="Valero, M. C., Velasco, E., Moreno, F., Hernandez-Chico, C. <strong>Characterization of four mutations in the neurofibromatosis type 1 gene by denaturing gradient gel electrophoresis (DGGE).</strong> Hum. Molec. Genet. 3: 639-641, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8069310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8069310</a>] [<a href="https://doi.org/10.1093/hmg/3.4.639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8069310">Valero et al. (1994)</a> and designated 5242C-T in exon 29. They proposed that this site, in a CpG residue, is a hotspot for mutation in the NF1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1757093+8069310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0005 NEUROFIBROMATOSIS, TYPE I</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> rs137854550 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854550;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/rs137854550?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=rs137854550" 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=rs137854550" 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=RCV000000364 OR RCV000489593 OR RCV000626644 OR RCV000762990 OR RCV002305424 OR RCV002310992 OR RCV003460397 OR RCV004798706" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000364, RCV000489593, RCV000626644, RCV000762990, RCV002305424, RCV002310992, RCV003460397, RCV004798706" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000364...</a>
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<p>In a patient with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>) and affected members of his family, <a href="#57" class="mim-tip-reference" title="Li, Y., Bollag, G., Clark, R., Stevens, J., Conroy, L., Fults, D., Ward, K., Friedman, E., Samowitz, W., Robertson, M., Bradley, P., McCormick, F., White, R., Cawthon, R. <strong>Somatic mutations in the neurofibromatosis 1 gene in human tumors.</strong> Cell 69: 275-281, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1568247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1568247</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90408-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1568247">Li et al. (1992)</a> found an AAG-to-GAG transition at codon 1423 in the NF1 gene, resulting in the substitution of glutamic acid for lysine (K1423E). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1568247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 same mutation or a mutation in the same codon leading to substitution of glutamine for lysine through an A-to-C transversion was also observed by <a href="#57" class="mim-tip-reference" title="Li, Y., Bollag, G., Clark, R., Stevens, J., Conroy, L., Fults, D., Ward, K., Friedman, E., Samowitz, W., Robertson, M., Bradley, P., McCormick, F., White, R., Cawthon, R. <strong>Somatic mutations in the neurofibromatosis 1 gene in human tumors.</strong> Cell 69: 275-281, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1568247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1568247</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90408-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1568247">Li et al. (1992)</a> as a somatic mutation in adenocarcinoma of the colon, myelodysplastic syndrome, and anaplastic astrocytoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1568247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0006 NEUROFIBROMATOSIS, TYPE I</strong>
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<span class="mim-text-font">
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NF1, 1-BP INS, 5662C
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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">rs267606596 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606596;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=rs267606596" 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=rs267606596" 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=RCV000000365" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000365" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000365</a>
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</span>
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<span class="mim-text-font">
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<p>In 2 unrelated patients with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>), <a href="#101" class="mim-tip-reference" title="Upadhyaya, M., Shen, M., Cherryson, A., Farnham, J., Maynard, J., Huson, S. M., Harper, P. S. <strong>Analysis of mutations at the neurofibromatosis 1 (NF1) locus.</strong> Hum. Molec. Genet. 1: 735-740, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302608</a>] [<a href="https://doi.org/10.1093/hmg/1.9.735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302608">Upadhyaya et al. (1992)</a> found insertion of a cytosine within codon 1818 of the NF1 gene that changed the reading frame and resulted in 23 altered amino acids prior to the inappropriate introduction of a stop codon at amino acid 1841. The insertion created a recognition site for enzyme MnlI. (The authors incorrectly stated in their abstract and the legend of their Figure 3 that there was a nucleotide insertion at 'codon 5662.' The nucleotide insertion at residue 5662 occurs within codon 1818 in their cDNA clone of NF1, as correctly represented in the sequence shown in their Figure 3.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 NEUROFIBROMATOSIS, TYPE I</strong>
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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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NF1, 1-BP INS, FS1841TER
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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">rs267606597 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606597;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=rs267606597" 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=rs267606597" 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=RCV000000366" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000366" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000366</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 patient with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>), <a href="#101" class="mim-tip-reference" title="Upadhyaya, M., Shen, M., Cherryson, A., Farnham, J., Maynard, J., Huson, S. M., Harper, P. S. <strong>Analysis of mutations at the neurofibromatosis 1 (NF1) locus.</strong> Hum. Molec. Genet. 1: 735-740, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302608</a>] [<a href="https://doi.org/10.1093/hmg/1.9.735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302608">Upadhyaya et al. (1992)</a> found an insertion of thymidine in codon 1823, resulting in a shift of the reading frame, the generation of 18 amino acids different from those of the normal protein, and a gene product that terminated prematurely at amino acid 1840 by the creation of a stop codon at 1841. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 NEUROFIBROMATOSIS, TYPE I</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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NF1, LEU2143MET
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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">rs137854551 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854551;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=rs137854551" 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=rs137854551" 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=RCV000000367" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000367" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000367</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 neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>), <a href="#101" class="mim-tip-reference" title="Upadhyaya, M., Shen, M., Cherryson, A., Farnham, J., Maynard, J., Huson, S. M., Harper, P. S. <strong>Analysis of mutations at the neurofibromatosis 1 (NF1) locus.</strong> Hum. Molec. Genet. 1: 735-740, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302608</a>] [<a href="https://doi.org/10.1093/hmg/1.9.735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302608">Upadhyaya et al. (1992)</a> found a heterozygous 6639C-A transversion in the NF1 gene, resulting in a leu2143-to-met (L2143M) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 NEUROFIBROMATOSIS, TYPE I</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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NF1, TYR2213ASN
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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> rs267606598 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606598;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/rs267606598?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=rs267606598" 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=rs267606598" 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=RCV000000368" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000368" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000368</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 neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>), <a href="#101" class="mim-tip-reference" title="Upadhyaya, M., Shen, M., Cherryson, A., Farnham, J., Maynard, J., Huson, S. M., Harper, P. S. <strong>Analysis of mutations at the neurofibromatosis 1 (NF1) locus.</strong> Hum. Molec. Genet. 1: 735-740, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302608</a>] [<a href="https://doi.org/10.1093/hmg/1.9.735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302608">Upadhyaya et al. (1992)</a> found a heterozygous 6724T-G transversion in the NF1 gene, resulting in a tyr2213-to-asn (Y2213N) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<a id="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 WATSON SYNDROME</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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NF1, 42-BP DUP
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</div>
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</span>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000000369" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000369" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000369</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 family in which Watson syndrome (WTSN; <a href="/entry/193520">193520</a>) had occurred in 3 generations, <a href="#92" class="mim-tip-reference" title="Tassabehji, M., Strachan, T., Sharland, M., Colley, A., Donnai, D., Harris, R., Thakker, N. <strong>Tandem duplication within a neurofibromatosis type I (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome.</strong> Am. J. Hum. Genet. 53: 90-95, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8317503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8317503</a>]" pmid="8317503">Tassabehji et al. (1993)</a> demonstrated an almost perfect in-frame tandem duplication of 42 bases in exon 28 of the NF1 gene. Unlike the mutations previously described in classic NF1 which result predominantly in null alleles, the mutation in this family would be expected to result in a mutant neurofibromin product. The affected mother had multiple cafe-au-lait patches, freckling in the axillary and groin, low-set posteriorly rotated ears, a squint, and an IQ of 56. She had no Lisch nodules or neurofibromata. A daughter, aged 3.5 years, had multiple cafe-au-lait spots, mild pectus carinatum, hypertelorism with epicanthic folds, a squint, low-set posteriorly rotated ears, and moderate global developmental delay. Her twin brother had ptosis, mild cubitus valgus, bilateral undescended testes, and mild pulmonic valvular stenosis by echocardiography. Neither child had Lisch nodules or neurofibromata. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8317503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0011" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0011 WATSON SYNDROME</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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NF1, 80-KB DEL
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</div>
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</span>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000000370" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000370" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000370</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="#101" class="mim-tip-reference" title="Upadhyaya, M., Shen, M., Cherryson, A., Farnham, J., Maynard, J., Huson, S. M., Harper, P. S. <strong>Analysis of mutations at the neurofibromatosis 1 (NF1) locus.</strong> Hum. Molec. Genet. 1: 735-740, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302608</a>] [<a href="https://doi.org/10.1093/hmg/1.9.735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302608">Upadhyaya et al. (1992)</a> found an 80-kb deletion at the NF1 locus in a patient with Watson syndrome (WTSN; <a href="/entry/193520">193520</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0012" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0012 NEUROFIBROMATOSIS, TYPE I</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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NF1, ARG1947TER
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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">rs137854552 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854552;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=rs137854552" 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=rs137854552" 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=RCV000000371 OR RCV000418287 OR RCV000492774 OR RCV000762995 OR RCV001009602 OR RCV003460398 OR RCV004547450 OR RCV004558221 OR RCV004562178 OR RCV004668704" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000371, RCV000418287, RCV000492774, RCV000762995, RCV001009602, RCV003460398, RCV004547450, RCV004558221, RCV004562178, RCV004668704" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000371...</a>
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<p>A C-to-T transition changing arginine-1947 to a stop codon (R1947X) in the NF1 gene has been described in multiple Caucasian and Japanese families with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>), suggesting that this codon, CGA, is a hotspot for mutation, presumably because it contains a CpG dinucleotide. (Numbering of codons is based on <a href="#63" class="mim-tip-reference" title="Marchuk, D. A., Saulino, A. M., Tavakkol, R., Swaroop, M., Wallace, M. R., Andersen, L. B., Mitchell, A. L., Gutmann, D. H., Boguski, M., Collins, F. S. <strong>cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product.</strong> Genomics 11: 931-940, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1783401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1783401</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90017-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1783401">Marchuk et al. (1991)</a>.) The mutation was described in 3 unrelated Caucasians (<a href="#3" class="mim-tip-reference" title="Ainsworth, P. J., Rodenhiser, D. I., Costa, M. T. <strong>Identification and characterization of sporadic and inherited mutations in exon 31 of the neurofibromatosis (NF1) gene.</strong> Hum. Genet. 91: 151-156, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8385067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8385067</a>] [<a href="https://doi.org/10.1007/BF00222716" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8385067">Ainsworth et al., 1993</a>; <a href="#18" class="mim-tip-reference" title="Cawthon, R. M., Viskochil, D., O'Connell, P., Buchberg, A., Andersen, L., Wallace, M., Marchuk, D., Stevens, J., Culver, M., Xu, G., Collins, F. S., Jenkins, N., Copeland, N., White, R. <strong>Identification and characterization of several genes between or nearby neurofibromatosis type I translocation breakpoint. (Abstract)</strong> Am. J. Hum. Genet. 47 (suppl.): A109, 1990."None>Cawthon et al., 1990</a>; <a href="#28" class="mim-tip-reference" title="Estivill, X., Lazaro, C., Casals, T., Ravella, A. <strong>Recurrence of a nonsense mutation in the NF1 gene causing classical neurofibromatosis type 1.</strong> Hum. Genet. 88: 185-188, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1757093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1757093</a>] [<a href="https://doi.org/10.1007/BF00206069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1757093">Estivill et al., 1991</a>); at least 2 of these cases were sporadic. <a href="#42" class="mim-tip-reference" title="Horiuchi, T., Hatta, N., Matsumoto, M., Ohtsuka, H., Collins, F. S., Kobayashi, Y., Fujita, S. <strong>Nonsense mutations at arg-1947 in two cases of familial neurofibromatosis type 1 in Japanese.</strong> Hum. Genet. 93: 81-83, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7903661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7903661</a>] [<a href="https://doi.org/10.1007/BF00218920" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7903661">Horiuchi et al. (1994)</a> reported the same mutation in 2 unrelated familial cases of NF1. That these represented independent mutations was indicated by the fact that in the 2 families the affected individuals differed with regard to a polymorphism located within the NF1 gene. The frequency of the arg1947-to-ter mutation may be as high as 8% in Japanese and at least 1% in Caucasians. Studying one of the patients with the arg1947-to-ter mutation, <a href="#42" class="mim-tip-reference" title="Horiuchi, T., Hatta, N., Matsumoto, M., Ohtsuka, H., Collins, F. S., Kobayashi, Y., Fujita, S. <strong>Nonsense mutations at arg-1947 in two cases of familial neurofibromatosis type 1 in Japanese.</strong> Hum. Genet. 93: 81-83, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7903661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7903661</a>] [<a href="https://doi.org/10.1007/BF00218920" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7903661">Horiuchi et al. (1994)</a> showed that both the normal and the mutant allele were transcribed in a lymphoblastoid cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1757093+8385067+1783401+7903661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#39" class="mim-tip-reference" title="Heim, R. A., Silverman, L. M., Farber, R. A., Kam-Morgan, L. N. W., Luce, M. C. <strong>Screening for truncated NF1 proteins. (Letter)</strong> Nature Genet. 8: 218-219, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874161</a>] [<a href="https://doi.org/10.1038/ng1194-218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874161">Heim et al. (1994)</a> stated that the R1947X mutation had been reported in 6 unrelated patients with NF1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#55" class="mim-tip-reference" title="Lazaro, C., Kruyer, H., Gaona, A., Estivill, X. <strong>Two further cases of mutation R1947X in the NF1 gene: screening for a relatively common recurrent mutation.</strong> Hum. Genet. 96: 361-363, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7649559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7649559</a>] [<a href="https://doi.org/10.1007/BF00210425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7649559">Lazaro et al. (1995)</a> presented 2 further cases of the R1947X mutation in the NF1 gene. They stated that a total of 9 cases of the R1947X mutation had been reported, giving a frequency of about 2%. They developed an allele-specific oligonucleotide hybridization assay for the efficient screening of a large number of samples for this relatively common recurrent mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7649559" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 sample of 56 unrelated Korean patients with NF1, <a href="#74" class="mim-tip-reference" title="Park, K. C., Choi, H. O., Park, K. H., Kim, K. H., Eun, H. C. <strong>A nonsense mutation at arg-1947 in the NF1 gene in a case of neurofibromatosis type 1 in a Korean patient.</strong> J. Hum. Genet. 45: 84-85, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10721668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10721668</a>] [<a href="https://doi.org/10.1007/s100380050016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10721668">Park et al. (2000)</a> identified 1 with the R1947X mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10721668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs267606599 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606599;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/rs267606599?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=rs267606599" 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=rs267606599" 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=RCV000000373 OR RCV000680818 OR RCV001009591 OR RCV001018701 OR RCV002381233 OR RCV004547451" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000373, RCV000680818, RCV001009591, RCV001018701, RCV002381233, RCV004547451" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000373...</a>
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<p><a href="#78" class="mim-tip-reference" title="Purandare, S. M., Lanyon, W. G., Arngrimsson, R., Connor, J. M. <strong>Characterisation of a novel splice donor mutation affecting position +1 in intron 18 of the NF-1 gene.</strong> Hum. Molec. Genet. 4: 767-768, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7633431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7633431</a>] [<a href="https://doi.org/10.1093/hmg/4.4.767" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7633431">Purandare et al. (1995)</a> identified a G-to-A transition at position +1 of intron 18 of the NF1 gene in a 41-year-old Caucasian female in whom the diagnosis of neurofibromatosis (NF1; <a href="/entry/162200">162200</a>) was first made at the age of 28 years when she was admitted to hospital for a grand mal seizure. A son was also affected. The mutation resulted in skipping of exon 18 which did not cause a shift in the reading frame but resulted in an in-frame loss of 123 nucleotides from the mRNA and the corresponding 41 amino acids from the protein. <a href="#78" class="mim-tip-reference" title="Purandare, S. M., Lanyon, W. G., Arngrimsson, R., Connor, J. M. <strong>Characterisation of a novel splice donor mutation affecting position +1 in intron 18 of the NF-1 gene.</strong> Hum. Molec. Genet. 4: 767-768, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7633431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7633431</a>] [<a href="https://doi.org/10.1093/hmg/4.4.767" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7633431">Purandare et al. (1995)</a> referred to 3 previously reported splice donor site mutations in the NF1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7633431" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs267606600 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606600;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=rs267606600" 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=rs267606600" 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=RCV000000374 OR RCV000164295 OR RCV000414730 OR RCV001001001 OR RCV002288457 OR RCV003460399 OR RCV004797745 OR RCV005016220" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000374, RCV000164295, RCV000414730, RCV001001001, RCV002288457, RCV003460399, RCV004797745, RCV005016220" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000374...</a>
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<p><a href="#80" class="mim-tip-reference" title="Robinson, P. N., Buske, A., Neumann, R., Tinschert, S., Nurnberg, P. <strong>Recurrent 2-bp deletion in exon 10c of the NF1 gene in two cases of von Recklinghausen neurofibromatosis.</strong> Hum. Mutat. 7: 85-88, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8664912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8664912</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)7:1<85::AID-HUMU17>3.0.CO;2-O" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8664912">Robinson et al. (1996)</a> described a recurrent 2-bp deletion (1541delAG) in exon 10c of the NF1 gene in 2 unrelated patients with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>): one sporadic and one familial case. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8664912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs137854553 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854553;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=rs137854553" 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=rs137854553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#110" class="mim-tip-reference" title="Wu, R., Legius, E., Robberecht, W., Dumoulin, M., Cassiman, J.-J., Fryns, J.-P. <strong>Neurofibromatosis type I gene mutation in a patient with features of LEOPARD syndrome.</strong> Hum. Mutat. 8: 51-56, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8807336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8807336</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)8:1<51::AID-HUMU7>3.0.CO;2-S" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8807336">Wu et al. (1996)</a> found a de novo met1035-to-arg (M1035R) missense mutation resulting from a T-to-G transversion in exon 18 of the NF1 gene in a 32-year-old woman with a prior diagnosis of LEOPARD syndrome (<a href="/entry/151100">151100</a>), who was found to have neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>). At birth, a heart murmur was detected resulting from subvalvular muscular aortic stenosis and valvular aortic stenosis. The skin showed multiple dark lentigines together with a few larger cafe-au-lait patches. The same lentigines were present in the armpits and groin and were not raised. The patient attended a special school for children with mild mental retardation. At the age of 21 years, mitral insufficiency was demonstrated resulting from a double orifice mitral valve. The patient had macrocrania (head circumference 58 cm), apparent hypertelorism, and a coarse face with broad neck. Neurofibromas were not present at the age of 32, and no Lisch nodules were seen by slit-lamp examination. The mutation was absent in the parents, who were clinically normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8807336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs137854554 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854554;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=rs137854554" 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=rs137854554" 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=RCV000000376 OR RCV001810827 OR RCV002326656" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000376, RCV001810827, RCV002326656" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000376...</a>
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<p><a href="#100" class="mim-tip-reference" title="Upadhyaya, M., Osborn, M. J., Maynard, J., Kim, M. R., Tamanoi, F., Cooper, D. N. <strong>Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene.</strong> Hum. Genet. 99: 88-92, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9003501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9003501</a>] [<a href="https://doi.org/10.1007/s004390050317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9003501">Upadhyaya et al. (1997)</a> identified 14 novel mutations in the GAP-related domain of neurofibromin in patients with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>). One of these mutations was a change at nucleotide 4173 from A to T, changing codon 1391 from AGA (arg) to AGT (ser) (R1391S). The effect of this R1391S missense mutation was studied by in vitro expression of a site-directed mutant and by GAP activity assay. The mutant protein was found to be some 300-fold less active than wildtype NF1 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9003501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs267606601 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606601;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=rs267606601" 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=rs267606601" 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=RCV000000377" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000377" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000377</a>
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<p>In 5 affected members of a family with spinal neurofibromatosis with cafe-au-lait macules (<a href="/entry/162210">162210</a>), <a href="#6" class="mim-tip-reference" title="Ars, E., Kruyer, H., Gaona, A., Casquero, P., Rosell, J., Volpini, V., Serra, E., Lazaro, C., Estivill, X. <strong>A clinical variant of neurofibromatosis type 1: familial spinal neurofibromatosis with a frameshift mutation in the NF1 gene.</strong> Am. J. Hum. Genet. 62: 834-841, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529361</a>] [<a href="https://doi.org/10.1086/301803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529361">Ars et al. (1998)</a> identified a 1-bp insertion (8042insA) in exon 46 of the NF1 gene. The mutation was predicted to result in a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9529361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs137854555 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854555;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=rs137854555" 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=rs137854555" 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=RCV000000378 OR RCV000660063 OR RCV001007974" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000378, RCV000660063, RCV001007974" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000378...</a>
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<p>Among 20 children with juvenile myelomonocytic leukemia (JMML; <a href="/entry/607785">607785</a>), <a href="#83" class="mim-tip-reference" title="Side, L. E., Emanuel, P. D., Taylor, B., Franklin, J., Thompson, P., Castleberry, R. P., Shannon, K. M. <strong>Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1.</strong> Blood 92: 267-272, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9639526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9639526</a>]" pmid="9639526">Side et al. (1998)</a> found 3 with truncating mutations in the NF1 gene. One of the children, a 3-year-old boy, had a G-to-A transition at nucleotide 4614, which converted codon 1538 from tryptophan to stop in exon 27a (W1538X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9639526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0020 LEUKEMIA, JUVENILE MYELOMONOCYTIC</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000000379" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000379" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000379</a>
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<p>In a 19-month-old boy with juvenile myelomonocytic leukemia (JMML/Mo7; <a href="/entry/607785">607785</a>), <a href="#83" class="mim-tip-reference" title="Side, L. E., Emanuel, P. D., Taylor, B., Franklin, J., Thompson, P., Castleberry, R. P., Shannon, K. M. <strong>Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1.</strong> Blood 92: 267-272, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9639526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9639526</a>]" pmid="9639526">Side et al. (1998)</a> found in cloned cDNA aberrant splicing resulting in a shift in the reading frame. Genomic DNA showed an alteration (6579,G-A,+18) in the splice donor consensus sequence flanking exon 34. This mutation introduced an additional 17 nucleotides containing a novel BglI restriction enzyme site into the patient's cDNA. <a href="#83" class="mim-tip-reference" title="Side, L. E., Emanuel, P. D., Taylor, B., Franklin, J., Thompson, P., Castleberry, R. P., Shannon, K. M. <strong>Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1.</strong> Blood 92: 267-272, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9639526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9639526</a>]" pmid="9639526">Side et al. (1998)</a> identified this restriction site in amplified cDNA derived from the patient's EBV cell line RNA, thus confirming that this mutation existed in the germline. Furthermore, loss of heterozygosity was demonstrated, indicating inactivation of another NF1 allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9639526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs267606602 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606602;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=rs267606602" 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=rs267606602" 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=RCV000000380 OR RCV000190422" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000380, RCV000190422" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000380...</a>
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<p>In a 6-month-old boy with juvenile myelomonocytic leukemia (JMML; <a href="/entry/607785">607785</a>), <a href="#83" class="mim-tip-reference" title="Side, L. E., Emanuel, P. D., Taylor, B., Franklin, J., Thompson, P., Castleberry, R. P., Shannon, K. M. <strong>Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1.</strong> Blood 92: 267-272, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9639526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9639526</a>]" pmid="9639526">Side et al. (1998)</a> described a splice mutation in the NF1 gene. Cloned cDNA showed abnormal splicing of 7 nucleotides between exons 10c and 11. The authors had previously found the same mutation in a child with familial NF1 and myelodysplasia syndrome (<a href="#84" class="mim-tip-reference" title="Side, L., Taylor, B., Cayouette, M., Conner, E., Thompson, P., Luce, M., Shannon, K. <strong>Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders.</strong> New Eng. J. Med. 336: 1713-1720, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9180088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9180088</a>] [<a href="https://doi.org/10.1056/NEJM199706123362404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9180088">Side et al. (1997)</a>); genomic DNA sequence showed an abnormal splice acceptor sequence upstream of exon 11 (1642-8A-G) creating a cryptic splice site and consequent frameshift and premature stop codon at codon 555. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9180088+9639526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 NEUROFIBROMATOSIS, TYPE I</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> rs137854556 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854556;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/rs137854556?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=rs137854556" 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=rs137854556" 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=RCV000000381 OR RCV002267796 OR RCV002354143" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000381, RCV002267796, RCV002354143" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000381...</a>
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<p>In a family with a classic multisymptomatic NF1 phenotype (<a href="/entry/162200">162200</a>), including a malignant schwannoma, <a href="#50" class="mim-tip-reference" title="Klose, A., Ahmadian, M. R., Schuelke, M., Scheffzek, K., Hoffmeyer, S., Gewies, A., Schmitz, F., Kaufmann, D., Peters, H., Wittinghofer, A., Nurnberg, P. <strong>Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1 (NF1).</strong> Hum. Molec. Genet. 7: 1261-1268, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668168</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668168">Klose et al. (1998)</a> found an arg1276-to-pro (R1276P) mutation in the arginine finger of the GAP-related domain (GRD) of the neurofibromin gene, resulting in disruption of the most essential catalytic element for Ras-GAP activity. <a href="#50" class="mim-tip-reference" title="Klose, A., Ahmadian, M. R., Schuelke, M., Scheffzek, K., Hoffmeyer, S., Gewies, A., Schmitz, F., Kaufmann, D., Peters, H., Wittinghofer, A., Nurnberg, P. <strong>Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1 (NF1).</strong> Hum. Molec. Genet. 7: 1261-1268, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668168</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668168">Klose et al. (1998)</a> presented data demonstrating that the R1276P mutation, unlike previously reported missense mutations of the GRD region, did not impair the secondary and tertiary protein structure. It neither reduced the level of cellular neurofibromin nor influenced its binding to Ras substantially, but it did completely disable GAP activity. The findings provided direct evidence that failure of neurofibromin GAP activity is a critical element in NF1 pathogenesis. The findings suggested that therapeutic approaches aimed at the reduction of the Ras-GTP levels in neural crest-derived cells can be expected to relieve most of the NF1 symptoms. The proband was the first child of unaffected, nonconsanguineous parents. She developed multiple cafe-au-lait spots within the first year of life. Her language and motor development were mildly retarded, and she complained of incoordination throughout life. Around puberty, multiple cutaneous neurofibromas developed which worsened at the time of each of her 3 pregnancies. At the age of 31 years, routine MRI of the brain revealed multiple areas of increased T2 signal intensity in the midbrain and a small optic glioma. Because of recurrent paresthesias in her left leg, an MRI scan of the spine was done 2 years later which revealed multiple schwannomas within the vertebral foramina. The largest tumor in the lumbar region, with a volume of approximately 8 ml, was surgically removed. Histologically, there was no evidence of malignancy at that time. Eight months later, the patient suffered a relapse with rapid tumor growth. At the time of reoperation, the retroperitoneal tumor had reached a volume of 800 ml and showed numerous necrotic and anaplastic areas with a proliferation rate up to 60%. The patient died of widespread metastatic disease at the age of 34 years. Her 3 male children, ages 4, 8, and 12 years, all fulfilled the NF1 diagnostic criteria. The 2 elder sons were macrocephalic. Language and motor development of all children was retarded to a similar extent and on the same time scale as in their mother. A cranial MRI scan in the 2 elder brothers showed increased T2 signal intensities similar to those in their mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 NEUROFIBROMATOSIS, TYPE I</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> rs137854557 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854557;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/rs137854557?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=rs137854557" 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=rs137854557" 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=RCV000000382 OR RCV000492667 OR RCV000757556 OR RCV001009573 OR RCV001257527 OR RCV001813925 OR RCV002504731 OR RCV003460400 OR RCV004737131 OR RCV004783716" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000382, RCV000492667, RCV000757556, RCV001009573, RCV001257527, RCV001813925, RCV002504731, RCV003460400, RCV004737131, RCV004783716" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000382...</a>
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<p>Among the 9 NF1 exon 10b mutations identified by <a href="#67" class="mim-tip-reference" title="Messiaen, L. M., Callens, T., Roux, K. J., Mortier, G. R., De Paepe, A., Abramowicz, M., Pericak-Vance, M. A., Vance, J. M., Wallace, M. R. <strong>Exon 10b of the NF1 gene represents a mutational hotspot and harbors a recurrent missense mutation Y489C associated with aberrant splicing.</strong> Genet. Med. 1: 248-253, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11258625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11258625</a>] [<a href="https://doi.org/10.1097/00125817-199909000-00002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11258625">Messiaen et al. (1999)</a> in 232 unrelated patients with neurofibromatosis type I (<a href="/entry/162200">162200</a>), 2 were recurrent: an A-to-G transition at nucleotide 1466, resulting in a tyr489-to-cys substitution (Y489C), and a T-to-C transition at nucleotide 1523, resulting in a leu508-to-pro substitution (L508P; <a href="#0024">613113.0024</a>). The Y489C mutation caused skipping of the last 62 nucleotides of exon 10b, while the L508P mutation was undetectable by the protein truncation test. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11258625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0024 NEUROFIBROMATOSIS, TYPE I</strong>
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NF1, LEU508PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137854558 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854558;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=rs137854558" 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=rs137854558" 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=RCV000000383" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000383" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000383</a>
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<p>For discussion of the leu508-to-pro (L508P) mutation in the NF1 gene that was found in compound heterozygous state in patients with neurofibromatosis I (<a href="/entry/162200">162200</a>) by <a href="#67" class="mim-tip-reference" title="Messiaen, L. M., Callens, T., Roux, K. J., Mortier, G. R., De Paepe, A., Abramowicz, M., Pericak-Vance, M. A., Vance, J. M., Wallace, M. R. <strong>Exon 10b of the NF1 gene represents a mutational hotspot and harbors a recurrent missense mutation Y489C associated with aberrant splicing.</strong> Genet. Med. 1: 248-253, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11258625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11258625</a>] [<a href="https://doi.org/10.1097/00125817-199909000-00002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11258625">Messiaen et al. (1999)</a>, see <a href="#0023">613113.0023</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11258625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0025 NEUROFIBROMATOSIS, TYPE I</strong>
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NF1, IVS9DS, 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">rs267606603 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606603;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=rs267606603" 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=rs267606603" 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=RCV000000384 OR RCV001547975" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000384, RCV001547975" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000384...</a>
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<p>In a patient with type I neurofibromatosis (NF1; <a href="/entry/162200">162200</a>), <a href="#27" class="mim-tip-reference" title="Eisenbarth, I., Beyer, K., Krone, W., Assum, G. <strong>Toward a survey of somatic mutation of the NF1 gene in benign neurofibromas of patients with neurofibromatosis type 1.</strong> Am. J. Hum. Genet. 66: 393-401, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677298</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677298[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/10.1086/302747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677298">Eisenbarth et al. (2000)</a> identified a germline G-to-A transition at nucleotide 1260+1, the splice donor site of intron 9 of the NF1 gene, leading to the inclusion of 13 bp of intervening sequence into the NF1 messenger. The mutant allele was present in all tissues tested. In a neurofibroma from this patient, an additional C-to-T transition at nucleotide 4021 (Q1341X; <a href="#0026">613113.0026</a>), a presumed 'second hit' somatic mutation, was identified. Another neurofibroma from the same patient showed a C-to-T transition at nucleotide 4084 (R1362X; <a href="#0027">613113.0027</a>), a presumed further 'second hit' somatic mutation. Both somatic mutations led to premature stop codons in the NF1 message. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10677298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0026 NEUROFIBROMATOSIS, TYPE I, SOMATIC</strong>
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NF1, GLN1341TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137854559 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854559;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=rs137854559" 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=rs137854559" 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=RCV000000385 OR RCV001810828" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000385, RCV001810828" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000385...</a>
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<p>For discussion of the gln1341-to-ter (Q1341X) mutation in the NF1 gene that was found in a patient with type I neurofibromatosis (NF1; <a href="/entry/162200">162200</a>) by <a href="#27" class="mim-tip-reference" title="Eisenbarth, I., Beyer, K., Krone, W., Assum, G. <strong>Toward a survey of somatic mutation of the NF1 gene in benign neurofibromas of patients with neurofibromatosis type 1.</strong> Am. J. Hum. Genet. 66: 393-401, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677298</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677298[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/10.1086/302747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677298">Eisenbarth et al. (2000)</a>, see <a href="#0025">613113.0025</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10677298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0027 NEUROFIBROMATOSIS, TYPE I, SOMATIC</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> rs137854560 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854560;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/rs137854560?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=rs137854560" 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=rs137854560" 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=RCV000000372 OR RCV000483061 OR RCV000492495 OR RCV002504730" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000372, RCV000483061, RCV000492495, RCV002504730" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000372...</a>
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<p>For discussion of the arg1362-to-ter (R1362X) mutation in the NF1 gene that was found in a patient with type I neurofibromatosis (NF1; <a href="/entry/162200">162200</a>) by <a href="#27" class="mim-tip-reference" title="Eisenbarth, I., Beyer, K., Krone, W., Assum, G. <strong>Toward a survey of somatic mutation of the NF1 gene in benign neurofibromas of patients with neurofibromatosis type 1.</strong> Am. J. Hum. Genet. 66: 393-401, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677298</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677298[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/10.1086/302747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677298">Eisenbarth et al. (2000)</a>, see <a href="#0025">613113.0025</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10677298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0028 NEUROFIBROMATOSIS, FAMILIAL SPINAL</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">rs137854561 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854561;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=rs137854561" 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=rs137854561" 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=RCV000000386 OR RCV002354144" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000386, RCV002354144" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000386...</a>
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<p>In a patient with spinal neurofibromatosis but without cafe-au-lait macules (<a href="/entry/162210">162210</a>), <a href="#47" class="mim-tip-reference" title="Kaufmann, D., Muller, R., Bartelt, B., Wolf, M., Kunzi-Rapp, K., Hanemann, C. O., Fahsold, R., Hein, C., Vogel, W., Assum, G. <strong>Spinal neurofibromatosis without cafe-au-lait macules in two families with null mutations of the NF1 gene.</strong> Am. J. Hum. Genet. 69: 1395-1400, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704931</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11704931[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/10.1086/324648" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704931">Kaufmann et al. (2001)</a> identified a leu2067-to-pro (L2067P) mutation in exon 33 of the NF1 gene. Her clinically unaffected 61-year-old father had the same NF1 mutation in his blood cells. Additional molecular investigations to exclude mosaicism were not feasible and additional clinical investigations through MRI scans could not be performed. The L2067P mutation yielded an unstable product of approximately 50% normal neurofibromin levels, indicating functional haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704931" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0029 NEUROFIBROMATOSIS, TYPE I</strong>
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NEUROFIBROMATOSIS, FAMILIAL SPINAL, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606604 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606604;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=rs267606604" 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=rs267606604" 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=RCV000000387 OR RCV000000388 OR RCV001582455 OR RCV002316183 OR RCV004566663" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000387, RCV000000388, RCV001582455, RCV002316183, RCV004566663" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000387...</a>
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<p>In a patient with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>), <a href="#29" class="mim-tip-reference" title="Fahsold, R., Hoffmeyer, S., Mischung, C., Gille, C., Ehlers, C., Kucukceylan, N., Abdel-Nour, M., Gewies, A., Peters, H., Kaufmann, D., Buske, A., Tinschert, S., Nurnberg, P. <strong>Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain.</strong> Am. J. Hum. Genet. 66: 790-818, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10712197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10712197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10712197[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/10.1086/302809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10712197">Fahsold et al. (2000)</a> identified an A-to-G transition in the NF1 gene splice acceptor site of exon 31 (IVS31-5A-G), resulting in the addition of 4 bases to exon 32 and a premature stop codon at amino acid 1995. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10712197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 affected members of a family with spinal neurofibromatosis without cafe-au-lait macules (<a href="/entry/162210">162210</a>), <a href="#47" class="mim-tip-reference" title="Kaufmann, D., Muller, R., Bartelt, B., Wolf, M., Kunzi-Rapp, K., Hanemann, C. O., Fahsold, R., Hein, C., Vogel, W., Assum, G. <strong>Spinal neurofibromatosis without cafe-au-lait macules in two families with null mutations of the NF1 gene.</strong> Am. J. Hum. Genet. 69: 1395-1400, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704931</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11704931[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/10.1086/324648" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704931">Kaufmann et al. (2001)</a> identified the exon 31 splice site mutation. Noting that the same mutation had been reported in a patient with classic NF1, the authors concluded that a modifying gene may compensate for some of the effects of neurofibromin deficiency. The splice site NF1 mutation resulted in instability of the neurofibromin protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704931" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0030 NEUROFIBROMATOSIS, TYPE I</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000000389" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000389" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000389</a>
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<p><a href="#99" class="mim-tip-reference" title="Upadhyaya, M., Majounie, E., Thompson, P., Han, S., Consoli, C., Krawczak, M., Cordeiro, I., Cooper, D. N. <strong>Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1.</strong> Hum. Genet. 112: 12-17, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12483293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12483293</a>] [<a href="https://doi.org/10.1007/s00439-002-0840-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12483293">Upadhyaya et al. (2003)</a> described a Portuguese family in which 3 members had clinical features of neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>) and each had a different underlying defect in the NF1 gene. A 12-year-old boy who had multiple cafe-au-lait spots on his trunk and legs as well as developmental delay had a heterozygous 1.5-Mb deletion including the entire NF1 gene. The mutation was associated with the maternally derived chromosomal haplotype. His 10-year-old brother, who exhibited multiple cafe-au-lait spots and macrocephaly but whose development was within the normal range, was heterozygous for a CGA-to-TGA transition in exon 22 of the NF1 gene, resulting in an arg1241-to-ter mutation (<a href="#0031">613113.0031</a>). This mutation had previously been described; its recurrence was thought to have been mediated by 5-methylcytosine deamination because it occurred in a hypermutable CpG dinucleotide. The brothers' 26-year-old female first cousin once removed (a first cousin of their father) exhibited multiple cafe-au-lait spots, bilateral Lisch nodules, and multiple dermal neurofibromas. She also showed severe scoliosis and several plexiform neurofibromas in the clavicular region, but her development was within the normal range. She was found to carry a frameshift mutation, 5406insT (<a href="#0032">613113.0032</a>), in exon 29 of the NF1 gene. None of the parents had any clinical evidence of NF1 and none had a mutation in the NF1 gene. There was also no evidence of mosaicism. <a href="#99" class="mim-tip-reference" title="Upadhyaya, M., Majounie, E., Thompson, P., Han, S., Consoli, C., Krawczak, M., Cordeiro, I., Cooper, D. N. <strong>Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1.</strong> Hum. Genet. 112: 12-17, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12483293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12483293</a>] [<a href="https://doi.org/10.1007/s00439-002-0840-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12483293">Upadhyaya et al. (2003)</a> speculated about the mechanism of this unusual situation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12483293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0031 NEUROFIBROMATOSIS, TYPE I</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">rs137854562 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854562;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=rs137854562" 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=rs137854562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the arg1241-to-ter (R1241X) mutation in the NF1 gene that was found in heterozygous state in 1 of 3 members of a family with clinical features of neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>) by <a href="#99" class="mim-tip-reference" title="Upadhyaya, M., Majounie, E., Thompson, P., Han, S., Consoli, C., Krawczak, M., Cordeiro, I., Cooper, D. N. <strong>Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1.</strong> Hum. Genet. 112: 12-17, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12483293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12483293</a>] [<a href="https://doi.org/10.1007/s00439-002-0840-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12483293">Upadhyaya et al. (2003)</a>, see <a href="#0030">613113.0030</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12483293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Fahsold, R., Hoffmeyer, S., Mischung, C., Gille, C., Ehlers, C., Kucukceylan, N., Abdel-Nour, M., Gewies, A., Peters, H., Kaufmann, D., Buske, A., Tinschert, S., Nurnberg, P. <strong>Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain.</strong> Am. J. Hum. Genet. 66: 790-818, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10712197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10712197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10712197[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/10.1086/302809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10712197">Fahsold et al. (2000)</a> described a CGA-to-TGA transition in the NF1 gene, resulting in an R1241X mutation, as the cause of neurofibromatosis type I. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10712197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs267606605 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606605;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=rs267606605" 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=rs267606605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the 1-bp insertion (5406insT) in the NF1 gene that was found in heterozygous state in 1 of 3 members of a family with clinical features of neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>) by <a href="#99" class="mim-tip-reference" title="Upadhyaya, M., Majounie, E., Thompson, P., Han, S., Consoli, C., Krawczak, M., Cordeiro, I., Cooper, D. N. <strong>Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1.</strong> Hum. Genet. 112: 12-17, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12483293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12483293</a>] [<a href="https://doi.org/10.1007/s00439-002-0840-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12483293">Upadhyaya et al. (2003)</a>, see <a href="#0030">613113.0030</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12483293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs267606606 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606606;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/rs267606606?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=rs267606606" 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=rs267606606" 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=RCV000000392 OR RCV000000393 OR RCV000196290 OR RCV000215737 OR RCV000384725 OR RCV002496217 OR RCV003162200 OR RCV003466770" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000392, RCV000000393, RCV000196290, RCV000215737, RCV000384725, RCV002496217, RCV003162200, RCV003466770" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000392...</a>
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<p><a href="#15" class="mim-tip-reference" title="Carey, J. C., Stevenson, D. A., Ota, M., Neil, S., Viskochil, D. H. <strong>Is there an NF/Noonan syndrome: Part 2: documentation of the clinical and molecular aspects of an important family.</strong> Proc. Greenwood Genet. Center 17: 152-153, 1997."None>Carey et al. (1997)</a> described a 3-bp deletion in exon 17 of the NF1 gene in affected members of a family with neurofibromatosis-Noonan syndrome (NFNS; <a href="/entry/601321">601321</a>). The 2970delAAT mutation resulted in deletion of met991. The clinical features of the 3 subjects were tabulated by <a href="#23" class="mim-tip-reference" title="De Luca, A., Bottillo, I., Sarkozy, A., Carta, C., Neri, C., Bellacchio, E., Schirinzi, A., Conti, E., Zampino, G., Battaglia, A., Majore, S., Rinaldi, M. M., Carella, M., Marino, B., Pizzuti, A., Digilio, M. C., Tartaglia, M., Dallapiccola, B. <strong>NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome.</strong> Am. J. Hum. Genet. 77: 1092-1101, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16380919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16380919</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16380919[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/10.1086/498454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16380919">De Luca et al. (2005)</a>. <a href="#90" class="mim-tip-reference" title="Stevenson, D. A., Viskochil, D. H., Rope, A. F., Carey, J. C. <strong>Clinical and molecular aspects of an informative family with neurofibromatosis type 1 and Noonan phenotype.</strong> Clin. Genet. 69: 246-253, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16542390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16542390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16542390[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/10.1111/j.1399-0004.2006.00576.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16542390">Stevenson et al. (2006)</a> reported a follow-up of this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16380919+16542390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#98" class="mim-tip-reference" title="Upadhyaya, M., Huson, S. M., Davies, M., Thomas, N., Chuzhanova, N., Giovannini, S., Evans, D. G., Howard, E., Kerr, B., Griffiths, S., Consoli, C., Side, L., and 15 others. <strong>An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 80: 140-151, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160901</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160901[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/10.1086/510781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160901">Upadhyaya et al. (2007)</a> reported this mutation in 47 affected individuals from 21 unrelated families with a similar phenotype, lacking cutaneous neurofibromas or clinically obvious plexiform neurofibromas. One of the families had been reported by <a href="#90" class="mim-tip-reference" title="Stevenson, D. A., Viskochil, D. H., Rope, A. F., Carey, J. C. <strong>Clinical and molecular aspects of an informative family with neurofibromatosis type 1 and Noonan phenotype.</strong> Clin. Genet. 69: 246-253, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16542390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16542390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16542390[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/10.1111/j.1399-0004.2006.00576.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16542390">Stevenson et al. (2006)</a>; another was reported by <a href="#17" class="mim-tip-reference" title="Castle, B., Baser, M. E., Huson, S. M., Cooper, D. N., Upadhyaya, M. <strong>Evaluation of genotype-phenotype correlations in neurofibromatosis type 1.</strong> J. Med. Genet. 40: e109, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14569132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14569132</a>] [<a href="https://doi.org/10.1136/jmg.40.10.e109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14569132">Castle et al. (2003)</a> and had a diagnosis of Watson syndrome (WTSN; <a href="/entry/193520">193520</a>). The in-frame 3-bp deletion in exon 17 was predicted to result in the loss of 1 of 2 adjacent methionines, either codon 991 or codon 992, in conjunction with a silent ACA-to-ACG change of codon 990. These 2 methionine residues are located in a highly conserved region of neurofibromin and are expected, therefore, to have a functional role in the protein. This was said to have been the first study to correlate a specific small mutation of the NF1 gene with the expression of a particular clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17160901+14569132+16542390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#53" class="mim-tip-reference" title="Koczkowska, M., Callens, T., Gomes, A., Sharp, A., Chen, Y., Hicks, A. D., Aylsworth, A. S., Azizi, A. A., Basel, D. G., Bellus, G., Bird, L. M., Blazo, M. A., and 58 others. <strong>Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.</strong> Genet. Med. 21: 867-876, 2019. Note: Erratum: Genet. Med. 21: 764-765, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30190611/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30190611</a>] [<a href="https://doi.org/10.1038/s41436-018-0269-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30190611">Koczkowska et al. (2019)</a> performed a standardized phenotypic assessment on 135 individuals from 103 unrelated families carrying the NF1 p.Met992del mutation. None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. None had optic gliomas or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. Of 119 patients evaluated, 15 (12.6%) had Noonan-like features. The authors concluded that NF patients carrying this variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30190611" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs267606607 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606607;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=rs267606607" 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=rs267606607" 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 neurofibromatosis-Noonan syndrome (NFNS; <a href="/entry/601321">601321</a>), <a href="#8" class="mim-tip-reference" title="Baralle, D., Mattocks, C., Kalidas, K., Elmslie, F., Whittaker, J., Lees, M., Ragge, N., Patton, M. A., Winter, R. M., ffrench-Constant, C. <strong>Different mutations in the NF1 gene are associated with neurofibromatosis-Noonan syndrome (NFNS).</strong> Am. J. Med. Genet. 119A: 1-8, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707950</a>] [<a href="https://doi.org/10.1002/ajmg.a.20023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707950">Baralle et al. (2003)</a> identified a 3-bp deletion, 4312delGAA, in exon 25 of the NF1 gene. The patient was a 6-year-old boy with more than 6 cafe-au-lait macules. There were no other features of neurofibromatosis type I, but his mother had a single cafe-au-lait macule and Lisch nodules, low hairline, and short neck. He had ptosis, epicanthal folds, low posterior hairline, and low-set ears. On echocardiogram he had pulmonic stenosis. No neurofibromas were present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs267606608 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606608;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=rs267606608" 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=rs267606608" 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=RCV000000395" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000395" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000395</a>
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<p>In a patient with neurofibromatosis-Noonan syndrome (NFNS; <a href="/entry/601321">601321</a>), <a href="#8" class="mim-tip-reference" title="Baralle, D., Mattocks, C., Kalidas, K., Elmslie, F., Whittaker, J., Lees, M., Ragge, N., Patton, M. A., Winter, R. M., ffrench-Constant, C. <strong>Different mutations in the NF1 gene are associated with neurofibromatosis-Noonan syndrome (NFNS).</strong> Am. J. Med. Genet. 119A: 1-8, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707950</a>] [<a href="https://doi.org/10.1002/ajmg.a.20023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707950">Baralle et al. (2003)</a> identified a 2-bp insertion, 4095insTG, in exon 23-2 of the NF1 gene. The patient was a 20-year-old man with 7 cafe-au-lait macules, axillary freckling, 10 neurofibromas, Lisch nodules, and scoliosis with a structural cervical vertebral abnormality. He had downslanting palpebral fissures, ptosis, a short, broad neck, widely spaced nipples, and an atrial septal defect. He was of short stature and needed extra help in mainstream school. There was no family history of similar findings. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs267606609 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606609;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=rs267606609" 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=rs267606609" 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=RCV000000396" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000396" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000396</a>
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<p>In a patient with severe neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>), <a href="#19" class="mim-tip-reference" title="Colapietro, P., Gervasini, C., Natacci, F., Rossi, L., Riva, P., Larizza, L. <strong>NF1 exon 7 skipping and sequence alterations in exonic splice enhancers (ESEs) in a neurofibromatosis 1 patient.</strong> Hum. Genet. 113: 551-554, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13680360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13680360</a>] [<a href="https://doi.org/10.1007/s00439-003-1009-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13680360">Colapietro et al. (2003)</a> found a G-to-A transition and a C-to-A transversion at nucleotide positions 57 and 58, respectively, of the 154-bp long NF1 exon 7, neither of which was present in the proband's parents or 50 healthy controls. RT-PCR analysis showed the expected fragment from exon 4b to 8 together with a shortened one with in-frame skipping of exon 7. Direct sequencing of genomic DNA revealed 2 exonic heterozygous changes at nucleotides 20075 (G-A transition) and 20076 (C-A transversion), which belong to contiguous codons. The first substitution occurred in the third base of the codon, changing it from CAG to CAA, both encoding glutamine (Q315Q); the second changed the CTG codon for leucine to the ATG codon for methionine (L316M). The use of previously established sequence matrices for the scoring of putative ESE motifs showed that the adjacent silent and missense mutations were located within highly conserved overlapping stretches of 7 nucleotides with a close similarity to the ESE-specific consensus sequences recognized by the SC35 (<a href="/entry/600813">600813</a>) and SF2/ASF (<a href="/entry/600812">600812</a>) arginine/serine-rich (SR) proteins. The combined occurrence of both consecutive alterations decreased the motif score for both SR proteins below their threshold levels. As the aberrant transcript was consistently expressed, a protein lacking 58 amino acids was predicted. Thus, the contiguous internal exon 7 mutations appear to have caused exon 7 skipping as a result of the missplicing caused by abrogation of functional ESEs (see <a href="#16" class="mim-tip-reference" title="Cartegni, L., Chew, S. L., Krainer, A. R. <strong>Listening to silence and understanding nonsense: exonic mutations that affect splicing.</strong> Nature Rev. Genet. 3: 285-298, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11967553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11967553</a>] [<a href="https://doi.org/10.1038/nrg775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11967553">Cartegni et al. (2002)</a> and <a href="#30" class="mim-tip-reference" title="Fairbrother, W. G., Yeh, R.-F., Sharp, P. A., Burge, C. B. <strong>Predictive identification of exonic splicing enhancers in human genes.</strong> Science 297: 1007-1013, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12114529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12114529</a>] [<a href="https://doi.org/10.1126/science.1073774" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12114529">Fairbrother et al. (2002)</a>). The male proband in the study of <a href="#19" class="mim-tip-reference" title="Colapietro, P., Gervasini, C., Natacci, F., Rossi, L., Riva, P., Larizza, L. <strong>NF1 exon 7 skipping and sequence alterations in exonic splice enhancers (ESEs) in a neurofibromatosis 1 patient.</strong> Hum. Genet. 113: 551-554, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13680360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13680360</a>] [<a href="https://doi.org/10.1007/s00439-003-1009-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13680360">Colapietro et al. (2003)</a> was the third child of healthy unrelated parents. At the age of 1 year, he underwent uronephrectomy because of right renal dysplasia. At the age of 3 years, an optic glioma was identified and surgically excised. The diagnosis of NF1 was made when he was 9 years old on the basis of the presence of cafe-au-lait spots, optic glioma, and Lisch nodules of the iris. Cerebral MRI at the age of 11 years revealed multiple hamartomas and a right hemisphere cerebral venous angioma. The patient showed borderline mental retardation, a height in the 10th percentile, and an occipitofrontal head circumference in the 97th percentile. At the age of 20 years, he showed macrocephaly, numerous cafe-au-lait spots, small cutaneous neurofibromas, a plexiform neck neurofibroma, and axillary and inguinal freckling. Scoliosis, winged scapulae, and bilateral genu valgum were also present. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11967553+12114529+13680360" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1567852567 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1567852567;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=rs1567852567" 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=rs1567852567" 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=RCV000000397" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000397" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000397</a>
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<p>In a patient with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>), <a href="#64" class="mim-tip-reference" title="Maris, J. M., Weiss, M. J., Mosse, Y., Hii, G., Guo, C., White, P. S., Hogarty, M. D., Mirensky, T., Brodeur, G. M., Rebbeck, T. R., Urbanek, M., Shusterman, S. <strong>Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13.</strong> Cancer Res. 62: 6651-6658, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12438263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12438263</a>]" pmid="12438263">Maris et al. (2002)</a> identified a 1-bp deletion in the NF1 gene, 3775delT. The mutation was not present in the patient's parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12438263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#69" class="mim-tip-reference" title="Mosse, Y. P., Laudenslager, M., Khazi, D., Carlisle, A. J., Winter, C. L., Rappaport, E., Maris, J. M. <strong>Germline PHOX2B mutation in hereditary neuroblastoma. (Letter)</strong> Am. J. Hum. Genet. 75: 727-730, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15338462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15338462</a>] [<a href="https://doi.org/10.1086/424530" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15338462">Mosse et al. (2004)</a> showed that the patient originally described by <a href="#64" class="mim-tip-reference" title="Maris, J. M., Weiss, M. J., Mosse, Y., Hii, G., Guo, C., White, P. S., Hogarty, M. D., Mirensky, T., Brodeur, G. M., Rebbeck, T. R., Urbanek, M., Shusterman, S. <strong>Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13.</strong> Cancer Res. 62: 6651-6658, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12438263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12438263</a>]" pmid="12438263">Maris et al. (2002)</a> also had neuroblastoma (<a href="/entry/256700">256700</a>) and Hirschsprung disease (<a href="/entry/142623">142623</a>), which were caused by a 1-bp deletion in the PHOX2B gene (676delG; <a href="/entry/603851#0007">603851.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12438263+15338462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs137854563 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854563;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=rs137854563" 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=rs137854563" 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=RCV000000398 OR RCV000000399 OR RCV002476903 OR RCV002496218" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000398, RCV000000399, RCV002476903, RCV002496218" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000398...</a>
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<p>In a patient with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>), <a href="#29" class="mim-tip-reference" title="Fahsold, R., Hoffmeyer, S., Mischung, C., Gille, C., Ehlers, C., Kucukceylan, N., Abdel-Nour, M., Gewies, A., Peters, H., Kaufmann, D., Buske, A., Tinschert, S., Nurnberg, P. <strong>Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain.</strong> Am. J. Hum. Genet. 66: 790-818, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10712197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10712197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10712197[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/10.1086/302809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10712197">Fahsold et al. (2000)</a> identified a 1070T-C transition in exon 8 of the NF1 gene, resulting in a leu357-to-pro (L357P) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10712197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 7 affected members of a family with spinal neurofibromatosis (<a href="/entry/162210">162210</a>) originally reported by <a href="#76" class="mim-tip-reference" title="Poyhonen, M., Leisti, E.-L., Kytola, S., Leisti, J. <strong>Hereditary spinal neurofibromatosis: a rare form of NF1?</strong> J. Med. Genet. 34: 184-187, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9132486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9132486</a>] [<a href="https://doi.org/10.1136/jmg.34.3.184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9132486">Poyhonen et al. (1997)</a>, <a href="#68" class="mim-tip-reference" title="Messiaen, L., Riccardi, V., Peltonen, J., Maertens, O., Callens, T., Karvonen, S. L., Leisti, E.-L., Koivunen, J., Vandenbroucke, I., Stephens, K., Poyhonen, M. <strong>Independent NF1 mutations in two large families with spinal neurofibromatosis.</strong> J. Med. Genet. 40: 122-126, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566521</a>] [<a href="https://doi.org/10.1136/jmg.40.2.122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566521">Messiaen et al. (2003)</a> identified the L357P mutation. The mutation was not detected in 200 normal chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12566521+9132486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0039 NEUROFIBROMATOSIS, FAMILIAL SPINAL</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">rs267606610 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606610;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=rs267606610" 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=rs267606610" 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=RCV000000400" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000400" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000400</a>
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<p>In affected members of a family with spinal neurofibromatosis (NF1; <a href="/entry/162210">162210</a>) originally reported by <a href="#77" class="mim-tip-reference" title="Pulst, S.-M., Riccardi, V. M., Fain, P., Korenberg, J. R. <strong>Familial spinal neurofibromatosis: clinical and DNA linkage analysis.</strong> Neurology 41: 1923-1927, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1745350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1745350</a>] [<a href="https://doi.org/10.1212/wnl.41.12.1923" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1745350">Pulst et al. (1991)</a>, <a href="#68" class="mim-tip-reference" title="Messiaen, L., Riccardi, V., Peltonen, J., Maertens, O., Callens, T., Karvonen, S. L., Leisti, E.-L., Koivunen, J., Vandenbroucke, I., Stephens, K., Poyhonen, M. <strong>Independent NF1 mutations in two large families with spinal neurofibromatosis.</strong> J. Med. Genet. 40: 122-126, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566521</a>] [<a href="https://doi.org/10.1136/jmg.40.2.122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566521">Messiaen et al. (2003)</a> identified an A-to-C transversion at position +3 of the donor splice site of exon 39 of the NF1 gene (7126+3A-C), resulting in the skipping of exon 39. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12566521+1745350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 NEUROFIBROMATOSIS, TYPE I</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000000401" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000401" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000401</a>
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<p>In a patient with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>) who had onset of neurofibromatous neuropathy at the age of 42 years, <a href="#32" class="mim-tip-reference" title="Ferner, R. E., Hughes, R. A. C., Hall, S. M., Upadhyaya, M., Johnson, M. R. <strong>Neurofibromatous neuropathy in neurofibromatosis 1 (NF1).</strong> J. Med. Genet. 41: 837-841, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520408</a>] [<a href="https://doi.org/10.1136/jmg.2004.021683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520408">Ferner et al. (2004)</a> identified a 1-bp deletion (4071delC) in exon 23.2 of the NF1 gene, resulting in a premature stop codon. The deletion was predicted to generate a truncated neurofibromin of 1,383 amino acids. Neuroimaging studies showed the presence of multiple spinal nerve root neurofibromas. A high-grade malignant peripheral nerve sheath tumor (MPNST) had been removed from the left iliac fossa previously, with no recurrence. Benign flexiform neurofibroma was present in the left abdominal wall. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15520408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs137854564 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854564;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=rs137854564" 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=rs137854564" 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=RCV000000402 OR RCV000680822" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000402, RCV000680822" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000402...</a>
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<p>In a patient with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>) who had onset of neurofibromatous neuropathy at the age of 17 years, <a href="#32" class="mim-tip-reference" title="Ferner, R. E., Hughes, R. A. C., Hall, S. M., Upadhyaya, M., Johnson, M. R. <strong>Neurofibromatous neuropathy in neurofibromatosis 1 (NF1).</strong> J. Med. Genet. 41: 837-841, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520408</a>] [<a href="https://doi.org/10.1136/jmg.2004.021683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520408">Ferner et al. (2004)</a> identified a 1243T-C transition in the NF1 gene, resulting in a leu1243-to-pro (L1243P) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15520408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0042 NEUROFIBROMATOSIS, TYPE I</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">rs137854565 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854565;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=rs137854565" 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=rs137854565" 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=RCV000000403" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000403" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000403</a>
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<p>By cDNA-based mutation detection analysis, <a href="#113" class="mim-tip-reference" title="Zatkova, A., Messiaen, L., Vandenbroucke, I., Wieser, R., Fonatsch, C., Krainer, A. R., Wimmer, K. <strong>Disruption of exonic splicing enhancer elements is the principal cause of exon skipping associated with seven nonsense or missense alleles of NF1.</strong> Hum. Mutat. 24: 491-501, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523642</a>] [<a href="https://doi.org/10.1002/humu.20103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15523642">Zatkova et al. (2004)</a> studied 7 nonsense or missense alleles of NF1 that caused exon skipping and showed that disruption of exonic splicing enhancer (ESE) elements was responsible. One of the 7 mutations was a novel nonsense mutation, a 5719G-T transversion, resulting in a glu1904-to-ter (G1904X) substitution in exon 30. The phenotype was neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15523642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs137854566 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137854566;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/rs137854566?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=rs137854566" 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=rs137854566" 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=RCV000000404" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000404" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000404</a>
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<p><a href="#11" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., Passetti, F., de Oliveira, P. S. L., Messiaen, L., Gelb, B. D., Kim, C. A., Krieger, J. E. <strong>Neurofibromatosis -Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient.</strong> Am. J. Med. Genet. 136A: 242-245, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15948193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15948193</a>] [<a href="https://doi.org/10.1002/ajmg.a.30813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15948193">Bertola et al. (2005)</a> described a 14-year-old girl with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>), caused by a de novo mutation in the NF1 gene, and Noonan syndrome (<a href="/entry/163950">163950</a>), caused by a mutation in the PTPN11 gene (<a href="/entry/176876#0023">176876.0023</a>) inherited from her father. The NF1 mutation was a 2531A-G transition resulting in a leu844-to-arg substitution. The proband had pulmonary stenosis and aortic coarctation requiring surgery and also had a pilocytic astrocytoma in the suprasellar region involving the optic chiasm and forming the third ventricle. She had cafe-au-lait spots and axillary freckling typical of neurofibromatosis and marked hypertelorism characteristic of Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15948193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=RCV000000405 OR RCV004791184" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000405, RCV004791184" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000405...</a>
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<p>In a mother and son with a mild form of neurofibromatosis I (NF1; <a href="/entry/162200">162200</a>), <a href="#94" class="mim-tip-reference" title="Thiel, C., Wilken, M., Zenker, M., Sticht, H., Fahsold, R., Gusek-Schneider, G.-C., Rauch, A. <strong>Independent NF1 and PTPN11 mutations in a family with neurofibromatosis-Noonan syndrome.</strong> Am. J. Med. Genet. 149A: 1263-1267, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19449407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19449407</a>] [<a href="https://doi.org/10.1002/ajmg.a.32837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19449407">Thiel et al. (2009)</a> identified a heterozygous mutation (4661+1G-C) in intron 27 of the NF1 gene, resulting in the skipping of exon 27a and potentially affecting the GAP-related domain. Both patients had cafe-au-lait spots and mild myopia, but no neurofibromas, Lisch nodules, or optic gliomas. The daughter of the mother, who also carried the NF1 mutation, was found to be compound heterozygous with a mutation in the PTPN11 gene (T2I; <a href="/entry/176876#0027">176876.0027</a>). In addition to features of neurofibromatosis I, she also had features of Noonan syndrome (<a href="/entry/163950">163950</a>), including hypertelorism, low-set ears, poor growth, sternal deformity, valvular pulmonic stenosis, and delayed development. The PTPN11 mutation was predicted to destabilize the inactive form of PTPN11, resulting in increased basal activity and a gain of function. The girl also developed bilateral optic gliomas before age 2 years, which may be explained by an additive effect of both the NF1 and PTPN11 mutations on the Ras pathway. Compound heterozygosity for mutations in NF1 and PTPN11 were also reported by <a href="#11" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., Passetti, F., de Oliveira, P. S. L., Messiaen, L., Gelb, B. D., Kim, C. A., Krieger, J. E. <strong>Neurofibromatosis -Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient.</strong> Am. J. Med. Genet. 136A: 242-245, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15948193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15948193</a>] [<a href="https://doi.org/10.1002/ajmg.a.30813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15948193">Bertola et al. (2005)</a> in a patient with a combination of neurofibromatosis I and Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19449407+15948193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 affected members of a 5-generation family with neurofibromatosis-Noonan syndrome (NFNS; <a href="/entry/601321">601321</a>), <a href="#72" class="mim-tip-reference" title="Nystrom, A. M., Ekvall, S., Allanson, J., Edeby, C., Elinder, M., Holmstrom, G., Bondeson, M. L., Anneren, G. <strong>Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1.</strong> Clin. Genet. 76: 524-534, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19845691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19845691</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01233.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19845691">Nystrom et al. (2009)</a> identified a heterozygous 4168C-T transition in exon 24 of the NF1 gene, resulting in a leu1390-to-phe (L1390F) substitution in the highly conserved GAP-related domain. The family was originally reported by <a href="#2" class="mim-tip-reference" title="Ahlbom, B. E., Dahl, N., Zetterqvist, P., Anneren, G. <strong>Noonan syndrome with cafe-au-lait spots and multiple lentigines syndrome are not linked to the neurofibromatosis type 1 locus.</strong> Clin. Genet. 48: 85-89, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7586657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7586657</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1995.tb04061.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7586657">Ahlbom et al. (1995)</a> as having Noonan syndrome based on dysmorphic facial features, short stature, pulmonary stenosis, and short neck. Upon reevaluation, <a href="#72" class="mim-tip-reference" title="Nystrom, A. M., Ekvall, S., Allanson, J., Edeby, C., Elinder, M., Holmstrom, G., Bondeson, M. L., Anneren, G. <strong>Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1.</strong> Clin. Genet. 76: 524-534, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19845691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19845691</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01233.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19845691">Nystrom et al. (2009)</a> found that several family members had cafe-au-lait spots, axillary freckling, Lisch nodules, and multiple nevi, consistent with NF1, but that all family members lacked dermal and superficial plexiform neurofibromas. The authors concluded that the clinical diagnosis was consistent with NFNS. <a href="#72" class="mim-tip-reference" title="Nystrom, A. M., Ekvall, S., Allanson, J., Edeby, C., Elinder, M., Holmstrom, G., Bondeson, M. L., Anneren, G. <strong>Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1.</strong> Clin. Genet. 76: 524-534, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19845691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19845691</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01233.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19845691">Nystrom et al. (2009)</a> postulated that the L1390F mutation resulted in impaired GTPase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7586657+19845691" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=RCV000033171 OR RCV000442381 OR RCV000626737 OR RCV001003806 OR RCV002310996 OR RCV003231110 OR RCV003460540 OR RCV004798752 OR RCV005016317" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033171, RCV000442381, RCV000626737, RCV001003806, RCV002310996, RCV003231110, RCV003460540, RCV004798752, RCV005016317" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033171...</a>
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<p>In a girl with aniridia, microphthalmia, microcephaly, and cafe-au-lait macules, <a href="#40" class="mim-tip-reference" title="Henderson, R. A., Williamson, K., Cumming, S., Clarke, M. P., Lynch, S. A., Hanson, I. M., FitzPatrick, D. R., Sisodiya, S., van Heyningen, V. <strong>Inherited PAX6, NF1 and OTX2 mutations in a child with microphthalmia and aniridia.</strong> Europ. J. Hum. Genet. 15: 898-901, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17406642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17406642</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17406642">Henderson et al. (2007)</a> identified heterozygosity for a 574C-T transition in exon 4b of the NF1 gene, resulting in an arg192-to-ter (R192X) substitution, as well as heterozygous mutations in the PAX6 (R38W; <a href="/entry/607108#0026">607108.0026</a>) and OTX2 (Y179X; <a href="/entry/600037#0004">600037.0004</a>) genes. Her mother, who carried the NF1 and PAX6 mutations, had NF1 (<a href="/entry/162200">162200</a>) with the typical eye defects of retinal fibroma, optic nerve glioma, and gross Lisch nodules on the iris; in addition, although her eyes were of normal size, she had eyes were of normal size, she had small corneas, and also had cataracts, optic nerve hypoplasia, nystagmus, and mild iris stromal hypoplasia with normal-sized pupils. The proband's father, who had multiple ocular defects (MCOPS5; <a href="/entry/610125">610125</a>), had previously been studied by <a href="#79" class="mim-tip-reference" title="Ragge, N. K., Brown, A. G., Poloschek, C. M., Lorenz, B., Henderson, R. A., Clarke, M. P., Russell-Eggitt, I., Fielder, A., Gerrelli, D., Martinez-Barbera, J. P., Ruddle, P., Hurst, J., and 9 others. <strong>Heterozygous mutations of OTX2 cause severe ocular malformations.</strong> Am. J. Hum. Genet. 76: 1008-1022, 2005. Note: Erratum: Am. J. Hum. Genet. 77: 334 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15846561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15846561</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15846561[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/10.1086/430721" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15846561">Ragge et al. (2005)</a> and was heterozygous for the OTX2 nonsense mutation. <a href="#40" class="mim-tip-reference" title="Henderson, R. A., Williamson, K., Cumming, S., Clarke, M. P., Lynch, S. A., Hanson, I. M., FitzPatrick, D. R., Sisodiya, S., van Heyningen, V. <strong>Inherited PAX6, NF1 and OTX2 mutations in a child with microphthalmia and aniridia.</strong> Europ. J. Hum. Genet. 15: 898-901, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17406642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17406642</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17406642">Henderson et al. (2007)</a> noted that the proband's phenotype was surprisingly mild, given that mutations in PAX6, OTX2, or NF1 can cause a variety of severe developmental defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15846561+17406642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Hum. Mutat. 9: 548-554, 1997.
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<div class="">
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<p class="mim-text-font">
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Vogel, K. S., Brannan, C. I., Jenkins, N. A., Copeland, N. G., Parada, L. F.
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<strong>Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons.</strong>
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Cell 82: 733-742, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7671302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7671302</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7671302" 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/10.1016/0092-8674(95)90470-0" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="105" class="mim-anchor"></a>
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<a id="Wallace1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Wallace, M. R., Andersen, L. B., Saulino, A. M., Gregory, P. E., Glover, T. W., Collins, F. S.
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<strong>A de novo Alu insertion results in neurofibromatosis type 1.</strong>
|
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Nature 353: 864-866, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1719426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1719426</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1719426" 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/10.1038/353864a0" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="106" class="mim-anchor"></a>
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<a id="Wallace1990" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Wallace, M. R., Marchuk, D. A., Andersen, L. B., Letcher, R., Odeh, H. M., Saulino, A. M., Fountain, J. W., Brereton, A., Nicholson, J., Mitchell, A. L., Brownstein, B. H., Collins, F. S.
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<strong>Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients.</strong>
|
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Science 249: 181-186, 1990. Note: Erratum: Science 250: 1749 only, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2134734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2134734</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2134734" 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/10.1126/science.2134734" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="107" class="mim-anchor"></a>
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<a id="Weeber2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weeber, E. J., Sweatt, J. D.
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<strong>Molecular neurobiology of human cognition.</strong>
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Neuron 33: 845-848, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11906692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11906692</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11906692" 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/s0896-6273(02)00634-7" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="108" class="mim-anchor"></a>
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<a id="Weiming1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weiming, X., Yu, Q., Lizhi, L., Ponder, M., Wallace, M., Gangfeng, X., Ponder, B.
|
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<strong>Molecular analysis of neurofibromatosis type 1 mutations.</strong>
|
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Hum. Mutat. 1: 474-477, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301957</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301957" 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/humu.1380010604" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="109" class="mim-anchor"></a>
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<a id="Wiest2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wiest, V., Eisenbarth, I., Schmegner, C., Krone, W., Assum, G.
|
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<strong>Somatic NF1 mutation spectra in a family with neurofibromatosis type 1: toward a theory of genetic modifiers.</strong>
|
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Hum. Mutat. 22: 423-427, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14635100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14635100</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14635100" 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/humu.10272" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="110" class="mim-anchor"></a>
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<a id="Wu1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, R., Legius, E., Robberecht, W., Dumoulin, M., Cassiman, J.-J., Fryns, J.-P.
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<strong>Neurofibromatosis type I gene mutation in a patient with features of LEOPARD syndrome.</strong>
|
|
Hum. Mutat. 8: 51-56, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8807336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8807336</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8807336" 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/(SICI)1098-1004(1996)8:1<51::AID-HUMU7>3.0.CO;2-S" target="_blank">Full Text</a>]
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<li>
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<a id="111" class="mim-anchor"></a>
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<a id="Xu1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xu, G., O'Connell, P., Stevens, J., White, R.
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<strong>Characterization of human adenylate kinase 3 (AK3) cDNA and mapping of the AK3 pseudogene to an intron of the NF1 gene.</strong>
|
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Genomics 13: 537-542, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1639383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1639383</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1639383" 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(92)90122-9" target="_blank">Full Text</a>]
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<a id="112" class="mim-anchor"></a>
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<a id="Xu1990" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xu, G., O'Connell, P., Viskochil, D., Cawthon, R., Robertson, M., Culver, M., Dunn, D., Stevens, J., Gesteland, R., White, R., Weiss, R.
|
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<strong>The neurofibromatosis type 1 gene encodes a protein related to GAP.</strong>
|
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Cell 62: 599-608, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2116237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2116237</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2116237" 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/10.1016/0092-8674(90)90024-9" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="113" class="mim-anchor"></a>
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<a id="Zatkova2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zatkova, A., Messiaen, L., Vandenbroucke, I., Wieser, R., Fonatsch, C., Krainer, A. R., Wimmer, K.
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<strong>Disruption of exonic splicing enhancer elements is the principal cause of exon skipping associated with seven nonsense or missense alleles of NF1.</strong>
|
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Hum. Mutat. 24: 491-501, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523642/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523642</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15523642" 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/humu.20103" target="_blank">Full Text</a>]
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</p>
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</ol>
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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="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 03/04/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse - updated : 4/29/2016<br>Paul J. Converse - updated : 3/3/2016<br>Marla J. F. O'Neill - updated : 2/22/2013<br>Cassandra L. Kniffin - updated : 12/23/2010<br>Cassandra L. Kniffin - updated : 11/8/2010<br>George E. Tiller - updated : 6/23/2010<br>Patricia A. Hartz - updated : 3/18/2010
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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="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Carol A. Bocchini : 11/6/2009
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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="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 05/01/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/22/2022<br>alopez : 03/04/2020<br>carol : 05/15/2019<br>carol : 10/05/2018<br>mgross : 03/20/2017<br>joanna : 08/04/2016<br>joanna : 07/01/2016<br>mgross : 4/29/2016<br>carol : 3/4/2016<br>mgross : 3/3/2016<br>carol : 8/18/2015<br>mcolton : 8/11/2015<br>carol : 10/1/2013<br>joanna : 8/5/2013<br>carol : 4/3/2013<br>carol : 2/22/2013<br>carol : 1/9/2013<br>terry : 11/13/2012<br>carol : 3/16/2012<br>wwang : 1/10/2011<br>ckniffin : 12/23/2010<br>wwang : 11/12/2010<br>ckniffin : 11/8/2010<br>wwang : 7/1/2010<br>terry : 6/23/2010<br>carol : 5/25/2010<br>alopez : 4/30/2010<br>carol : 4/9/2010<br>mgross : 3/18/2010<br>terry : 3/18/2010<br>carol : 12/1/2009<br>terry : 11/24/2009<br>carol : 11/23/2009<br>ckniffin : 11/17/2009<br>ckniffin : 11/17/2009<br>terry : 11/9/2009<br>terry : 11/9/2009<br>carol : 11/6/2009
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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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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 613113
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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NEUROFIBROMIN 1; NF1
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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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<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">
|
|
NEUROFIBROMIN
|
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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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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: NF1</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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<p>
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<span class="mim-text-font">
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|
|
<strong>SNOMEDCT:</strong> 1003465006, 128832006, 277587001, 403820003, 445227008, 715344006, 92824003;
|
|
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|
|
|
<strong>ICD10CM:</strong> C93.3, C93.30, Q85.01;
|
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|
|
<strong>ICD9CM:</strong> 237.71;
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</span>
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</p>
|
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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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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: 17q11.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 17:31,094,927-31,377,677 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
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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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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
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<th>
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Inheritance
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="5">
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<span class="mim-font">
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17q11.2
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</span>
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</td>
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<td>
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<span class="mim-font">
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Leukemia, juvenile myelomonocytic
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</span>
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</td>
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<td>
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<span class="mim-font">
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607785
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; Somatic mutation
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Neurofibromatosis-Noonan syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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601321
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Neurofibromatosis, familial spinal
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</span>
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</td>
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<td>
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<span class="mim-font">
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162210
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Neurofibromatosis, type 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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162200
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Watson syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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193520
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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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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<h4>
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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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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</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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<p>The NF1 gene encodes neurofibromin, a cytoplasmic protein that is predominantly expressed in neurons, Schwann cells, oligodendrocytes, and leukocytes. It is a multidomain molecule with the capacity to regulate several intracellular processes, including the RAS (see 190020)-cyclic AMP pathway, the ERK (600997)/MAP (see 600178) kinase cascade, adenylyl cyclase, and cytoskeletal assembly (summary by Trovo-Marqui and Tajara, 2006). </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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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</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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<p>Buchberg et al. (1990) sequenced a portion of the murine NF1 gene and showed that the predicted amino acid sequence is nearly the same as the corresponding region of the human NF1 gene product. Computer searches identified homology between the mouse NF1 gene and the Ira1 and Ira2 genes identified in Saccharomyces cerevisiae, which negatively regulate the RAS-cyclic AMP pathway. RAS proteins are involved in the control of proliferation and differentiation in mammalian cells. Their activity is modulated by their ability to bind and hydrolyze guanine nucleotides. GTP-binding activates RAS, whereas GTP hydrolysis inactivates RAS. Mutant forms of RAS found in human tumors have greatly decreased GTPase activity, resulting in accumulation of RAS in the GTP-bound active form. </p><p>Xu et al. (1990) extended the known open reading frame of the human NF1 gene by cDNA walking and sequencing. The new sequence predicted 2,485 amino acids of the NF1 peptide. A 360-residue region showed significant similarity to the catalytic domains of both human and bovine GTPase-activating protein (GAP, or RASA1; 139150). Xu et al. (1990) suggested that NF1 encodes a cytoplasmic GAP-like protein that may be involved in the control of cell growth by interacting with proteins such as the RAS gene product. </p><p>Marchuk et al. (1991) reported an extensive cDNA walk resulting in the cloning of the complete coding region of the NF1 transcript. Analysis of the sequences revealed an open reading frame of 2,818 amino acids, although alternatively spliced products may code for different protein isoforms. </p><p>To study the NF1 gene product, Gutmann et al. (1991) raised antibodies against both fusion proteins and synthetic peptides. A specific protein of about 250 kD was identified by both immunoprecipitation and immunoblotting. The protein was found in all tissues and cell lines examined and was detected in human, rat, and mouse tissues. Based on the homology between the NF1 gene product and members of the GAP superfamily, the name NF1-GAP-related protein (NF1-GRD) was suggested. DeClue et al. (1991) raised rabbit antisera to a bacterially synthesized peptide corresponding to the GAP-related domain of NF1 (NF1-GRD). The sera specifically detected a 280-kD protein in lysates of HeLa cells. This protein corresponded to the NF1 gene product, as shown by several criteria. NF1 was present in a large molecular mass complex in fibroblast and schwannoma cell lines and appeared to associate with a very large (400-500 kD) protein in both cell lines. </p><p>Daston et al. (1992) raised antibodies against peptides coded by portions of the NF1 cDNA. These antibodies specifically recognized a 220-kD protein, called neurofibromin, in both human and rat spinal cord. Neurofibromin was most abundant in the nervous system. Immunostaining of tissue sections indicated that neurons, oligodendrocytes, and nonmyelinating Schwann cells contained neurofibromin, whereas astrocytes and myelinating Schwann cells did not. </p><p>Trovo-Marqui and Tajara (2006) stated that 4 splicing exons (9a, 10a-2, 23a, and 48a) are responsible for the production of 5 human neurofibromin isoforms (II, 3, 4, 9a, and 10a-2), which exhibit differential expression in distinct tissues. Neurofibromin II, named GRD2 (domain II-related GAP), is the result of the insertion of exon 23a, is expressed in Schwann cells, and has a reduced capacity of acting as GAP. Neurofibromins 3 and 4, which contain exon 48a and both exons 23a and 48a, respectively, are expressed in muscle tissue, mainly in cardiac and skeleton muscles. Neurofibromin 9a (also called 9br) is the result of the inclusion of exon 9a and shows limited neuronal expression. Isoform 10a-2 is the result of insertion of exon 10a-2, which introduces a transmembrane domain. This isoform has been observed in the majority of human tissues analyzed. </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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<h4>
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<span class="mim-font">
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<strong>Gene Structure</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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<p>Xu et al. (1990) found that 3 active genes, called OMGP (164345), EVI2B (158381), and EVI2A (158380), lie within an intron of NF1 but in opposite orientation. </p><p>Xu et al. (1992) found a pseudogene of the AK3L1 gene (103030) in an intron of the NF1 gene. It appeared to be a processed pseudogene since it lacked introns and contained a polyadenylate tract; it nevertheless retained coding potential because the open reading frame was not impaired by any observed base substitutions. </p><p>Heim et al. (1994) cited evidence that the NF1 gene spans approximately 350 kb of genomic DNA, encodes an mRNA of 11 to 13 kb, and contains at least 56 exons. </p><p>Li et al. (1995) showed that the 5-prime end of the NF1 gene is embedded in a CpG island containing a NotI restriction site and that the remainder of the gene lies in the adjacent 35-kb NotI fragment. In their efforts to develop a comprehensive screen for NF1 mutations, they isolated genomic DNA clones that together contain the entire NF1 cDNA sequence. They identified all intron-exon boundaries of the coding region and established that it contains at least 59 exons. The 3-prime untranslated region of the NF1 gene was found to span approximately 3.5 kb and to be continuous with the stop codon. </p><p>Trovo-Marqui and Tajara (2006) stated that the NF1 gene contains 61 exons. </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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<h4>
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<span class="mim-font">
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<strong>Mapping</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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<p>Barker et al. (1987) demonstrated that the gene responsible for neurofibromatosis type I (NF1; 162200) is located in the pericentromeric region of chromosome 17. </p><p>Wallace et al. (1990) identified a large transcript from the candidate NF1 region on chromosome 17q11.2 that was disrupted in 3 patients with neurofibromatosis type I. The changes disrupted expression of the NF1 transcript in all 3 patients, consistent with the hypothesis that it acts as a tumor suppressor. </p><p><strong><em>Pseudogenes</em></strong></p><p>
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Legius et al. (1992) characterized an NF1-related locus on chromosome 15. The nonprocessed NF1 pseudogene (NF1P1) can produce additional fragments in Southern blotting, pulsed field gel, and PCR experiments with some NF1 cDNA probes or oligonucleotides. In addition, certain regions of the NF1 gene cross-hybridize with a locus on chromosome 14. These loci can cause confusion in the mutation analysis of patients with NF1. </p><p>Numerous NF1 pseudogenes have been identified in the human genome. Those in 2q21, 14q11, and 22q11 form a subset with a similar genomic organization and a high sequence homology. By PCR and fluorescence in situ hybridization, Luijten et al. (2001) studied the extent of the homology of the regions surrounding these NF1 pseudogenes. They found that a fragment of at least 640 kb is homologous between the 3 regions. Based on previous studies and these new findings, they proposed a model for the spreading of the NF1 pseudogene-containing regions. A fragment of approximately 640 kb was first duplicated in chromosome region 2q21 and transposed to 14q11. Subsequently, this fragment was duplicated in 14q11 and transposed to 22q11. A part of the 640-kb fragment in 14q11, with a length of about 430 kb, was further duplicated to a variable extent in 14q11. In addition, Luijten et al. (2001) identified sequences that may facilitate the duplication and transposition of the 640-kb and 430-kb fragments. </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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<h4>
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<span class="mim-font">
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<strong>Gene Function</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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<p>DeClue et al. (1992) presented evidence implicating the NF1 protein as a tumor suppressor gene product that negatively regulates p21(ras) (see 190020) and defined a 'positive' growth role for RAS activity in NF1 malignancies. </p><p>Basu et al. (1992) presented evidence supporting the hypothesis that NF1 is a tumor-suppressor gene whose product acts upstream of the RAS proteins. They showed that the RAS proteins in malignant tumor cell lines from patients with NF1 were in a constitutively activated state as measured by the ratio of the guanine nucleotides bound to them, i.e., the ratio of GTP (active) to GDP (inactive). Transforming mutants of p21(ras) bind large amounts of GTP, whereas wildtype p21(ras) is almost entirely GDP-bound. </p><p>Nakafuku et al. (1993) took advantage of the yeast RAS system to isolate mutants in the RAS GTPase activating protein-related domain of the NF1 gene product (NF1-GRD) that can act as antioncogenes specific for oncogenic RAS. They demonstrated that these mutant NF1-GRDs, when expressed in mammalian cells, were able to induce morphologic reversion of RAS-transformed NIH 3T3 cells. </p><p>Johnson et al. (1993) stated that in schwannoma cell lines from patients with neurofibromatosis, loss of neurofibromin is associated with impaired regulation of GTP/RAS. They analyzed other neural crest-derived tumor cell lines and showed that some melanoma and neuroblastoma cell lines established from tumors occurring in patients without neurofibromatosis also contained reduced or undetectable levels of neurofibromin, with concomitant genetic abnormalities of the NF1 locus. In contrast to the schwannoma cell lines, however, GTP/RAS was appropriately regulated in the melanoma and neuroblastoma lines that were deficient in neurofibromin, even when HRAS (190020) was overexpressed. These results demonstrated that some neural crest tumors not associated with neurofibromatosis have acquired somatically inactivated NF1 genes and suggested a tumor-suppressor function for neurofibromin that is independent of RAS GTPase activation. </p><p>Silva et al. (1997) cited several studies that suggested a role of neurofibromin in brain function. The expression of the NF1 gene is largely restricted to neuronal tissues in the adult. This GTPase-activating protein may act as a negative regulator of neurotrophin (see BDNF; 113505)-mediated signaling. They also noted immunohistochemical studies that suggested that activation of astrocytes may be common in the brain of NF1 patients. </p><p>In a review of the molecular neurobiology of human cognition, Weeber and Sweatt (2002) presented an overview of the RAS-ERK-CREB pathway, including the function of NF1. The authors discussed publications that implicated dysfunction of this signal transduction cascade in cognitive defects, including mental retardation caused by mutation in the NF1 gene. </p><p>Vogel et al. (1995) used a targeted disruption of the NF1 gene in mice to examine the role of neurofibromin in the acquisition of neurotrophin dependence in embryonic neurons. They showed that both neural crest- and placode-derived sensory neurons isolated from NF1 -/- embryos develop, extend neurites, and survive in the absence of neurotrophins, whereas their wildtype counterparts die rapidly unless nerve growth factor (162030) or BDNF is added to the culture medium. Moreover, NF1 -/- sympathetic neurons survive for extended periods and acquire mature morphology in the presence of NGF-blocking antibodies. These results were considered by Vogel et al. (1995) as consistent with a model wherein neurofibromin acts as a negative regulator of neurotrophin-mediated signaling for survival of embryonic peripheral neurons. </p><p>For the most part the NF1 tumor suppressor acts through the interaction of its GRD with the product of the RAS protooncogene. Skuse et al. (1996) discovered an mRNA editing site within the NF1 mRNA. Editing at this site changes a cytidine at nucleotide 2914 to a uridine, creating an in-frame translation stop codon. The edited transcript, if translated, would produce a protein truncated in the N-terminal region of the GRD, thereby inactivating the NF1 tumor-suppressor function. Analysis of RNA from a variety of cell lines, tumors, and peripheral blood cells revealed that the NF1 mRNA undergoes editing, to different extents, in every cell type studied. Three tumors analyzed as part of their study, an astrocytoma, a neurofibroma, and a neurofibrosarcoma, each had levels of NF1 mRNA editing substantially higher than did peripheral blood leukocytes. To investigate the role played by editing in NF1 tumorigenesis, Cappione et al. (1997) analyzed RNA from 19 NF1 and 4 non-NF1 tumors. (The authors referred to the editing site as nucleotide 3916.) They observed varying levels in NF1 mRNA editing in different tumors, with a higher range of editing in more malignant tumors (e.g., neurofibrosarcomas) compared to benign tumors (cutaneous neurofibromas). Plexiform neurofibromas had an intermediate range of levels of NF1 mRNA editing. The constitutional levels of NF1 mRNA editing varied slightly in NF1 individuals but were consistent with the levels observed in non-NF1 individuals. In every case, there was a greater level of NF1 mRNA editing in the tumor than in the nontumor tissue from the same patient. These results suggested to Cappione et al. (1997) that inappropriately high levels of NF1 mRNA editing indeed plays a role in NF1 tumorigenesis and that editing may result in the functional equivalent of biallelic inactivation of the NF1 tumor suppressor. </p><p>Mukhopadhyay et al. (2002) studied C-to-U RNA editing in peripheral nerve sheath tumor samples (PNSTs) from 34 patients with NF1. Whereas most showed low levels of RNA editing, 8 of the 34 tumors demonstrated 3 to 12% C-to-U editing of NF1 RNA. These tumors demonstrated 2 distinguishing characteristics. First, these PNSTs expressed APOBEC1 (600130) mRNA, the catalytic deaminase of the holoenzyme that edits APOB (107730) RNA. Second, NF1 RNA from these PNSTs contained increased proportions of an alternatively spliced exon, 23A, downstream of the edited base in which editing occurs preferentially. These findings, together with results of both in vivo and in vitro experiments with APOBEC1, strongly suggested an important mechanistic linkage between NF1 RNA splicing and C-to-U editing and provided a basis for understanding the heterogeneity of posttranscriptional regulation of NF1 expression. </p><p>The NF1 tumor suppressor protein is thought to restrict cell proliferation by functioning as a Ras-specific guanosine triphosphatase-activating protein. However, The et al. (1997) found that Drosophila homozygous for null mutations of an NF1 homolog show no obvious signs of perturbed RAS1-mediated signaling. Loss of NF1 resulted in a reduction in size of larvae, pupae, and adults. This size defect was not modified by manipulating RAS1 signaling but was restored by expression of activated adenosine 3-prime, 5-prime-monophosphate -dependent protein kinase (PKA; see 176911). Thus, NF1 and PKA appear to interact in a pathway that controls the overall growth of Drosophila. Guo et al. (1997) showed, from a study of Drosophila NF1 mutants, that NF1 is essential for the cellular response to the neuropeptide PACAP38 (pituitary adenylyl cyclase-adenosine activating polypeptide) at the neuromuscular junction. The peptide induced a 3-prime, 5-prime-monophosphate (cAMP) pathway. This response was eliminated in NF1 mutants. NF1 appeared to regulate the rutabaga-encoded adenylyl cyclase rather than the RAS-RAF pathway. Moreover, the NF1 defect was rescued by the exposure of cells to pharmacologic treatment that increased concentrations of cAMP. </p><p>Gutmann (2001) reviewed the functions of neurofibromin and merlin, the product of the NF2 gene (607379), in tumor suppression and cell-cell signaling, respectively. </p><p>Trovo-Marqui and Tajara (2006) provided a detailed review of neurofibromin and its role in neurofibromatosis. </p><p>Using a proteomic approach, Phan et al. (2010) showed that ETEA (FAF2; 616935) interacted with NF1. Overexpression of ETEA downregulated NF1 in human cells. ETEA ubiquitinated the GAP-related domain of NF1 in a UBX domain-dependent manner in vitro. Silencing of ETEA increased NF1 levels and downregulated RAS activity. </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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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</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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<p><strong><em>Neurofibromatosis Type I</em></strong></p><p>
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Using pulsed field gel electrophoresis, Upadhyaya et al. (1990) identified a 90-kb deletion in the proximal portion of 17q in 1 of 90 unrelated patients with neurofibromatosis I. Viskochil et al. (1990) detected deletions of 190, 40, and 11 kb in the gene located at the 17q translocation breakpoint in 3 patients with NF1. </p><p>In an NF1 patient, Wallace et al. (1991) identified an insertion of an Alu sequence in an intron of the NF1 gene, resulting in deletion of the downstream exon during splicing and a frameshift (613113.0001). </p><p>Cawthon et al. (1990) identified 2 different point mutations in the NF1 gene (L348P; 613113.0003 and R365X; 613113.0004) in patients with NF1.</p><p>Upadhyaya et al. (1992) identified multiple germline NF1 mutations (see, e.g., 613113.0006-613113.0009) in patients with NF1. </p><p>Weiming et al. (1992) identified mutations in the NF1 gene in at most 3% of NF1 subjects in an analysis that covered 17% of the coding sequence by SSCP and a larger region by Southern blotting. The results suggested that most NF1 mutations lie elsewhere in the coding sequence or outside it. </p><p>Collins (1993) developed FISH techniques to detect large deletions in the NF1 gene.</p><p>By denaturing gradient gel electrophoresis (DGGE), Valero et al. (1994) screened 70 unrelated NF1 patients for mutations in exons 29 and 31. Of the 4 mutations that were identified, 3 consisted of C-to-T transitions resulting in nonsense mutations: 2 in exon 29 (5242C-T; 613113.0004 and 5260C-T) and 1 in exon 31 (5839C-T). The fourth mutation consisted of a 2-bp deletion in exon 31, 5843delAA, resulting in a premature stop codon. The 5839C-T mutation had previously been reported in 3 independent studies, suggesting that this position is a mutation hotspot within the NF1 gene. It occurs in a CpG residue. </p><p>Heim et al. (1994) stated that although mutations had been sought in several hundred NF1 patients, by August 1994, only 70 germline mutations had been reported in a total of 78 individuals; only the R1947X (613113.0012) mutation had been seen in as many as 6 unrelated patients. NF1 mutations that had been identified included 14 large (more than 25 bp) deletions, 3 large insertions, 18 small (less than 25 bp) deletions, 8 small insertions, 6 nonsense mutations, 14 missense mutations, and 7 intronic mutations. At least 56 (80%) of the 70 mutations potentially encode a truncated protein because of premature translation termination. </p><p>Abernathy et al. (1997) stated that about half of NF1 cases represent new mutations and fewer than 100 constitutional mutations had been reported. They used a combined heteroduplex/SSCP approach to search for mutations in the NF1 gene in a set of 67 unrelated NF1 patients and identified 26 mutations and/or variants in 45 of the 59 exons tested. Disease-causing mutations were found in 19% (13 of 67) of cases studied. The mutations included splice mutations, insertions, deletions, and point changes. </p><p>Maynard et al. (1997) screened exon 16 of the NF1 gene in 465 unrelated NF1 patients. Nine novel mutations were identified: 3 nonsense, 2 single-base deletions, 1 7-bp duplication, 2 missense, and 1 recurrent splice site mutation. No mutations had been reported previously in exon 16, which is the largest exon (441 bp) of NF1. The previous absence of mutation identification in exon 16 suggested to the authors that codons in this region may have a lower propensity to mutate. </p><p>Stop, or nonsense, mutations can have a number of effects. In the case of several genes, they affect mRNA metabolism and reduce the amount of detectable mRNA. Also, in the NF1 gene, a correlation between a high proportion of stop mutations and unequal expression of the 2 alleles is demonstrable. A second, less common outcome is that mRNA containing a nonsense mutation is translated and results in a truncated protein. A third possible outcome is an abnormally spliced mRNA induced by a premature-termination codon (PTC) in the skipped exon. This was demonstrated in several disease genes, including the CFTR gene (Hull et al., 1994) and the fibrillin gene (Dietz et al., 1993). Hoffmeyer et al. (1998) characterized several stop mutations localized within a few basepairs in exons 7 and 37 of the NF1 gene and noticed complete skipping of either exon in some cases. Because skipping of exons 7 and 37 does not lead to a frameshift, premature termination codons are avoided. Hoffmeyer et al. (1998) found that some other stop mutations in the same general region did not lead to a skip. Calculations of minimum-free-energy structures of the respective regions suggested that both changes in the secondary structure of mRNA and creation or disruption of exonic sequences relevant for the splicing process may in fact cause these different splice phenomena observed in the NF1 gene. </p><p>Mutation analysis in NF1 has been hampered by the large size of the gene (350 kb with 60 exons), the high rate of new mutations, lack of mutational clustering, and the presence of numerous homologous loci. Mutation detection methods based on the direct analysis of the RNA transcript of the gene permit the rapid screening of large multiexonic genes. However, detection of frameshift or nonsense mutations can be limited by instability of the mutant mRNA species due to nonsense-mediated decay. To determine the frequency of this allelic exclusion, Osborn and Upadhyaya (1999) analyzed total lymphocyte RNA from 15 NF1 patients with known truncation mutations and a panel of 40 NF1 patients with unknown mutations. The level of expression of the mutant message was greatly reduced in 2 of the 15 samples (13%), and in 3 of the 18 informative samples from the panel of 40. A coupled RT-PCR and protein truncation test method was subsequently applied to screen RNA from the panel of 40 unrelated NF1 patients. Aberrant polypeptide bands were identified and characterized in 21 samples (53%); each of these had a different mutation. The mutations were uniformly distributed across the gene, and 14 represented novel changes, providing further information on the germline mutational spectrum of the NF1 gene. </p><p>The mutation rate in the NF1 gene is one of the highest known in humans, with approximately 50% of all NF1 patients presenting with novel mutations (review by Huson and Hughes, 1994). Despite the high frequency of this disorder in all populations, relatively few mutations had been identified at the molecular level, with most unique to 1 family. A limited number of mutation 'hotspots' had been identified: R1947X in exon 31 (613113.0012), and the 4-bp region between nucleotides 6789 and 6792 in exon 37, both implicated in about 2% of NF1 patients (review by Upadhyaya and Cooper (1998)). Messiaen et al. (1999) identified another mutation hotspot in exon 10b. By analyzing 232 unrelated NF1 patients, they identified 9 mutations in exon 10b, indicating that this exon is mutated in almost 4% of NF1 patients. Two mutations, Y489C (613113.0023) and L508P (613113.0024), were recurrent, whereas the others were unique. The authors suggested that since 10b shows the highest mutation rate of any of the 60 NF1 exons, it should be given priority in mutation analysis. </p><p>Fahsold et al. (2000) performed a mutation screen of the NF1 gene in more than 500 unrelated patients with NF1. For each patient, the whole coding sequence and all splice sites were studied for aberrations, either by the protein truncation test (PTT), temperature-gradient gel electrophoresis (TGGE) of genomic PCR products, or, most often, by direct genomic sequencing of all individual exons. Of the variants found, they concluded that 161 different ones were novel. Mutation-detection efficiencies of the various screening methods were similar: 47.1% for PTT, 53.7% for TGGE, and 54.9% for direct sequencing. Of all sequence variants found, less than 20% represented C-to-T or G-to-A transitions within a CpG dinucleotide, and only 6 different mutations also occurred in NF1 pseudogenes, with 5 being typical C-to-T transitions in a CpG. Thus, neither frequent deamination of 5-methylcytosines nor interchromosomal gene conversion can account for the high mutation rate of the NF1 gene. As opposed to the truncating mutations, the 28 (10.1%) missense or single-amino-acid-deletion mutations identified clustered in 2 distinct regions, the GAP-related domain and an upstream gene segment comprising exons 11 to 17. The latter forms a so-called cysteine/serine-rich domain with 3 cysteine pairs suggestive of ATP binding, as well as 3 potential cAMP-dependent protein kinase recognition sites obviously phosphorylated by PKA. Coincidence of mutated amino acids and those conserved between human and Drosophila strongly suggested significant functional relevance of this region, with major roles played by exons 12a and 15 and part of exon 16. </p><p>Ars et al. (2000) applied a whole NF1 cDNA screening methodology to the study of 80 unrelated NF1 patients and identified 44 different mutations, 32 being novel, in 52 of the patients. Mutations were detected in 87% of the familial cases and in 51% of the sporadic ones. At least 15 of the 80 NF1 patients (19%) had recurrence of a previously observed mutation. The study showed that in 50% of the patients in whom the mutations were identified, these resulted in splicing alterations. Most of the splicing mutations did not involve the conserved AG/GT dinucleotides of the donor and acceptor splice sites. One frameshift, 2 nonsense, and 2 missense mutations were also responsible for alterations in mRNA splicing. Location and type of mutation within the NF1 gene and its putative effect at the protein level did not indicate any relationship to any specific clinical feature of NF1. The high proportion of aberrant spliced transcripts detected in NF1 patients stressed the importance of studying mutations at both the genomic and RNA level. Ars et al. (2000) raised the possibility that part of the clinical variability in NF1 is related to mutations affecting mRNA splicing, which is the most common molecular defect in NF1. </p><p>Messiaen et al. (2000) studied 67 unrelated NF1 patients fulfilling the NIH diagnostic criteria (Stumpf et al., 1988; Gutmann et al., 1997), 29 familial and 38 sporadic cases, using a cascade of complementary techniques. They performed a protein truncation test starting from puromycin-treated EBV cell lines and, if no mutation was found, continued with heteroduplex, FISH, Southern blot, and cytogenetic analysis. The authors identified the germline mutation in 64 of 67 patients, and 32 of the mutations were novel. The mutation spectrum consisted of 25 nonsense, 12 frameshift, 19 splice mutations, 6 missense and/or small in-frame deletions, 1 deletion of the entire NF1 gene, and a translocation t(14;17)(q32;q11.2). Their data suggested that exons 10a-10c and 37 are mutation-rich regions and that together with some recurrent mutations they may account for almost 30% of the mutations in classic NF1 patients. Messiaen et al. (2000) found a high frequency of unusual splice mutations outside of the AG/GT 5-prime and 3-prime splice sites. As some of these mutations formed stable transcripts, it remained possible that a truncated neurofibromin was formed. </p><p>Skuse and Cappione (1997) reviewed the possible molecular basis of the wide clinical variability in NF1 observed even among affected members of the same family (Huson et al., 1989). The complexities of alternative splicing and RNA editing may be involved. Skuse and Cappione (1997) suggested that the classical 2-hit model for tumor suppressor inactivation used to explain NF1 tumorigenesis can be expanded to include post-transcriptional mechanisms that regulate NF1 gene expression. Aberrations in these mechanisms may play a role in the observed clinical variability. </p><p>Eisenbarth et al. (2000) described a systematic approach of searching for somatic inactivation of the NF1 gene in neurofibromas. In the course of these studies, they identified 2 novel intragenic polymorphisms: a tetranucleotide repeat and a 21-bp duplication. Among 7 neurofibromas from 4 different NF1 patients, they detected 3 tumor-specific point mutations and 2 LOH events. The results suggested that small subtle mutations occur with similar frequency to that of LOH in benign neurofibromas and that somatic inactivation of the NF1 gene is a general event in these tumors. Eisenbarth et al. (2000) concluded that the spectrum of somatic mutations occurring in various tumors from individual NF1 patients may contribute to the understanding of variable expressivity of the NF1 phenotype. </p><p>Klose et al. (1998) identified a novel missense mutation in the NF1 gene (R1276P; 613113.0022) in a patient with a classic multisymptomatic NF1 phenotype, including a malignant schwannoma. The mutation specifically abolished the Ras-GTPase-activating function of neurofibromin. The authors suggested that therapeutic approaches aimed at the reduction of the Ras-GTP levels in neural crest-derived cells may relieve NF1 symptoms. </p><p>Kluwe et al. (1999) stated that plexiform neurofibroma can be found in about 30% of NF1 patients, often causing severe clinical symptoms. They examined 14 such tumors from 10 NF1 patients for loss of heterozygosity at the NF1 gene using 4 intragenic polymorphic markers. LOH was found in 8 tumors from 5 patients, and was suspected in 1 additional tumor from another patient. They interpreted these findings as suggesting that loss of the second allele, and thus inactivation of both alleles of the NF1 gene, is associated with the development of plexiform neurofibromas. The 14 plexiform neurofibromas were also examined for mutation in the TP53 gene; no mutations were found. </p><p>Faravelli et al. (1999) reported a family in which 7 members developed brain tumors which in 4 were confirmed as gliomas. Three of these individuals had a clinical history strongly suggestive of NF1. Two individuals with very mild features of NF1 insufficient to meet diagnostic criteria carried a splice site mutation in intron 29 of the NF1 gene, creating a frameshift and premature protein termination. Faravelli et al. (1999) noted the unusually high incidence of brain tumors in this family with the NF1 phenotype and suggested that some cases of familial glioma may be explained by mutations in the NF1 gene. </p><p>Kluwe et al. (2003) examined 20 patients with spinal tumors from 17 families for clinical symptoms associated with NF1 and for NF1 mutations. Typical NF1 features were found in 12 patients from 11 families. Typical NF1 mutations were found in 10 of the 11 index patients in this group, including 8 truncating mutations, 1 missense mutation, and 1 deletion of the entire NF1 gene. Eight patients from 6 families had no or only a few additional NF1-associated symptoms besides multiple spinal tumors, which were distributed symmetrically in all cases and affected all 38 nerve roots in 6 patients. Only mild NF1 mutations were found in 4 of the 6 index patients in the latter group, including 1 splicing mutation, 2 missense mutations, and 1 nonsense mutation in exon 47 at the 3-prime end of the gene. The data indicated that patients with spinal tumors can have various NF1 symptoms and NF1 mutations; however, patients with no or only a few additional NF1 symptoms may be a subgroup or may have a distinct form of NF1, probably associated with milder NF1 mutations or other genetic alterations. </p><p>The underestimates of NF1 gene mutations in neurofibromatosis type I have been attributed to the large size of the NF1 gene, the considerable frequency of gross deletions, and the common occurrence of splicing defects that are only detectable by cDNA analysis. A number of splicing errors do not affect the canonical GT splice donor or AG splice acceptor, or create novel splice sites, but may exert their effect by means of an altered interaction between an exonic splice enhancer (ESE) and mRNA splicing factors (Messiaen et al., 2000; Liu et al., 2001). Colapietro et al. (2003) reported skipping of exon 7 and sequence alterations in ESEs in a patient with severe NF1 (613113.0036). </p><p>The analysis of somatic NF1 gene mutations in neurofibromas from NF1 patients shows that each neurofibroma results from an individual second hit mutation; thus, factors that influence somatic mutation rates may be regarded as potential modifiers of NF1. Wiest et al. (2003) performed a mutation screen of numerous neurofibromas from 2 NF1 patients and found a predominance of point mutations, small deletions, and insertions as second hit mutations in both patients. Seven novel mutations were reported. Together with the results of studies that showed LOH as the predominant second hit in neurofibromas of other patients, these results suggest that in different patients different factors may influence the somatic mutation rate and thereby the severity of the disease. </p><p>Not only can mutations in nucleotides at the ends of introns result in abnormalities of splicing, but nonsense, missense, and even translationally silent mutations have been shown to cause exon skipping. The analysis of individual mutations of this kind can shed light on basic pre-mRNA splicing mechanisms. Using cDNA-based mutation detection analysis, Zatkova et al. (2004) identified 1 missense and 6 nonsense mutations (e.g., 613113.0042) that lead to different extents of exon-lacking transcripts in NF1 patients. They confirmed mutation-associated exon skipping in a heterologous hybrid minigene context. Because of evidence that the disruption of functional ESE sequences is frequently the mechanism underlying mutation-associated exon skipping, Zatkova et al. (2004) examined the wildtype and mutant NF1 sequences with 2 available ESE prediction programs. Either or both programs predicted the disruption of ESE motifs in 6 of the 7 analyzed mutations. To ascertain the function of the predicted ESEs, Zatkova et al. (2004) quantitatively measured their ability to rescue splicing of an enhancer-dependent exon, and found that all 7 mutant ESEs had reduced splicing enhancement activity compared to the wildtype sequences. The results suggested that the wildtype sequences function as ESE elements, whose disruption is responsible for the mutation-associated exon skipping observed in NF1 patients. Furthermore, this study illustrated the utility of ESE prediction programs for delineating candidate sequences that may serve as ESE elements. </p><p>In a girl with aniridia (106210), microphthalmia, microcephaly, and cafe-au-lait macules, Henderson et al. (2007) identified heterozygous mutations in the PAX6 (R38W; 607108.0026), NF1 (R192X; 613113.0046), and OTX2 (Y179X; 600037.0004) genes. Her mother, who carried the NF1 and PAX6 mutations, had NF1 with typical eye defects; in addition, although her eyes were of normal size, she had small corneas, and also had cataracts, optic nerve hypoplasia, nystagmus, and mild iris stromal hypoplasia with normal-sized pupils. The proband's father, who had multiple ocular defects (MCOPS5; 610125), had previously been studied by Ragge et al. (2005) and was heterozygous for the OTX2 nonsense mutation. Henderson et al. (2007) noted that the proband's phenotype was surprisingly mild, given that mutations in PAX6, OTX2, or NF1 can cause a variety of severe developmental defects. </p><p>Sabbagh et al. (2009) examined the phenotypic correlations between affected relatives in 750 NF1 patients from 275 multiplex families collected through the NF-France Network. Twelve NF1-related clinical features, including 5 quantitative traits (number of cafe-au-lait spots of small size and of large size, and number of cutaneous, subcutaneous, and plexiform neurofibromas) and 7 binary ones, were scored. All clinical features studied, with the exception of neoplasms, showed significant familial aggregation after adjusting for age and sex. For most of them, patterns of familial correlations indicated a strong genetic component with no apparent influence of the constitutional NF1 mutation. Heritability estimates of the 5 quantitative traits ranged from 0.26 to 0.62. Nine tag SNPs in NF1 were genotyped in 1,132 individuals from 313 NF1 families. No significant deviations of transmission of any of the NF1 variants to affected offspring was found for any of the 12 clinical features examined, based on single marker or haplotype analysis. Sabbagh et al. (2009) concluded that genetic modifiers, unlinked to the NF1 locus, contribute to the variable expressivity of the disease. </p><p><strong><em>Juvenile Myelomonocytic Leukemia</em></strong></p><p>
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Juvenile myelomonocytic leukemia (JMML; 607785) is a pediatric myelodysplastic syndrome that is associated with neurofibromatosis type I. The NF1 gene regulates the growth of immature myeloid cells by accelerating guanosine triphosphate hydrolysis on RAS proteins. Side et al. (1998) undertook a study to determine if the NF1 gene is involved in the pathogenesis of JMML in children without a clinical diagnosis of NF1. An in vitro transcription and translation system was used to screen JMML marrows from 20 children for NF1 mutations that resulted in a truncated protein. SSCP analysis was used to detect RAS point mutations in these samples. Side et al. (1998) confirmed mutations of NF1 in 3 cases of JMML, 1 of which also showed loss of the normal NF1 allele. An NF1 mutation was detected in normal tissue from the only patient tested, suggesting that JMML may be the presenting feature of NF1 in some children. Activating RAS mutations were found in 4 patients; as expected, none of these samples harbored NF1 mutations. Because 10 to 14% of children with JMML had a clinical diagnosis of NF1, these data were consistent with the existence of NF1 mutations in approximately 30% of JMML cases. </p><p>The risk of malignant myeloid disorders in young children with NF1 is 200 to 500 times the normal risk. Neurofibromin, the protein encoded by the NF1 gene, negatively regulates signals transduced by Ras proteins. Genetic and biochemical data support the hypothesis that NF1 functions as a tumor-suppressor gene in immature myeloid cells. This hypothesis was further supported by the demonstration by Side et al. (1997) that both NF1 alleles were inactivated in bone marrow cells from children with NF1 complicated by malignant myeloid disorders. Using an in vitro transcription and translation system, they screened bone marrow samples from 18 such children for NF1 mutations that cause a truncated protein. Mutations were confirmed by direct sequencing of genomic DNA from the patients, and from the affected parents in cases of familial NF1. Side et al. (1997) found that the normal NF1 allele was absent in bone marrow samples from 5 of 8 children who had truncating mutations of the NF1 gene. </p><p><strong><em>Neurofibromatosis-Noonan Syndrome</em></strong></p><p>
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The overlap syndrome neurofibromatosis-Noonan syndrome (601321) shows features of both disorders, as was first noted by Allanson et al. (1985). Colley et al. (1996) examined 94 sequentially identified patients with NF1 from their genetic register and found Noonan features in 12. Carey et al. (1997) identified a 3-bp deletion of exon 17 of the NF1 gene in a family with NFNS (613113.0033). Stevenson et al. (2006) provided a follow-up of this family. Baralle et al. (2003) identified mutations in the NF1 gene in 2 patients with the overlap syndrome (613113.0034 and 613113.0035). </p><p>Bertola et al. (2005) provided molecular evidence of the concurrence of neurofibromatosis and Noonan syndrome in a patient with a de novo missense mutation in the NF1 gene (613113.0043) and a mutation in the PTPN11 gene (176876.0023) inherited from her father. The proposita was noted to have cafe-au-lait spots at birth. Valvar and infundibular pulmonary stenosis and aortic coarctation were diagnosed at 20 months of age and surgically corrected at 3 years of age. As illustrated, the patient had marked hypertelorism and proptosis as well as freckling and cafe-au-lait spots. Lisch nodules were present. At the age of 8 years, a pilocytic astrocytoma in the suprasellar region involving the optic chiasm (first presenting symptomatically at 2 years of age), was partially resected. The father, who was diagnosed with Noonan syndrome, had downslanting palpebral fissures and prominent nasal labial folds. He was of short stature (159 cm) and had pectus excavatum. Electrocardiogram showed left-anterior hemiblock and complete right bundle branch block. </p><p>In a study of 17 unrelated subjects with NFNS, De Luca et al. (2005) found NF1 gene defects in 16. Remarkably, there was a high prevalence of in-frame defects affecting exons 24 and 25, which encode a portion of the GAP-related domain. No defect was observed in PTPN11 (176876), which is the usual site of mutations causing classic Noonan syndrome. De Luca et al. (2005) stated that including their study, 18 distinct NF1 gene mutations had been described in 22 unrelated patients with NFNS. </p><p><strong><em>Watson Syndrome</em></strong></p><p>
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Watson syndrome (193520) is an autosomal dominant disorder characterized by pulmonic stenosis, cafe-au-lait spots, decreased intellectual ability, and short stature. Most affected individuals have relative macrocephaly and Lisch nodules and about one-third of those affected have neurofibromas. Because of clinical similarities between Watson syndrome and neurofibromatosis, Allanson et al. (1991) performed linkage studies in families with Watson syndrome, using probes known to flank the NF1 gene on chromosome 17, and found tight linkage. In a patient with Watson syndrome, Upadhyaya et al. (1992) identified an 80-kb deletion in the NF1 gene (613113.0011). Tassabehji et al. (1993) demonstrated an almost perfect in-frame tandem duplication of 42 bases in exon 28 of the NF1 gene in 3 members of a family with Watson syndrome (613113.0010). </p><p><strong><em>Spinal Neurofibromatosis</em></strong></p><p>
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In all 5 affected members of 3-generation family with spinal neurofibromatosis (162210) and cafe-au-lait spots, Ars et al. (1998) identified a frameshift mutation in the NF1 gene (613113.0018). </p><p>In affected members of 2 families with spinal neurofibromas but no cafe-au-lait macules, Kaufmann et al. (2001) identified 2 different mutations in the NF1 gene (613113.0028 and 613113.0029, respectively). Both NF1 mutations caused a reduction in neurofibromin of approximately 50%, with no truncated protein present in the cells. The findings demonstrated that typical NF1 null mutations can result in a phenotype that is distinct from classic NF1, showing only a small spectrum of the NF1 symptoms, such as multiple spinal tumors, but not completely fitting the current clinical criteria for spinal NF. </p><p><strong><em>Role in Cancer</em></strong></p><p>
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Desmoplastic neurotropic melanoma (DNM) is an uncommon melanoma subtype that shares morphologic characteristics with nerve sheath tumors. For that reason, Gutzmer et al. (2000) analyzed 15 DNMs and 20 melanomas without morphologic features of desmoplasia or neuroid differentiation (i.e., common melanomas) for LOH at the NF1 locus and flanking regions. Allelic loss was detected in 10 of 15 (67%) DNMs but in only 1 of 20 (5%) common melanomas. LOH was most frequently observed at marker IVS38, located in intron 38 of NF1. These data suggested a role for NF1 in the pathogenesis of DNM and supported the hypothesis that exon 37 may encode a functional domain. </p><p>The Cancer Genome Atlas Research Network (2008) reported the interim integrative analysis of DNA copy number, gene expression, and DNA methylation aberrations in 206 glioblastomas and nucleotide sequence alterations in 91 of the 206 glioblastomas. The RTK/RAS/PI3K signaling pathway was altered in 88% of glioblastomas. NF1 was found to be an important gene in glioblastoma, with mutation or homozygous deletion of the NF1 gene present in 18% of tumors. </p>
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<p>See 162200 for a discussion of animal models of neurofibromatosis type I.</p><p>Ruiz-Lozano and Chien (2003) commented on how it is possible to apply Cre-loxP technology to track the cardiac morphogenic signals mediated by neurofibromin. A growing list of mouse lines that express Cre in specific cardiovascular cell lineages was available. </p><p>Gene transcription may be regulated by remote enhancer or insulator regions through chromosome looping. Using a modification of chromosome conformation capture and fluorescence in situ hybridization, Ling et al. (2006) found that 1 allele of the Igf2 (147470)/H19 (103280) imprinting control region (ICR) on mouse chromosome 7 colocalized with 1 allele of Wsb1 (610091)/Nf1 on chromosome 17. Omission of CCCTC-binding factor (CTCF; 604167) or deletion of the maternal ICR abrogated this association and altered Wsb1/Nf1 gene expression. Ling et al. (2006) concluded that CTCF mediates an interchromosomal association, perhaps by directing distant DNA segments to a common transcription factory, and the data provided a model for long-range allele-specific associations between gene regions on different chromosomes that suggested a framework for DNA recombination and RNA trans-splicing. </p><p>To investigate the function of NF1 in skeletal development, Kolanczyk et al. (2007) created mice with Nf1 knockout directed to undifferentiated mesenchymal cells of developing limbs. Inactivation of Nf1 in limbs resulted in bowing of the tibia, diminished growth, abnormal vascularization of skeletal tissues, and fusion of the hip joints and other joint abnormalities. Tibial bowing was caused by decreased stability of the cortical bone due to a high degree of porosity, decreased stiffness, and reduction in the mineral content, as well as hyperosteoidosis. Accordingly, cultured osteoblasts showed increased proliferation and decreased ability to differentiate and mineralize. The reduced growth in Nf1-knockout mice was due to reduced proliferation and differentiation of chondrocytes. </p><p>Lubeck et al. (2015) found that mice lacking both Nf1 and Rasa1 (139150) in T cells, but not those lacking either Nf1 or Rasa1 alone, developed T-cell acute lymphoblastic leukemia/lymphoma (see 613065) that originated at an early point in T-cell development and was dependent on activating mutations in Notch1 (190198). Lubeck et al. (2015) concluded that RASA1 and NF1 are co-tumor suppressors in the T-cell lineage. </p>
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<p>Gervasini et al. (2002) reported a direct tandem duplication of the NF1 gene identified in 17q11.2 by high-resolution FISH. FISH on stretched chromosomes with locus-specific probes revealed the duplication of the NF1 gene from the promoter to the 3-prime untranslated region (UTR), but with at least the absence of exon 22. Duplication was probably present in the human-chimpanzee-gorilla common ancestor, as demonstrated by the finding of the duplicated NF1 gene at orthologous chromosome loci. The authors suggested that the NF1 intrachromosomal duplication may contribute to the high whole-gene mutation rate by gene conversion. In contrast to the findings of Gervasini et al. (2002), however, Kehrer-Sawatzki et al. (2002) studied a female NF1 patient with reciprocal translocation t(17;22)(q11.2; q11.2) and determined that there is a single NF1 gene in the 17q11.2 region. Kehrer-Sawatzki and Messiaen (2003) analyzed another reciprocal translocation, a t(14;17)(q32;q11.2), described in a large family with NF1, which disrupted the NF1 gene (Messiaen et al., 2000) and again reported findings inconsistent with a duplication of the NF1 gene at 17q11.2 as proposed by Gervasini et al. (2002). </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>46 Selected Examples):</strong>
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<strong>.0001 NEUROFIBROMATOSIS, TYPE I</strong>
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NF1, ALU INS
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ClinVar: RCV000000360
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<p>In a patient with neurofibromatosis type I (NF1; 162200), Wallace et al. (1991) demonstrated a de novo heterozygous Alu repetitive element insertion into an intron of the NF1 gene, which resulted in deletion of the downstream exon during splicing and consequently shifted the reading frame. The patient was an isolated case in his family. The insertion, 300-500 bp, began 44 bp upstream of exon 6. This previously undescribed mechanism of mutation indicated that Alu retrotransposition is an ongoing process in the human germline. Alu elements had been involved in the generation of disease mutation by recombination (e.g., in familial hypercholesterolemia (143890) and ADA deficiency) or point mutation (e.g., in gyrate atrophy of the choroid and retina 258870; 613349.0023), but not as a new element. </p>
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<strong>.0002 NEUROFIBROMATOSIS, TYPE I</strong>
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NF1, 5-BP DEL
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SNP: rs2151538841,
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ClinVar: RCV000000361
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<p>In 2 patients with neurofibromatosis type I (162200), a 35-year-old man and his daughter, Stark et al. (1991) demonstrated a 5-bp deletion (CCACC or CACCT) and an adjacent transversion, located about 500 bp downstream from the region that codes for a functional domain of the NF1 gene product. The mutation was demonstrable by heteroduplex analysis. The deletion removed the proximal half of a small potential stem-loop and interrupted the reading frame in exon 1. A severely truncated protein with a grossly altered carboxy terminus lacking one-third of its sequence was the predicted consequence. Stark et al. (1992) found that both alleles were expressed in primary cultures of neurofibroma cells and melanocytes from a cafe-au-lait macule of the proband, thus excluding loss of heterozygosity. The authors used the 5-bp deletion for the presymptomatic diagnosis of the 18-month-old third son of the proband. </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>.0003 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
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NF1, LEU348PRO
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|
<br />
|
|
|
|
SNP: rs199474792,
|
|
|
|
|
|
|
|
ClinVar: RCV000000362, RCV000059211
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
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|
|
<div>
|
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<span class="mim-text-font">
|
|
<p>Cawthon et al. (1990) identified point mutations in a 4-kb sequence of the transcript of the NF1 gene at a translocation breakpoint associated with neurofibromatosis type I (162200). One mutant allele contained a T-to-C transition that caused a leu348-to-pro (L348P) substitution, and the second harbored a C-to-T insertion that changed an arg365 to a stop codon (R365X; 613113.0004).</p>
|
|
</span>
|
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</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>
|
|
<span class="mim-font">
|
|
<strong>.0004 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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NF1, ARG365TER
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<br />
|
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|
|
SNP: rs267606595,
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|
|
ClinVar: RCV000000363
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Independently, Cawthon et al. (1990) and Estivill et al. (1991) identified a new mutation in exon 4 of the NF1 gene, a 1087C-T transition (numbering of Cawthon et al., 1990), resulting in an arg365-to-ter (R365X) substitution, in patients with neurofibromatosis type I (NF1; 162200). Although a different numbering system was used, this is the same mutation as that found by Valero et al. (1994) and designated 5242C-T in exon 29. They proposed that this site, in a CpG residue, is a hotspot for mutation in the NF1 gene. </p>
|
|
</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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, LYS1423GLU
|
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|
|
|
<br />
|
|
|
|
SNP: rs137854550,
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|
|
|
|
|
gnomAD: rs137854550,
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|
|
|
|
|
ClinVar: RCV000000364, RCV000489593, RCV000626644, RCV000762990, RCV002305424, RCV002310992, RCV003460397, RCV004798706
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with neurofibromatosis type I (NF1; 162200) and affected members of his family, Li et al. (1992) found an AAG-to-GAG transition at codon 1423 in the NF1 gene, resulting in the substitution of glutamic acid for lysine (K1423E). </p><p>The same mutation or a mutation in the same codon leading to substitution of glutamine for lysine through an A-to-C transversion was also observed by Li et al. (1992) as a somatic mutation in adenocarcinoma of the colon, myelodysplastic syndrome, and anaplastic astrocytoma. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, 1-BP INS, 5662C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606596,
|
|
|
|
|
|
|
|
ClinVar: RCV000000365
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with neurofibromatosis type I (NF1; 162200), Upadhyaya et al. (1992) found insertion of a cytosine within codon 1818 of the NF1 gene that changed the reading frame and resulted in 23 altered amino acids prior to the inappropriate introduction of a stop codon at amino acid 1841. The insertion created a recognition site for enzyme MnlI. (The authors incorrectly stated in their abstract and the legend of their Figure 3 that there was a nucleotide insertion at 'codon 5662.' The nucleotide insertion at residue 5662 occurs within codon 1818 in their cDNA clone of NF1, as correctly represented in the sequence shown in their Figure 3.) </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, 1-BP INS, FS1841TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606597,
|
|
|
|
|
|
|
|
ClinVar: RCV000000366
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with neurofibromatosis type I (NF1; 162200), Upadhyaya et al. (1992) found an insertion of thymidine in codon 1823, resulting in a shift of the reading frame, the generation of 18 amino acids different from those of the normal protein, and a gene product that terminated prematurely at amino acid 1840 by the creation of a stop codon at 1841. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, LEU2143MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854551,
|
|
|
|
|
|
|
|
ClinVar: RCV000000367
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with neurofibromatosis type I (NF1; 162200), Upadhyaya et al. (1992) found a heterozygous 6639C-A transversion in the NF1 gene, resulting in a leu2143-to-met (L2143M) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, TYR2213ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606598,
|
|
|
|
|
|
gnomAD: rs267606598,
|
|
|
|
|
|
ClinVar: RCV000000368
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with neurofibromatosis type I (NF1; 162200), Upadhyaya et al. (1992) found a heterozygous 6724T-G transversion in the NF1 gene, resulting in a tyr2213-to-asn (Y2213N) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 WATSON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, 42-BP DUP
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000000369
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family in which Watson syndrome (WTSN; 193520) had occurred in 3 generations, Tassabehji et al. (1993) demonstrated an almost perfect in-frame tandem duplication of 42 bases in exon 28 of the NF1 gene. Unlike the mutations previously described in classic NF1 which result predominantly in null alleles, the mutation in this family would be expected to result in a mutant neurofibromin product. The affected mother had multiple cafe-au-lait patches, freckling in the axillary and groin, low-set posteriorly rotated ears, a squint, and an IQ of 56. She had no Lisch nodules or neurofibromata. A daughter, aged 3.5 years, had multiple cafe-au-lait spots, mild pectus carinatum, hypertelorism with epicanthic folds, a squint, low-set posteriorly rotated ears, and moderate global developmental delay. Her twin brother had ptosis, mild cubitus valgus, bilateral undescended testes, and mild pulmonic valvular stenosis by echocardiography. Neither child had Lisch nodules or neurofibromata. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 WATSON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, 80-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000000370
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Upadhyaya et al. (1992) found an 80-kb deletion at the NF1 locus in a patient with Watson syndrome (WTSN; 193520). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, ARG1947TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854552,
|
|
|
|
|
|
|
|
ClinVar: RCV000000371, RCV000418287, RCV000492774, RCV000762995, RCV001009602, RCV003460398, RCV004547450, RCV004558221, RCV004562178, RCV004668704
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>A C-to-T transition changing arginine-1947 to a stop codon (R1947X) in the NF1 gene has been described in multiple Caucasian and Japanese families with neurofibromatosis type I (NF1; 162200), suggesting that this codon, CGA, is a hotspot for mutation, presumably because it contains a CpG dinucleotide. (Numbering of codons is based on Marchuk et al. (1991).) The mutation was described in 3 unrelated Caucasians (Ainsworth et al., 1993; Cawthon et al., 1990; Estivill et al., 1991); at least 2 of these cases were sporadic. Horiuchi et al. (1994) reported the same mutation in 2 unrelated familial cases of NF1. That these represented independent mutations was indicated by the fact that in the 2 families the affected individuals differed with regard to a polymorphism located within the NF1 gene. The frequency of the arg1947-to-ter mutation may be as high as 8% in Japanese and at least 1% in Caucasians. Studying one of the patients with the arg1947-to-ter mutation, Horiuchi et al. (1994) showed that both the normal and the mutant allele were transcribed in a lymphoblastoid cell line. </p><p>Heim et al. (1994) stated that the R1947X mutation had been reported in 6 unrelated patients with NF1. </p><p>Lazaro et al. (1995) presented 2 further cases of the R1947X mutation in the NF1 gene. They stated that a total of 9 cases of the R1947X mutation had been reported, giving a frequency of about 2%. They developed an allele-specific oligonucleotide hybridization assay for the efficient screening of a large number of samples for this relatively common recurrent mutation. </p><p>In a sample of 56 unrelated Korean patients with NF1, Park et al. (2000) identified 1 with the R1947X mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, IVS18DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606599,
|
|
|
|
|
|
gnomAD: rs267606599,
|
|
|
|
|
|
ClinVar: RCV000000373, RCV000680818, RCV001009591, RCV001018701, RCV002381233, RCV004547451
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Purandare et al. (1995) identified a G-to-A transition at position +1 of intron 18 of the NF1 gene in a 41-year-old Caucasian female in whom the diagnosis of neurofibromatosis (NF1; 162200) was first made at the age of 28 years when she was admitted to hospital for a grand mal seizure. A son was also affected. The mutation resulted in skipping of exon 18 which did not cause a shift in the reading frame but resulted in an in-frame loss of 123 nucleotides from the mRNA and the corresponding 41 amino acids from the protein. Purandare et al. (1995) referred to 3 previously reported splice donor site mutations in the NF1 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, 2-BP DEL, 1541AG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606600,
|
|
|
|
|
|
|
|
ClinVar: RCV000000374, RCV000164295, RCV000414730, RCV001001001, RCV002288457, RCV003460399, RCV004797745, RCV005016220
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Robinson et al. (1996) described a recurrent 2-bp deletion (1541delAG) in exon 10c of the NF1 gene in 2 unrelated patients with neurofibromatosis type I (NF1; 162200): one sporadic and one familial case. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, MET1035ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854553,
|
|
|
|
|
|
|
|
ClinVar: RCV000000375
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Wu et al. (1996) found a de novo met1035-to-arg (M1035R) missense mutation resulting from a T-to-G transversion in exon 18 of the NF1 gene in a 32-year-old woman with a prior diagnosis of LEOPARD syndrome (151100), who was found to have neurofibromatosis type I (NF1; 162200). At birth, a heart murmur was detected resulting from subvalvular muscular aortic stenosis and valvular aortic stenosis. The skin showed multiple dark lentigines together with a few larger cafe-au-lait patches. The same lentigines were present in the armpits and groin and were not raised. The patient attended a special school for children with mild mental retardation. At the age of 21 years, mitral insufficiency was demonstrated resulting from a double orifice mitral valve. The patient had macrocrania (head circumference 58 cm), apparent hypertelorism, and a coarse face with broad neck. Neurofibromas were not present at the age of 32, and no Lisch nodules were seen by slit-lamp examination. The mutation was absent in the parents, who were clinically normal. </p>
|
|
</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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, ARG1391SER
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|
|
|
|
<br />
|
|
|
|
SNP: rs137854554,
|
|
|
|
|
|
|
|
ClinVar: RCV000000376, RCV001810827, RCV002326656
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Upadhyaya et al. (1997) identified 14 novel mutations in the GAP-related domain of neurofibromin in patients with neurofibromatosis type I (NF1; 162200). One of these mutations was a change at nucleotide 4173 from A to T, changing codon 1391 from AGA (arg) to AGT (ser) (R1391S). The effect of this R1391S missense mutation was studied by in vitro expression of a site-directed mutant and by GAP activity assay. The mutant protein was found to be some 300-fold less active than wildtype NF1 protein. </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>.0017 REMOVED FROM DATABASE</strong>
|
|
</span>
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|
</h4>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
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|
</div>
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|
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<div>
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|
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|
<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 NEUROFIBROMATOSIS, FAMILIAL SPINAL</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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|
|
|
NF1, 1-BP INS, 8042A
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|
<br />
|
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|
|
SNP: rs267606601,
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|
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|
|
ClinVar: RCV000000377
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 affected members of a family with spinal neurofibromatosis with cafe-au-lait macules (162210), Ars et al. (1998) identified a 1-bp insertion (8042insA) in exon 46 of the NF1 gene. The mutation was predicted to result in a truncated protein. </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>.0019 LEUKEMIA, JUVENILE MYELOMONOCYTIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, TRP1538TER
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs137854555,
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|
|
|
|
ClinVar: RCV000000378, RCV000660063, RCV001007974
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Among 20 children with juvenile myelomonocytic leukemia (JMML; 607785), Side et al. (1998) found 3 with truncating mutations in the NF1 gene. One of the children, a 3-year-old boy, had a G-to-A transition at nucleotide 4614, which converted codon 1538 from tryptophan to stop in exon 27a (W1538X). </p>
|
|
</span>
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|
</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>
|
|
<span class="mim-font">
|
|
<strong>.0020 LEUKEMIA, JUVENILE MYELOMONOCYTIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, IVS34, G-A, +18
|
|
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|
|
<br />
|
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|
|
|
|
|
|
ClinVar: RCV000000379
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 19-month-old boy with juvenile myelomonocytic leukemia (JMML/Mo7; 607785), Side et al. (1998) found in cloned cDNA aberrant splicing resulting in a shift in the reading frame. Genomic DNA showed an alteration (6579,G-A,+18) in the splice donor consensus sequence flanking exon 34. This mutation introduced an additional 17 nucleotides containing a novel BglI restriction enzyme site into the patient's cDNA. Side et al. (1998) identified this restriction site in amplified cDNA derived from the patient's EBV cell line RNA, thus confirming that this mutation existed in the germline. Furthermore, loss of heterozygosity was demonstrated, indicating inactivation of another NF1 allele. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 LEUKEMIA, JUVENILE MYELOMONOCYTIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
NEUROFIBROMATOSIS, TYPE I, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, IVS11, A-G, -8
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606602,
|
|
|
|
|
|
|
|
ClinVar: RCV000000380, RCV000190422
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-month-old boy with juvenile myelomonocytic leukemia (JMML; 607785), Side et al. (1998) described a splice mutation in the NF1 gene. Cloned cDNA showed abnormal splicing of 7 nucleotides between exons 10c and 11. The authors had previously found the same mutation in a child with familial NF1 and myelodysplasia syndrome (Side et al. (1997)); genomic DNA sequence showed an abnormal splice acceptor sequence upstream of exon 11 (1642-8A-G) creating a cryptic splice site and consequent frameshift and premature stop codon at codon 555. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, ARG1276PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854556,
|
|
|
|
|
|
gnomAD: rs137854556,
|
|
|
|
|
|
ClinVar: RCV000000381, RCV002267796, RCV002354143
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with a classic multisymptomatic NF1 phenotype (162200), including a malignant schwannoma, Klose et al. (1998) found an arg1276-to-pro (R1276P) mutation in the arginine finger of the GAP-related domain (GRD) of the neurofibromin gene, resulting in disruption of the most essential catalytic element for Ras-GAP activity. Klose et al. (1998) presented data demonstrating that the R1276P mutation, unlike previously reported missense mutations of the GRD region, did not impair the secondary and tertiary protein structure. It neither reduced the level of cellular neurofibromin nor influenced its binding to Ras substantially, but it did completely disable GAP activity. The findings provided direct evidence that failure of neurofibromin GAP activity is a critical element in NF1 pathogenesis. The findings suggested that therapeutic approaches aimed at the reduction of the Ras-GTP levels in neural crest-derived cells can be expected to relieve most of the NF1 symptoms. The proband was the first child of unaffected, nonconsanguineous parents. She developed multiple cafe-au-lait spots within the first year of life. Her language and motor development were mildly retarded, and she complained of incoordination throughout life. Around puberty, multiple cutaneous neurofibromas developed which worsened at the time of each of her 3 pregnancies. At the age of 31 years, routine MRI of the brain revealed multiple areas of increased T2 signal intensity in the midbrain and a small optic glioma. Because of recurrent paresthesias in her left leg, an MRI scan of the spine was done 2 years later which revealed multiple schwannomas within the vertebral foramina. The largest tumor in the lumbar region, with a volume of approximately 8 ml, was surgically removed. Histologically, there was no evidence of malignancy at that time. Eight months later, the patient suffered a relapse with rapid tumor growth. At the time of reoperation, the retroperitoneal tumor had reached a volume of 800 ml and showed numerous necrotic and anaplastic areas with a proliferation rate up to 60%. The patient died of widespread metastatic disease at the age of 34 years. Her 3 male children, ages 4, 8, and 12 years, all fulfilled the NF1 diagnostic criteria. The 2 elder sons were macrocephalic. Language and motor development of all children was retarded to a similar extent and on the same time scale as in their mother. A cranial MRI scan in the 2 elder brothers showed increased T2 signal intensities similar to those in their mother. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, TYR489CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854557,
|
|
|
|
|
|
gnomAD: rs137854557,
|
|
|
|
|
|
ClinVar: RCV000000382, RCV000492667, RCV000757556, RCV001009573, RCV001257527, RCV001813925, RCV002504731, RCV003460400, RCV004737131, RCV004783716
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Among the 9 NF1 exon 10b mutations identified by Messiaen et al. (1999) in 232 unrelated patients with neurofibromatosis type I (162200), 2 were recurrent: an A-to-G transition at nucleotide 1466, resulting in a tyr489-to-cys substitution (Y489C), and a T-to-C transition at nucleotide 1523, resulting in a leu508-to-pro substitution (L508P; 613113.0024). The Y489C mutation caused skipping of the last 62 nucleotides of exon 10b, while the L508P mutation was undetectable by the protein truncation test. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, LEU508PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854558,
|
|
|
|
|
|
|
|
ClinVar: RCV000000383
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the leu508-to-pro (L508P) mutation in the NF1 gene that was found in compound heterozygous state in patients with neurofibromatosis I (162200) by Messiaen et al. (1999), see 613113.0023. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, IVS9DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606603,
|
|
|
|
|
|
|
|
ClinVar: RCV000000384, RCV001547975
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with type I neurofibromatosis (NF1; 162200), Eisenbarth et al. (2000) identified a germline G-to-A transition at nucleotide 1260+1, the splice donor site of intron 9 of the NF1 gene, leading to the inclusion of 13 bp of intervening sequence into the NF1 messenger. The mutant allele was present in all tissues tested. In a neurofibroma from this patient, an additional C-to-T transition at nucleotide 4021 (Q1341X; 613113.0026), a presumed 'second hit' somatic mutation, was identified. Another neurofibroma from the same patient showed a C-to-T transition at nucleotide 4084 (R1362X; 613113.0027), a presumed further 'second hit' somatic mutation. Both somatic mutations led to premature stop codons in the NF1 message. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 NEUROFIBROMATOSIS, TYPE I, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, GLN1341TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854559,
|
|
|
|
|
|
|
|
ClinVar: RCV000000385, RCV001810828
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gln1341-to-ter (Q1341X) mutation in the NF1 gene that was found in a patient with type I neurofibromatosis (NF1; 162200) by Eisenbarth et al. (2000), see 613113.0025. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 NEUROFIBROMATOSIS, TYPE I, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, ARG1362TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854560,
|
|
|
|
|
|
gnomAD: rs137854560,
|
|
|
|
|
|
ClinVar: RCV000000372, RCV000483061, RCV000492495, RCV002504730
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the arg1362-to-ter (R1362X) mutation in the NF1 gene that was found in a patient with type I neurofibromatosis (NF1; 162200) by Eisenbarth et al. (2000), see 613113.0025. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 NEUROFIBROMATOSIS, FAMILIAL SPINAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, LEU2067PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137854561,
|
|
|
|
|
|
|
|
ClinVar: RCV000000386, RCV002354144
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with spinal neurofibromatosis but without cafe-au-lait macules (162210), Kaufmann et al. (2001) identified a leu2067-to-pro (L2067P) mutation in exon 33 of the NF1 gene. Her clinically unaffected 61-year-old father had the same NF1 mutation in his blood cells. Additional molecular investigations to exclude mosaicism were not feasible and additional clinical investigations through MRI scans could not be performed. The L2067P mutation yielded an unstable product of approximately 50% normal neurofibromin levels, indicating functional haploinsufficiency. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0029 NEUROFIBROMATOSIS, TYPE I</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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NEUROFIBROMATOSIS, FAMILIAL SPINAL, 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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|
NF1, IVS31AS, A-G, -5
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<br />
|
|
|
|
SNP: rs267606604,
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|
ClinVar: RCV000000387, RCV000000388, RCV001582455, RCV002316183, RCV004566663
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|
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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 neurofibromatosis type I (NF1; 162200), Fahsold et al. (2000) identified an A-to-G transition in the NF1 gene splice acceptor site of exon 31 (IVS31-5A-G), resulting in the addition of 4 bases to exon 32 and a premature stop codon at amino acid 1995. </p><p>In affected members of a family with spinal neurofibromatosis without cafe-au-lait macules (162210), Kaufmann et al. (2001) identified the exon 31 splice site mutation. Noting that the same mutation had been reported in a patient with classic NF1, the authors concluded that a modifying gene may compensate for some of the effects of neurofibromin deficiency. The splice site NF1 mutation resulted in instability of the neurofibromin 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>.0030 NEUROFIBROMATOSIS, TYPE I</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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NF1, DEL
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<br />
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ClinVar: RCV000000389
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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>Upadhyaya et al. (2003) described a Portuguese family in which 3 members had clinical features of neurofibromatosis type I (NF1; 162200) and each had a different underlying defect in the NF1 gene. A 12-year-old boy who had multiple cafe-au-lait spots on his trunk and legs as well as developmental delay had a heterozygous 1.5-Mb deletion including the entire NF1 gene. The mutation was associated with the maternally derived chromosomal haplotype. His 10-year-old brother, who exhibited multiple cafe-au-lait spots and macrocephaly but whose development was within the normal range, was heterozygous for a CGA-to-TGA transition in exon 22 of the NF1 gene, resulting in an arg1241-to-ter mutation (613113.0031). This mutation had previously been described; its recurrence was thought to have been mediated by 5-methylcytosine deamination because it occurred in a hypermutable CpG dinucleotide. The brothers' 26-year-old female first cousin once removed (a first cousin of their father) exhibited multiple cafe-au-lait spots, bilateral Lisch nodules, and multiple dermal neurofibromas. She also showed severe scoliosis and several plexiform neurofibromas in the clavicular region, but her development was within the normal range. She was found to carry a frameshift mutation, 5406insT (613113.0032), in exon 29 of the NF1 gene. None of the parents had any clinical evidence of NF1 and none had a mutation in the NF1 gene. There was also no evidence of mosaicism. Upadhyaya et al. (2003) speculated about the mechanism of this unusual situation. </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>.0031 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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NF1, ARG1241TER
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<br />
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|
|
SNP: rs137854562,
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|
|
ClinVar: RCV000000390, RCV000129869, RCV000578991, RCV003466769, RCV004668705, RCV004737132
|
|
|
|
|
|
</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 arg1241-to-ter (R1241X) mutation in the NF1 gene that was found in heterozygous state in 1 of 3 members of a family with clinical features of neurofibromatosis type I (NF1; 162200) by Upadhyaya et al. (2003), see 613113.0030. </p><p>Fahsold et al. (2000) described a CGA-to-TGA transition in the NF1 gene, resulting in an R1241X mutation, as the cause of neurofibromatosis type I. </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>.0032 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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NF1, 1-BP INS, 5406T
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<br />
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SNP: rs267606605,
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ClinVar: RCV000000391, RCV000492318, RCV002272259
|
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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>For discussion of the 1-bp insertion (5406insT) in the NF1 gene that was found in heterozygous state in 1 of 3 members of a family with clinical features of neurofibromatosis type I (NF1; 162200) by Upadhyaya et al. (2003), see 613113.0030. </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>.0033 NEUROFIBROMATOSIS-NOONAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
|
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<div>
|
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<span class="mim-text-font">
|
|
WATSON SYNDROME, INCLUDED
|
|
</span>
|
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</div>
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|
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<div>
|
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<span class="mim-text-font">
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|
|
|
NF1, 3-BP DEL, 2970AAT
|
|
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<br />
|
|
|
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SNP: rs267606606,
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|
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gnomAD: rs267606606,
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|
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ClinVar: RCV000000392, RCV000000393, RCV000196290, RCV000215737, RCV000384725, RCV002496217, RCV003162200, RCV003466770
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
<p>Carey et al. (1997) described a 3-bp deletion in exon 17 of the NF1 gene in affected members of a family with neurofibromatosis-Noonan syndrome (NFNS; 601321). The 2970delAAT mutation resulted in deletion of met991. The clinical features of the 3 subjects were tabulated by De Luca et al. (2005). Stevenson et al. (2006) reported a follow-up of this family. </p><p>Upadhyaya et al. (2007) reported this mutation in 47 affected individuals from 21 unrelated families with a similar phenotype, lacking cutaneous neurofibromas or clinically obvious plexiform neurofibromas. One of the families had been reported by Stevenson et al. (2006); another was reported by Castle et al. (2003) and had a diagnosis of Watson syndrome (WTSN; 193520). The in-frame 3-bp deletion in exon 17 was predicted to result in the loss of 1 of 2 adjacent methionines, either codon 991 or codon 992, in conjunction with a silent ACA-to-ACG change of codon 990. These 2 methionine residues are located in a highly conserved region of neurofibromin and are expected, therefore, to have a functional role in the protein. This was said to have been the first study to correlate a specific small mutation of the NF1 gene with the expression of a particular clinical phenotype. </p><p>Koczkowska et al. (2019) performed a standardized phenotypic assessment on 135 individuals from 103 unrelated families carrying the NF1 p.Met992del mutation. None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. None had optic gliomas or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. Of 119 patients evaluated, 15 (12.6%) had Noonan-like features. The authors concluded that NF patients carrying this variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation. </p>
|
|
</span>
|
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</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>.0034 NEUROFIBROMATOSIS-NOONAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
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<span class="mim-text-font">
|
|
|
|
NF1, 3-BP DEL, 4312GAA
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<br />
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|
|
SNP: rs267606607,
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|
|
ClinVar: RCV000000394, RCV000544772, RCV002326657, RCV003156210, RCV003466771, RCV004547452
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with neurofibromatosis-Noonan syndrome (NFNS; 601321), Baralle et al. (2003) identified a 3-bp deletion, 4312delGAA, in exon 25 of the NF1 gene. The patient was a 6-year-old boy with more than 6 cafe-au-lait macules. There were no other features of neurofibromatosis type I, but his mother had a single cafe-au-lait macule and Lisch nodules, low hairline, and short neck. He had ptosis, epicanthal folds, low posterior hairline, and low-set ears. On echocardiogram he had pulmonic stenosis. No neurofibromas were present. </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>.0035 NEUROFIBROMATOSIS-NOONAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, 2-BP INS, 4095TG
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs267606608,
|
|
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|
|
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|
|
ClinVar: RCV000000395
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with neurofibromatosis-Noonan syndrome (NFNS; 601321), Baralle et al. (2003) identified a 2-bp insertion, 4095insTG, in exon 23-2 of the NF1 gene. The patient was a 20-year-old man with 7 cafe-au-lait macules, axillary freckling, 10 neurofibromas, Lisch nodules, and scoliosis with a structural cervical vertebral abnormality. He had downslanting palpebral fissures, ptosis, a short, broad neck, widely spaced nipples, and an atrial septal defect. He was of short stature and needed extra help in mainstream school. There was no family history of similar findings. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0036 NEUROFIBROMATOSIS TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, 20075G-A, 20076C-A
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs267606609,
|
|
|
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|
|
|
|
ClinVar: RCV000000396
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe neurofibromatosis type I (NF1; 162200), Colapietro et al. (2003) found a G-to-A transition and a C-to-A transversion at nucleotide positions 57 and 58, respectively, of the 154-bp long NF1 exon 7, neither of which was present in the proband's parents or 50 healthy controls. RT-PCR analysis showed the expected fragment from exon 4b to 8 together with a shortened one with in-frame skipping of exon 7. Direct sequencing of genomic DNA revealed 2 exonic heterozygous changes at nucleotides 20075 (G-A transition) and 20076 (C-A transversion), which belong to contiguous codons. The first substitution occurred in the third base of the codon, changing it from CAG to CAA, both encoding glutamine (Q315Q); the second changed the CTG codon for leucine to the ATG codon for methionine (L316M). The use of previously established sequence matrices for the scoring of putative ESE motifs showed that the adjacent silent and missense mutations were located within highly conserved overlapping stretches of 7 nucleotides with a close similarity to the ESE-specific consensus sequences recognized by the SC35 (600813) and SF2/ASF (600812) arginine/serine-rich (SR) proteins. The combined occurrence of both consecutive alterations decreased the motif score for both SR proteins below their threshold levels. As the aberrant transcript was consistently expressed, a protein lacking 58 amino acids was predicted. Thus, the contiguous internal exon 7 mutations appear to have caused exon 7 skipping as a result of the missplicing caused by abrogation of functional ESEs (see Cartegni et al. (2002) and Fairbrother et al. (2002)). The male proband in the study of Colapietro et al. (2003) was the third child of healthy unrelated parents. At the age of 1 year, he underwent uronephrectomy because of right renal dysplasia. At the age of 3 years, an optic glioma was identified and surgically excised. The diagnosis of NF1 was made when he was 9 years old on the basis of the presence of cafe-au-lait spots, optic glioma, and Lisch nodules of the iris. Cerebral MRI at the age of 11 years revealed multiple hamartomas and a right hemisphere cerebral venous angioma. The patient showed borderline mental retardation, a height in the 10th percentile, and an occipitofrontal head circumference in the 97th percentile. At the age of 20 years, he showed macrocephaly, numerous cafe-au-lait spots, small cutaneous neurofibromas, a plexiform neck neurofibroma, and axillary and inguinal freckling. Scoliosis, winged scapulae, and bilateral genu valgum were also present. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0037 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
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NF1, 1-BP DEL, 3775T
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|
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<br />
|
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|
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SNP: rs1567852567,
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ClinVar: RCV000000397
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</span>
|
|
</div>
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|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with neurofibromatosis type I (NF1; 162200), Maris et al. (2002) identified a 1-bp deletion in the NF1 gene, 3775delT. The mutation was not present in the patient's parents. </p><p>Mosse et al. (2004) showed that the patient originally described by Maris et al. (2002) also had neuroblastoma (256700) and Hirschsprung disease (142623), which were caused by a 1-bp deletion in the PHOX2B gene (676delG; 603851.0007). </p>
|
|
</span>
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</div>
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|
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0038 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
NEUROFIBROMATOSIS, FAMILIAL SPINAL, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, LEU357PRO
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<br />
|
|
|
|
SNP: rs137854563,
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|
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ClinVar: RCV000000398, RCV000000399, RCV002476903, RCV002496218
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|
|
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</span>
|
|
</div>
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|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with neurofibromatosis type I (NF1; 162200), Fahsold et al. (2000) identified a 1070T-C transition in exon 8 of the NF1 gene, resulting in a leu357-to-pro (L357P) substitution. </p><p>In 7 affected members of a family with spinal neurofibromatosis (162210) originally reported by Poyhonen et al. (1997), Messiaen et al. (2003) identified the L357P mutation. The mutation was not detected in 200 normal chromosomes. </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>.0039 NEUROFIBROMATOSIS, FAMILIAL SPINAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
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<span class="mim-text-font">
|
|
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|
NF1, IVS39DS, A-C, +3
|
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<br />
|
|
|
|
SNP: rs267606610,
|
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|
|
ClinVar: RCV000000400
|
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|
|
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</span>
|
|
</div>
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with spinal neurofibromatosis (NF1; 162210) originally reported by Pulst et al. (1991), Messiaen et al. (2003) identified an A-to-C transversion at position +3 of the donor splice site of exon 39 of the NF1 gene (7126+3A-C), resulting in the skipping of exon 39. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
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</div>
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0040 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, 1-BP DEL, 4071C
|
|
|
|
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<br />
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ClinVar: RCV000000401
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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 neurofibromatosis type I (NF1; 162200) who had onset of neurofibromatous neuropathy at the age of 42 years, Ferner et al. (2004) identified a 1-bp deletion (4071delC) in exon 23.2 of the NF1 gene, resulting in a premature stop codon. The deletion was predicted to generate a truncated neurofibromin of 1,383 amino acids. Neuroimaging studies showed the presence of multiple spinal nerve root neurofibromas. A high-grade malignant peripheral nerve sheath tumor (MPNST) had been removed from the left iliac fossa previously, with no recurrence. Benign flexiform neurofibroma was present in the left abdominal wall. </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>.0041 NEUROFIBROMATOSIS, TYPE I</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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NF1, LEU1243PRO
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<br />
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SNP: rs137854564,
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ClinVar: RCV000000402, RCV000680822
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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 neurofibromatosis type I (NF1; 162200) who had onset of neurofibromatous neuropathy at the age of 17 years, Ferner et al. (2004) identified a 1243T-C transition in the NF1 gene, resulting in a leu1243-to-pro (L1243P) substitution. </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>.0042 NEUROFIBROMATOSIS, TYPE I</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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NF1, GLU1904TER
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<br />
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SNP: rs137854565,
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ClinVar: RCV000000403
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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 cDNA-based mutation detection analysis, Zatkova et al. (2004) studied 7 nonsense or missense alleles of NF1 that caused exon skipping and showed that disruption of exonic splicing enhancer (ESE) elements was responsible. One of the 7 mutations was a novel nonsense mutation, a 5719G-T transversion, resulting in a glu1904-to-ter (G1904X) substitution in exon 30. The phenotype was neurofibromatosis type I (NF1; 162200). </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>.0043 NEUROFIBROMATOSIS, TYPE I</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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NF1, LEU844ARG
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<br />
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SNP: rs137854566,
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gnomAD: rs137854566,
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ClinVar: RCV000000404
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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>Bertola et al. (2005) described a 14-year-old girl with neurofibromatosis type I (NF1; 162200), caused by a de novo mutation in the NF1 gene, and Noonan syndrome (163950), caused by a mutation in the PTPN11 gene (176876.0023) inherited from her father. The NF1 mutation was a 2531A-G transition resulting in a leu844-to-arg substitution. The proband had pulmonary stenosis and aortic coarctation requiring surgery and also had a pilocytic astrocytoma in the suprasellar region involving the optic chiasm and forming the third ventricle. She had cafe-au-lait spots and axillary freckling typical of neurofibromatosis and marked hypertelorism characteristic of Noonan syndrome. </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>.0044 NEUROFIBROMATOSIS, TYPE I</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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NF1, IVS27DS, G-C, +1
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<br />
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SNP: rs1555619056,
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ClinVar: RCV000000405, RCV004791184
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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 mother and son with a mild form of neurofibromatosis I (NF1; 162200), Thiel et al. (2009) identified a heterozygous mutation (4661+1G-C) in intron 27 of the NF1 gene, resulting in the skipping of exon 27a and potentially affecting the GAP-related domain. Both patients had cafe-au-lait spots and mild myopia, but no neurofibromas, Lisch nodules, or optic gliomas. The daughter of the mother, who also carried the NF1 mutation, was found to be compound heterozygous with a mutation in the PTPN11 gene (T2I; 176876.0027). In addition to features of neurofibromatosis I, she also had features of Noonan syndrome (163950), including hypertelorism, low-set ears, poor growth, sternal deformity, valvular pulmonic stenosis, and delayed development. The PTPN11 mutation was predicted to destabilize the inactive form of PTPN11, resulting in increased basal activity and a gain of function. The girl also developed bilateral optic gliomas before age 2 years, which may be explained by an additive effect of both the NF1 and PTPN11 mutations on the Ras pathway. Compound heterozygosity for mutations in NF1 and PTPN11 were also reported by Bertola et al. (2005) in a patient with a combination of neurofibromatosis I and Noonan syndrome. </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>.0045 NEUROFIBROMATOSIS-NOONAN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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NF1, LEU1390PHE
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<br />
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SNP: rs199474789,
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|
|
ClinVar: RCV000023983, RCV000059194, RCV000195735
|
|
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 5-generation family with neurofibromatosis-Noonan syndrome (NFNS; 601321), Nystrom et al. (2009) identified a heterozygous 4168C-T transition in exon 24 of the NF1 gene, resulting in a leu1390-to-phe (L1390F) substitution in the highly conserved GAP-related domain. The family was originally reported by Ahlbom et al. (1995) as having Noonan syndrome based on dysmorphic facial features, short stature, pulmonary stenosis, and short neck. Upon reevaluation, Nystrom et al. (2009) found that several family members had cafe-au-lait spots, axillary freckling, Lisch nodules, and multiple nevi, consistent with NF1, but that all family members lacked dermal and superficial plexiform neurofibromas. The authors concluded that the clinical diagnosis was consistent with NFNS. Nystrom et al. (2009) postulated that the L1390F mutation resulted in impaired GTPase activity. </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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|
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|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0046 NEUROFIBROMATOSIS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
NF1, ARG192TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397514641,
|
|
|
|
|
|
gnomAD: rs397514641,
|
|
|
|
|
|
ClinVar: RCV000033171, RCV000442381, RCV000626737, RCV001003806, RCV002310996, RCV003231110, RCV003460540, RCV004798752, RCV005016317
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with aniridia, microphthalmia, microcephaly, and cafe-au-lait macules, Henderson et al. (2007) identified heterozygosity for a 574C-T transition in exon 4b of the NF1 gene, resulting in an arg192-to-ter (R192X) substitution, as well as heterozygous mutations in the PAX6 (R38W; 607108.0026) and OTX2 (Y179X; 600037.0004) genes. Her mother, who carried the NF1 and PAX6 mutations, had NF1 (162200) with the typical eye defects of retinal fibroma, optic nerve glioma, and gross Lisch nodules on the iris; in addition, although her eyes were of normal size, she had eyes were of normal size, she had small corneas, and also had cataracts, optic nerve hypoplasia, nystagmus, and mild iris stromal hypoplasia with normal-sized pupils. The proband's father, who had multiple ocular defects (MCOPS5; 610125), had previously been studied by Ragge et al. (2005) and was heterozygous for the OTX2 nonsense mutation. Henderson et al. (2007) noted that the proband's phenotype was surprisingly mild, given that mutations in PAX6, OTX2, or NF1 can cause a variety of severe developmental defects. </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>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
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<div>
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<p />
|
|
</div>
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<div>
|
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<ol>
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<li>
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<p class="mim-text-font">
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Abernathy, C. R., Rasmussen, S. A., Stalker, H. J., Zori, R., Driscoll, D. J., Williams, C. A., Kousseff, B. G., Wallace, M. R.
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<strong>NF1 mutation analysis using a combined heteroduplex/SSCP approach.</strong>
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Hum. Mutat. 9: 548-554, 1997.
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Ahlbom, B. E., Dahl, N., Zetterqvist, P., Anneren, G.
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<strong>Noonan syndrome with cafe-au-lait spots and multiple lentigines syndrome are not linked to the neurofibromatosis type 1 locus.</strong>
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Clin. Genet. 48: 85-89, 1995.
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Ainsworth, P. J., Rodenhiser, D. I., Costa, M. T.
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Allanson, J. E., Hall, J. G., Van Allen, M. I.
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<p class="mim-text-font">
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Allanson, J. E., Upadhyaya, M., Watson, G. H., Partington, M., MacKenzie, A., Lahey, D., MacLeod, H., Sarfarazi, M., Broadhead, W., Harper, P. S., Huson, S. M.
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<strong>Watson syndrome: is it a subtype of type 1 neurofibromatosis?</strong>
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J. Med. Genet. 28: 752-756, 1991.
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<p class="mim-text-font">
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Ars, E., Kruyer, H., Gaona, A., Casquero, P., Rosell, J., Volpini, V., Serra, E., Lazaro, C., Estivill, X.
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<strong>A clinical variant of neurofibromatosis type 1: familial spinal neurofibromatosis with a frameshift mutation in the NF1 gene.</strong>
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Am. J. Hum. Genet. 62: 834-841, 1998.
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[PubMed: 9529361]
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<p class="mim-text-font">
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Ars, E., Serra, E., Garcia, J., Kruyer, H., Gaona, A., Lazaro, C., Estivill, X.
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<strong>Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1.</strong>
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Hum. Molec. Genet. 9: 237-247, 2000. Note: Erratum: Hum. Molec. Genet. 9: 659 only, 2000.
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<p class="mim-text-font">
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Baralle, D., Mattocks, C., Kalidas, K., Elmslie, F., Whittaker, J., Lees, M., Ragge, N., Patton, M. A., Winter, R. M., ffrench-Constant, C.
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<strong>Different mutations in the NF1 gene are associated with neurofibromatosis-Noonan syndrome (NFNS).</strong>
|
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Am. J. Med. Genet. 119A: 1-8, 2003.
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[PubMed: 12707950]
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<p class="mim-text-font">
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Barker, D., Wright, E., Nguyen, K., Cannon, L., Fain, P., Goldgar, D., Bishop, D. T., Carey, J., Baty, B., Kivlin, J., Willard, H., Waye, J. S., Greig, G., Leinwand, L., Nakamura, Y., O'Connell, P., Leppert, M., Lalouel, J.-M., White, R., Skolnick, M.
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<strong>Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17.</strong>
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Science 236: 1100-1102, 1987.
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[PubMed: 3107130]
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[Full Text: https://doi.org/10.1126/science.3107130]
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<p class="mim-text-font">
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Basu, T. N., Gutmann, D. H., Fletcher, J. A., Glover, T. W., Collins, F. S., Downward, J.
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<strong>Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients.</strong>
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Nature 356: 713-715, 1992.
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<p class="mim-text-font">
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Bertola, D. R., Pereira, A. C., Passetti, F., de Oliveira, P. S. L., Messiaen, L., Gelb, B. D., Kim, C. A., Krieger, J. E.
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<strong>Neurofibromatosis -Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient.</strong>
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Am. J. Med. Genet. 136A: 242-245, 2005.
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<p class="mim-text-font">
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Buchberg, A. M., Cleveland, L. S., Jenkins, N. A., Copeland, N. G.
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<strong>Sequence homology shared by neurofibromatosis type-1 gene and IRA-1 and IRA-2 negative regulators of the RAS cyclic AMP pathway.</strong>
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Nature 347: 291-294, 1990.
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[PubMed: 2169593]
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Cancer Genome Atlas Research Network.
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<strong>Comprehensive genomic characterization defines human glioblastoma genes and core pathways.</strong>
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Nature 455: 1061-1068, 2008. Note: Erratum: Nature 494: 506 only, 2013.
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[PubMed: 18772890]
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[Full Text: https://doi.org/10.1038/nature07385]
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</p>
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<li>
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<p class="mim-text-font">
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|
Cappione, A. J., French, B. L., Skuse, G. R.
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<strong>A potential role for NF1 mRNA editing in the pathogenesis of NF1 tumors.</strong>
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Am. J. Hum. Genet. 60: 305-312, 1997.
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[PubMed: 9012403]
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</p>
|
|
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Contributors:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 03/04/2020<br>Paul J. Converse - updated : 4/29/2016<br>Paul J. Converse - updated : 3/3/2016<br>Marla J. F. O'Neill - updated : 2/22/2013<br>Cassandra L. Kniffin - updated : 12/23/2010<br>Cassandra L. Kniffin - updated : 11/8/2010<br>George E. Tiller - updated : 6/23/2010<br>Patricia A. Hartz - updated : 3/18/2010
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Creation Date:
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alopez : 05/01/2024<br>carol : 02/22/2022<br>alopez : 03/04/2020<br>carol : 05/15/2019<br>carol : 10/05/2018<br>mgross : 03/20/2017<br>joanna : 08/04/2016<br>joanna : 07/01/2016<br>mgross : 4/29/2016<br>carol : 3/4/2016<br>mgross : 3/3/2016<br>carol : 8/18/2015<br>mcolton : 8/11/2015<br>carol : 10/1/2013<br>joanna : 8/5/2013<br>carol : 4/3/2013<br>carol : 2/22/2013<br>carol : 1/9/2013<br>terry : 11/13/2012<br>carol : 3/16/2012<br>wwang : 1/10/2011<br>ckniffin : 12/23/2010<br>wwang : 11/12/2010<br>ckniffin : 11/8/2010<br>wwang : 7/1/2010<br>terry : 6/23/2010<br>carol : 5/25/2010<br>alopez : 4/30/2010<br>carol : 4/9/2010<br>mgross : 3/18/2010<br>terry : 3/18/2010<br>carol : 12/1/2009<br>terry : 11/24/2009<br>carol : 11/23/2009<br>ckniffin : 11/17/2009<br>ckniffin : 11/17/2009<br>terry : 11/9/2009<br>terry : 11/9/2009<br>carol : 11/6/2009
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