14399 lines
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Entry
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- *606945 - LOW DENSITY LIPOPROTEIN RECEPTOR; LDLR
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- OMIM
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<p>
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<span class="h4">*606945</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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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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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="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#populationGenetics">Population Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606945">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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</div>
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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=ENSG00000130164;t=ENST00000558518" 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=3949" 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=606945" 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=ENSG00000130164;t=ENST00000558518" 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_000527,NM_001195798,NM_001195799,NM_001195800,NM_001195803,NM_001406861,XM_011528010,XM_047438831" 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_000527" 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=606945" 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=06091&isoform_id=06091_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/LDLR" 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/126073,307121,619786,1381234,4261791,4504975,6691161,7690049,13347121,15680298,21629648,30583561,32187681,41058942,62088398,77157502,87298849,119604574,119604575,119604576,119604577,119604578,194380684,194382908,194386604,194390612,225131047,306411087,306411097,307775412,307775414,307775416,307775422,308171318,768002424,800909295,800909297,1720337420,1843423323,1843423325,1843423327,1843423329,1843423331,1843423333,1843423335,1843423337,1843423339,1843423341,1843423343,1843423345,1843423347,1843423349,1843423351,1843423353,1843423355,1843423357,1843423359,1843423361,1843423363,1843423365,1843423367,2217321263,2241236972,2462565402,2462565404" 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/P01130" 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=3949" 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=ENSG00000130164;t=ENST00000558518" 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=LDLR" 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=LDLR" 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+3949" 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/LDLR" 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:3949" 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/3949" 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=chr19&hgg_gene=ENST00000558518.6&hgg_start=11089463&hgg_end=11133820&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:6547" 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:6547" 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/ldlr" 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=606945[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=606945[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://gnomad.broadinstitute.org/gene/ENSG00000130164" 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=LDLR" 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=LDLR" 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=LDLR" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://databases.lovd.nl/shared/genes/LDLR" title="Hypercholesterolemia, Familial" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Hypercholesterolemia, Fami…</a></div><div style="margin-left: 0.5em;"><a href="http://www.umd.be/LDLR/" title="UMD Locus Specific Databases" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">UMD Locus Specific Databas…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=LDLR&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/PA227" 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:6547" 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/FBgn0051092.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:96765" 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/LDLR#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:96765" 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/3949/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/results?search_type=advanced&omia_id=000499,001160" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=3949" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00020481;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-031217-1" 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:3949" 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=LDLR&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> 397915002, 441665004<br />
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<strong>ICD10CM:</strong> E78.00<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>
|
|
606945
|
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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>
|
|
<h3>
|
|
<span class="mim-font">
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LOW DENSITY LIPOPROTEIN RECEPTOR; LDLR
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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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=LDLR" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">LDLR</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/19/288?start=-3&limit=10&highlight=288">19p13.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:11089463-11133820&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'})">19:11,089,463-11,133,820</a> </span>
|
|
</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
|
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|
</th>
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<th>
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|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/19/288?start=-3&limit=10&highlight=288">
|
|
19p13.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Hypercholesterolemia, familial, 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/143890"> 143890 </a>
|
|
|
|
</span>
|
|
</td>
|
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<td>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<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 low density lipoprotein receptor is a cell surface receptor that plays an important role in cholesterol homeostasis.</p>
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<p>The low density lipoprotein receptor is synthesized as a 120-kD glycoprotein precursor that undergoes change to a 160-kD mature glycoprotein through the covalent addition of a 40-kD protein (<a href="#129" class="mim-tip-reference" title="Tolleshaug, H., Goldstein, J. L., Schneider, W. J., Brown, M. S. <strong>Posttranslational processing of the LDL receptor and its genetic disruption in familial hypercholesterolemia.</strong> Cell 30: 715-724, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6291781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6291781</a>] [<a href="https://doi.org/10.1016/0092-8674(82)90276-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6291781">Tolleshaug et al., 1982</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6291781" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#141" class="mim-tip-reference" title="Yamamoto, T., Davis, C. G., Brown, M. S., Schneider, W. J., Casey, M. L., Goldstein, J. L., Russell, D. W. <strong>The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA.</strong> Cell 39: 27-38, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6091915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6091915</a>] [<a href="https://doi.org/10.1016/0092-8674(84)90188-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6091915">Yamamoto et al. (1984)</a> reported that the human LDL receptor is an 839-amino acid protein rich in cysteine, with multiple copies of the Alu family of repetitive DNAs. <a href="#109" class="mim-tip-reference" title="Russell, D. W., Schneider, W. J., Yamamoto, T., Luskey, K. L., Brown, M. S., Goldstein, J. L. <strong>Domain map of the LDL receptor: sequence homology with the epidermal growth factor precursor.</strong> Cell 37: 577-585, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6327078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6327078</a>] [<a href="https://doi.org/10.1016/0092-8674(84)90388-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6327078">Russell et al. (1984)</a> demonstrated DNA sequence homology of the LDL receptor with the epidermal growth factor receptor (EGF; <a href="/entry/131530">131530</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6091915+6327078" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#120" class="mim-tip-reference" title="Sudhof, T. C., Goldstein, J. L., Brown, M. S., Russell, D. W. <strong>The LDL receptor gene: a mosaic of exons shared with different proteins.</strong> Science 228: 815-822, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2988123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2988123</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=2988123[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.2988123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2988123">Sudhof et al. (1985)</a> found that 13 of the 18 exons of the gene encode protein sequences that are homologous to sequences in other proteins: 5 encode a sequence similar to one in C9 component of complement (<a href="/entry/120940">120940</a>); 3 encode a sequence similar to a repeat sequence in the precursor for EGF and in 3 proteins of the blood clotting system--factor IX (<a href="/entry/300746">300746</a>), factor X (<a href="/entry/613872">613872</a>), and protein C (<a href="/entry/612283">612283</a>), and 5 other exons encode nonrepeated sequences that are shared only with the EGF precursor. Since the LDL receptor is a mosaic protein built up of exons shared with different proteins, it is a member of several supergene families. <a href="#33" class="mim-tip-reference" title="Gilbert, W. <strong>Genes-in-pieces revisited.</strong> Science 228: 823-824, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4001923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4001923</a>] [<a href="https://doi.org/10.1126/science.4001923" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4001923">Gilbert (1985)</a> commented on the relevance of these findings to understanding the significance of 'split genes' and 'exon shuffling' during evolution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4001923+2988123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#30" class="mim-tip-reference" title="Francke, U., Brown, M. S., Goldstein, J. L. <strong>Assignment of the human gene for the low density lipoprotein receptor to chromosome 19: synteny of a receptor, a ligand, and a genetic disease.</strong> Proc. Nat. Acad. Sci. 81: 2826-2830, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6326146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6326146</a>] [<a href="https://doi.org/10.1073/pnas.81.9.2826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6326146">Francke et al. (1984)</a> assigned the LDL receptor to chromosome 19 on the basis of expression studies in hamster-human somatic cell hybrids. The LDLR gene was regionalized to 19p13.1-p13.3 by in situ hybridization (<a href="#91" class="mim-tip-reference" title="Lindgren, V., Luskey, K. L., Russell, D. W., Francke, U. <strong>Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes.</strong> Proc. Nat. Acad. Sci. 82: 8567-8571, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3866240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3866240</a>] [<a href="https://doi.org/10.1073/pnas.82.24.8567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3866240">Lindgren et al., 1985</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6326146+3866240" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Frank, S. L., Taylor, B. A., Lusis, A. J. <strong>Linkage of the mouse LDL receptor gene on chromosome 9.</strong> Genomics 5: 646-648, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2575592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2575592</a>] [<a href="https://doi.org/10.1016/0888-7543(89)90037-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2575592">Frank et al. (1989)</a> identified RFLPs of the mouse LDL receptor gene and used them to map the gene, designated Ldlr, to the proximal region of chromosome 9. Using interspecific backcrosses, they established the order and interval distances for this and several other loci on mouse chromosome 9, namely, Apoa4 (<a href="/entry/107690">107690</a>), which is on chromosome 11 in man, and mannosephosphate isomerase (<a href="/entry/154550">154550</a>), which is on chromosome 15 in man. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2575592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#13" class="mim-tip-reference" title="Brown, M. S., Goldstein, J. L. <strong>Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme at reductase activity.</strong> Proc. Nat. Acad. Sci. 71: 788-792, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4362634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4362634</a>] [<a href="https://doi.org/10.1073/pnas.71.3.788" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4362634">Brown and Goldstein (1974)</a> described LDL binding to cultured fibroblasts in a manner consistent with a receptor, and found that this binding resulted in suppression of cholesterol synthesis by the cell via repression of HMG CoA reductase. In a review article, <a href="#15" class="mim-tip-reference" title="Brown, M. S., Goldstein, J. L. <strong>Receptor-mediated endocytosis: insights from the lipoprotein receptor system.</strong> Proc. Nat. Acad. Sci. 76: 3330-3337, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/226968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">226968</a>] [<a href="https://doi.org/10.1073/pnas.76.7.3330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="226968">Brown and Goldstein (1979)</a> described the mechanism of receptor-mediated endocytosis using the LDL receptor as the prototypic example, thus further describing its role in cholesterol metabolism. Normally, LDL is bound at the cell membrane and taken into the cell ending up in lysosomes where the protein is degraded and the cholesterol is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=226968+4362634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#92" class="mim-tip-reference" title="Lo, J. C., Wang, Y., Tumanov, A. V., Bamji, M., Yao, Z., Reardon, C. A., Getz, G. S., Fu, Y.-X. <strong>Lymphotoxin beta receptor-dependent control of lipid homeostasis.</strong> Science 316: 285-288, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17431181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17431181</a>] [<a href="https://doi.org/10.1126/science.1137221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17431181">Lo et al. (2007)</a> observed that inhibition of lymphotoxin (see <a href="/entry/153440">153440</a>) and LIGHT (TNFSF14; <a href="/entry/604520">604520</a>) signaling with a soluble lymphotoxin B receptor (LTBR; <a href="/entry/600979">600979</a>) decoy protein attenuated the dyslipidemia in LDL receptor-deficient mice, which lack the ability to control lipid levels in the blood. The authors concluded that the immune system directly influences lipid metabolism and that lymphotoxin modulating agents may represent a novel therapeutic route for the treatment of dyslipidemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17431181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>LDL Receptor as a Viral Receptor</em></strong></p><p>
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Hepatitis C virus (HCV), the principal viral cause of chronic hepatitis, is not readily replicated in cell culture systems, making it difficult to ascertain information on cell receptors for the virus. However, several observations from studies on the role of HCV in mixed cryoglobulinemia provided some insight into HCV entry into cells. Evidence indicated that HCV and other viruses enter cells through the mediation of LDL receptors: by the demonstration that endocytosis of these viruses correlates with LDL receptor activity, by complete inhibition of detectable endocytosis by anti-LDL receptor antibody, by inhibition with anti-apolipoprotein E and anti-apolipoprotein B antibodies, by chemical methods abrogating lipoprotein/LDL receptor interactions, and by inhibition with the endocytosis inhibitor phenylarsine oxide. <a href="#3" class="mim-tip-reference" title="Agnello, V., Abel, G., Elfahal, M., Knight, G. B., Zhang, Q.-X. <strong>Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor.</strong> Proc. Nat. Acad. Sci. 96: 12766-12771, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10535997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10535997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10535997[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.22.12766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10535997">Agnello et al. (1999)</a> provided confirmatory evidence by the lack of detectable LDL receptor on cells known to be resistant to infection by one of these viruses, bovine viral diarrheal virus (BVDV). Endocytosis via the LDL receptor was shown to be mediated by complexing of the virus to very low density lipoprotein (VLDL) or LDL, but not high density lipoprotein (HDL). Studies using LDL receptor-deficient cells or a cytolytic BVDV system indicated that the LDL receptor may be the main but not exclusive means of cell entry of these viruses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10535997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Atherogenic lipoprotein phenotype (<a href="/entry/108725">108725</a>) shows close linkage to the LDLR locus; indeed, the mutation(s) responsible for this phenotype may reside in the LDLR gene rather than in a separate, closely situated gene.</p><p><a href="#142" class="mim-tip-reference" title="Zelcer, N., Hong, C., Boyadjian, R., Tontonoz, P. <strong>LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor.</strong> Science 325: 100-104, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19520913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19520913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19520913[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1168974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19520913">Zelcer et al. (2009)</a> demonstrated that the sterol-responsive nuclear liver X receptor (LXR) (see <a href="/entry/600380">600380</a>) helps maintain cholesterol homeostasis, not only through promotion of cholesterol efflux but also through suppression of LDL uptake. LXR inhibits the LDLR pathway through the transcriptional induction of IDOL (MYLIP; <a href="/entry/610082">610082</a>), an E3 ubiquitin ligase that triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby targeting it for degradation. LXR ligand reduced, whereas LXR knockout increased, LDLR protein levels in vivo in a tissue-selective manner. IDOL knockdown in hepatocytes increased LDLR protein levels and promoted LDL uptake. Conversely, <a href="#142" class="mim-tip-reference" title="Zelcer, N., Hong, C., Boyadjian, R., Tontonoz, P. <strong>LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor.</strong> Science 325: 100-104, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19520913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19520913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19520913[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1168974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19520913">Zelcer et al. (2009)</a> found that adenovirus-mediated expression of IDOL in mouse liver promoted LDLR degradation and elevated plasma LDL levels. <a href="#142" class="mim-tip-reference" title="Zelcer, N., Hong, C., Boyadjian, R., Tontonoz, P. <strong>LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor.</strong> Science 325: 100-104, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19520913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19520913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19520913[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1168974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19520913">Zelcer et al. (2009)</a> concluded that the LXR-IDOL-LDLR axis defines a complementary pathway to sterol response element-binding proteins for sterol regulation of cholesterol uptake. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19520913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#105" class="mim-tip-reference" title="Rudenko, G., Henry, L., Henderson, K., Ichtchenko, K., Brown, M. S., Goldstein, J. L., Deisenhofer, J. <strong>Structure of the LDL receptor extracellular domain at endosomal pH.</strong> Science 298: 2353-2358, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12459547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12459547</a>] [<a href="https://doi.org/10.1126/science.1078124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12459547">Rudenko et al. (2002)</a> described the crystal structure of the LDL receptor extracellular domain at endosomal pH. The ligand-binding domain (modules R2 to R7) folds back as an arc over the epidermal growth factor precursor homology domain (the modules A, B, beta propeller, and C). The modules R4 and R5, which are critical for lipoprotein binding, associate with the beta propeller via their calcium-binding loop. <a href="#105" class="mim-tip-reference" title="Rudenko, G., Henry, L., Henderson, K., Ichtchenko, K., Brown, M. S., Goldstein, J. L., Deisenhofer, J. <strong>Structure of the LDL receptor extracellular domain at endosomal pH.</strong> Science 298: 2353-2358, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12459547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12459547</a>] [<a href="https://doi.org/10.1126/science.1078124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12459547">Rudenko et al. (2002)</a> proposed a mechanism for lipoprotein release in the endosome whereby the beta propeller functions as an alternate substrate for the ligand-binding domain, binding in a calcium-dependent way and promoting lipoprotein release. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12459547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#14" class="mim-tip-reference" title="Brown, M. S., Goldstein, J. L. <strong>Analysis of a mutant strain of human fibroblasts with a defect in the internalization of receptor-bound low density lipoproteins.</strong> Cell 9: 663-674, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/189940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">189940</a>] [<a href="https://doi.org/10.1016/0092-8674(76)90130-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="189940">Brown and Goldstein (1976)</a> found that one of the LDLR mutations in a patient (J.D.) with familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>) was able to bind LDL normally, but internalization of the receptor-bound protein failed to occur. The internalization defect was a tyr807-to-cys (Y207C; <a href="#0019">606945.0019</a>) substitution inherited from his father; he also had binding defect (null allele) inherited from his mother (<a href="#17" class="mim-tip-reference" title="Davis, C. G., Lehrman, M. A., Russell, D. W., Anderson, R. G. W., Brown, M. S., Goldstein, J. L. <strong>The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors.</strong> Cell 45: 15-24, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3955657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3955657</a>] [<a href="https://doi.org/10.1016/0092-8674(86)90533-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3955657">Davis et al., 1986</a>). <a href="#77" class="mim-tip-reference" title="Lehrman, M. A., Goldstein, J. L., Brown, M. S., Russell, D. W., Schneider, W. J. <strong>Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain.</strong> Cell 41: 735-743, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3924410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3924410</a>] [<a href="https://doi.org/10.1016/s0092-8674(85)80054-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3924410">Lehrman et al. (1985)</a> had previously identified a nonsense and a frameshift mutation in the LDLR gene that truncated the cytoplasmic domain, resulting in internalization-defective LDL receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3924410+189940+3955657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with homozygous familial hypercholesterolemia-1, <a href="#43" class="mim-tip-reference" title="Hobbs, H. H., Brown, M. S., Goldstein, J. L., Russell, D. W. <strong>Deletion of exon encoding cysteine-rich repeat of low density lipoprotein receptor alters its binding specificity in a subject with familial hypercholesterolemia.</strong> J. Biol. Chem. 261: 13114-13120, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3020025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3020025</a>]" pmid="3020025">Hobbs et al. (1986)</a> described an LDL receptor mutant in which 1 of the 7 repeating units constituting the ligand-binding domain had been deleted. The deletion arose by homologous recombination by repetitive Alu sequences in intron 4 and intron 5 of the gene. The deletion removed exon 5, which normally encodes the sixth repeat of the ligand binding domain. In the resultant mRNA, exon 4 was found to be spliced to exon 6, preserving the reading frame. The resulting shortened protein reaches the cell surface and reacts with antireceptor antibodies but does not bind LDL. It does, however, bind VLDL, a lipoprotein that contains apoprotein E as well as apoprotein B-100. The findings in this instructive case supported the hypothesis that the 7 repeated sequences in the receptor constitute the LDL-binding domain, that the sixth repeat is required for binding of LDL but not of VLDL, and that deletion of a single repeat can alter the binding specificity of the LDL receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3020025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Horsthemke, B., Beisiegel, U., Dunning, A., Havinga, J. R., Williamson, R., Humphries, S. <strong>Unequal crossing-over between two Alu-repetitive DNA sequences in the low-density-lipoprotein-receptor gene: a possible mechanism for the defect in a patient with familial hypercholesterolaemia.</strong> Europ. J. Biochem. 164: 77-81, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3549308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3549308</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1987.tb10995.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3549308">Horsthemke et al. (1987)</a> analyzed DNA from 70 patients in the UK with heterozygous familial hypercholesterolemia. In most, the restriction fragment pattern of the LDLR gene was indistinguishable from normal; however, 3 patients were found to have a deletion of about 1 kb in the central portion of the gene. In 2 patients, the deletion included all or part of exon 5 (<a href="#0027">606945.0027</a>); in the third, the deletion included exon 7 (<a href="#0033">606945.0033</a>). Including a previously described patient with a deletion in the 3-prime part of the gene, these results indicated that 4 out of 70 patients, or 6%, have deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3549308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#74" class="mim-tip-reference" title="Langlois, S., Kastelein, J. J. P., Hayden, M. R. <strong>Characterization of six partial deletions in the low-density-lipoprotein (LDL) receptor gene causing familial hypercholesterolemia (FH).</strong> Am. J. Hum. Genet. 43: 60-68, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2837085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2837085</a>]" pmid="2837085">Langlois et al. (1988)</a> screened 234 unrelated heterozygotes for FH to detect major rearrangements in the LDLR gene. Total genomic DNA was analyzed by Southern blot hybridization to probes encompassing exons 1 to 18 of the LDLR gene. Six different mutations were detected and characterized by use of exon-specific probes and detailed restriction mapping. The frequency of deletions in the <a href="#74" class="mim-tip-reference" title="Langlois, S., Kastelein, J. J. P., Hayden, M. R. <strong>Characterization of six partial deletions in the low-density-lipoprotein (LDL) receptor gene causing familial hypercholesterolemia (FH).</strong> Am. J. Hum. Genet. 43: 60-68, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2837085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2837085</a>]" pmid="2837085">Langlois et al. (1988)</a> study was 2.5% (6 out of 234 patients). An illustration of previously mapped deletions and the deletions identified in this study (a total of 16) suggested that particular areas in the LDLR gene are susceptible to deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2837085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Japanese subject with homozygous hypercholesterolemia, <a href="#78" class="mim-tip-reference" title="Lehrman, M. A., Goldstein, J. L., Russell, D. W., Brown, M. S. <strong>Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia.</strong> Cell 48: 827-835, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3815525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3815525</a>] [<a href="https://doi.org/10.1016/0092-8674(87)90079-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3815525">Lehrman et al. (1987)</a> found a 7.8-kb deletion in LDLR (<a href="#0029">606945.0029</a>). The deletion joined intron 15 to the middle of exon 18, which encodes the 3-prime untranslated region, thereby removing all 3-prime splice acceptor sites distal to intron 15. The mRNA should produce a truncated receptor that lacks the normal membrane-COOH terminus. The truncated protein was such that more than 90% of the receptor was secreted from the cell, and the receptors remaining on the surface showed defective internalization. The deletion resulted from recombination between 2 repetitive sequences of the Alu family, one in intron 15 and the other in exon 18. <a href="#78" class="mim-tip-reference" title="Lehrman, M. A., Goldstein, J. L., Russell, D. W., Brown, M. S. <strong>Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia.</strong> Cell 48: 827-835, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3815525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3815525</a>] [<a href="https://doi.org/10.1016/0092-8674(87)90079-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3815525">Lehrman et al. (1987)</a> stated that Alu sequences had been found at the deletion joints of all 4 gross deletions that had been characterized in LDLR. Because of these and similar findings in connection with deletions in the gamma-delta-beta-globin cluster, recombination between Alu sequences appears to be a frequent cause of deletions in the human genome (see EVOLUTION). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3815525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Horsthemke, B., Beisiegel, U., Dunning, A., Havinga, J. R., Williamson, R., Humphries, S. <strong>Unequal crossing-over between two Alu-repetitive DNA sequences in the low-density-lipoprotein-receptor gene: a possible mechanism for the defect in a patient with familial hypercholesterolaemia.</strong> Europ. J. Biochem. 164: 77-81, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3549308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3549308</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1987.tb10995.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3549308">Horsthemke et al. (1987)</a> suggested that unequal crossing-over between 2 Alu-repetitive DNA sequences was responsible for an intragenic deletion of the LDLR gene leading to familial hypercholesterolemia. A 4-kb deletion had occurred between an Alu-repetitive sequence in intron 12 and a sequence in intron 14. The deletion eliminated exons 13 and 14 and changed the reading frame of the resulting spliced mRNA such that a stop codon was created in the following exon (<a href="#0032">606945.0032</a>). The truncated receptor protein appeared to be rapidly degraded. The deletion was presumably caused by an unequal crossover event between 2 homologous chromosomes at meiosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3549308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#47" class="mim-tip-reference" title="Hobbs, H. H., Leitersdorf, E., Goldstein, J. L., Brown, M. S., Russell, D. W. <strong>Multiple CRM- mutations in familial hypercholesterolemia: evidence for 13 alleles, including four deletions.</strong> J. Clin. Invest. 81: 909-917, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3343347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3343347</a>] [<a href="https://doi.org/10.1172/JCI113402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3343347">Hobbs et al. (1988)</a> found that 16 of 132 cell strains (12%) from persons with the clinical syndrome of homozygous familial hypercholesterolemia synthesized no immunodetectable LDL receptor protein, indicating the presence of 2 mutant genes that failed to produce crossreacting material (CRM-negative mutants). DNA and mRNA from all but one of these CRM-negative patients were available for study. Haplotype analysis based on 10 RFLPs suggested that the 30 CRM-negative genes represented by these 15 individuals had included 13 different mutant alleles. Four of the alleles produced no mRNA; 3 of these 4 had large deletions ranging from 6 to 20 kb that eliminated the promoter region of the gene. The reason for the lack of mRNA in the fourth allele was not apparent. Three alleles encoded mRNAs of abnormal size. One of the abnormal mRNAs was produced by a gene harboring a deletion, and another was produced by a gene with a complex rearrangement. The third abnormal-sized mRNA (3.1 kb larger than normal) was produced by an allele that had no detectable alteration as judged by Southern blotting. The other 6 mRNA-positive alleles appeared normal by Southern blotting and produced normal-sized mRNA but no receptor protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3343347" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 20 mutant LDL receptor genes, <a href="#140" class="mim-tip-reference" title="Yamakawa, K., Takada, K., Yanagi, H., Tsuchiya, S., Kawai, K., Nakagawa, S., Kajiyama, G., Hamaguchi, H. <strong>Three novel partial deletions of the low-density lipoprotein (LDL) receptor gene in familial hypercholesterolemia.</strong> Hum. Genet. 82: 317-321, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2544509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2544509</a>] [<a href="https://doi.org/10.1007/BF00273989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2544509">Yamakawa et al. (1989)</a> found 4 different deletion mutations (20%). None of these had been reported previously in Caucasians. Three of them were novel and one was similar to a previously described Japanese mutation. In 3 of the 4 deletions, the rearrangements were related to intron 15 in which there are many Alu sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2544509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Rudiger, N. S., Heinsvig, E. M., Hansen, F. A., Faergeman, O., Bolund, L., Gregersen, N. <strong>DNA deletions in the low density lipoprotein (LDL) receptor gene in Danish families with familial hypercholesterolemia.</strong> Clin. Genet. 39: 451-462, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1863993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1863993</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1991.tb03057.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1863993">Rudiger et al. (1991)</a> reviewed previously described deletions in the LDLR gene in cases of familial hypercholesterolemia and reported the finding of a deletion in 3 of 25 unrelated patients with FH. Two of these were equivalent to previously described LDLR alterations, thus supporting a notion of recombination hotspots which involve Alu sequences. In at least 4 cases (FH626, PO, JA, and FH-DK3), a deletion of exon 5 of the LDLR gene has been found as the defect responsible for FH. The FH626 mutation was characterized by <a href="#43" class="mim-tip-reference" title="Hobbs, H. H., Brown, M. S., Goldstein, J. L., Russell, D. W. <strong>Deletion of exon encoding cysteine-rich repeat of low density lipoprotein receptor alters its binding specificity in a subject with familial hypercholesterolemia.</strong> J. Biol. Chem. 261: 13114-13120, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3020025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3020025</a>]" pmid="3020025">Hobbs et al. (1986)</a> and found to involve Alu repeat sequences in introns 4 and 5. <a href="#106" class="mim-tip-reference" title="Rudiger, N. S., Heinsvig, E. M., Hansen, F. A., Faergeman, O., Bolund, L., Gregersen, N. <strong>DNA deletions in the low density lipoprotein (LDL) receptor gene in Danish families with familial hypercholesterolemia.</strong> Clin. Genet. 39: 451-462, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1863993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1863993</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1991.tb03057.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1863993">Rudiger et al. (1991)</a> characterized FH-DK3 and likewise found involvement of 2 Alu repeated sequences present in introns 4 and 5. The crossover breakpoints involve sequences similar to those reported for FH626 but not at identical positions in the 5-prime end. By use of denaturing gradient gel electrophoresis (DGGE) in combination with PCR, <a href="#131" class="mim-tip-reference" title="Top, B., Uitterlinden, A. G., van der Zee, A., Kastelein, J. J. P., Gevers Leuven, J. A., Havekes, L. M., Frants, R. R. <strong>Absence of mutations in the promoter region of the low density lipoprotein receptor gene in a large number of familial hypercholesterolaemia patients as revealed by denaturing gradient gel electrophoresis.</strong> Hum. Genet. 89: 561-565, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1634234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1634234</a>] [<a href="https://doi.org/10.1007/BF00219185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1634234">Top et al. (1992)</a> found no evidence of a promoter mutation in the LDLR gene in 350 heterozygotes for FH. <a href="#44" class="mim-tip-reference" title="Hobbs, H. H., Brown, M. S., Goldstein, J. L. <strong>Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.</strong> Hum. Mutat. 1: 445-466, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301956</a>] [<a href="https://doi.org/10.1002/humu.1380010602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301956">Hobbs et al. (1992)</a> reviewed 71 mutations in the LDL receptor gene that had been characterized at the molecular level and added 79 additional mutations. Furthermore, they reviewed the insight that all 150 mutations provided into the structure/function relationship of the receptor protein and the clinical manifestations of FH. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1863993+3020025+1634234+1301956" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Feussner, G., Dobmeyer, J., Nissen, H., Hansen, T. S. <strong>Unusual Xanthomas in a young patient with heterozygous familial hypercholesterolemia and type III hyperlipoproteinemia.</strong> Am. J. Med. Genet. 65: 149-154, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8911609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8911609</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19961016)65:2<149::AID-AJMG14>3.0.CO;2-Q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8911609">Feussner et al. (1996)</a> described a 20-year-old man with a combination of heterozygous FH caused by splice mutation (<a href="#0054">606945.0054</a>) and type III hyperlipoproteinemia (<a href="/entry/107741">107741</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8911609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#76" class="mim-tip-reference" title="Lee, W. K., Haddad, L., Macleod, M. J., Dorrance, A. M., Wilson, D. J., Gaffney, D., Dominiczak, M. H., Packard, C. J., Day, I. N., Humphries, S. E., Dominiczak, A. F. <strong>Identification of a common low density lipoprotein receptor mutation (C163Y) in the West of Scotland.</strong> J. Med. Genet. 35: 573-578, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9678702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9678702</a>] [<a href="https://doi.org/10.1136/jmg.35.7.573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9678702">Lee et al. (1998)</a> studied 80 unrelated individuals with FH from the West of Scotland. Microsatellite analysis using D19S394 was informative in 20 of 23 families studied. In these families, there was no inconsistency with segregation of the FH phenotype with the LDLR locus. Using SSCP, <a href="#76" class="mim-tip-reference" title="Lee, W. K., Haddad, L., Macleod, M. J., Dorrance, A. M., Wilson, D. J., Gaffney, D., Dominiczak, M. H., Packard, C. J., Day, I. N., Humphries, S. E., Dominiczak, A. F. <strong>Identification of a common low density lipoprotein receptor mutation (C163Y) in the West of Scotland.</strong> J. Med. Genet. 35: 573-578, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9678702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9678702</a>] [<a href="https://doi.org/10.1136/jmg.35.7.573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9678702">Lee et al. (1998)</a> also detected mutations in exon 4 of the LDLR gene in 15 of 80 of these individuals; 7 of 15 had the same cys163-to-tyr mutation (<a href="#0058">606945.0058</a>). <a href="#76" class="mim-tip-reference" title="Lee, W. K., Haddad, L., Macleod, M. J., Dorrance, A. M., Wilson, D. J., Gaffney, D., Dominiczak, M. H., Packard, C. J., Day, I. N., Humphries, S. E., Dominiczak, A. F. <strong>Identification of a common low density lipoprotein receptor mutation (C163Y) in the West of Scotland.</strong> J. Med. Genet. 35: 573-578, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9678702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9678702</a>] [<a href="https://doi.org/10.1136/jmg.35.7.573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9678702">Lee et al. (1998)</a> concluded that microsatellite analysis using D19S394 is useful in tracking the LDLR gene in families and could be used in conjunction with LDL cholesterol levels to diagnose FH, especially in children and young adults, in whom phenotypic diagnosis can be difficult. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9678702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Jensen, J. M., Kruse, T. A., Brorholt-Petersen, J. U., Christiansen, T. M., Jensen, H. K., Kolvraa, S., Faergeman, O. <strong>Linking genotype to aorto-coronary atherosclerosis: a model using familial hypercholesterolemia and aorto-coronary calcification.</strong> Ann. Hum. Genet. 63: 511-520, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11246453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11246453</a>] [<a href="https://doi.org/10.1017/S0003480099007800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11246453">Jensen et al. (1999)</a> studied 17 families with mutations in the LDLR gene as a model in which to test formally for linkage directly between an atherogenic genotype and ischemic heart disease or aortocoronary calcified atherosclerosis. The aortocoronary calcification was significantly associated with age and plasma cholesterol. Sex, hypertension, body mass index, and smoking were not associated with the aortocoronary calcification. Nonparametric analysis indicated significant linkage of the LDLR locus to aortic (p less than 0.00005) and to aortocoronary calcified atherosclerosis (p less than 0.00001). Assuming a dominant mode of inheritance, significant linkage was detected for aortic (lod = 3.89) and aortocoronary calcified atherosclerosis (lod = 4.10). <a href="#55" class="mim-tip-reference" title="Jensen, J. M., Kruse, T. A., Brorholt-Petersen, J. U., Christiansen, T. M., Jensen, H. K., Kolvraa, S., Faergeman, O. <strong>Linking genotype to aorto-coronary atherosclerosis: a model using familial hypercholesterolemia and aorto-coronary calcification.</strong> Ann. Hum. Genet. 63: 511-520, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11246453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11246453</a>] [<a href="https://doi.org/10.1017/S0003480099007800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11246453">Jensen et al. (1999)</a> suggested that the atherogenicity of variations in other genes could be assessed by a similar approach. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11246453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#139" class="mim-tip-reference" title="Yamakawa, K., Okafuji, T., Iwamura, Y., Yuzawa, K., Satoh, J., Hattori, N., Yamanouchi, Y., Yanagi, H., Kawai, K., Tsuchiya, S., Russell, D. W., Hamaguchi, H. <strong>TaqI polymorphism in the LDL receptor gene and a TaqI 1.5-kb band associated with familial hypercholesterolemia.</strong> Hum. Genet. 80: 1-5, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2901393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2901393</a>] [<a href="https://doi.org/10.1007/BF00451446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2901393">Yamakawa et al. (1988)</a> described a TaqI polymorphism in the LDLR gene which should be useful in the study of FH. <a href="#86" class="mim-tip-reference" title="Leitersdorf, E., van der Westhuyzen, D. R., Coetzee, G. A., Hobbs, H. H. <strong>Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners.</strong> J. Clin. Invest. 84: 954-961, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2569482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2569482</a>] [<a href="https://doi.org/10.1172/JCI114258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2569482">Leitersdorf et al. (1989)</a> used 10 different RFLPs to construct 123 differing haplotypes from 20 pedigrees. The 5 most common haplotypes accounted for 67.5% of the sample. Heterozygosity and polymorphism information content (PIC) for each site were determined. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2901393+2569482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#59" class="mim-tip-reference" title="Kathiresan, S., Melander, O., Anevski, D., Guiducci, C., Burtt, N. P., Roos, C., Hirschhorn, J. N., Berglund, G., Hedblad, B., Groop, L., Altshuler, D. M., Newton-Cheh, C., Orho-Melander, M. <strong>Polymorphisms associated with cholesterol and risk of cardiovascular events.</strong> New Eng. J. Med. 358: 1240-1249, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18354102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18354102</a>] [<a href="https://doi.org/10.1056/NEJMoa0706728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18354102">Kathiresan et al. (2008)</a> studied SNPs in 9 genes in 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. All 9 SNPs had been associated with elevated LDL or lowered HDL. One of the SNPs, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1529729;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1529729</a> in the SMARCA4 gene, was highly correlated with variants in LDLR. <a href="#59" class="mim-tip-reference" title="Kathiresan, S., Melander, O., Anevski, D., Guiducci, C., Burtt, N. P., Roos, C., Hirschhorn, J. N., Berglund, G., Hedblad, B., Groop, L., Altshuler, D. M., Newton-Cheh, C., Orho-Melander, M. <strong>Polymorphisms associated with cholesterol and risk of cardiovascular events.</strong> New Eng. J. Med. 358: 1240-1249, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18354102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18354102</a>] [<a href="https://doi.org/10.1056/NEJMoa0706728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18354102">Kathiresan et al. (2008)</a> replicated the associations with the 9 SNPs and created a genotype score on the basis of the number of unfavorable alleles. With increasing genotype scores, the level of LDL cholesterol increased, whereas the level of HDL cholesterol decreased. At 10-year follow-up, the genotype score was found to be an independent risk factor for incident cardiovascular disease (myocardial infarction, ischemic stroke, or death from coronary heart disease); the score did not improve risk discrimination but modestly improved clinical risk reclassification for individual subjects beyond standard clinical factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18354102" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#6" class="mim-tip-reference" title="Aulchenko, Y. S., Ripatti, S., Lindqvist, I., Boomsma, D., Heid, I. M., Pramstaller, P. P., Penninx, B. W. J. H., Janssens, A. C. J. W., Wilson, W. F., Spector, T., Martin, N. G., Pedersen, N. L. <strong>{and 45 others}: Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.</strong> Nature Genet. 41: 47-55, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19060911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19060911</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19060911[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/ng.269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19060911">Aulchenko et al. (2009)</a> reported a genomewide association (GWA) study of loci affecting total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. This study included a total of 17,797 to 22,562 individuals aged 18 to 104 years from geographic regions spanning from the Nordic countries to Southern Europe. <a href="#6" class="mim-tip-reference" title="Aulchenko, Y. S., Ripatti, S., Lindqvist, I., Boomsma, D., Heid, I. M., Pramstaller, P. P., Penninx, B. W. J. H., Janssens, A. C. J. W., Wilson, W. F., Spector, T., Martin, N. G., Pedersen, N. L. <strong>{and 45 others}: Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.</strong> Nature Genet. 41: 47-55, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19060911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19060911</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19060911[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/ng.269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19060911">Aulchenko et al. (2009)</a> established 22 loci associated with serum lipid levels at a genomewide significance level (P less than 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. Association of the LDLR gene region identified by <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2228671;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2228671</a> was found with total cholesterol levels (P = 9.3 x 10(-24)). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19060911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient diagnosed with probable heterozygous FH, <a href="#11" class="mim-tip-reference" title="Bourbon, M., Sun, X.-M., Soutar, A. K. <strong>A rare polymorphism in the low density lipoprotein (LDL) gene that affects mRNA splicing.</strong> Atherosclerosis 195: e17, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17335829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17335829</a>] [<a href="https://doi.org/10.1016/j.atherosclerosis.2007.01.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17335829">Bourbon et al. (2007)</a> analyzed the LDLR gene and identified a novel variant initially assumed to be a silent polymorphism (R385R; <a href="#0065">606945.0065</a>); however, analysis of mRNA from the patient's cells showed that the mutation introduces a new 5-prime acceptor splice site that causes a 31-bp deletion predicted to result in premature termination. The variant was subsequently also found in a Chinese homozygous FH patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17335829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Defesche, J. C., Schuurman, E. J. M., Klaaijsen, L. N., Khoo, K. L., Wiegman, A., Stalenhoef, A. F. H. <strong>Silent exonic mutations in the low-density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing.</strong> Clin. Genet. 73: 573-578, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18400033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18400033</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.00999.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18400033">Defesche et al. (2008)</a> analyzed the LDLR gene in 1,350 patients clinically diagnosed with familial hypercholesterolemia who were negative for functional DNA variation in the LDLR, APOB (<a href="/entry/107730">107730</a>), and PCSK9 (<a href="/entry/607786">607786</a>) genes. The authors examined the effects of 128 seemingly neutral exonic and intronic DNA variants and identified the R385R variant in 2 Chinese families and a G186G (<a href="#0066">606945.0066</a>) variant that clearly affected a donor splice site and segregated with hypercholesterolemia in 35 unrelated Dutch families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18400033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 metaanalysis of plasma lipid concentrations in greater than 100,000 individuals of European descent, <a href="#127" class="mim-tip-reference" title="Teslovich, T. M., Musunuru, K., Smith, A. V., Edmondson, A. C., Stylianou, I. M., Koseki, M., Pirruccello, J. P., Ripatti, S., Chasman, D. I., Willer, C. J., Johansen, C. T., Fouchier, S. W., and 197 others. <strong>Biological, clinical and population relevance of 95 loci for blood lipids.</strong> Nature 466: 707-713, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20686565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20686565</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20686565[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/nature09270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20686565">Teslovich et al. (2010)</a> identified SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs6511720;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs6511720</a> near the LDLR gene as having an effect on LDL cholesterol concentrations with an effect size of -6.99 mg per deciliter and a P value of 4 x 10(-117). This variant was also found to affect coronary artery disease risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20686565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#72" class="mim-tip-reference" title="Kulseth, M. A., Berge, K. E., Bogsrud, M. P., Leren, T. P. <strong>Analysis of LDLR mRNA in patients with familial hypercholesterolemia revealed a normal mutation in intron 14, which activates a cryptic splice site.</strong> J. Hum. Genet. 55: 676-680, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20703241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20703241</a>] [<a href="https://doi.org/10.1038/jhg.2010.87" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20703241">Kulseth et al. (2010)</a> performed RNA analysis in 30 unrelated patients with clinically defined hypercholesterolemia but without any LDLR mutations detected by standard DNA analysis; sequencing of RT-PCR products from an index patient revealed that the major product contained an insertion of 81 bp from the 5-prime end of intron 14 of LDLR. DNA sequencing of exons 13 and 14 detected an intronic mutation (<a href="#0067">606945.0067</a>) that segregated in heterozygosity with elevated cholesterol in the proband's family. <a href="#72" class="mim-tip-reference" title="Kulseth, M. A., Berge, K. E., Bogsrud, M. P., Leren, T. P. <strong>Analysis of LDLR mRNA in patients with familial hypercholesterolemia revealed a normal mutation in intron 14, which activates a cryptic splice site.</strong> J. Hum. Genet. 55: 676-680, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20703241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20703241</a>] [<a href="https://doi.org/10.1038/jhg.2010.87" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20703241">Kulseth et al. (2010)</a> analyzed an additional 550 index patients and identified the same splice site mutation in 3 more probands. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20703241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Noting that large-scale genetic cascade screening for familial hypercholesterolemia showed that 15% of LDLR or APOB mutation carriers had LDLC levels below the 75th percentile, <a href="#53" class="mim-tip-reference" title="Huijgen, R., Kindt, I., Fouchier, S. W., Defesche, J. C., Hutten, B. A., Kastelein, J. J. P., Vissers, M. N. <strong>Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia.</strong> Hum. Mutat. 31: 752-760, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20506408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20506408</a>] [<a href="https://doi.org/10.1002/humu.21258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20506408">Huijgen et al. (2010)</a> proposed 3 criteria for determining pathogenicity of such mutations: mean LDLC greater than the 75th percentile, higher mean LDLC level in untreated than in treated carriers, and higher percentage of medication users in carriers than in noncarriers at screening. Applying these criteria to 46 mutations found in more than 50 untreated adults, 3 of the mutations were determined to be nonpathogenic: 1 in LDLR and 2 in APOB. Nonpathogenicity of the 3 variants was confirmed by segregation analysis. <a href="#53" class="mim-tip-reference" title="Huijgen, R., Kindt, I., Fouchier, S. W., Defesche, J. C., Hutten, B. A., Kastelein, J. J. P., Vissers, M. N. <strong>Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia.</strong> Hum. Mutat. 31: 752-760, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20506408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20506408</a>] [<a href="https://doi.org/10.1002/humu.21258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20506408">Huijgen et al. (2010)</a> emphasized that novel sequence changes in LDLR and APOB should be interpreted with caution before being incorporated into a cascade screening program. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20506408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#24" class="mim-tip-reference" title="Do, R., Stitziel, N. O., Won, H.-H., Berg Jorgensen, A., Duga, S., Merlini, P. A., Kiezun, A., Farrall, M., Goel, A., Zuk, O., Guella, I., Asselta, R., and 82 others. <strong>Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.</strong> Nature 518: 102-106, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25487149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25487149</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25487149[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/nature13917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25487149">Do et al. (2015)</a> sequenced the protein-coding regions of 9,793 genomes from patients with myocardial infarction (MI) at an early age (50 years or younger in males and 60 years or younger in females) along with MI-free controls. They identified 2 genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exomewide significance: LDLR and APOA5 (<a href="/entry/606368">606368</a>). Carriers of rare nonsynonymous mutations in LDLR were at 4.2-fold increased risk for MI, while carriers of null alleles in LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbor a rare, damaging mutation in LDLR; this estimate is similar to one made by <a href="#37" class="mim-tip-reference" title="Goldstein, J. L., Schrott, H. G., Hazzard, W. R., Bierman, E. L., Motulsky, A. G. <strong>Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia.</strong> J. Clin. Invest. 52: 1544-1568, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4718953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4718953</a>] [<a href="https://doi.org/10.1172/JCI107332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4718953">Goldstein et al. (1973)</a> using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol greater than 190 mg/dl. Carriers of rare nonsynonymous mutations in APOA5 were at 2.2-fold increased risk for MI. When compared with noncarriers, LDLR mutation carriers had higher plasma LDL cholesterol (see <a href="/entry/143890">143890</a>), whereas APOA5 mutation carriers had higher plasma triglycerides (see <a href="/entry/145750">145750</a>). Evidence has connected MI risk with coding-sequence mutations at 2 genes functionally related to APOA5, namely lipoprotein lipase (LPL; <a href="/entry/609708">609708</a>) and apolipoprotein C-III (APOC3; <a href="/entry/107720">107720</a>). <a href="#24" class="mim-tip-reference" title="Do, R., Stitziel, N. O., Won, H.-H., Berg Jorgensen, A., Duga, S., Merlini, P. A., Kiezun, A., Farrall, M., Goel, A., Zuk, O., Guella, I., Asselta, R., and 82 others. <strong>Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.</strong> Nature 518: 102-106, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25487149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25487149</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25487149[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/nature13917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25487149">Do et al. (2015)</a> concluded that LDL cholesterol as well as disordered metabolism of triglyceride-rich lipoproteins contributes to myocardial infarction risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4718953+25487149" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>LDLR Mutation Databases</em></strong></p><p>
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<a href="#134" class="mim-tip-reference" title="Varret, M., Rabes, J.-P., Collod-Beroud, G., Junien, C., Boileau, C., Beroud, C. <strong>Software and database for the analysis of mutations in the human LDL receptor gene.</strong> Nucleic Acids Res. 25: 172-180, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9016531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9016531</a>] [<a href="https://doi.org/10.1093/nar/25.1.172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9016531">Varret et al. (1997)</a> described a database of LDLR genes and provided a listing of the 210 mutations it contained as of the fall of 1996. <a href="#138" class="mim-tip-reference" title="Wilson, D. J., Gahan, M., Haddad, L., Heath, K., Whittall, R. A., Williams, R. R., Humphries, S. E., Day, I. N. M. <strong>A World Wide Web site for low-density lipoprotein receptor gene mutations in familial hypercholesterolemia: sequence-based, tabular, and direct submission data handling.</strong> Am. J. Cardiol. 81: 1509-1511, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9645910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9645910</a>] [<a href="https://doi.org/10.1016/s0002-9149(98)00215-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9645910">Wilson et al. (1998)</a> described an online database of LDLR mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9645910+9016531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Leigh, S., Futema, M., Whittall, R., Taylor-Beadling, A., Williams, M., den Dunnen, J. T., Humphries, S. E. <strong>The UCL low-density lipoprotein receptor gene variant database: pathogenicity update.</strong> J. Med. Genet. 54: 217-223, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27821657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27821657</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-104054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27821657">Leigh et al. (2017)</a> updated the University College of London (UCL) LDLR variant database according to the guidelines of the Association of Clinical Genetic Scientists. Of the 2,925 curated variants, representing 1,707 independent events, all 129 nonsense variants, 337 small frameshift variants, and 117/118 large rearrangements were classified as likely or clearly pathogenic. Of the 795 missense variants, 115 were clearly not or unlikely pathogenic, 605 were likely pathogenic, and 75 were variants of unknown significance; 111/181 intronic variants, 4/35 synonymous variants, and 14/37 promoter variants were likely or clearly pathogenic. Overall, 112 (7%) of reported variants were variants of unknown significance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27821657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Modifiers</em></strong></p><p>
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<a href="#135" class="mim-tip-reference" title="Vergopoulos, A., Bajari, T., Jouma, M., Knoblauch, H., Aydin, A., Bahring, S., Mueller-Myhsok, B., Dresel, A., Joubran, R., Luft, F. C., Schuster, H. <strong>A xanthomatosis-susceptibility gene may exist in a Syrian family with familial hypercholesterolemia.</strong> Europ. J. Hum. Genet. 5: 315-323, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9412789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9412789</a>]" pmid="9412789">Vergopoulos et al. (1997)</a> presented findings suggesting the existence of a xanthomatosis susceptibility gene in a consanguineous Syrian kindred containing 6 individuals with homozygous FH (see <a href="/entry/602247">602247</a>). Half of the homozygotes had giant xanthomas, while half did not, even though their LDL cholesterol concentrations were elevated to similar degrees (more than 14 mmol/l). Heterozygous FH individuals in this family were also clearly distinguishable with respect to xanthoma size. By DNA analysis they identified a hitherto undescribed mutation in the LDLR gene in this family: a T-to-C transition at nucleotide 1999 in codon 646 of exon 14, resulting in an arginine for cysteine substitution. Segregation analysis suggested that a separate susceptibility gene may explain the formation of giant xanthomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9412789" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 13-year-old girl with severe hypercholesterolemia, <a href="#26" class="mim-tip-reference" title="Ekstrom, U., Abrahamson, M., Floren, C.-H., Tollig, H., Wettrell, G., Nilsson, G., Sun, X.-M., Soutar, A. K., Nilsson-Ehle, P. <strong>An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F).</strong> Clin. Genet. 55: 332-339, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10422803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10422803</a>] [<a href="https://doi.org/10.1034/j.1399-0004.1999.550506.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10422803">Ekstrom et al. (1999)</a> demonstrated compound heterozygosity for a cys240-to-phe mutation (<a href="#0059">606945.0059</a>) and a tyr167-to-ter mutation (<a href="#0045">606945.0045</a>) in the LDLR gene. Her 2 heterozygous sibs also carried the C240F mutation, but only one of them was hypercholesterolemic. The authors concluded that there may be cholesterol-lowering mechanisms that are activated by mutations in other genes (see <a href="/entry/143890">143890</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10422803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Knoblauch, H., Muller-Myhsok, B., Busjahn, A., Ben Avi, L., Bahring, S., Baron, H., Heath, S. C., Uhlmann, R., Faulhaber, H.-D., Shpitzen, S., Aydin, A., Reshef, A., and 11 others. <strong>A cholesterol-lowering gene maps to chromosome 13q.</strong> Am. J. Hum. Genet. 66: 157-166, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10631147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10631147</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10631147[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/10.1086/302704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10631147">Knoblauch et al. (2000)</a> studied an Arab family that carried the tyr807-to-cys substitution (<a href="#0019">606945.0019</a>). In this family, some heterozygous persons had normal LDL levels, while some homozygous individuals had LDL levels similar to those persons with heterozygous FH. The authors presented evidence for the existence of a cholesterol-lowering gene on 13q (<a href="/entry/604595">604595</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10631147" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Based on the finding from bioinformatic analysis that Alu repeats represent 85% of LDLR intronic sequences outside exon-intron junctions, <a href="#5" class="mim-tip-reference" title="Amsellem, S., Briffaut, D., Carrie, A., Rabes, J. P., Girardet, J. P., Fredenrich, A., Moulin, P., Krempf, M., Reznik, Y., Vialettes, B., de Gennes, J. L., Brukert, E., Benlian, P. <strong>Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia.</strong> Hum. Genet. 111: 501-510, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12436241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12436241</a>] [<a href="https://doi.org/10.1007/s00439-002-0813-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12436241">Amsellem et al. (2002)</a> designed a strategy to improve the exploration of genomic regions in the vicinity of exons in 110 FH subjects from an admixed population. In the first group of 42 patients found negative for mutations by former screening strategies, approximately half (22) were carriers of at least 1 heterozygous mutation. Among a second group of 68 patients recruited to correct for ascertainment bias toward exonic mutations, 37 (27%) mutation carriers had a splicing regulatory mutation. Of the 54 mutations identified, 13 were intronic and 18 were novel, nearly half of which were intronic. <a href="#5" class="mim-tip-reference" title="Amsellem, S., Briffaut, D., Carrie, A., Rabes, J. P., Girardet, J. P., Fredenrich, A., Moulin, P., Krempf, M., Reznik, Y., Vialettes, B., de Gennes, J. L., Brukert, E., Benlian, P. <strong>Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia.</strong> Hum. Genet. 111: 501-510, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12436241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12436241</a>] [<a href="https://doi.org/10.1007/s00439-002-0813-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12436241">Amsellem et al. (2002)</a> stated that their strategy of detecting the most likely disease-causing LDLR mutations outside of Alu-rich genomic regions revealed that intronic mutations may have a greater impact on the molecular basis of FH than previously reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12436241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#114" class="mim-tip-reference" title="Seftel, H. C., Baker, S. G., Sandler, M. P., Forman, M. B., Joffe, B. I., Mendelsohn, D., Jenkins, T., Mieny, C. J. <strong>A host of hypercholesterolaemic homozygotes in South Africa.</strong> Brit. Med. J. 281: 633-636, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7437743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7437743</a>] [<a href="https://doi.org/10.1136/bmj.281.6241.633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7437743">Seftel et al. (1980)</a> pointed to a high frequency of hypercholesterolemic homozygotes in South Africa. In a 7-year period, 34 homozygotes were seen in one clinic in Johannesburg. All were Afrikaners and most lived in Transvaal Province. The authors calculated the frequency of heterozygotes and homozygotes to be 1 in 100 and 1 in 30,000, respectively. The oldest of their patients was a 46-year-old woman. Of the 34, six were age 30 or older. The authors concluded that the high frequency of the gene is attributable to founder effect, as in the case of porphyria variegata (<a href="/entry/176200">176200</a>), lipoid proteinosis (<a href="/entry/247100">247100</a>), and sclerosteosis (<a href="/entry/269500">269500</a>). <a href="#132" class="mim-tip-reference" title="Torrington, M., Botha, J. L. <strong>Familial hypercholesterolaemia and church affiliation. (Letter)</strong> Lancet 318: 1120 only, 1981. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6118572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6118572</a>] [<a href="https://doi.org/10.1016/s0140-6736(81)91330-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6118572">Torrington and Botha (1981)</a> found that 20 of 26 families with FHC (77%) belonged to the Gereformeerde Kerk, whereas according to the 1970 census only 5% of the Afrikaans-speaking white population of South Africa belonged to this religious group. Again, the data were consistent with a founder effect. Using the LDLR activity of lymphocytes, <a href="#119" class="mim-tip-reference" title="Steyn, K., Weight, M. J., Dando, B. R., Christopher, K. J., Rossouw, J. E. <strong>The use of low density lipoprotein receptor activity of lymphocytes to determine the prevalence of familial hypercholesterolaemia in a rural South African community.</strong> J. Med. Genet. 26: 32-36, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2918524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2918524</a>] [<a href="https://doi.org/10.1136/jmg.26.1.32" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2918524">Steyn et al. (1989)</a> calculated the prevalence of heterozygous FHC in the permanent residents of a predominantly Afrikaans-speaking community in South Africa to be 1 in 71--the highest prevalence reported to date. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6118572+7437743+2918524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#45" class="mim-tip-reference" title="Hobbs, H. H., Brown, M. S., Russell, D. W., Davignon, J., Goldstein, J. L. <strong>Deletion in the gene for the low-density-lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia.</strong> New Eng. J. Med. 317: 734-737, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3627182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3627182</a>] [<a href="https://doi.org/10.1056/NEJM198709173171204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3627182">Hobbs et al. (1987)</a> found a large deletion (more than 10 kb) in the LDLR gene in 63% of French Canadians with heterozygous FH. The deletion also occurred in homozygous form in 4 of 7 French Canadian homozygotes. The deletion removed the promoter and first exon of the gene and abolished the production of mRNA for LDL receptor. The high frequency of the mutation was interpreted as representing founder effect; 8,000 ancestors account for present-day French Canadians and there has been relatively little outbreeding. The deletion has not been observed in any other ethnic group. It can be detected by analysis of genomic DNA from blood leukocytes, thus allowing direct diagnosis of FH in most affected French Canadians. <a href="#94" class="mim-tip-reference" title="Ma, Y. H., Betard, C., Roy, M., Davignon, J., Kessling, A. M. <strong>Identification of a second 'French Canadian' LDL receptor gene deletion and development of a rapid method to detect both deletions.</strong> Clin. Genet. 36: 219-228, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2805380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2805380</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1989.tb03194.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2805380">Ma et al. (1989)</a> identified a second 'French Canadian' LDLR gene deletion which was found in 4 of 80 heterozygotes (5%). The mutation consisted of a 5-kb deletion removing exons 2 and 3 of the LDLR gene, which corresponded to the first 2 repeats of the LDLR-binding domain (<a href="#0026">606945.0026</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2805380+3627182" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Leitersdorf, E., Tobin, E. J., Davignon, J., Hobbs, H. H. <strong>Common low-density lipoprotein receptor mutations in the French Canadian population.</strong> J. Clin. Invest. 85: 1014-1023, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2318961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2318961</a>] [<a href="https://doi.org/10.1172/JCI114531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2318961">Leitersdorf et al. (1990)</a> analyzed the LDL receptor genes of 11 French Canadian FH homozygotes. Only 3 different LDLR haplotypes were identified, and the coding region of the allele associated with each was sequenced. Three different missense mutations were found. Assays developed to detect each of these directly were applied to 130 FH heterozygotes from the greater Montreal area. The common deletion (<a href="#0025">606945.0025</a>) responsible for about 60% of cases (<a href="#45" class="mim-tip-reference" title="Hobbs, H. H., Brown, M. S., Russell, D. W., Davignon, J., Goldstein, J. L. <strong>Deletion in the gene for the low-density-lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia.</strong> New Eng. J. Med. 317: 734-737, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3627182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3627182</a>] [<a href="https://doi.org/10.1056/NEJM198709173171204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3627182">Hobbs et al., 1987</a>) and the smaller deletion (<a href="#0026">606945.0026</a>) identified by <a href="#94" class="mim-tip-reference" title="Ma, Y. H., Betard, C., Roy, M., Davignon, J., Kessling, A. M. <strong>Identification of a second 'French Canadian' LDL receptor gene deletion and development of a rapid method to detect both deletions.</strong> Clin. Genet. 36: 219-228, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2805380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2805380</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1989.tb03194.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2805380">Ma et al. (1989)</a> and found in about 5% of French Canadians were also sought. They were able to detect LDL receptor mutations in 76% of the subjects and 14% had 1 of the 3 missense mutations. In the Saguenay-Lac-Saint-Jean region of Quebec province, <a href="#18" class="mim-tip-reference" title="De Braekeleer, M. <strong>Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada).</strong> Hum. Hered. 41: 141-146, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1937486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1937486</a>] [<a href="https://doi.org/10.1159/000153992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1937486">De Braekeleer (1991)</a> estimated the prevalence of familial hypercholesterolemia as 1/122, compared to the usually estimated frequency of 1/500 for European populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2805380+3627182+2318961+1937486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Like the French Canadians, the South Afrikaners appear to have a unique form of mutation in the LDLR gene consistent with founder effect (<a href="#12" class="mim-tip-reference" title="Brink, P. A., Steyn, L. T., Coetzee, G. A., van der Westhuyzen, D. R. <strong>Familial hypercholesterolemia in South African Afrikaners: PvuII and StuI DNA polymorphisms in the LDL-receptor gene consistent with a predominating founder gene effect.</strong> Hum. Genet. 77: 32-35, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2887506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2887506</a>] [<a href="https://doi.org/10.1007/BF00284709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2887506">Brink et al., 1987</a>). Because of the presumed role of founder effect on the high frequency of familial hypercholesterolemia in South Africa, it is not surprising that <a href="#68" class="mim-tip-reference" title="Kotze, M. J., Langenhoven, E., Retief, A. E., Steyn, K., Marais, M. P., Grobbelaar, J. J., Oosthuizen, C. J. J., Weich, H. F. H., Benade, A. J. S. <strong>Haplotype associations of three DNA polymorphisms at the human low density lipoprotein receptor gene locus in familial hypercholesterolemia.</strong> J. Med. Genet. 24: 750-755, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3430554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3430554</a>] [<a href="https://doi.org/10.1136/jmg.24.12.750" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3430554">Kotze et al. (1987)</a> found a predominance of 2 haplotypes in 27 informative families with FH. In a study of homozygotes from the Afrikaner population in South Africa, <a href="#86" class="mim-tip-reference" title="Leitersdorf, E., van der Westhuyzen, D. R., Coetzee, G. A., Hobbs, H. H. <strong>Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners.</strong> J. Clin. Invest. 84: 954-961, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2569482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2569482</a>] [<a href="https://doi.org/10.1172/JCI114258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2569482">Leitersdorf et al. (1989)</a> found that 2 mutations account for more than 95% of the mutant LDL receptor genes. Both mutations were basepair substitutions that resulted in a single amino acid change and both could be detected readily with PCR and restriction analysis. The findings were considered consistent with the high frequency of FH being due to founder effect. <a href="#38" class="mim-tip-reference" title="Graadt van Roggen, F., van der Westhuyzen, D. R., Marais, A. D., Gevers, W., Coetzee, G. A. <strong>Low density lipoprotein receptor founder mutations in Afrikaner familial hypercholesterolaemic patients: a comparison of two geographical areas.</strong> Hum. Genet. 88: 204-208, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1757095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1757095</a>] [<a href="https://doi.org/10.1007/BF00206073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1757095">Graadt van Roggen et al. (1991)</a> studied the prevalence and distribution of the 3 common mutations in South Africa in 27 unrelated homozygous and 79 unrelated heterozygous FH Afrikaner patients from 2 regions of South Africa, the Transvaal and Cape Provinces. The 3 mutations were FH Afrikaner-1 (<a href="#0006">606945.0006</a>), FH Afrikaner-2 (<a href="#0009">606945.0009</a>), and FH Afrikaner-3 (<a href="#0044">606945.0044</a>). The relative distribution of each of the 3 mutations was similar in the 2 regions, with frequencies of 66, 27, and 7%, respectively. Defects other than the 3 common mutations were more frequent in the Cape than in the Transvaal; thus, the 3 known mutations accounted for 98% of FH alleles in the Transvaal and only 74% in the Cape Province. None of the patients carried the familial apolipoprotein B-100 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2569482+1757095+2887506+3430554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Schuster, H., Manke, C., Fischer, J., Keller, C., Wolfram, G., Zollner, N. <strong>Identification of the valine 408 to methionine mutation in the LDL receptor in a Greek patient with homozygous familial hypercholesterolemia.</strong> Clin. Genet. 48: 90-92, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7586658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7586658</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1995.tb04062.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7586658">Schuster et al. (1995)</a> identified yet another homozygote for the val408-to-met mutation (<a href="#0009">606945.0009</a>), a 12-year-old Greek boy living in Germany. The mutation was present in both his parents, his brother, grandmother, uncle, and cousin. The haplotype, using 6 RFLPs of the LDL receptor gene, was different from the one reported earlier in Afrikaner and Dutch FH patients. <a href="#112" class="mim-tip-reference" title="Schuster, H., Manke, C., Fischer, J., Keller, C., Wolfram, G., Zollner, N. <strong>Identification of the valine 408 to methionine mutation in the LDL receptor in a Greek patient with homozygous familial hypercholesterolemia.</strong> Clin. Genet. 48: 90-92, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7586658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7586658</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1995.tb04062.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7586658">Schuster et al. (1995)</a> concluded that the mutation in the Greek boy probably occurred independently. Furthermore, they speculated that, because the parents were from different areas in Greece, the mutation may be common in Greeks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7586658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Deletion of gly197 (<a href="#0005">606945.0005</a>) is the most prevalent LDL receptor mutation causing familial hypercholesterolemia in Ashkenazi Jewish individuals. Studying index cases from Israel, South Africa, Russia, the Netherlands, and the United States, <a href="#25" class="mim-tip-reference" title="Durst, R., Colombo, R., Shpitzen, S., Ben Avi, L., Friedlander, Y., Wexler, R., Raal, F. J., Marais, D. A., Defesche, J. C., Mandelshtam, M. Y., Kotze, M. J., Leitersdorf, E., Meiner, V. <strong>Recent origin and spread of a common Lithuanian mutation, G197del LDLR, causing familial hypercholesterolemia: positive selection is not always necessary to account for disease incidence among Ashkenazi Jews.</strong> Am. J. Hum. Genet. 68: 1172-1188, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309683</a>] [<a href="https://doi.org/10.1086/320123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309683">Durst et al. (2001)</a> found that all traced their ancestry to Lithuania. A highly conserved haplotype was identified in chromosomes carrying this deletion, suggesting a common founder. When 2 methods were used for analysis of linkage disequilibrium between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the deletion was found to be 20 +/- 7 generations, so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 14th century. This corresponds with the founding of the Jewish community of Lithuania (1338 A.D.), as well as with the great demographic expansion of Ashkenazi Jewish individuals in eastern Europe, which followed this settlement. <a href="#25" class="mim-tip-reference" title="Durst, R., Colombo, R., Shpitzen, S., Ben Avi, L., Friedlander, Y., Wexler, R., Raal, F. J., Marais, D. A., Defesche, J. C., Mandelshtam, M. Y., Kotze, M. J., Leitersdorf, E., Meiner, V. <strong>Recent origin and spread of a common Lithuanian mutation, G197del LDLR, causing familial hypercholesterolemia: positive selection is not always necessary to account for disease incidence among Ashkenazi Jews.</strong> Am. J. Hum. Genet. 68: 1172-1188, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309683</a>] [<a href="https://doi.org/10.1086/320123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309683">Durst et al. (2001)</a> could find no evidence supporting a selective evolutionary metabolic advantage. Therefore, the founder effect in a rapidly expanding population from a limited number of families remains a simple, parsimonious hypothesis explaining the spread of this mutation in Ashkenazi Jewish individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11309683" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Defesche, J. C., Kastelein, J. J. P. <strong>Molecular epidemiology of familial hypercholesterolaemia. (Letter)</strong> Lancet 352: 1643-1644, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9853432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9853432</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)61443-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9853432">Defesche and Kastelein (1998)</a> stated that more than 350 different mutations had been found in patients with familial hypercholesterolemia. They tabulated the preferential geographic distribution that has been demonstrated for some of the LDL receptor mutations. For example, in the West of Scotland about half of the index cases of FH were found to have the cys163-to-tyr mutation (<a href="#0058">606945.0058</a>). <a href="#20" class="mim-tip-reference" title="Defesche, J. C., Kastelein, J. J. P. <strong>Molecular epidemiology of familial hypercholesterolaemia. (Letter)</strong> Lancet 352: 1643-1644, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9853432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9853432</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)61443-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9853432">Defesche and Kastelein (1998)</a> commented on the geographic associations of LDL receptor mutations within the Netherlands. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9853432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Alu sequences are widely scattered in the genome, being present in 300,000 to 500,000 copies. They have been described, for example, in the genes for alpha-globin (see <a href="/entry/141800">141800</a>), gastrin (<a href="/entry/137250">137250</a>), gamma crystallin (<a href="/entry/123660">123660</a>), insulin-like growth factor II (<a href="/entry/147470">147470</a>), and soluble thymidine kinase. Each is about 300 bp long; thus Alu sequences represent about 3% of the total DNA. On the basis of structural similarity, the origin of Alu elements can be traced to the gene for 7SL RNA (<a href="#133" class="mim-tip-reference" title="Ullu, E., Tschudi, C. <strong>Alu sequences are processed 7SL RNA genes.</strong> Nature 312: 171-172, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6209580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6209580</a>] [<a href="https://doi.org/10.1038/312171a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6209580">Ullu and Tschudi, 1984</a>). The abundant cytoplasmic 7SL RNA functions in protein secretion as a component of the signal-recognition particle. This particle, consisting of 6 different polypeptides and 1 molecule of 7SL RNA, mediates the translocation of secretory proteins across the cytoplasmic reticulum. Although the 7SL RNA has a well-defined biologic function, that of the related Alu repeat remains unknown. Thus, the 7SL RNA gene may be a progenitor of a processed pseudogene, the Alu element, that has 'recently' spread to different locations in the human genome. The average Alu family member probably integrated into its present genomic location about 15-30 Myr ago. The Alu family is specific to primates, suggesting that these repeats were not present as little as 65 Myr ago. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6209580" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>According to the Alu family copy number, one would, on the average, expect to find 1 such repeat every 3 to 5 kb in the human genome if they are randomly distributed. However, studies of the albumin/alpha-fetoprotein family by <a href="#107" class="mim-tip-reference" title="Ruffner, D. E., Sprung, C. N., Minghetti, P. P., Gibbs, P. E. M., Dugaiczyk, A. <strong>Invasion of the human albumin-alpha-fetoprotein gene family by Alu, Kpn, and two novel repetitive DNA elements.</strong> Molec. Biol. Evol. 4: 1-9, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2451775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2451775</a>] [<a href="https://doi.org/10.1093/oxfordjournals.molbev.a040420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2451775">Ruffner et al. (1987)</a> and of the thymidine kinase (<a href="/entry/188300">188300</a>) and beta-tubulin (<a href="/entry/191130">191130</a>) genes by <a href="#116" class="mim-tip-reference" title="Slagel, V., Flemington, E., Traina-Dorge, V., Bradshaw, H., Deininger, P. <strong>Clustering and subfamily relationships of the Alu family in the human genome.</strong> Molec. Biol. Evol. 4: 19-29, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3128713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3128713</a>] [<a href="https://doi.org/10.1093/oxfordjournals.molbev.a040422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3128713">Slagel et al. (1987)</a> indicate clustering of Alu repeats in some parts of the genome. For example, the beta-tubulin gene has 10 of these repeats in less than 5 kb of a single intron and the thymidine kinase has 13 members within its introns in a region of about 10 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3128713+2451775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Some early studies of somatic hybrid cells suggested that the gene(s) for low density lipoprotein receptor may be on chromosome 5 or 21 or both (<a href="#95" class="mim-tip-reference" title="Maartmann-Moe, K., Wang, H. S., Donald, L. J., Hamerton, J. L., Berg, K. <strong>Data from hybrid cell lines raise the possibility that factors controlling the low density lipoprotein receptor activity may reside on human chromosome 21, 5 or both. (Abstract)</strong> Cytogenet. Cell Genet. 32: 295-296, 1982."None>Maartmann-Moe et al., 1982</a>).</p><p><a href="#90" class="mim-tip-reference" title="Li, H., Gyllensten, U. B., Cui, X., Saiki, R. K., Erlich, H. A., Arnheim, N. <strong>Amplification and analysis of DNA sequences in single human sperm and diploid cells.</strong> Nature 335: 414-417, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3419517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3419517</a>] [<a href="https://doi.org/10.1038/335414a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3419517">Li et al. (1988)</a> worked out a PCR method for analyzing DNA sequences in individual diploid cells and human sperm. They showed that 2 genetic loci could be coamplified from a single sperm, and proposed its use for genetic linkage studies. They analyzed the genotype of single sperm derived from an individual heterozygous at the LDLR locus and the HLA-DQ(alpha) locus and could show independent assortment. Individual sperm were drawn into a fine plastic needle under microscopic observation and delivered to a tube for lysis and amplification. Eighty individual sperm were analyzed for the study of independent assortment of LDLR and DQA. The method has great promise for fine mapping. <a href="#10" class="mim-tip-reference" title="Boehnke, M., Arnheim, N., Li, H., Collins, F. S. <strong>Fine-structure genetic mapping of human chromosomes using the polymerase chain reaction on single sperm: experimental design considerations.</strong> Am. J. Hum. Genet. 45: 21-32, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2568090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2568090</a>]" pmid="2568090">Boehnke et al. (1989)</a> described the experimental design and issues of sample size to be considered in the application of the method to the generation of fine-structure human genetic maps. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2568090+3419517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Using Ldlr -/- mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) transgene under control of the insulin promoter, which functions as a mouse model in which type 1 diabetes (<a href="/entry/125853">125853</a>) can be induced at will, <a href="#56" class="mim-tip-reference" title="Johansson, F., Kramer, F., Barnhart, S., Kanter, J. E., Vaisar, T., Merrill, R. D., Geng, L., Oka, K., Chan, L., Chait, A., Heinecke, J. W., Bornfeldt, K. E. <strong>Type 1 diabetes promotes disruption of advanced atherosclerotic lesions in LDL receptor-deficient mice.</strong> Proc. Nat. Acad. Sci. 105: 2082-2087, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252823</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252823[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0709958105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252823">Johansson et al. (2008)</a> administered a high-fat diet for 16 weeks to induce the development of advanced atherosclerotic lesions before inducing diabetes. After the onset of diabetes, there was increased intraplaque hemorrhage and plaque disruption, regardless of lesion size, in mice fed low- or high-fat diets for an additional 14 weeks. Furthermore, diabetes resulted in increased accumulation of monocytic cells positive for S100A9 (<a href="/entry/123886">123886</a>), a proinflammatory biomarker for cardiovascular events, and for a macrophage marker protein, without increasing lesion macrophage content, and S100A9 immunoreactivity correlated with intraplaque hemorrhage. Hyperglycemia was not sufficient to induce plaque disruption: aggressive lipid lowering, primarily of triglyceride-rich lipoproteins, prevented both plaque disruption and the increased S100A9 in diabetic atherosclerotic lesions. Conversely, oleate promoted macrophage differentiation into an S100A9-positive population in vitro, thereby mimicking the effects of diabetes. <a href="#56" class="mim-tip-reference" title="Johansson, F., Kramer, F., Barnhart, S., Kanter, J. E., Vaisar, T., Merrill, R. D., Geng, L., Oka, K., Chan, L., Chait, A., Heinecke, J. W., Bornfeldt, K. E. <strong>Type 1 diabetes promotes disruption of advanced atherosclerotic lesions in LDL receptor-deficient mice.</strong> Proc. Nat. Acad. Sci. 105: 2082-2087, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252823</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252823[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0709958105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252823">Johansson et al. (2008)</a> concluded that diabetes increases plaque disruption independently of effects on plaque initiation, through a mechanism that requires triglyceride-rich lipoproteins and is associated with an increased accumulation of S100A9-positive monocytic cells, and that this represents an important link between diabetes, plaque disruption, and the innate immune system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18252823" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#89" class="mim-tip-reference" title="Lewis, M. J., Malik, T. H., Ehrenstein, M. R., Boyle, J. J., Botto, M., Haskard, D. O. <strong>Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice.</strong> Circulation 120: 417-426, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19620499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19620499</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19620499[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/10.1161/CIRCULATIONAHA.109.868158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19620499">Lewis et al. (2009)</a> generated mice lacking C1qa (<a href="/entry/120550">120550</a>) and/or serum IgM (<a href="/entry/147020">147020</a>) as well as Ldlr and studied them on both low- and high-fat semisynthetic diets. On both diets, serum IgM/Ldlr -/- mice developed substantially larger and more complex en face and aortic root atherosclerotic lesions, with accelerated cholesterol crystal formation and increased smooth muscle content in aortic root lesions. TUNEL analysis revealed increased apoptosis in both C1qa/Ldlr -/- and serum IgM/Ldlr -/- mice. Overall lesions were larger in mice lacking IgM rather than C1q, suggesting that IgM protective mechanisms are partially independent of classic complement pathway activation and apoptotic cell clearance. <a href="#89" class="mim-tip-reference" title="Lewis, M. J., Malik, T. H., Ehrenstein, M. R., Boyle, J. J., Botto, M., Haskard, D. O. <strong>Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice.</strong> Circulation 120: 417-426, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19620499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19620499</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19620499[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/10.1161/CIRCULATIONAHA.109.868158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19620499">Lewis et al. (2009)</a> concluded that IgM antibodies play a central role in protection against atherosclerosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19620499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#16" class="mim-tip-reference" title="Childs, B. G., Baker, D. J., Wijshake, T., Conover, C. A., Campisi, J., van Deursen, J. M. <strong>Senescent intimal foam cells are deleterious at all stages of atherosclerosis.</strong> Science 354: 472-477, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27789842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27789842</a>] [<a href="https://doi.org/10.1126/science.aaf6659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27789842">Childs et al. (2016)</a> used transgenic and pharmacologic approaches to eliminate senescent cells in atherosclerosis-prone Ldlr-deficient mice and showed that these cells are detrimental throughout disease pathogenesis. <a href="#16" class="mim-tip-reference" title="Childs, B. G., Baker, D. J., Wijshake, T., Conover, C. A., Campisi, J., van Deursen, J. M. <strong>Senescent intimal foam cells are deleterious at all stages of atherosclerosis.</strong> Science 354: 472-477, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27789842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27789842</a>] [<a href="https://doi.org/10.1126/science.aaf6659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27789842">Childs et al. (2016)</a> found that foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis, where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines. In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease production. <a href="#16" class="mim-tip-reference" title="Childs, B. G., Baker, D. J., Wijshake, T., Conover, C. A., Campisi, J., van Deursen, J. M. <strong>Senescent intimal foam cells are deleterious at all stages of atherosclerosis.</strong> Science 354: 472-477, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27789842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27789842</a>] [<a href="https://doi.org/10.1126/science.aaf6659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27789842">Childs et al. (2016)</a> concluded that their results demonstrated that senescent cells are key drivers of atheroma formation and maturation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27789842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a homozygote with familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>) of Turkish ancestry, <a href="#84" class="mim-tip-reference" title="Leitersdorf, E., Hobbs, H. H. <strong>Personal Communication.</strong> Dallas, Tex. 12/1990."None>Leitersdorf and Hobbs (1990)</a> identified a CAG-to-TAG change in codon 12 converting glutamine to a stop codon.</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">rs387906301 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906301;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=rs387906301" 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=rs387906301" 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=RCV000237855" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000237855" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000237855</a>
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<p>In a South African black with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#83" class="mim-tip-reference" title="Leitersdorf, E., Hobbs, H. H., Fourie, A. M., Jacobs, M., van der Westhuyzen, D. R., Coetzee, G. A. <strong>Deletion in the first cysteine-rich repeat of low-density lipoprotein receptor impairs its transport but not lipoprotein binding in fibroblasts from a subject with familial hypercholesterolemia.</strong> Proc. Nat. Acad. Sci. 85: 7912-7916, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3263645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3263645</a>] [<a href="https://doi.org/10.1073/pnas.85.21.7912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3263645">Leitersdorf et al. (1988)</a> demonstrated deletion of aspartic acid-26 and glycine-27 due to deletion of the 6 nucleotides of codons 26 and 27: GCGATG. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3263645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#128" class="mim-tip-reference" title="Thiart, R., Scholtz, C. L., Vergotine, J., Hoogendijk, C. F., de Villiers, J. N. P., Nissen, H., Brusgaard, K., Gaffney, D., Hoffs, M. S., Vermaak, W. J. H., Kotze, M. J. <strong>Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia.</strong> J. Med. Genet. 37: 514-519, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10882754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10882754</a>] [<a href="https://doi.org/10.1136/jmg.37.7.514" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10882754">Thiart et al. (2000)</a> found this mutation in 28% of mutant alleles in 56 South African black patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10882754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 FH FRENCH CANADIAN 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908025 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908025;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/rs121908025?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=rs121908025" 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=rs121908025" 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=RCV000003870 OR RCV000622852 OR RCV000776466 OR RCV000844748 OR RCV002426484" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003870, RCV000622852, RCV000776466, RCV000844748, RCV002426484" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003870...</a>
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<p>This change in exon 3 is a class 3 binding-defective mutation (<a href="#85" class="mim-tip-reference" title="Leitersdorf, E., Tobin, E. J., Davignon, J., Hobbs, H. H. <strong>Common low-density lipoprotein receptor mutations in the French Canadian population.</strong> J. Clin. Invest. 85: 1014-1023, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2318961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2318961</a>] [<a href="https://doi.org/10.1172/JCI114531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2318961">Leitersdorf et al., 1990</a>). In the French Canadian population of a province in Quebec, <a href="#100" class="mim-tip-reference" title="Moorjani, S., Roy, M., Torres, A., Betard, C., Gagne, C., Lambert, M., Brun, D., Davignon, J., Lupien, P. <strong>Mutations of low-density-lipoprotein-receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolaemia.</strong> Lancet 341: 1303-1306, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8098448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8098448</a>] [<a href="https://doi.org/10.1016/0140-6736(93)90815-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8098448">Moorjani et al. (1993)</a> compared the clinical features of homozygous FH (FHCL1; <a href="/entry/143890">143890</a>) because of the relatively high frequency of a small number of mutations. In a comparison of 10 subjects who had the trp66-to-gly (W66G) mutation in exon 3 with 11 subjects who were homozygous for the 'greater than 10 kb' deletion of the promoter region in exon 1 (<a href="#0025">606945.0025</a>), they found the following: mean plasma cholesterol concentration was higher in the subjects with the deletion and there was no overlap in values in the 2 groups. Although the frequency of coronary heart disease was similar in the 2 groups, age of onset was earlier in subjects with the deletion; in addition, coronary deaths were more frequent and occurred at an earlier age in the deletion subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2318961+8098448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Grossman, M., Raper, S. E., Kozarsky, K., Stein, E. A., Engelhardt, J. F., Muller, D., Lupien, P. J., Wilson, J. M. <strong>Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia.</strong> Nature Genet. 6: 335-341, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8054972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8054972</a>] [<a href="https://doi.org/10.1038/ng0494-335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8054972">Grossman et al. (1994)</a> reported a 29-year-old woman with FH and a homozygous W66G mutation who underwent hepatocyte-directed ex vivo gene therapy with LDLR-expressing retroviruses. She tolerated the procedures well, liver biopsy after 4 months showed engraftment of the transgene, and there was no clinical or pathologic evidence for autoimmune hepatitis. The patient showed an improvement in serum lipids up to 18 months after the treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8054972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0004 FH PUERTO RICO</strong>
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LDLR, SER156LEU
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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> rs121908026 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908026;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/rs121908026?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=rs121908026" 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=rs121908026" 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=RCV000003871 OR RCV000161958 OR RCV000588687 OR RCV002345224" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003871, RCV000161958, RCV000588687, RCV002345224" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003871...</a>
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<p><a href="#48" class="mim-tip-reference" title="Hobbs, H. H., Leitersdorf, E., Leffert, C. C., Cryer, D. R., Brown, M. S., Goldstein, J. L. <strong>Evidence for a dominant gene that suppresses hypercholesterolemia in a family with defective low density lipoprotein receptors.</strong> J. Clin. Invest. 84: 656-664, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2760205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2760205</a>] [<a href="https://doi.org/10.1172/JCI114212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2760205">Hobbs et al. (1989)</a> found this missense mutation in a Puerto Rican kindred that appeared to have an independently segregating mutation that suppressed the hypercholesterolemia phenotype in some heterozygotes (see <a href="/entry/144020">144020</a>). The same mutation was identified in a German family by <a href="#113" class="mim-tip-reference" title="Schuster, H., Ostwald, P., Keller, P., Wolfram, G., Keller, C. <strong>Identification of the serine-156 to leucine mutation in the low-density lipoprotein receptor in a German family with familial hypercholesterolemia.</strong> Clin. Investig. 71: 172-175, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8096412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8096412</a>] [<a href="https://doi.org/10.1007/BF00180002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8096412">Schuster et al. (1993)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8096412+2760205" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 FH PISCATAWAY</strong>
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FH LITHUANIA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908027 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908027;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=rs121908027" 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=rs121908027" 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=RCV000211647 OR RCV000489033 OR RCV000589051 OR RCV002363056 OR RCV004017502" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000211647, RCV000489033, RCV000589051, RCV002363056, RCV004017502" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000211647...</a>
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<p><a href="#97" class="mim-tip-reference" title="Meiner, V., Landsberger, D., Berkman, N., Reshef, A., Segal, P., Seftel, H. C., van der Westhuyzen, D. R., Jeenah, M. S., Coetzee, G. A., Leitersdorf, E. <strong>A common Lithuanian mutation causing familial hypercholesterolemia in Ashkenazi Jews.</strong> Am. J. Hum. Genet. 49: 443-449, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1867200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1867200</a>]" pmid="1867200">Meiner et al. (1991)</a> found that the mutation was responsible for 35% of 71 Ashkenazi-Jewish FH (FHCL1; <a href="/entry/143890">143890</a>) families in Israel. Of the 25 Ashkenazi patients who carried the mutant allele, 16 were of Lithuanian origin. The mutation was not found in 47 non-Ashkenazi FH families. The mutation was found in 8 of 10 FH cases in the Jewish community in South Africa, which originated mainly from Lithuania. PCR amplification of a DNA fragment that includes the mutation in heterozygous individuals results in the formation of a heteroduplex that can be demonstrated by PAGE and used for molecular diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1867200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#96" class="mim-tip-reference" title="Mandelshtam, M., Chakir, K., Shevtsov, S., Golubkov, V., Skobeleva, N., Lipovetsky, B., Konstantinov, V., Denisenko, A., Gaitskhoki, V., Schwartz, E. <strong>Prevalence of Lithuanian mutation among St. Petersburg Jews with familial hypercholesterolemia.</strong> Hum. Mutat. 12: 255-258, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9744476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9744476</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)12:4<255::AID-HUMU6>3.0.CO;2-E" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9744476">Mandelshtam et al. (1998)</a> found this mutation in one-third (7 of 23) of familial hypercholesterolemia cases in St. Petersburg (Russia) Jews and in no patients of Russian descent. The mutation has also been called FH St. Petersburg. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9744476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0006" class="mim-anchor"></a>
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<strong>.0006 FH AFRIKANER 1</strong>
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FH MAINE
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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> rs121908028 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908028;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/rs121908028?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=rs121908028" 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=rs121908028" 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=RCV000003876 OR RCV000771320 OR RCV001823092 OR RCV002362555" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003876, RCV000771320, RCV001823092, RCV002362555" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003876...</a>
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<p><a href="#71" class="mim-tip-reference" title="Kotze, M. J., Warnich, L., Langenhoven, E., du Plessis, L., Retief, A. E. <strong>An exon 4 mutation identified in the majority of South African familial hypercholesterolaemics.</strong> J. Med. Genet. 27: 298-302, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2352257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2352257</a>] [<a href="https://doi.org/10.1136/jmg.27.5.298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2352257">Kotze et al. (1990)</a> demonstrated a cytosine-to-guanine base substitution at nucleotide 681 resulting in an amino acid change from aspartic acid to glutamic acid at residue 206 (D206E) in the cysteine-rich ligand-binding domain of the LDL receptor. The mutation gives rise to an additional DdeI restriction site; segregation of the mutation with the disease was confirmed in 5 large Afrikaner FH (FHCL1; <a href="/entry/143890">143890</a>) families. <a href="#71" class="mim-tip-reference" title="Kotze, M. J., Warnich, L., Langenhoven, E., du Plessis, L., Retief, A. E. <strong>An exon 4 mutation identified in the majority of South African familial hypercholesterolaemics.</strong> J. Med. Genet. 27: 298-302, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2352257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2352257</a>] [<a href="https://doi.org/10.1136/jmg.27.5.298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2352257">Kotze et al. (1990)</a> predicted that 65% of affected South African Afrikaners carry this particular base substitution which can be diagnosed by PCR amplification of genomic DNA followed by restriction enzyme analysis. Indeed, from analysis of 138 chromosomes of Afrikaner FH patients, <a href="#69" class="mim-tip-reference" title="Kotze, M. J., Langenhoven, E., Warnich, L., du Plessis, L., Retief, A. E. <strong>The molecular basis and diagnosis of familial hypercholesterolaemia in South African Afrikaners.</strong> Ann. Hum. Genet. 55: 115-121, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1952806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1952806</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1991.tb00404.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1952806">Kotze et al. (1991)</a> found this mutation in 91 (68.4%). <a href="#67" class="mim-tip-reference" title="Komuro, I., Kato, H., Nakagawa, T., Takahashi, K., Mimori, A., Takeuchi, F., Nishida, Y., Miyamoto, T. <strong>Case report: the longest-lived patient with homozygous familial hypercholesterolemia secondary to a defect in internalization of the LDL receptor.</strong> Am. J. Med. Sci. 294: 341-345, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3425583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3425583</a>] [<a href="https://doi.org/10.1097/00000441-198711000-00008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3425583">Komuro et al. (1987)</a> described a homozygote for defective internalization of the LDL receptor who survived to age 57. <a href="#84" class="mim-tip-reference" title="Leitersdorf, E., Hobbs, H. H. <strong>Personal Communication.</strong> Dallas, Tex. 12/1990."None>Leitersdorf and Hobbs (1990)</a> found the same mutation in an English American living in Maine. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3425583+1952806+2352257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#136" class="mim-tip-reference" title="Vergotine, J., Thiart, R., Langenhoven, E., Hillermann, R., De Jong, G., Kotze, M. J. <strong>Prenatal diagnosis of familial hypercholesterolemia: importance of DNA analysis in the high-risk South African population.</strong> Genet. Counsel. 12: 121-127, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11491306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11491306</a>]" pmid="11491306">Vergotine et al. (2001)</a> demonstrated the feasibility of prenatal diagnosis of homozygous familial hypercholesterolemia in an Afrikaner family with the D206E mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11491306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0007 FH MEXICO</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> rs121908029 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908029;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/rs121908029?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=rs121908029" 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=rs121908029" 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=RCV000003878 OR RCV000623885 OR RCV000735406 OR RCV000775232 OR RCV000844738 OR RCV002362556" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003878, RCV000623885, RCV000735406, RCV000775232, RCV000844738, RCV002362556" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003878...</a>
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<p>Codon 207 (GAG) is changed to AAG (<a href="#84" class="mim-tip-reference" title="Leitersdorf, E., Hobbs, H. H. <strong>Personal Communication.</strong> Dallas, Tex. 12/1990."None>Leitersdorf and Hobbs, 1990</a>). The same mutation was found in French Canadians with FHCL1 (<a href="/entry/143890">143890</a>) (<a href="#85" class="mim-tip-reference" title="Leitersdorf, E., Tobin, E. J., Davignon, J., Hobbs, H. H. <strong>Common low-density lipoprotein receptor mutations in the French Canadian population.</strong> J. Clin. Invest. 85: 1014-1023, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2318961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2318961</a>] [<a href="https://doi.org/10.1172/JCI114531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2318961">Leitersdorf et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2318961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs121908030 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908030;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/rs121908030?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=rs121908030" 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=rs121908030" 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=RCV000003880 OR RCV000791377 OR RCV000826215 OR RCV000985772 OR RCV002051612 OR RCV002371758 OR RCV004724728" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003880, RCV000791377, RCV000826215, RCV000985772, RCV002051612, RCV002371758, RCV004724728" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003880...</a>
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<p>In an African American patient with FHCL1 (<a href="/entry/143890">143890</a>), <a href="#84" class="mim-tip-reference" title="Leitersdorf, E., Hobbs, H. H. <strong>Personal Communication.</strong> Dallas, Tex. 12/1990."None>Leitersdorf and Hobbs (1990)</a> found a change of aspartic acid-283 (GAC) to asparagine (AAC).</p>
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<strong>.0009 FH AFRIKANER 2</strong>
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LDLR, VAL408MET
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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> rs28942078 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28942078;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/rs28942078?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=rs28942078" 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=rs28942078" 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=RCV000003882 OR RCV000775062 OR RCV000786355 OR RCV002381239 OR RCV004017225 OR RCV004745143" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003882, RCV000775062, RCV000786355, RCV002381239, RCV004017225, RCV004745143" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003882...</a>
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<p>This and the asp206-to-glu mutation (see <a href="#0006">606945.0006</a>) are frequent among Afrikaners with FHCL1 (<a href="/entry/143890">143890</a>). A GTG-to-ATG mutation is responsible (<a href="#86" class="mim-tip-reference" title="Leitersdorf, E., van der Westhuyzen, D. R., Coetzee, G. A., Hobbs, H. H. <strong>Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners.</strong> J. Clin. Invest. 84: 954-961, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2569482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2569482</a>] [<a href="https://doi.org/10.1172/JCI114258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2569482">Leitersdorf et al., 1989</a>). In a study of 138 chromosomes of Afrikaner FH patients, <a href="#69" class="mim-tip-reference" title="Kotze, M. J., Langenhoven, E., Warnich, L., du Plessis, L., Retief, A. E. <strong>The molecular basis and diagnosis of familial hypercholesterolaemia in South African Afrikaners.</strong> Ann. Hum. Genet. 55: 115-121, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1952806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1952806</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1991.tb00404.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1952806">Kotze et al. (1991)</a> found that 31 (23.3%) had this mutation. <a href="#113" class="mim-tip-reference" title="Schuster, H., Ostwald, P., Keller, P., Wolfram, G., Keller, C. <strong>Identification of the serine-156 to leucine mutation in the low-density lipoprotein receptor in a German family with familial hypercholesterolemia.</strong> Clin. Investig. 71: 172-175, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8096412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8096412</a>] [<a href="https://doi.org/10.1007/BF00180002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8096412">Schuster et al. (1993)</a> found the same mutation in a German family and showed that it existed on the same 7-RFLP haplotype as did the mutation described in South Africa and in the Netherlands, suggesting a common European origin. Similarly, <a href="#23" class="mim-tip-reference" title="Defesche, J. C., van Diermen, D. E., Lansberg, P. J., Lamping, R. J., Reymer, P. W. A., Hayden, M. R., Kastelein, J. J. P. <strong>South African founder mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia in the Dutch population.</strong> Hum. Genet. 92: 567-570, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7903269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7903269</a>] [<a href="https://doi.org/10.1007/BF00420940" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7903269">Defesche et al. (1993)</a> found the val408-to-met mutation in 19 (1.5%) of 1,268 FH patients of Dutch descent. In 9 of the patients carrying this mutation on one allele, the LDLR DNA haplotype was that observed in a South African FH patient homozygous for the same mutation. The remaining 10 Dutch FH patients all shared a common haplotype, partly identical to the Afrikaner haplotype, which could have arisen from a single recombinational event. With the exception of the family reported by <a href="#113" class="mim-tip-reference" title="Schuster, H., Ostwald, P., Keller, P., Wolfram, G., Keller, C. <strong>Identification of the serine-156 to leucine mutation in the low-density lipoprotein receptor in a German family with familial hypercholesterolemia.</strong> Clin. Investig. 71: 172-175, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8096412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8096412</a>] [<a href="https://doi.org/10.1007/BF00180002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8096412">Schuster et al. (1993)</a>, this mutation has been described only in persons of Dutch ancestry. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7903269+8096412+1952806+2569482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 class="mim-font">
|
|
<strong>.0010 FH ALGERIA</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
LDLR, ALA410THR
|
|
</div>
|
|
|
|
</span>
|
|
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|
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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> rs28942079 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28942079;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/rs28942079?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=rs28942079" 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=rs28942079" 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">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003883 OR RCV000806811 OR RCV000985760 OR RCV002381240 OR RCV004017226" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003883, RCV000806811, RCV000985760, RCV002381240, RCV004017226" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003883...</a>
|
|
</span>
|
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|
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|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>A GCT-to-ACT change is responsible for this variant (<a href="#143" class="mim-tip-reference" title="Zuliani, G., Hobbs, H. H. <strong>Personal Communication.</strong> Dallas, Tex. 1990."None>Zuliani and Hobbs, 1990</a>).</p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
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|
|
<div>
|
|
<a id="0011" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 FH KUWAIT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
LDLR, VAL502MET
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<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> rs28942080 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28942080;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/rs28942080?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=rs28942080" 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=rs28942080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003884 OR RCV000161992 OR RCV000587718 OR RCV000825622 OR RCV002399309" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003884, RCV000161992, RCV000587718, RCV000825622, RCV002399309" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003884...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>A GTG-to-ATG mutation is responsible for this variant (<a href="#143" class="mim-tip-reference" title="Zuliani, G., Hobbs, H. H. <strong>Personal Communication.</strong> Dallas, Tex. 1990."None>Zuliani and Hobbs, 1990</a>).</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0012" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 FH SAINT OMER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
LDLR, GLY525ASP
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28942081 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28942081;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=rs28942081" 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=rs28942081" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003885 OR RCV001175478" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003885, RCV001175478" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003885...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>A GGC-to-GAC mutation is responsible for this variant (<a href="#84" class="mim-tip-reference" title="Leitersdorf, E., Hobbs, H. H. <strong>Personal Communication.</strong> Dallas, Tex. 12/1990."None>Leitersdorf and Hobbs, 1990</a>).</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0013" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 FH GENOA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
LDLR, GLY528ASP
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<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> rs28941776 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28941776;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/rs28941776?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=rs28941776" 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=rs28941776" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003886 OR RCV000161997 OR RCV000587938 OR RCV002390088" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003886, RCV000161997, RCV000587938, RCV002390088" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003886...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>A GGT-to-GAT mutation is responsible for this variant (<a href="#84" class="mim-tip-reference" title="Leitersdorf, E., Hobbs, H. H. <strong>Personal Communication.</strong> Dallas, Tex. 12/1990."None>Leitersdorf and Hobbs, 1990</a>).</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0014" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 FH NAPLES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
LDLR, GLY544VAL
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28942082 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28942082;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=rs28942082" 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=rs28942082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003874 OR RCV000791454 OR RCV001195593 OR RCV002399308" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003874, RCV000791454, RCV001195593, RCV002399308" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003874...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p><a href="#28" class="mim-tip-reference" title="Esser, V., Russell, D. W. <strong>Transport-deficient mutations in the low density lipoprotein receptor: alterations in the cysteine-rich and cysteine-poor regions of the protein block intracellular transport.</strong> J. Biol. Chem. 263: 13276-13281, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2901412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2901412</a>]" pmid="2901412">Esser and Russell (1988)</a> found a GGC-to-GTC mutation as the basis of this variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2901412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0015" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 FH FRENCH CANADIAN 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
LDLR, CYS646TYR
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<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> rs28942083 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28942083;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/rs28942083?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=rs28942083" 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=rs28942083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000030131 OR RCV000313287 OR RCV000775084 OR RCV002415393" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030131, RCV000313287, RCV000775084, RCV002415393" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030131...</a>
|
|
</span>
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p><a href="#85" class="mim-tip-reference" title="Leitersdorf, E., Tobin, E. J., Davignon, J., Hobbs, H. H. <strong>Common low-density lipoprotein receptor mutations in the French Canadian population.</strong> J. Clin. Invest. 85: 1014-1023, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2318961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2318961</a>] [<a href="https://doi.org/10.1172/JCI114531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2318961">Leitersdorf et al. (1990)</a> found a TGT-to-TAT mutation in exon 14 as the basis of this variant. See <a href="#0003">606945.0003</a>, <a href="#0007">606945.0007</a>, <a href="#0025">606945.0025</a>, and <a href="#0026">606945.0026</a> for other French Canadian mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2318961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div>
|
|
<a id="0016" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 FH LEBANESE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
LDLR, CYS660TER
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
<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> rs121908031 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908031;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/rs121908031?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=rs121908031" 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=rs121908031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
|
|
|
|
|
|
<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003887 OR RCV000481771 OR RCV000590806 OR RCV000844750 OR RCV002415394 OR RCV004584310" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003887, RCV000481771, RCV000590806, RCV000844750, RCV002415394, RCV004584310" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003887...</a>
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<p><a href="#78" class="mim-tip-reference" title="Lehrman, M. A., Goldstein, J. L., Russell, D. W., Brown, M. S. <strong>Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia.</strong> Cell 48: 827-835, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3815525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3815525</a>] [<a href="https://doi.org/10.1016/0092-8674(87)90079-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3815525">Lehrman et al. (1987)</a> analyzed the nature of the LDLR mutation present in high frequency in Lebanon; the frequency of homozygotes is more than 10 times higher than in other parts of the world. It was on the basis of studies in Lebanon that <a href="#60" class="mim-tip-reference" title="Khachadurian, A. K. <strong>The inheritance of essential familial hypercholesterolemia.</strong> Am. J. Med. 37: 402-407, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14209286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14209286</a>] [<a href="https://doi.org/10.1016/0002-9343(64)90196-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14209286">Khachadurian (1964)</a> first established the existence of homozygous FHCL1 (<a href="/entry/143890">143890</a>). <a href="#78" class="mim-tip-reference" title="Lehrman, M. A., Goldstein, J. L., Russell, D. W., Brown, M. S. <strong>Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia.</strong> Cell 48: 827-835, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3815525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3815525</a>] [<a href="https://doi.org/10.1016/0092-8674(87)90079-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3815525">Lehrman et al. (1987)</a> demonstrated that the mutation involves a shortened receptor protein containing 3 domains: the region of clustered O-linked carbohydrates, the membrane-spanning region, and the cytoplasmic tail. The defect was attributable to a single nucleotide substitution that creates a premature termination codon at amino acid 660, eliminating 180 residues from the mature protein. The termination codon occurred in the middle of a cysteine-rich sequence that is part of the domain homologous to epidermal growth factor precursor. The truncated protein retains only 2 domains: a complete ligand-binding region (residues 1-292) and a partial epidermal growth factor precursor homology region (residues 293-659). The mutant gene lacks the portions that code for the membrane-spanning region and the cytoplasmic tail. After synthesis, most of the mutant receptor remains within the cell. The mutation creates a new restriction site for the enzyme HinfI, thus permitting diagnosis by Southern blotting of genomic DNA. <a href="#78" class="mim-tip-reference" title="Lehrman, M. A., Goldstein, J. L., Russell, D. W., Brown, M. S. <strong>Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia.</strong> Cell 48: 827-835, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3815525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3815525</a>] [<a href="https://doi.org/10.1016/0092-8674(87)90079-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3815525">Lehrman et al. (1987)</a> studied 4 unrelated Arab patients with homozygous familial hypercholesterolemia, 3 from Lebanon and 1 from Syria. They referred to this mutation as the Lebanese allele. In 5 Christian-Arab kindreds in Israel, <a href="#101" class="mim-tip-reference" title="Oppenheim, A., Friedlander, Y., Dann, E. J., Berkman, N., Schwartz, S. P., Leitersdorf, E. <strong>Hypercholesterolemia in five Israeli Christian-Arab kindreds is caused by the 'Lebanese' allele at the low density lipoprotein receptor gene locus and by an additional independent major factor.</strong> Hum. Genet. 88: 75-84, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1959928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1959928</a>] [<a href="https://doi.org/10.1007/BF00204933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1959928">Oppenheim et al. (1991)</a> found the 'Lebanese' allele in correlation with hypercholesterolemia. In addition, their results suggested the possible existence of an independent factor contributing to elevated LDL cholesterol levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3815525+14209286+1959928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0017 FH ZAMBIA</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> rs28942084 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28942084;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/rs28942084?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=rs28942084" 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=rs28942084" 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=RCV000003891 OR RCV000162007 OR RCV000775085 OR RCV000844731 OR RCV002415395 OR RCV004745144" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003891, RCV000162007, RCV000775085, RCV000844731, RCV002415395, RCV004745144" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003891...</a>
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<p>In an Asiatic Indian with FHCL1 (<a href="/entry/143890">143890</a>), <a href="#62" class="mim-tip-reference" title="Knight, B. L., Gavigan, S. J. P., Soutar, A. K., Patel, D. D. <strong>Defective processing and binding of low-density lipoprotein receptors in fibroblasts from a familial hypercholesterolaemic subject.</strong> Europ. J. Biochem. 179: 693-698, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2920733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2920733</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1989.tb14602.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2920733">Knight et al. (1989)</a> and <a href="#117" class="mim-tip-reference" title="Soutar, A. K., Knight, B. L., Patel, D. D. <strong>Identification of a point mutation in growth repeat C of the low density lipoprotein-receptor gene in a patient with homozygous familial hypercholesterolemia that affects ligand binding and intracellular movement of receptors.</strong> Proc. Nat. Acad. Sci. 86: 4166-4170, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2726768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2726768</a>] [<a href="https://doi.org/10.1073/pnas.86.11.4166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2726768">Soutar et al. (1989)</a> found a CCG-to-CTG mutation changing proline-664 to leucine. <a href="#62" class="mim-tip-reference" title="Knight, B. L., Gavigan, S. J. P., Soutar, A. K., Patel, D. D. <strong>Defective processing and binding of low-density lipoprotein receptors in fibroblasts from a familial hypercholesterolaemic subject.</strong> Europ. J. Biochem. 179: 693-698, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2920733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2920733</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1989.tb14602.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2920733">Knight et al. (1989)</a> found that the precursor form of the mutant receptor is converted more slowly than normal, and the mature form on the cell surface binds LDL less well than normal. <a href="#118" class="mim-tip-reference" title="Soutar, A. K., McCarthy, S. N., Seed, M., Knight, B. L. <strong>Relationship between apolipoprotein(a) phenotype, lipoprotein(a) concentration in plasma, and low density lipoprotein receptor function in a large kindred with familial hypercholesterolemia due to the pro664-to-leu mutation in the LDL receptor gene.</strong> J. Clin. Invest. 88: 483-492, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1830890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1830890</a>] [<a href="https://doi.org/10.1172/JCI115329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1830890">Soutar et al. (1991)</a> identified this mutation in a large Asian-Indian kindred containing 22 heterozygotes and 3 homozygotes. All the heterozygotes had a raised level of plasma total cholesterol and low density lipoprotein cholesterol, but were remarkably free from premature coronary disease. No correlation could be found between the apo(a) phenotype (<a href="/entry/152200">152200</a>) and the presence or absence of the LDLR mutation. There was, however, evidence for an inherited trait that markedly increased Lp(a) concentration, which did not segregate with either apo(a) or the defective LDLR allele. FH Zambia was found in a patient with familial hypercholesterolemia who was of Indian origin residing in Zambia. <a href="#104" class="mim-tip-reference" title="Rubinsztein, D. C., Coetzee, G. A., Marais, A. D., Leitersdorf, E., Seftel, H. C., van der Westhuyzen, D. R. <strong>Identification and properties of the proline-644-to-leucine mutant LDL receptor in South Africans of Indian origin.</strong> J. Lipid Res. 33: 1647-1655, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1464748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1464748</a>]" pmid="1464748">Rubinsztein et al. (1992)</a> found the same mutation in 4 South African families of Muslim religion who traced their origin to the vicinity of Surat in the Gujerat province of India. Functional studies suggested that the FH in these subjects was due to low steady-state levels of receptor molecules that are functionally normal but exhibit accelerated turnover. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1830890+1464748+2920733+2726768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 915 consecutive patients with FH and of Dutch descent, <a href="#22" class="mim-tip-reference" title="Defesche, J. C., van de Ree, M. A., Kastelein, J. J. P., van Diermen, D. E., Janssens, N. W. E., van Doormaal, J. J., Hayden, M. R. <strong>Detection of the pro664-to-leu mutation in the low-density lipoprotein receptor and its relation to lipoprotein(a) levels in patients with familial hypercholesterolemia of Dutch ancestry from The Netherlands and Canada.</strong> Clin. Genet. 42: 273-280, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1493640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1493640</a>]" pmid="1493640">Defesche et al. (1992)</a> found 7 persons with the C-to-T transition at nucleotide 2054 in exon 14. All the patients shared the same haplotype. Contrary to previous reports, no difference was found in plasma levels of Lp(a) between family members with the mutation in exon 14 and unaffected persons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1493640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0018 FH BAHRAIN</strong>
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LDLR, TRP792TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908032 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908032;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=rs121908032" 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=rs121908032" 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=RCV000003892" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003892" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003892</a>
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<p>In a Bahraini patient with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#77" class="mim-tip-reference" title="Lehrman, M. A., Goldstein, J. L., Brown, M. S., Russell, D. W., Schneider, W. J. <strong>Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain.</strong> Cell 41: 735-743, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3924410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3924410</a>] [<a href="https://doi.org/10.1016/s0092-8674(85)80054-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3924410">Lehrman et al. (1985)</a> found a change in the tryptophan-792 codon to a stop codon as the basis of this variant. Truncation of the cytoplasmic domain of the LDLR protein results in defective internalization. Recurrence of this mutation was observed by <a href="#93" class="mim-tip-reference" title="Loux, N., Benlian, P., Pastier, D., Boileau, C., Cambou, J. P., Monnier, L., Percheron, C., Junien, C. <strong>Recurrent mutation at aa 792 in the LDL receptor gene in a French patient.</strong> Hum. Genet. 87: 373-375, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1677927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1677927</a>] [<a href="https://doi.org/10.1007/BF00200923" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1677927">Loux et al. (1991)</a> in the course of a survey of 139 unrelated French FH subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3924410+1677927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs28942085 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28942085;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=rs28942085" 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=rs28942085" 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=RCV000003893 OR RCV000162025 OR RCV002426485 OR RCV002512729" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003893, RCV000162025, RCV002426485, RCV002512729" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003893...</a>
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<p>In an Italian patient with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#17" class="mim-tip-reference" title="Davis, C. G., Lehrman, M. A., Russell, D. W., Anderson, R. G. W., Brown, M. S., Goldstein, J. L. <strong>The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors.</strong> Cell 45: 15-24, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3955657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3955657</a>] [<a href="https://doi.org/10.1016/0092-8674(86)90533-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3955657">Davis et al. (1986)</a> found a TAT-to-TGT mutation in this internalization-defective allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3955657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 FH NASHVILLE</strong>
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LDLR, 4-BP INS, EX8
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs875989916 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs875989916;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=rs875989916" 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=rs875989916" 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=RCV000211651 OR RCV000588024 OR RCV000825618 OR RCV002284377 OR RCV002433922" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000211651, RCV000588024, RCV000825618, RCV002284377, RCV002433922" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000211651...</a>
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<p>In an American patient with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#84" class="mim-tip-reference" title="Leitersdorf, E., Hobbs, H. H. <strong>Personal Communication.</strong> Dallas, Tex. 12/1990."None>Leitersdorf and Hobbs (1990)</a> found insertion of 4 nucleotides in exon 8 causing frameshift and premature termination as the basis of this null allele.</p>
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<strong>.0021 FH PARIS 3</strong>
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LDLR, 4-BP INS, EX17
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906302 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906302;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=rs387906302" 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=rs387906302" 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=RCV000003895 OR RCV001256974" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003895, RCV001256974" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003895...</a>
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<span class="mim-text-font">
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<p>In a French patient with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#77" class="mim-tip-reference" title="Lehrman, M. A., Goldstein, J. L., Brown, M. S., Russell, D. W., Schneider, W. J. <strong>Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain.</strong> Cell 41: 735-743, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3924410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3924410</a>] [<a href="https://doi.org/10.1016/s0092-8674(85)80054-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3924410">Lehrman et al. (1985)</a> found insertion of 4 nucleotides in exon 17 causing frameshift and premature termination as the basis of this internalization-defective allele. <a href="#7" class="mim-tip-reference" title="Benlian, P., Amselem, S., Loux, N., Pastier, D., Giraud, G., de Gennes, J. L., Turpin, G., Monnier, L., Rieu, D., Douste-Blazy, P., Dastugue, B., Goossens, M., Junien, C. <strong>A LDL receptor gene homozygous mutation: PCR amplification, direct genomic sequencing, associated haplotype, rapid screening for frequency.</strong> Ann. Genet. 33: 65-69, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1978630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1978630</a>]" pmid="1978630">Benlian et al. (1990)</a> found the same duplication of 4 bases in exon 17 as the basis of familial hypercholesterolemia in a homozygous offspring of consanguineous French parents and in heterozygous relatives. The same mutation was not found in any normal individuals or in 158 other individuals with hypercholesterolemia type IIa. The duplication involved the third nucleotide of codon 796 and the 3 nucleotides of codon 797, resulting in a frameshift and a stop codon 20 basepairs downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3924410+1978630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0022" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0022 FH PORTUGAL</strong>
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</h4>
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<div style="float: left;">
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LDLR, ASP203ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906303 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906303;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=rs387906303" 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=rs387906303" 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=RCV000003896 OR RCV001851629 OR RCV002362557" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003896, RCV001851629, RCV002362557" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003896...</a>
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</span>
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<span class="mim-text-font">
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<p>In Portuguese patients with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#44" class="mim-tip-reference" title="Hobbs, H. H., Brown, M. S., Goldstein, J. L. <strong>Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.</strong> Hum. Mutat. 1: 445-466, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301956</a>] [<a href="https://doi.org/10.1002/humu.1380010602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301956">Hobbs et al. (1992)</a> identified a G-A transition in exon 4 of the LDLR gene, resulting in an asp203-to-asn (D203N) substitution. The mutation was not found in over 200 non-FH alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301956" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0023" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0023 FH ST. LOUIS</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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LDLR, EX2-8DUP
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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=RCV000237421" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000237421" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000237421</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 an American child homozygous for FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#78" class="mim-tip-reference" title="Lehrman, M. A., Goldstein, J. L., Russell, D. W., Brown, M. S. <strong>Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia.</strong> Cell 48: 827-835, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3815525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3815525</a>] [<a href="https://doi.org/10.1016/0092-8674(87)90079-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3815525">Lehrman et al. (1987)</a> found that the LDL receptor precursor was unusually long due to a duplication of 7 exons. Unequal crossing-over between homologous repetitive elements (Alu sequences) in intron 1 and intron 8 was the basis of the duplication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3815525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0024" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0024 FH PARIS 2</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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LDLR, EX2-5DUP
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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=RCV000237716" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000237716" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000237716</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 French patient with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#84" class="mim-tip-reference" title="Leitersdorf, E., Hobbs, H. H. <strong>Personal Communication.</strong> Dallas, Tex. 12/1990."None>Leitersdorf and Hobbs (1990)</a> found this mutation.</p>
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</span>
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</div>
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<a id="0025" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0025 FH FRENCH CANADIAN 1</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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FH DENVER
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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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<div style="float: left;">
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LDLR, PROMOTER/EX1 DEL
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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=RCV000003899" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003899" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003899</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>Deletion of the promoter and exon 1 of the LDLR gene resulting in a null allele is the mutation found in about 60% of French Canadian cases of FH (FHCL1; <a href="/entry/143890">143890</a>) in Quebec (<a href="#45" class="mim-tip-reference" title="Hobbs, H. H., Brown, M. S., Russell, D. W., Davignon, J., Goldstein, J. L. <strong>Deletion in the gene for the low-density-lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia.</strong> New Eng. J. Med. 317: 734-737, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3627182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3627182</a>] [<a href="https://doi.org/10.1056/NEJM198709173171204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3627182">Hobbs et al., 1987</a>; <a href="#85" class="mim-tip-reference" title="Leitersdorf, E., Tobin, E. J., Davignon, J., Hobbs, H. H. <strong>Common low-density lipoprotein receptor mutations in the French Canadian population.</strong> J. Clin. Invest. 85: 1014-1023, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2318961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2318961</a>] [<a href="https://doi.org/10.1172/JCI114531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2318961">Leitersdorf et al., 1990</a>). <a href="#85" class="mim-tip-reference" title="Leitersdorf, E., Tobin, E. J., Davignon, J., Hobbs, H. H. <strong>Common low-density lipoprotein receptor mutations in the French Canadian population.</strong> J. Clin. Invest. 85: 1014-1023, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2318961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2318961</a>] [<a href="https://doi.org/10.1172/JCI114531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2318961">Leitersdorf et al. (1990)</a> quoted work indicating that all persons with the 'French Canadian deletion' trace their ancestry to a small town northeast of Montreal called Kamouraska, thus illustrating founder effect. Founder effect was suggested as well by the fact that the mutation was also found in France where it was, however, rare (<a href="#32" class="mim-tip-reference" title="Fumeron, F., Grandchamp, B., Fricker, J., Krempf, M., Wolf, L.-M., Khayat, M.-C., Boiffard, O., Apfelbaum, M. <strong>Presence of the French Canadian deletion in a French patient with familial hypercholesterolemia. (Letter)</strong> New Eng. J. Med. 326: 69 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1727071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1727071</a>] [<a href="https://doi.org/10.1056/NEJM199201023260118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1727071">Fumeron et al., 1992</a>). The same mutation was found in a non-French Canadian Caucasian in Denver, Colorado (<a href="#47" class="mim-tip-reference" title="Hobbs, H. H., Leitersdorf, E., Goldstein, J. L., Brown, M. S., Russell, D. W. <strong>Multiple CRM- mutations in familial hypercholesterolemia: evidence for 13 alleles, including four deletions.</strong> J. Clin. Invest. 81: 909-917, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3343347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3343347</a>] [<a href="https://doi.org/10.1172/JCI113402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3343347">Hobbs et al., 1988</a>). <a href="#9" class="mim-tip-reference" title="Betard, C., Kessling, A. M., Roy, M., Chamberland, A., Lussier-Cacan, S., Davignon, J. <strong>Molecular genetic evidence for a founder effect in familial hypercholesterolemia among French Canadians.</strong> Hum. Genet. 88: 529-536, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1348044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1348044</a>] [<a href="https://doi.org/10.1007/BF00219339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1348044">Betard et al. (1992)</a> found that the 10-kb deletion had the same haplotype, called the B haplotype. They identified 15 different haplotypes for the normal allele in heterozygotes. Thus, founder effect is again supported. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3627182+1348044+3343347+2318961+1727071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>(It is more accurate to state that Kamouraska is northeast of Quebec City on the south side of the St. Lawrence River. See <a href="/entry/609313">609313</a> for a unique form of erythrokeratodermia variabilis, designated the Kamouraska type and symbolized EKV3, that has been identified in families living in the same region of Quebec.)</p><p><a href="#115" class="mim-tip-reference" title="Simard, L. R., Viel, J., Lambert, M., Paradis, G., Levy, E., Delvin, E. E., Mitchell, G. A. <strong>The delta > 15 kb deletion French Canadian founder mutation in familial hypercholesterolemia: rapid polymerase chain reaction-based diagnostic assay and prevalence in Quebec.</strong> Clin. Genet. 65: 202-208, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14756670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14756670</a>] [<a href="https://doi.org/10.1111/j.0009-9163.2004.00223.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14756670">Simard et al. (2004)</a> identified the breakpoint of the more than 15-kb deletion involving the promoter and exon 1 of the LDLR gene, as well as the breakpoint of the 5-kb deletion of exons 2 and 3 (<a href="#0026">606945.0026</a>), which accounts for 5% of French Canadian FH cases. Both deletions appeared to be the result of homologous recombination by unequal crossing over between the left arms of Alu repeats. <a href="#115" class="mim-tip-reference" title="Simard, L. R., Viel, J., Lambert, M., Paradis, G., Levy, E., Delvin, E. E., Mitchell, G. A. <strong>The delta > 15 kb deletion French Canadian founder mutation in familial hypercholesterolemia: rapid polymerase chain reaction-based diagnostic assay and prevalence in Quebec.</strong> Clin. Genet. 65: 202-208, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14756670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14756670</a>] [<a href="https://doi.org/10.1111/j.0009-9163.2004.00223.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14756670">Simard et al. (2004)</a> determined that 55% of the LDLR gene is composed of Alu elements; thus, it is not surprising that most LDLR rearrangements involve at least 1 Alu. They developed a rapid PCR-based assay for these 2 'French Canadian' deletions. Screening of a representative population sample of 943 French Canadian youths whose LDL cholesterol levels were above the 50th percentile allowed <a href="#115" class="mim-tip-reference" title="Simard, L. R., Viel, J., Lambert, M., Paradis, G., Levy, E., Delvin, E. E., Mitchell, G. A. <strong>The delta > 15 kb deletion French Canadian founder mutation in familial hypercholesterolemia: rapid polymerase chain reaction-based diagnostic assay and prevalence in Quebec.</strong> Clin. Genet. 65: 202-208, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14756670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14756670</a>] [<a href="https://doi.org/10.1111/j.0009-9163.2004.00223.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14756670">Simard et al. (2004)</a> to estimate the prevalence of the more than 15-kb allele as 0.11% (95% confidence interval, 0.03 to 0.38). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14756670" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0026 FH FRENCH CANADIAN 5</strong>
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FH TONAMI 2<br />
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LDLR, EX2-3DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003901" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003901" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003901</a>
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<p><a href="#94" class="mim-tip-reference" title="Ma, Y. H., Betard, C., Roy, M., Davignon, J., Kessling, A. M. <strong>Identification of a second 'French Canadian' LDL receptor gene deletion and development of a rapid method to detect both deletions.</strong> Clin. Genet. 36: 219-228, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2805380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2805380</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1989.tb03194.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2805380">Ma et al. (1989)</a> found deletion of exons 2 and 3 in a French Canadian patient with FH (FHCL1; <a href="/entry/143890">143890</a>). The same mutation was found in 2 Japanese patients with homozygous FH and called FH Tonami-2 (<a href="#57" class="mim-tip-reference" title="Kajinami, K., Fujita, H., Koizumi, J., Mabuchi, H., Takeda, R., Ohta, M. <strong>Genetically determined mild type of familial hypercholesterolemia including normocholesterolemic patients: FH-Tonami-2.</strong> Circulation 80 (suppl. 2): 278 only, 1989."None>Kajinami et al., 1989</a>) and FH Tsukuba-1 (<a href="#140" class="mim-tip-reference" title="Yamakawa, K., Takada, K., Yanagi, H., Tsuchiya, S., Kawai, K., Nakagawa, S., Kajiyama, G., Hamaguchi, H. <strong>Three novel partial deletions of the low-density lipoprotein (LDL) receptor gene in familial hypercholesterolemia.</strong> Hum. Genet. 82: 317-321, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2544509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2544509</a>] [<a href="https://doi.org/10.1007/BF00273989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2544509">Yamakawa et al., 1989</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2805380+2544509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 FH PARIS 1</strong>
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LDLR, EX5DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555803632 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555803632;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=rs1555803632" 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=rs1555803632" 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=RCV000237282" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000237282" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000237282</a>
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<p>In a French patient with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#43" class="mim-tip-reference" title="Hobbs, H. H., Brown, M. S., Goldstein, J. L., Russell, D. W. <strong>Deletion of exon encoding cysteine-rich repeat of low density lipoprotein receptor alters its binding specificity in a subject with familial hypercholesterolemia.</strong> J. Biol. Chem. 261: 13114-13120, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3020025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3020025</a>]" pmid="3020025">Hobbs et al. (1986)</a> found deletion of exon 5 of the LDLR gene. <a href="#50" class="mim-tip-reference" title="Horsthemke, B., Beisiegel, U., Dunning, A., Havinga, J. R., Williamson, R., Humphries, S. <strong>Unequal crossing-over between two Alu-repetitive DNA sequences in the low-density-lipoprotein-receptor gene: a possible mechanism for the defect in a patient with familial hypercholesterolaemia.</strong> Europ. J. Biochem. 164: 77-81, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3549308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3549308</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1987.tb10995.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3549308">Horsthemke et al. (1987)</a> found the same mutation in 2 English patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3549308+3020025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0028" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0028 FH CAPE TOWN 2</strong>
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FH LEUVEN<br />
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FH LEIDEN 1
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LDLR, EX7-8DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003889 OR RCV000575461" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003889, RCV000575461" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003889...</a>
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<p>In South African patients with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#42" class="mim-tip-reference" title="Henderson, H. E., Berger, G. M. B., Marais, A. D. <strong>A new LDL receptor gene deletion mutation in the South African population.</strong> Hum. Genet. 80: 371-374, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3198114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3198114</a>] [<a href="https://doi.org/10.1007/BF00273653" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3198114">Henderson et al. (1988)</a> detected a hitherto undescribed 2.5-kb deletion in the central region of the LDLR gene, most likely including all of exons 7 and 8. The same mutation was present in a Dutch patient in Leuven (<a href="#108" class="mim-tip-reference" title="Russell, D. W., Lehrman, M. A., Sudhof, T. C., Yamamoto, T., Davis, C. G., Hobbs, H. H., Brown, M. S., Goldstein, J. L. <strong>The LDL receptor in familial hypercholesterolemia: use of human mutations to dissect a membrane protein.</strong> Cold Spring Harbor Symp. Quant. Biol. 51: 811-819, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3472763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3472763</a>] [<a href="https://doi.org/10.1101/sqb.1986.051.01.094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3472763">Russell et al., 1986</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3472763+3198114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0029" class="mim-anchor"></a>
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<strong>.0029 FH ROCHESTER</strong>
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FH OSAKA 1<br />
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FH HELSINKI
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LDLR, EX16-18DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003905" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003905" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003905</a>
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<p>In an American patient with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#77" class="mim-tip-reference" title="Lehrman, M. A., Goldstein, J. L., Brown, M. S., Russell, D. W., Schneider, W. J. <strong>Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain.</strong> Cell 41: 735-743, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3924410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3924410</a>] [<a href="https://doi.org/10.1016/s0092-8674(85)80054-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3924410">Lehrman et al. (1985)</a> found deletion of exons 16, 17, and part of 18, due apparently to Alu-Alu recombination. The same mutation was found in Japanese by <a href="#78" class="mim-tip-reference" title="Lehrman, M. A., Goldstein, J. L., Russell, D. W., Brown, M. S. <strong>Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia.</strong> Cell 48: 827-835, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3815525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3815525</a>] [<a href="https://doi.org/10.1016/0092-8674(87)90079-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3815525">Lehrman et al. (1987)</a> and in many Finns by <a href="#1" class="mim-tip-reference" title="Aalto-Setala, K., Helve, E., Kovanen, P. T., Kontula, K. <strong>Finnish type of low density lipoprotein receptor gene mutation (FH-Helsinki) deletes exons encoding the carboxy-terminal part of the receptor and creates an internalization-defective phenotype.</strong> J. Clin. Invest. 84: 499-505, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2760198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2760198</a>] [<a href="https://doi.org/10.1172/JCI114192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2760198">Aalto-Setala et al. (1989)</a>. A 9.5-kb deletion extended from intron 15 to exon 18. Because of loss of the domains encoded by exons 16, 17, and 18, the carboxy-terminal portion of the normal receptor, comprising amino acids 750-839, has been replaced by an unrelated stretch of 55 amino acids. This particular mutation was found in 23 of 46 unrelated Finnish FH patients with an established functional defect of LDLR. In cultured fibroblasts, both receptor-mediated binding and internalization of LDL were reduced on the average by 25 and 50%, respectively. <a href="#1" class="mim-tip-reference" title="Aalto-Setala, K., Helve, E., Kovanen, P. T., Kontula, K. <strong>Finnish type of low density lipoprotein receptor gene mutation (FH-Helsinki) deletes exons encoding the carboxy-terminal part of the receptor and creates an internalization-defective phenotype.</strong> J. Clin. Invest. 84: 499-505, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2760198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2760198</a>] [<a href="https://doi.org/10.1172/JCI114192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2760198">Aalto-Setala et al. (1989)</a> referred to the mutation as FH-Helsinki. <a href="#103" class="mim-tip-reference" title="Rodningen, O. K., Rosby, O., Tonstad, S., Ose, L., Berg, K., Leren, T. P. <strong>A 9.6 kilobase deletion in the low density lipoprotein receptor gene in Norwegian familial hypercholesterolemia subjects.</strong> Clin. Genet. 42: 288-295, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1362925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1362925</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1992.tb03258.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1362925">Rodningen et al. (1992)</a> found the same mutation in 3 out of 181 (1.7%) unrelated Norwegian FH subjects. All 3 showed the same haplotype. <a href="#2" class="mim-tip-reference" title="Aalto-Setala, K., Koivisto, U.-M., Miettinen, T. A., Gylling, H., Kesaniemi, Y. A., Savolainen, M., Pyorala, K., Ebeling, T., Mononen, I., Turtola, H., Viikari, J., Kontula, K. <strong>Prevalence and geographical distribution of major LDL receptor gene rearrangements in Finland.</strong> J. Intern. Med. 231: 227-234, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1372927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1372927</a>] [<a href="https://doi.org/10.1111/j.1365-2796.1992.tb00528.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1372927">Aalto-Setala et al. (1992)</a> found that the FH-Helsinki mutation was present in 75 (38%) of 199 unrelated Finnish patients with hypercholesterolemia. The prevalence ranged from 26 to 58% in different areas of Finland, with the striking exception of the North Karelia region where only 1 of 26 (4%) FH patients carried the FH-Helsinki allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3815525+1372927+2760198+3924410+1362925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0030" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0030 FH VANCOUVER 4</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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FH VANCOUVER 5
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</span>
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<span class="mim-text-font">
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<div style="float: left;">
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LDLR, EX2-6DEL
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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=RCV000003907" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003907" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003907</a>
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<p><a href="#74" class="mim-tip-reference" title="Langlois, S., Kastelein, J. J. P., Hayden, M. R. <strong>Characterization of six partial deletions in the low-density-lipoprotein (LDL) receptor gene causing familial hypercholesterolemia (FH).</strong> Am. J. Hum. Genet. 43: 60-68, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2837085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2837085</a>]" pmid="2837085">Langlois et al. (1988)</a> found 2 instances of deletion of exons 2-6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2837085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0031" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0031 FH VANCOUVER 3</strong>
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<span class="mim-text-font">
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<div style="float: left;">
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LDLR, EX3-8DEL
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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=RCV000003909" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003909" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003909</a>
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</span>
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<span class="mim-text-font">
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<p><a href="#74" class="mim-tip-reference" title="Langlois, S., Kastelein, J. J. P., Hayden, M. R. <strong>Characterization of six partial deletions in the low-density-lipoprotein (LDL) receptor gene causing familial hypercholesterolemia (FH).</strong> Am. J. Hum. Genet. 43: 60-68, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2837085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2837085</a>]" pmid="2837085">Langlois et al. (1988)</a> found an instance of deletion of exons 3-8. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2837085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0032" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0032 FH LONDON 1</strong>
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</h4>
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<span class="mim-text-font">
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FH ITALY 1<br />
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FH VANCOUVER 1
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</span>
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<span class="mim-text-font">
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<div style="float: left;">
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LDLR, EX13-14DEL
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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=RCV000238262" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000238262" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000238262</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In an English patient with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#50" class="mim-tip-reference" title="Horsthemke, B., Beisiegel, U., Dunning, A., Havinga, J. R., Williamson, R., Humphries, S. <strong>Unequal crossing-over between two Alu-repetitive DNA sequences in the low-density-lipoprotein-receptor gene: a possible mechanism for the defect in a patient with familial hypercholesterolaemia.</strong> Europ. J. Biochem. 164: 77-81, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3549308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3549308</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1987.tb10995.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3549308">Horsthemke et al. (1987)</a> found deletion of exons 13 and 14. <a href="#47" class="mim-tip-reference" title="Hobbs, H. H., Leitersdorf, E., Goldstein, J. L., Brown, M. S., Russell, D. W. <strong>Multiple CRM- mutations in familial hypercholesterolemia: evidence for 13 alleles, including four deletions.</strong> J. Clin. Invest. 81: 909-917, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3343347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3343347</a>] [<a href="https://doi.org/10.1172/JCI113402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3343347">Hobbs et al. (1988)</a> found the same mutation in an Italian patient and <a href="#74" class="mim-tip-reference" title="Langlois, S., Kastelein, J. J. P., Hayden, M. R. <strong>Characterization of six partial deletions in the low-density-lipoprotein (LDL) receptor gene causing familial hypercholesterolemia (FH).</strong> Am. J. Hum. Genet. 43: 60-68, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2837085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2837085</a>]" pmid="2837085">Langlois et al. (1988)</a> found it in Vancouver. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3549308+3343347+2837085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<a id="0033" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0033 FH LONDON 2</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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LDLR, EX7DEL
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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=RCV000003913" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003913" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003913</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 an English patient with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#50" class="mim-tip-reference" title="Horsthemke, B., Beisiegel, U., Dunning, A., Havinga, J. R., Williamson, R., Humphries, S. <strong>Unequal crossing-over between two Alu-repetitive DNA sequences in the low-density-lipoprotein-receptor gene: a possible mechanism for the defect in a patient with familial hypercholesterolaemia.</strong> Europ. J. Biochem. 164: 77-81, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3549308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3549308</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1987.tb10995.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3549308">Horsthemke et al. (1987)</a> found deletion of exon 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3549308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<div>
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<div>
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<a id="0034" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0034 FH OSAKA 2</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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LDLR, EX7-14DEL
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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=RCV000003914" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003914" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003914</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 Japanese patient with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#98" class="mim-tip-reference" title="Miyake, Y., Tajima, S., Funahashi, T., Yamamoto, A. <strong>Analysis of a recycling-impaired mutant of low density lipoprotein receptor in familial hypercholesterolemia.</strong> J. Biol. Chem. 264: 16584-16590, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2777800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2777800</a>]" pmid="2777800">Miyake et al. (1989)</a> found deletion of exons 7 to 14. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2777800" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0035" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0035 FH VANCOUVER 2</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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LDLR, EX17DEL
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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=RCV000238491" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000238491" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000238491</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="#75" class="mim-tip-reference" title="Langlois, S. <strong>Personal Communication.</strong> Vancouver, British Columbia, Canada 1989."None>Langlois (1989)</a> found deletion of exon 17 in a patient in Vancouver, B.C.</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="0036" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0036 FH VANCOUVER 6</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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LDLR, EX4-6DEL
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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=RCV000238046 OR RCV000509511" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000238046, RCV000509511" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000238046...</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="#74" class="mim-tip-reference" title="Langlois, S., Kastelein, J. J. P., Hayden, M. R. <strong>Characterization of six partial deletions in the low-density-lipoprotein (LDL) receptor gene causing familial hypercholesterolemia (FH).</strong> Am. J. Hum. Genet. 43: 60-68, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2837085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2837085</a>]" pmid="2837085">Langlois et al. (1988)</a> found deletion of exons 4 to 6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2837085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<br />
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</div>
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<div>
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<div>
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<a id="0037" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0037 FH REYKJAVIK</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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LDLR, EX9-10DEL
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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=RCV000237483" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000237483" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000237483</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 the Icelandic population, <a href="#126" class="mim-tip-reference" title="Taylor, R., Bryant, J., Gudnason, V., Sigurdsson, G., Humphries, S. <strong>A study of familial hypercholesterolaemia in Iceland using RFLPs.</strong> J. Med. Genet. 26: 494-498, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2570157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2570157</a>] [<a href="https://doi.org/10.1136/jmg.26.8.494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2570157">Taylor et al. (1989)</a> found this deletion in patients with familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>). However, in 17 unrelated families from Iceland, <a href="#126" class="mim-tip-reference" title="Taylor, R., Bryant, J., Gudnason, V., Sigurdsson, G., Humphries, S. <strong>A study of familial hypercholesterolaemia in Iceland using RFLPs.</strong> J. Med. Genet. 26: 494-498, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2570157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2570157</a>] [<a href="https://doi.org/10.1136/jmg.26.8.494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2570157">Taylor et al. (1989)</a> identified at least 4 different haplotypes, indicating that FH is a heterogeneous disease even in this small, geographically isolated population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2570157" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0038" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0038 FH TONAMI 1</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;">
|
|
LDLR, EX15DEL
|
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</div>
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</span>
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<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000237642" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000237642" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000237642</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="#58" class="mim-tip-reference" title="Kajinami, K., Mabuchi, H., Itoh, H., Michishita, I., Takeda, M., Wakasugi, T., Koizumi, J., Takeda, R. <strong>New variant of low density lipoprotein receptor gene FH-Tonami.</strong> Arteriosclerosis 8: 187-192, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2831865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2831865</a>] [<a href="https://doi.org/10.1161/01.atv.8.2.187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2831865">Kajinami et al. (1988)</a> found deletion of exon 15 in a Japanese patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2831865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0039" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0039 FH TSUKUBA 2</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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LDLR, EX16-17DEL
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</div>
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</span>
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<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000237703" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000237703" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000237703</a>
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p><a href="#140" class="mim-tip-reference" title="Yamakawa, K., Takada, K., Yanagi, H., Tsuchiya, S., Kawai, K., Nakagawa, S., Kajiyama, G., Hamaguchi, H. <strong>Three novel partial deletions of the low-density lipoprotein (LDL) receptor gene in familial hypercholesterolemia.</strong> Hum. Genet. 82: 317-321, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2544509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2544509</a>] [<a href="https://doi.org/10.1007/BF00273989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2544509">Yamakawa et al. (1989)</a> found deletion of exons 16 and 17 in a Japanese patient with FH (FHCL1; <a href="/entry/143890">143890</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2544509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0040" class="mim-anchor"></a>
|
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<h4>
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|
<span class="mim-font">
|
|
<strong>.0040 FH BALTIMORE-1</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
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<div style="float: left;">
|
|
LDLR, EX17-18DEL
|
|
</div>
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|
</span>
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<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003920" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003920" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003920</a>
|
|
</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an American Caucasian with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#49" class="mim-tip-reference" title="Hobbs, H. H., Russell, D. W., Brown, M. S., Goldstein, J. L. <strong>The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein.</strong> Annu. Rev. Genet. 24: 133-170, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2088165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2088165</a>] [<a href="https://doi.org/10.1146/annurev.ge.24.120190.001025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2088165">Hobbs et al. (1990)</a> found a deletion from intron 16 to the 3-prime flanking region of the LDLR gene, resulting in the deletion of exons 17 and 18. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2088165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></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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<a id="0041" class="mim-anchor"></a>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0041 FH LEIDEN 2</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
LDLR, EX16DEL
|
|
</div>
|
|
|
|
</span>
|
|
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003921" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003921" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003921</a>
|
|
</span>
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|
</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
<p>In Dutch patients with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#130" class="mim-tip-reference" title="Top, B., Koeleman, B. P. C., Gevers Leuven, J. A., Havekes, L. M., Frants, R. R. <strong>Rearrangements in the LDL receptor gene in Dutch familial hypercholesterolemic patients and the presence of a common 4 kb deletion.</strong> Atherosclerosis 83: 127-136, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1978682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1978682</a>] [<a href="https://doi.org/10.1016/0021-9150(90)90158-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1978682">Top et al. (1990)</a> found that deletion of the 5-prime part of exon 16 was a frequent mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1978682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0042" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0042 FH POTENZA</strong>
|
|
</span>
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
|
|
<div style="float: left;">
|
|
LDLR, EX13-15DEL
|
|
</div>
|
|
|
|
</span>
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|
|
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|
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|
|
<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003922" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003922" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003922</a>
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In an Italian patient with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#79" class="mim-tip-reference" title="Lehrman, M. A., Russell, D. W., Goldstein, J. L., Brown, M. S. <strong>Exon-Alu recombination deletes 5 kilobases from the low density lipoprotein receptor gene, producing a null phenotype in familial hypercholesterolemia.</strong> Proc. Nat. Acad. Sci. 83: 3679-3683, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3012527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3012527</a>] [<a href="https://doi.org/10.1073/pnas.83.11.3679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3012527">Lehrman et al. (1986)</a> found deletion of exons 14 and 15 and part of 13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3012527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0043" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0043 FH BOLOGNA 2</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
|
|
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<div style="float: left;">
|
|
LDLR, EX13-15DUP
|
|
</div>
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|
</span>
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<span class="mim-text-font">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000238544" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000238544" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000238544</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">
|
|
<p>In a survey of Italian patients with FH (FHCL1; <a href="/entry/143890">143890</a>), <a href="#87" class="mim-tip-reference" title="Lelli, N., Ghisellini, M., Calandra, S., Gaddi, A., Ciarrocchi, A., Coviello, D. A., Bertolini, S. <strong>Duplication of exons 13, 14 and 15 of the LDL-receptor gene in a patient with heterozygous familial hypercholesterolemia.</strong> Hum. Genet. 86: 359-362, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1999337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1999337</a>] [<a href="https://doi.org/10.1007/BF00201833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1999337">Lelli et al. (1991)</a> identified a heterozygous patient with an insertion in the LDLR gene that represented a duplication of exons 13, 14, and 15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1999337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<strong>.0044 FH AFRIKANER 3</strong>
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LDLR, ASP154ASN
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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> rs121908033 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908033;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/rs121908033?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=rs121908033" 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=rs121908033" 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=RCV000003924 OR RCV000775043 OR RCV001090451 OR RCV002336075" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003924, RCV000775043, RCV001090451, RCV002336075" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003924...</a>
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<p><a href="#38" class="mim-tip-reference" title="Graadt van Roggen, F., van der Westhuyzen, D. R., Marais, A. D., Gevers, W., Coetzee, G. A. <strong>Low density lipoprotein receptor founder mutations in Afrikaner familial hypercholesterolaemic patients: a comparison of two geographical areas.</strong> Hum. Genet. 88: 204-208, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1757095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1757095</a>] [<a href="https://doi.org/10.1007/BF00206073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1757095">Graadt van Roggen et al. (1991)</a> found a G-to-A transition in codon 154 resulting in substitution of asparagine for aspartic acid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1757095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0045" class="mim-anchor"></a>
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<h4>
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<strong>.0045 FH DRUZE</strong>
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</h4>
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LDLR, TYR167TER
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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> rs121908034 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908034;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/rs121908034?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=rs121908034" 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=rs121908034" 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=RCV000003925 OR RCV001186871 OR RCV002345225 OR RCV004017227" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003925, RCV001186871, RCV002345225, RCV004017227" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003925...</a>
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<p>In FH (FHCL1; <a href="/entry/143890">143890</a>) families from 2 distinct Druze villages from the Golan Heights in northern Israel, <a href="#73" class="mim-tip-reference" title="Landsberger, D., Meiner, V., Reshef, A., Levy, Y., van der Westhuyzen, D. R., Coetzee, G. A., Leitersdorf, E. <strong>A nonsense mutation in the LDL receptor gene leads to familial hypercholesterolemia in the Druze sect.</strong> Am. J. Hum. Genet. 50: 427-433, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1734722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1734722</a>]" pmid="1734722">Landsberger et al. (1992)</a> found a TAC-to-TAG substitution in codon 167, changing the sense from tyrosine to stop. The mutation was in exon 4, which encodes the fourth repeat of the binding domain of the mature receptor. <a href="#73" class="mim-tip-reference" title="Landsberger, D., Meiner, V., Reshef, A., Levy, Y., van der Westhuyzen, D. R., Coetzee, G. A., Leitersdorf, E. <strong>A nonsense mutation in the LDL receptor gene leads to familial hypercholesterolemia in the Druze sect.</strong> Am. J. Hum. Genet. 50: 427-433, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1734722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1734722</a>]" pmid="1734722">Landsberger et al. (1992)</a> presented demographic data concerning the Druze. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1734722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0046" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0046 FH PAVIA</strong>
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</span>
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</h4>
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</div>
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<div style="float: left;">
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LDLR, EX2-12DEL
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</div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000237383 OR RCV000505253" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000237383, RCV000505253" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000237383...</a>
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</span>
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<span class="mim-text-font">
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<p><a href="#8" class="mim-tip-reference" title="Bertolini, S., Lelli, N., Coviello, D. A., Ghisellini, M., Masturzo, P., Tiozzo, R., Elicio, N., Gaddi, A., Calandra, S. <strong>A large deletion in the LDL receptor gene--the cause of familial hypercholesterolemia in three Italian families: a study that dates back to the 17th century (FH-Pavia).</strong> Am. J. Hum. Genet. 51: 123-134, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1609792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1609792</a>]" pmid="1609792">Bertolini et al. (1992)</a> found a large rearrangement of the LDLR gene in 3 apparently unrelated families segregating for FH (FHCL1; <a href="/entry/143890">143890</a>) living in northern Italy. Southern blot analysis demonstrated heterozygosity for a 25-kb deletion eliminating exons 2-12. The affected subjects possessed 2 LDL receptor mRNA species: one of normal size (5.3 kb) and one of smaller size (3.5 kb). In the latter mRNA, the coding sequence of exon 1 was joined to the coding sequence of exon 13, causing a change in the reading frame and thereby giving rise to a premature stop codon. The predicted receptor protein, a short polypeptide of 29 amino acids, would be expected to be devoid of any function. <a href="#8" class="mim-tip-reference" title="Bertolini, S., Lelli, N., Coviello, D. A., Ghisellini, M., Masturzo, P., Tiozzo, R., Elicio, N., Gaddi, A., Calandra, S. <strong>A large deletion in the LDL receptor gene--the cause of familial hypercholesterolemia in three Italian families: a study that dates back to the 17th century (FH-Pavia).</strong> Am. J. Hum. Genet. 51: 123-134, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1609792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1609792</a>]" pmid="1609792">Bertolini et al. (1992)</a> found a common ancestor for the 3 families who had lived in the 17th century in a region called Lomellina in southwest Lombardy, near Pavia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1609792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0047" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0047 FH NORTH KARELIA</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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LDLR, 7-BP DEL, EX6
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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">rs387906304 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906304;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=rs387906304" 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=rs387906304" 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=RCV000003927 OR RCV000810136 OR RCV004791195" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003927, RCV000810136, RCV004791195" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003927...</a>
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</span>
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<p><a href="#65" class="mim-tip-reference" title="Koivisto, U.-M., Turtola, H., Aalto-Setala, K., Top, B., Frants, R. R., Kovanen, P. T., Syvanen, A.-C., Kontula, K. <strong>The familial hypercholesterolemia (FH)-North Karelia mutation of the low density lipoprotein receptor gene deletes seven nucleotides of exon 6 and is a common cause of FH in Finland.</strong> J. Clin. Invest. 90: 219-228, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1634609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1634609</a>] [<a href="https://doi.org/10.1172/JCI115839" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1634609">Koivisto et al. (1992)</a> identified a mutation found in many Finnish patients with heterozygous FH (FHCL1; <a href="/entry/143890">143890</a>). The mutation, designated FH North Karelia (FH-NK) , deleted 7 nucleotides from exon 6 of the LDLR gene, caused a translational frameshift, and was predicted to result in a truncated receptor protein. The mutation was found in 69 (34%) of 201 unrelated Finnish FH patients and was especially frequent (prevalence 79%) in patients from eastern Finland. FH Helsinki (<a href="#0029">606945.0029</a>) and FH North Karelia together account for about two-thirds of FH mutations in Finland. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1634609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Finnish North Karelia, with a population of about 180,000, <a href="#137" class="mim-tip-reference" title="Vuorio, A. F., Turtola, H., Piilahti, K.-M., Repo, P., Kanninen, T., Kontula, K. <strong>Familial hypercholesterolemia in the Finnish North Karelia: a molecular, clinical, and genealogical study.</strong> Arterioscler. Thromb. Vasc. Biol. 17: 3127-3138, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9409302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9409302</a>] [<a href="https://doi.org/10.1161/01.atv.17.11.3127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9409302">Vuorio et al. (1997)</a> found that the FH-NK mutation accounts for 84% (340 of 407) of FH cases, while the FH-Helsinki allele was found in 4% (18 cases). The minimum prevalence of FH in North Karelia was estimated to be 1 in 441 inhabitants; in 1 commune, a frequency of 1 in 143 was found. By use of parish and tax records, they identified a common ancestor for most of the North Karelian FH-NK persons in the village of Puso, located within an area where the FH prevalence is the highest. DNA analysis indicated that 2% of subjects aged 1 to 25 years would have been diagnosed as false-negative and 7% as false-positive FH patients on the basis of LDL cholesterol determinations alone. Coronary heart disease (CHD) was present in 65 (30%) of the 179 FH gene carriers aged 25 years or more, and 19 individuals had a previous history of acute myocardial infarction. The average age at onset of CHD was 42 years for males and 48 years for females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9409302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0048" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0048 FH LONDON 3</strong>
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</h4>
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LDLR, CYS210TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908035 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908035;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=rs121908035" 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=rs121908035" 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=RCV000003928 OR RCV000775046 OR RCV002362558" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003928, RCV000775046, RCV002362558" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003928...</a>
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<span class="mim-text-font">
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<p>In an Irish subject with familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>), 1 of 200 patients attending lipid clinics in the London area, <a href="#40" class="mim-tip-reference" title="Gudnason, V., King-Underwood, L., Seed, M., Sun, X.-M., Soutar, A. K., Humphries, S. E. <strong>Identification of recurrent and novel mutations in exon 4 of the LDL receptor gene in patients with familial hypercholesterolemia in the United Kingdom.</strong> Arterioscler. Thromb. 13: 56-63, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8093663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8093663</a>] [<a href="https://doi.org/10.1161/01.atv.13.1.56" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8093663">Gudnason et al. (1993)</a> found a GCG-to-GAG transversion changing cys210 to a stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8093663" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0049 FH LONDON 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906305 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906305;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/rs387906305?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=rs387906305" 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=rs387906305" 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=RCV000003929 OR RCV000517763 OR RCV000844736 OR RCV001201362 OR RCV002362559" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003929, RCV000517763, RCV000844736, RCV001201362, RCV002362559" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003929...</a>
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<p>In 5 patients of British extraction with familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>), <a href="#40" class="mim-tip-reference" title="Gudnason, V., King-Underwood, L., Seed, M., Sun, X.-M., Soutar, A. K., Humphries, S. E. <strong>Identification of recurrent and novel mutations in exon 4 of the LDL receptor gene in patients with familial hypercholesterolemia in the United Kingdom.</strong> Arterioscler. Thromb. 13: 56-63, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8093663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8093663</a>] [<a href="https://doi.org/10.1161/01.atv.13.1.56" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8093663">Gudnason et al. (1993)</a> found deletion of the last 2 bases (694 and 695) of codon 206 (GAC). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8093663" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0050 FH OSAKA 3</strong>
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LDLR, ASP412HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908036 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908036;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=rs121908036" 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=rs121908036" 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=RCV000003930 OR RCV001851630" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003930, RCV001851630" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003930...</a>
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<p>In a Japanese patient with homozygous familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>), <a href="#99" class="mim-tip-reference" title="Miyake, Y., Tajima, S., Funahashi, T., Yamamura, T., Yamamoto, A. <strong>A point mutation of low-density-lipoprotein receptor causing rapid degradation of the receptor.</strong> Europ. J. Biochem. 210: 1-7, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1446662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1446662</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1992.tb17383.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1446662">Miyake et al. (1992)</a> identified a G-to-C transversion in exon 9 which was predicted to change asp412 to his. The amino acid change occurred in the epidermal growth factor precursor homology domain of the LDL receptor. Both in the fibroblasts of the patient and in transfected COS-1 cells, the mutant protein showed impaired processing and rapid degradation. Members of the family carrying the mutant gene in heterozygous state showed higher serum cholesterol levels than the others; however, cholesterol levels were also influenced by the apolipoprotein E phenotype. The mutant LDLR reported by <a href="#99" class="mim-tip-reference" title="Miyake, Y., Tajima, S., Funahashi, T., Yamamura, T., Yamamoto, A. <strong>A point mutation of low-density-lipoprotein receptor causing rapid degradation of the receptor.</strong> Europ. J. Biochem. 210: 1-7, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1446662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1446662</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1992.tb17383.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1446662">Miyake et al. (1992)</a> is designated here FH Osaka-3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1446662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0051 FH AFRIKANER 4</strong>
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LDLR, 18-BP DUP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906306 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906306;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=rs387906306" 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=rs387906306" 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=RCV000003931 OR RCV001201377 OR RCV003457636" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003931, RCV001201377, RCV003457636" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003931...</a>
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<p><a href="#70" class="mim-tip-reference" title="Kotze, M. J., Theart, L., Peeters, A., Langenhoven, E. <strong>A de novo duplication in the low density lipoprotein receptor gene.</strong> Hum. Mutat. 6: 181-183, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581403</a>] [<a href="https://doi.org/10.1002/humu.1380060212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581403">Kotze et al. (1995)</a> identified a de novo duplication in the LDLR gene in the course of screening hypercholesterolemics who did not have 1 of the 3 known mutations responsible for the high frequency of FH (FHCL1; <a href="/entry/143890">143890</a>) (more than 1/100) in South African Afrikaners. The de novo duplication of 18 basepairs in exon 4 occurred after nucleotide 678 (or 681) of their sequence. The authors suggested that the resultant change is severe, because the corresponding duplicated amino acids 200-205 (or 201-206) are highly conserved in E/apo B binding repeat 5 of LDLC. One of the daughters of the index patient inherited the defective LDLR gene, which was absent in both grandparents. <a href="#70" class="mim-tip-reference" title="Kotze, M. J., Theart, L., Peeters, A., Langenhoven, E. <strong>A de novo duplication in the low density lipoprotein receptor gene.</strong> Hum. Mutat. 6: 181-183, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581403</a>] [<a href="https://doi.org/10.1002/humu.1380060212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581403">Kotze et al. (1995)</a> suggested that this was the first report of a molecularly characterized de novo mutation associated with FH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7581403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0052" class="mim-anchor"></a>
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<strong>.0052 FH TURKU</strong>
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LDLR, GLY823ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908037 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908037;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=rs121908037" 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=rs121908037" 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=RCV000003932 OR RCV001523922" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003932, RCV001523922" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003932...</a>
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<p>Two deletions, designated FH-Helsinki (<a href="#0029">606945.0029</a>) and FH-North Karelia (<a href="#0047">606945.0047</a>), account for the mutations present in approximately 60 to 70% of all heterozygous FH (<a href="/entry/143890">143890</a>) probands in Finland. <a href="#66" class="mim-tip-reference" title="Koivisto, U.-M., Viikari, J. S., Kontula, K. <strong>Molecular characterization of minor gene rearrangements in Finnish patients with heterozygous familial hypercholesterolemia: identification of two common missense mutations (Gly823-to-Asp and Leu380-to-His) and eight rare mutations of the LDL receptor gene.</strong> Am. J. Hum. Genet. 57: 789-797, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7573037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7573037</a>]" pmid="7573037">Koivisto et al. (1995)</a> screened the DNA samples from a cohort representing the remaining 30% of heterozygous patients by amplifying all 18 exons of the LDLR gene by PCR and searching for DNA variations with the SSCP technique. Ten novel mutations were identified, comprising 2 nonsense and 7 missense mutations, as well as 1 frameshift mutation caused by a 13-bp deletion. <a href="#66" class="mim-tip-reference" title="Koivisto, U.-M., Viikari, J. S., Kontula, K. <strong>Molecular characterization of minor gene rearrangements in Finnish patients with heterozygous familial hypercholesterolemia: identification of two common missense mutations (Gly823-to-Asp and Leu380-to-His) and eight rare mutations of the LDL receptor gene.</strong> Am. J. Hum. Genet. 57: 789-797, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7573037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7573037</a>]" pmid="7573037">Koivisto et al. (1995)</a> found a single nucleotide change, substituting adenine for guanine at position 2533 of their sequence and resulting in a gly823-to-asp amino acid change, in DNA samples from 14 unrelated FH probands (FHCL1; <a href="/entry/143890">143890</a>). The mutation, designated FH-Turku, affected the sequence encoding the putative basolateral sorting signal of the LDL receptor protein. The FH-Turku gene and another point mutation, FH-Pori (leu380 to his; <a href="#0053">606945.0053</a>), accounted for approximately 8% of the FH-causing gene alterations in Finland and were found to be particularly common among FH patients from the southwestern part of the country. The FH-Turku missense mutation was the one closest to the C terminus of LDLR identified to date. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7573037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#64" class="mim-tip-reference" title="Koivisto, U.-M., Hubbard, A. L., Mellman, I. <strong>A novel cellular phenotype for familial hypercholesterolemia due to a defect in polarized targeting of LDL receptor.</strong> Cell 105: 575-585, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11389828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11389828</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00371-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11389828">Koivisto et al. (2001)</a> showed that the FH-Turku mutant receptor is mistargeted to the apical surface in both Madin-Darby canine kidney (MDCK) cells and hepatic epithelial cells, resulting in reduced endocytosis of LDL from the basolateral/sinusoidal surface. Consequently, virally encoded mutant receptor fails to mediate cholesterol clearance in LDL receptor-deficient mice, suggesting that a defect in polarized LDL receptor expression in hepatocytes underlies the hypercholesterolemia in patients harboring this allele. This evidence directly links the pathogenesis of a human disease to defects in basolateral targeting signals, providing a genetic confirmation of these signals in maintaining epithelial cell polarity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11389828" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0053 FH PORI</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">rs121908038 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908038;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=rs121908038" 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=rs121908038" 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=RCV000003933 OR RCV001220262 OR RCV002345226 OR RCV004794323" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003933, RCV001220262, RCV002345226, RCV004794323" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003933...</a>
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<p>See <a href="#0052">606945.0052</a> and <a href="#66" class="mim-tip-reference" title="Koivisto, U.-M., Viikari, J. S., Kontula, K. <strong>Molecular characterization of minor gene rearrangements in Finnish patients with heterozygous familial hypercholesterolemia: identification of two common missense mutations (Gly823-to-Asp and Leu380-to-His) and eight rare mutations of the LDL receptor gene.</strong> Am. J. Hum. Genet. 57: 789-797, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7573037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7573037</a>]" pmid="7573037">Koivisto et al. (1995)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7573037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=RCV000003934 OR RCV000058917 OR RCV000791438 OR RCV000844753 OR RCV002321469 OR RCV003944798 OR RCV004584311" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003934, RCV000058917, RCV000791438, RCV000844753, RCV002321469, RCV003944798, RCV004584311" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003934...</a>
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<p>In Norway, <a href="#88" class="mim-tip-reference" title="Leren, T. P., Solberg, K., Rodningen, O. K., Tonstad, S., Ose, L. <strong>Two founder mutations in the LDL receptor gene in Norwegian familial hypercholesterolemia subjects.</strong> Atherosclerosis 111: 175-182, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7718019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7718019</a>] [<a href="https://doi.org/10.1016/0021-9150(94)90091-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7718019">Leren et al. (1994)</a> identified a splice mutation, a G-to-A change of the first base of intron 3 destroying the conserved GT splice donor site of intron 3 of the LDLR gene. The same mutation was reported in patients with FH (FHCL1; <a href="/entry/143890">143890</a>) in England (<a href="#122" class="mim-tip-reference" title="Sun, X.-M., Patel, D. D., Bhatnager, D., Knight, B. L., Soutar, A. K. <strong>Characterization of a splice-site mutation in the gene for the LDL receptor associated with an unpredictably severe clinical phenotype in English patients with heterozygous FH.</strong> Arterioscler. Thromb. Vasc. Biol. 15: 219-227, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7749829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7749829</a>] [<a href="https://doi.org/10.1161/01.atv.15.2.219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7749829">Sun et al., 1995</a>) and Germany (<a href="#29" class="mim-tip-reference" title="Feussner, G., Dobmeyer, J., Nissen, H., Hansen, T. S. <strong>Unusual Xanthomas in a young patient with heterozygous familial hypercholesterolemia and type III hyperlipoproteinemia.</strong> Am. J. Med. Genet. 65: 149-154, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8911609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8911609</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19961016)65:2<149::AID-AJMG14>3.0.CO;2-Q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8911609">Feussner et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7718019+8911609+7749829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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LDLR, ASN543HIS AND 9-BP DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003935 OR RCV000211626 OR RCV000211657 OR RCV000825620 OR RCV001034619 OR RCV001034620 OR RCV001176084 OR RCV001529505 OR RCV001553637 OR RCV001553638 OR RCV001699069 OR RCV002408915 OR RCV002444850" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003935, RCV000211626, RCV000211657, RCV000825620, RCV001034619, RCV001034620, RCV001176084, RCV001529505, RCV001553637, RCV001553638, RCV001699069, RCV002408915, RCV002444850" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003935...</a>
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<p>During a survey of mutations of the LDL receptor gene in Danish patients with familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>), using SSCP analysis, <a href="#54" class="mim-tip-reference" title="Jensen, H. K., Jensen, T. G., Faergeman, O., Jensen, L. G., Andresen, B. S., Corydon, M. J., Andreasen, P. H., Hansen, P. S., Heath, F., Bolund, L., Gregersen, N. <strong>Two mutations in the same low-density lipoprotein receptor allele act in synergy to reduce receptor function in heterozygous familial hypercholesterolemia.</strong> Hum. Mutat. 9: 437-444, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9143924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9143924</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:5<437::AID-HUMU10>3.0.CO;2-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9143924">Jensen et al. (1997)</a> observed different patterns in exons 11 and 17 from 2 apparently unrelated FH index cases indicating the presence of 2 different mutations. No other mutations were identified by analysis of the remaining 16 exons and the promoter region. The mutation in exon 11 was found to be a 1690A-C transversion, causing an N543H amino acid substitution. In exon 17, they identified a 9-bp deletion of nucleotides 2393-2405 (2393del9). This sequence contains a 4-bp repeat of the nucleotides TCCT at the end. It was therefore likely that the 9-bp deletion had occurred due to 'slipped mispairing mutagenesis,' involving mispairing of the 4-bp repeat during replication. The deletion did not cause a frameshift, and the mutant allele coded, therefore, for an LDL receptor protein lacking 3 amino acids in the membrane-spanning domain: leu778, val779, and phe780. The 2 mutations were in the same allele of the LDLR gene. Each of these mutations alone had little or no effect on receptor function in transfected COS cells, but when both mutations were present simultaneously, receptor function, as assessed by flow cytometric measurement of fluorescent LDL uptake in cells, was reduced by 75%. Immunostainable receptors on the cell surface were decreased by 80% as measured by flow cytometry. The 2 mutations therefore acted in synergy to affect receptor function, possibly during intracellular receptor transport, since Northern blot analysis suggested that mRNA levels were unaffected. <a href="#54" class="mim-tip-reference" title="Jensen, H. K., Jensen, T. G., Faergeman, O., Jensen, L. G., Andresen, B. S., Corydon, M. J., Andreasen, P. H., Hansen, P. S., Heath, F., Bolund, L., Gregersen, N. <strong>Two mutations in the same low-density lipoprotein receptor allele act in synergy to reduce receptor function in heterozygous familial hypercholesterolemia.</strong> Hum. Mutat. 9: 437-444, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9143924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9143924</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:5<437::AID-HUMU10>3.0.CO;2-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9143924">Jensen et al. (1997)</a> noted that double mutations had been reported in several clinically relevant genes, such as the HEXA gene (<a href="/entry/606869#0036">606869.0036</a>) and the CFTR gene (<a href="/entry/602421">602421</a>) (<a href="#111" class="mim-tip-reference" title="Savov, A., Angelicheva, D., Balassopoulou, A., Jordanova, A., Noussia-Arvanitakis, S., Kalaydjieva, L. <strong>Double mutant alleles: are they rare?</strong> Hum. Molec. Genet. 4: 1169-1171, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528204</a>] [<a href="https://doi.org/10.1093/hmg/4.7.1169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528204">Savov et al., 1995</a>). In most of these disorders, one mutation was found to be causative, and the other modified the onset or severity of the disease. The common methionine-valine polymorphism in the PRNP gene (<a href="/entry/176640#0005">176640.0005</a>) modifies both qualitatively and quantitatively the phenotypic expression of the pathogenic D178N mutation (<a href="/entry/176640#0010">176640.0010</a>) resulting in 2 different disorders: fatal familial insomnia and familial Creutzfeldt-Jakob disease (<a href="#34" class="mim-tip-reference" title="Goldfarb, L. G., Petersen, R. B., Tabaton, M., Brown, P., LeBlanc, A. C., Montagna, P., Cortelli, P., Julien, J., Vital, C., Pendelbury, W. W., Haltia, M., Wills, P. R., and 9 others. <strong>Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism.</strong> Science 258: 806-808, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1439789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1439789</a>] [<a href="https://doi.org/10.1126/science.1439789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1439789">Goldfarb et al., 1992</a>). <a href="#54" class="mim-tip-reference" title="Jensen, H. K., Jensen, T. G., Faergeman, O., Jensen, L. G., Andresen, B. S., Corydon, M. J., Andreasen, P. H., Hansen, P. S., Heath, F., Bolund, L., Gregersen, N. <strong>Two mutations in the same low-density lipoprotein receptor allele act in synergy to reduce receptor function in heterozygous familial hypercholesterolemia.</strong> Hum. Mutat. 9: 437-444, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9143924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9143924</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:5<437::AID-HUMU10>3.0.CO;2-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9143924">Jensen et al. (1997)</a> stated that in the case of the LDLR double mutant, there appeared to be a true synergistic action. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8528204+9143924+1439789" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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LDLR, IVS4, T-C, +2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs200238879 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200238879;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=rs200238879" 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=rs200238879" 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=RCV000003936 OR RCV001201185 OR RCV002362560" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003936, RCV001201185, RCV002362560" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003936...</a>
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<p><a href="#41" class="mim-tip-reference" title="Gudnason, V., Sigurdsson, G., Nissen, H., Humphries, S. E. <strong>Common founder mutation in the LDL receptor gene causing familial hypercholesterolemia in the Icelandic population.</strong> Hum. Mutat. 10: 36-44, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9222758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9222758</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)10:1<36::AID-HUMU5>3.0.CO;2-K" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9222758">Gudnason et al. (1997)</a> stated that haplotype analysis in 18 apparently unrelated families with FH (FHCL1; <a href="/entry/143890">143890</a>) in Iceland has identified at least 5 different chromosomes cosegregating with hypercholesterolemia. The most common haplotype was identified in 11 of the 18 families, indicating a founder mutation. By using SSCP analysis and direct sequencing of amplified DNA, <a href="#41" class="mim-tip-reference" title="Gudnason, V., Sigurdsson, G., Nissen, H., Humphries, S. E. <strong>Common founder mutation in the LDL receptor gene causing familial hypercholesterolemia in the Icelandic population.</strong> Hum. Mutat. 10: 36-44, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9222758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9222758</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)10:1<36::AID-HUMU5>3.0.CO;2-K" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9222758">Gudnason et al. (1997)</a> identified a T-to-C transition in the second nucleotide in the 5-prime part of intron 4 of the LDLR gene. This mutation was present in 10 of the 18 families. In half of the cases, these families could be traced to a common ancestor by going back no further than the 18th century. The mutation was predicted to affect correct splicing of exon 4, and analysis at the cellular level demonstrated an abnormal mRNA containing intron 4 sequence in lymphoblastoid cells from a patient carrying the mutation. Translation of the mRNA would lead to a premature stop codon and a truncated nonfunctional protein of 285 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9222758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs121908039 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908039;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/rs121908039?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=rs121908039" 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=rs121908039" 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=RCV000003937 OR RCV000587146 OR RCV000826197 OR RCV001535532 OR RCV002345227" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003937, RCV000587146, RCV000826197, RCV001535532, RCV002345227" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003937...</a>
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<p><a href="#76" class="mim-tip-reference" title="Lee, W. K., Haddad, L., Macleod, M. J., Dorrance, A. M., Wilson, D. J., Gaffney, D., Dominiczak, M. H., Packard, C. J., Day, I. N., Humphries, S. E., Dominiczak, A. F. <strong>Identification of a common low density lipoprotein receptor mutation (C163Y) in the West of Scotland.</strong> J. Med. Genet. 35: 573-578, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9678702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9678702</a>] [<a href="https://doi.org/10.1136/jmg.35.7.573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9678702">Lee et al. (1998)</a> reported that in the West of Scotland, in the Glasco area, about half of the index cases of familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>) were found to have the cys163-to-tyr mutation of the LDLR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9678702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0059 HYPERCHOLESTEROLEMIA, FAMILIAL, 1</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> rs121908040 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908040;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/rs121908040?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=rs121908040" 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=rs121908040" 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=RCV000003938 OR RCV000776469 OR RCV000825593 OR RCV002051613 OR RCV002408448 OR RCV004998074" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003938, RCV000776469, RCV000825593, RCV002051613, RCV002408448, RCV004998074" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003938...</a>
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<p>In a 13-year-old girl with severe hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>), <a href="#26" class="mim-tip-reference" title="Ekstrom, U., Abrahamson, M., Floren, C.-H., Tollig, H., Wettrell, G., Nilsson, G., Sun, X.-M., Soutar, A. K., Nilsson-Ehle, P. <strong>An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F).</strong> Clin. Genet. 55: 332-339, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10422803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10422803</a>] [<a href="https://doi.org/10.1034/j.1399-0004.1999.550506.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10422803">Ekstrom et al. (1999)</a> demonstrated compound heterozygosity for a cys240-to-phe mutation and a tyr167-to-ter mutation (<a href="#0045">606945.0045</a>) in the LDLR gene. Fibroblasts from the patient showed very low cholesterol esterification rate, LDL uptake, and degradation as compared to normal fibroblasts. Her 2 heterozygous sibs also carried the C240F mutation, but only one of them was hypercholesterolemic. <a href="#26" class="mim-tip-reference" title="Ekstrom, U., Abrahamson, M., Floren, C.-H., Tollig, H., Wettrell, G., Nilsson, G., Sun, X.-M., Soutar, A. K., Nilsson-Ehle, P. <strong>An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F).</strong> Clin. Genet. 55: 332-339, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10422803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10422803</a>] [<a href="https://doi.org/10.1034/j.1399-0004.1999.550506.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10422803">Ekstrom et al. (1999)</a> expressed the C240F mutant in LDLR-deficient CHOldlA7 cells. The transfected cells produced a detectable protein but were unable to mediate uptake or degradation of LDL. The authors concluded that there may be cholesterol-lowering mechanisms that can be activated, perhaps by mutations in known or hitherto unknown genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10422803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0060 HYPERCHOLESTEROLEMIA, FAMILIAL, 1</strong>
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LDLR, TRP23TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607213 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607213;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=rs267607213" 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=rs267607213" 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=RCV000003939 OR RCV000775022 OR RCV000786354 OR RCV000844726 OR RCV002381241" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003939, RCV000775022, RCV000786354, RCV000844726, RCV002381241" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003939...</a>
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<p>In patients with familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>), <a href="#44" class="mim-tip-reference" title="Hobbs, H. H., Brown, M. S., Goldstein, J. L. <strong>Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.</strong> Hum. Mutat. 1: 445-466, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301956</a>] [<a href="https://doi.org/10.1002/humu.1380010602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301956">Hobbs et al. (1992)</a> identified a trp23-to-ter mutation in the LDLR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301956" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0061 HYPERCHOLESTEROLEMIA, FAMILIAL, 1</strong>
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LDLR, CYS25SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908041 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908041;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=rs121908041" 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=rs121908041" 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=RCV000003940" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003940" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003940</a>
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<p>In a Japanese patient with familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>), <a href="#125" class="mim-tip-reference" title="Takahashi, M., Ikeda, U., Takahashi, S., Hattori, H., Iwasaki, T., Ishihara, M., Egashira, T., Honma, S., Asano, Y., Shimada, K. <strong>A novel mutation in exon 2 of the low-density lipoprotein-receptor gene in a patient with homozygous familial hypercholesterolemia. (Letter)</strong> Clin. Genet. 59: 290-292, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11298688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11298688</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2001.590414.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11298688">Takahashi et al. (2001)</a> identified a G-to-C transversion at nucleotide 137 of the LDLR gene, resulting in a cys25-to-ser (C25S) amino acid substitution in the ligand-binding site (mutation class 2B: slow transport and processing). The patient first noticed xanthomas on both elbows at the age of 5 years. These continued to increase in number and size. At age 40 years, xanthomas were present on elbows, palms, knees, and feet. Clinical manifestations of myocardial ischemia developed at age 41. Selective LDL filtration was initiated after plasma apheresis through a macromolecular exclusion filter. With bimonthly treatments, her LDL cholesterol decreased by approximately 50% and the xanthomas regressed markedly, almost disappearing with 5 years of treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11298688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0062 HYPERCHOLESTEROLEMIA, FAMILIAL, 1</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> rs121908042 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908042;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/rs121908042?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=rs121908042" 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=rs121908042" 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=RCV000003941" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003941" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003941</a>
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<p><a href="#102" class="mim-tip-reference" title="Pisciotta, L., Cantafora, A., De Stefano, F., Langheim, S., Calandra, S., Bertolini, S. <strong>A 'de novo' mutation of the LDL-receptor gene as the cause of familial hypercholesterolemia.</strong> Biochim. Biophys. Acta 1587: 7-11, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12009418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12009418</a>] [<a href="https://doi.org/10.1016/s0925-4439(02)00047-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12009418">Pisciotta et al. (2002)</a> identified a de novo LDLR mutation in a 47-year-old white male who at the age of 43 had suffered a myocardial infarction. He was heterozygous for a G-to-C transversion in exon 4, which resulted in a serine for cysteine substitution at position 88 (C88S) of the receptor protein. The mutation was not found in his parents (nonpaternity was excluded), but it was present in his 9-year-old son, who had familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>). Haplotype analysis indicated that this de novo mutation occurred in the paternal germline. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12009418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0063" class="mim-anchor"></a>
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<strong>.0063 HYPERCHOLESTEROLEMIA, FAMILIAL, 1</strong>
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LDLR, IVS14, 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">rs145787161 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs145787161;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=rs145787161" 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=rs145787161" 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=RCV000003942 OR RCV000775089 OR RCV001787369 OR RCV002426486 OR RCV003398438" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003942, RCV000775089, RCV001787369, RCV002426486, RCV003398438" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003942...</a>
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<p><a href="#123" class="mim-tip-reference" title="Takada, D., Emi, M., Ezura, Y., Nobe, Y., Kawamura, K., Iino, Y., Katayama, Y., Xin, Y., Wu, L. L., Larringa-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. N. <strong>Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred.</strong> J. Hum. Genet. 47: 656-664, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522687</a>] [<a href="https://doi.org/10.1007/s100380200101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522687">Takada et al. (2002)</a> described a novel splice site mutation in the LDLR gene, IVS14+1G-A, which genealogic research confirmed was shared by 14 of 1,135 members of an American Caucasian pedigree descended from a common ancestor and affected with familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>). The mutation resulted in an abruptly truncated LDLR protein, reducing functional LDLR activity by half in heterozygous carriers of the mutant allele. <a href="#123" class="mim-tip-reference" title="Takada, D., Emi, M., Ezura, Y., Nobe, Y., Kawamura, K., Iino, Y., Katayama, Y., Xin, Y., Wu, L. L., Larringa-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. N. <strong>Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred.</strong> J. Hum. Genet. 47: 656-664, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522687</a>] [<a href="https://doi.org/10.1007/s100380200101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522687">Takada et al. (2002)</a> stated this was the largest familial hypercholesterolemia kindred described, and of 208 members screened for this LDLR mutation, 94 carriers and 114 noncarriers were identified. Strikingly lower total cholesterol and LDL cholesterol values were observed among most of the LDLR mutation carriers who were simultaneously homozygous for the -265C allele of the -265C-T polymorphism of the APOA2 gene (<a href="/entry/107670#0002">107670.0002</a>). In vitro transfection assays showed that transcriptional activity of the APOA2 promoter was reduced by 30% in the -265C allele as compared with the -265T allele. The variant of the APOA2 gene was associated with reduced plasma LDL cholesterol only in familial hypercholesterolemia patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12522687" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the same large family reported by <a href="#123" class="mim-tip-reference" title="Takada, D., Emi, M., Ezura, Y., Nobe, Y., Kawamura, K., Iino, Y., Katayama, Y., Xin, Y., Wu, L. L., Larringa-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. N. <strong>Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred.</strong> J. Hum. Genet. 47: 656-664, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522687</a>] [<a href="https://doi.org/10.1007/s100380200101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522687">Takada et al. (2002)</a>, <a href="#124" class="mim-tip-reference" title="Takada, D., Ezura, Y., Ono, S., Iino, Y., Katayama, Y., Xin, Y., Wu, L. L., Larringa-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. M., Emi, M. <strong>Growth hormone receptor variant (L526I) modifies plasma HDL cholesterol phenotype in familial hypercholesterolemia: intra-familial association study in an eight-generation hyperlipidemic kindred.</strong> Am. J. Med. Genet. 121A: 136-140, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12910492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12910492</a>] [<a href="https://doi.org/10.1002/ajmg.a.20172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12910492">Takada et al. (2003)</a> found that a SNP in the growth hormone receptor gene (GHR), resulting in a L526I (<a href="/entry/600946#0028">600946.0028</a>) substitution, influenced plasma levels of high density lipoprotein (HDL) cholesterol in affected family members with the LDLR mutation. The lowest levels of plasma HDL were observed among leu/leu homozygotes, highest levels among ile/ile homozygotes, and intermediate levels among leu/ile heterozygotes. No such effect was observed among noncarriers of the LDLR mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12522687+12910492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the pedigree reported by <a href="#123" class="mim-tip-reference" title="Takada, D., Emi, M., Ezura, Y., Nobe, Y., Kawamura, K., Iino, Y., Katayama, Y., Xin, Y., Wu, L. L., Larringa-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. N. <strong>Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred.</strong> J. Hum. Genet. 47: 656-664, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522687</a>] [<a href="https://doi.org/10.1007/s100380200101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522687">Takada et al. (2002)</a>, <a href="#110" class="mim-tip-reference" title="Sato, K., Emi, M., Ezura, Y., Fujita, Y., Takada, D., Ishigami, T., Umemura, S., Xin, Y., Wu, L. L., Larrinaga-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. N. <strong>Soluble epoxide hydrolase variant (glu287arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred.</strong> J. Hum. Genet. 49: 29-34, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14673705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14673705</a>] [<a href="https://doi.org/10.1007/s10038-003-0103-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14673705">Sato et al. (2004)</a> demonstrated a significant modification of the phenotype of familial hypercholesterolemia resulting from the IVS14+1G-A mutation by the arg287 variation in the EPHX2 gene (<a href="/entry/132811#0001">132811.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14673705+12522687" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs387906307 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906307;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=rs387906307" 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=rs387906307" 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=RCV000003943 OR RCV002512730" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003943, RCV002512730" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003943...</a>
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<p>In a patient with familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>), <a href="#19" class="mim-tip-reference" title="Dedoussis, G. V. Z., Pitsavos, C., Kelberman, D., Skoumas, J., Prassa, M. E., Choumerianou, D. M., Stefanadis, C., Humphries, S. E., Toutouzas, P. <strong>FH-Pyrgos: a novel mutation in the promoter (-45delT) of the low-density lipoprotein receptor gene associated with familial hypercholesterolemia.</strong> Clin. Genet. 64: 414-419, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14616764/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14616764</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00164.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14616764">Dedoussis et al. (2003)</a> identified a novel mutation in repeat 3 of the LDLR gene promoter, -45delT. Analysis of a neutral polymorphism in LDLR mRNA from the patient's white blood cells showed that the expression of 1 allele was significantly reduced, and cells had only 24% of LDLR activity by binding and uptake of iodine-labeled LDL. Transient transfection studies using a luciferase gene reporter revealed that the -45delT mutation considerably reduced the transcriptional activity of the LDLR promoter and strongly suggested that the mutation was the cause of the familial hypercholesterolemia phenotype. The proband was a female in her late thirties; her father was reported to have elevated cholesterol levels and had undergone bypass surgery at the age of 70. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14616764" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs121908043 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908043;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/rs121908043?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=rs121908043" 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=rs121908043" 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=RCV000003944 OR RCV000588218 OR RCV002354146" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003944, RCV000588218, RCV002354146" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003944...</a>
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<p>In a patient diagnosed with probable heterozygous familial hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>), who had tendinous xanthomas and angina since the age of 29 years, <a href="#11" class="mim-tip-reference" title="Bourbon, M., Sun, X.-M., Soutar, A. K. <strong>A rare polymorphism in the low density lipoprotein (LDL) gene that affects mRNA splicing.</strong> Atherosclerosis 195: e17, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17335829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17335829</a>] [<a href="https://doi.org/10.1016/j.atherosclerosis.2007.01.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17335829">Bourbon et al. (2007)</a> identified heterozygosity for a 1216C-A transversion in exon 9 of the LDLR gene, resulting in a synonymous arg385-to-arg (R385R) change. However, analysis of mRNA from the patient's cells showed that the mutation introduces a new 5-prime acceptor splice site that is used to the exclusion of the natural splice site and causes a 31-bp deletion predicted to result in premature termination 4 codons beyond the change. Review of previous LDLR gene sequencing data revealed that the same base substitution was present in a Chinese homozygous FH patient in whom no other mutation in LDLR had been found. The authors stated that the difference in origins of the 2 patients suggested that the mutation was very unlikely to have been inherited from a common ancestor and that it might be present in other populations as well. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17335829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Defesche, J. C., Schuurman, E. J. M., Klaaijsen, L. N., Khoo, K. L., Wiegman, A., Stalenhoef, A. F. H. <strong>Silent exonic mutations in the low-density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing.</strong> Clin. Genet. 73: 573-578, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18400033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18400033</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.00999.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18400033">Defesche et al. (2008)</a> analyzed the LDLR gene in 1,350 patients clinically diagnosed with familial hypercholesterolemia who were negative for functional DNA variation in known hypercholesterolemia genes and identified the R385R variant in 2 probands, both of Chinese origin, and their family members. In view of the faint band representing the aberrantly spliced mRNA on gel electrophoresis, the authors suggested that this DNA variant likely leads to nonsense-mediated mRNA decay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18400033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs121908044 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908044;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=rs121908044" 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=rs121908044" 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=RCV000003945 OR RCV001389663 OR RCV002254902 OR RCV002362561" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003945, RCV001389663, RCV002254902, RCV002362561" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003945...</a>
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<p>In 35 unrelated Dutch patients clinically diagnosed with familial hypercholesterolemia who were negative for functional DNA variation in known hypercholesterolemia genes, <a href="#21" class="mim-tip-reference" title="Defesche, J. C., Schuurman, E. J. M., Klaaijsen, L. N., Khoo, K. L., Wiegman, A., Stalenhoef, A. F. H. <strong>Silent exonic mutations in the low-density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing.</strong> Clin. Genet. 73: 573-578, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18400033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18400033</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.00999.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18400033">Defesche et al. (2008)</a> identified a 621C-T transition in exon 4 of the LDLR gene, resulting in a synonymous gly186-to-gly (G186G) change, that introduces a 3-prime splice donor site with a higher 'probability score' than the naturally occurring 3-prime splice site 75 bp downstream. Analysis of cDNA synthesized from total RNA revealed that the aberrant splicing results in a 75-bp in-frame deletion and a stable mRNA, predicted to produce an LDLR protein lacking a 25-amino acid fragment (gly186 to cys210). The variant was found in homozygosity in 2 of the probands, who had LDL cholesterol levels of 14.8 and 10.5 mmol/L, respectively, and who both suffered myocardial infarctions before the age of 20 years. The variant was also identified in 62 first-degree relatives of the index cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18400033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs587776886 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776886;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/rs587776886?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=rs587776886" 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=rs587776886" 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=RCV000023602" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023602" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023602</a>
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<p>In a proband with clinically defined hypercholesterolemia (FHCL1; <a href="/entry/143890">143890</a>), <a href="#72" class="mim-tip-reference" title="Kulseth, M. A., Berge, K. E., Bogsrud, M. P., Leren, T. P. <strong>Analysis of LDLR mRNA in patients with familial hypercholesterolemia revealed a normal mutation in intron 14, which activates a cryptic splice site.</strong> J. Hum. Genet. 55: 676-680, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20703241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20703241</a>] [<a href="https://doi.org/10.1038/jhg.2010.87" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20703241">Kulseth et al. (2010)</a> identified heterozygosity for a splice site mutation (2140+86C-G) in intron 14 of the LDLR gene, activating a cryptic splice site that results in aberrantly spliced mRNA containing an 81-bp insertion. Twelve of 23 family members tested were heterozygous for the mutation, and carriers had significantly increased total cholesterol levels compared to noncarriers. The 2140+86C-G mutation was found in 3 additional probands with hypercholesterolemia, and in 1 proband's family the mutation was found in 6 of 7 tested family members, who all had LDL cholesterol levels above the 97th percentile. RT-PCR analysis in 1 affected individual from that family showed that the mutant allele mainly gave rise to aberrantly spliced mRNA, but contributed 21% normal transcripts. Transfection studies in CHO cells demonstrated retention of mutant LDLR in the endoplasmic reticulum, presumably due to protein misfolding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20703241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#Allen1980" class="mim-tip-reference" title="Allen, J. M., Thompson, G. R., Myant, N. B., Steiner, R., Oakley, C. M. <strong>Cardiovascular complications of homozygous familial hypercholesterolaemia.</strong> Brit. Heart J. 44: 361-368, 1980.">Allen et al. (1980)</a>; <a href="#Elston1976" class="mim-tip-reference" title="Elston, R. C., Namboodiri, K. K., Go, R. C. P., Siervogel, R. M., Glueck, C. J. <strong>Probable linkage between essential familial hypercholesterolemia and third complement component (C3).</strong> Cytogenet. Cell Genet. 16: 294-297, 1976.">Elston et al. (1976)</a>; <a href="#Goldstein1977" class="mim-tip-reference" title="Goldstein, J. L., Brown, M. S., Stone, N. J. <strong>Genetics of the LDL receptor: evidence that the mutations affecting binding and internalization are allelic.</strong> Cell 12: 629-641, 1977.">Goldstein et al. (1977)</a>; <a href="#Goldstein1975" class="mim-tip-reference" title="Goldstein, J. L., Dana, S. E., Brunschede, G. Y., Brown, M. S. <strong>Genetic heterogeneity in familial hypercholesterolemia: evidence for two different mutations affecting functions of low-density lipoprotein receptor.</strong> Proc. Nat. Acad. Sci. 72: 1092-1096, 1975.">Goldstein et al. (1975)</a>; <a href="#Hobbs1985">Hobbs et al. (1985)</a>; <a href="#Horsthemke1987" class="mim-tip-reference" title="Horsthemke, B., Dunning, A., Humphries, S. <strong>Identification of deletions in the human low density lipoprotein receptor gene.</strong> J. Med. Genet. 24: 144-147, 1987.">Horsthemke et al.
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(1987)</a>; <a href="#Horsthemke1985" class="mim-tip-reference" title="Horsthemke, B., Kessling, A. M., Seed, M., Wynn, V., Williamson, R., Humphries, S. E. <strong>Identification of a deletion in the low density lipoprotein (LDL) receptor gene in a patient with familial hypercholesterolaemia.</strong> Hum. Genet. 71: 75-78, 1985.">Horsthemke et al. (1985)</a>; <a href="#Kingsley1984" class="mim-tip-reference" title="Kingsley, D. M., Krieger, M. <strong>Receptor-mediated endocytosis of low density lipoprotein: somatic cell mutants define multiple genes required for expression of surface-receptor activity.</strong> Proc. Nat. Acad. Sci. 81: 5454-5458, 1984.">Kingsley and Krieger (1984)</a>; <a href="#Lehrman1987" class="mim-tip-reference" title="Lehrman, M. A., Russell, D. W., Goldstein, J. L., Brown, M. S. <strong>Alu-Alu recombination deletes splice acceptor sites and produces secreted low density lipoprotein receptor in a subject with familial hypercholesterolemia.</strong> J. Biol. Chem. 262: 3354-3361, 1987.">Lehrman et al. (1987)</a>; <a href="#Lehrman1985" class="mim-tip-reference" title="Lehrman, M. A., Schneider, W. J., Sudhof, T. C., Brown, M. S., Goldstein, J. L., Russell, D. W. <strong>Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains.</strong> Science 227: 140-146, 1985.">Lehrman et al. (1985)</a>; <a href="#Sudhof1985" class="mim-tip-reference" title="Sudhof, T. C., Russell, D. W., Goldstein, J. L., Brown, M. S., Sanchez-Pescador, R., Bell, G. I. <strong>Cassette of eight exons shared by genes for LDL receptor and EGF precursor.</strong> Science 228: 893-895, 1985.">Sudhof et al. (1985)</a>
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Aalto-Setala, K., Helve, E., Kovanen, P. T., Kontula, K.
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<strong>Finnish type of low density lipoprotein receptor gene mutation (FH-Helsinki) deletes exons encoding the carboxy-terminal part of the receptor and creates an internalization-defective phenotype.</strong>
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J. Clin. Invest. 84: 499-505, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2760198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2760198</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2760198" 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/10.1172/JCI114192" target="_blank">Full Text</a>]
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Aalto-Setala, K., Koivisto, U.-M., Miettinen, T. A., Gylling, H., Kesaniemi, Y. A., Savolainen, M., Pyorala, K., Ebeling, T., Mononen, I., Turtola, H., Viikari, J., Kontula, K.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1372927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1372927</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1372927" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2796.1992.tb00528.x" target="_blank">Full Text</a>]
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Agnello, V., Abel, G., Elfahal, M., Knight, G. B., Zhang, Q.-X.
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<strong>Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor.</strong>
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Proc. Nat. Acad. Sci. 96: 12766-12771, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10535997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10535997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10535997[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10535997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.96.22.12766" target="_blank">Full Text</a>]
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Allen, J. M., Thompson, G. R., Myant, N. B., Steiner, R., Oakley, C. M.
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<strong>Cardiovascular complications of homozygous familial hypercholesterolaemia.</strong>
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Brit. Heart J. 44: 361-368, 1980.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7426196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7426196</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7426196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/hrt.44.4.361" target="_blank">Full Text</a>]
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Amsellem, S., Briffaut, D., Carrie, A., Rabes, J. P., Girardet, J. P., Fredenrich, A., Moulin, P., Krempf, M., Reznik, Y., Vialettes, B., de Gennes, J. L., Brukert, E., Benlian, P.
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<strong>Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia.</strong>
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Hum. Genet. 111: 501-510, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12436241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12436241</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12436241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Aulchenko, Y. S., Ripatti, S., Lindqvist, I., Boomsma, D., Heid, I. M., Pramstaller, P. P., Penninx, B. W. J. H., Janssens, A. C. J. W., Wilson, W. F., Spector, T., Martin, N. G., Pedersen, N. L.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19060911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19060911</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19060911[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19060911" 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/ng.269" target="_blank">Full Text</a>]
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Benlian, P., Amselem, S., Loux, N., Pastier, D., Giraud, G., de Gennes, J. L., Turpin, G., Monnier, L., Rieu, D., Douste-Blazy, P., Dastugue, B., Goossens, M., Junien, C.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1978630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1978630</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1978630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bertolini, S., Lelli, N., Coviello, D. A., Ghisellini, M., Masturzo, P., Tiozzo, R., Elicio, N., Gaddi, A., Calandra, S.
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<strong>A large deletion in the LDL receptor gene--the cause of familial hypercholesterolemia in three Italian families: a study that dates back to the 17th century (FH-Pavia).</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1609792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1609792</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1609792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Betard, C., Kessling, A. M., Roy, M., Chamberland, A., Lussier-Cacan, S., Davignon, J.
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<strong>Molecular genetic evidence for a founder effect in familial hypercholesterolemia among French Canadians.</strong>
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Hum. Genet. 88: 529-536, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1348044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1348044</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1348044" 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/10.1007/BF00219339" target="_blank">Full Text</a>]
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Boehnke, M., Arnheim, N., Li, H., Collins, F. S.
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<strong>Fine-structure genetic mapping of human chromosomes using the polymerase chain reaction on single sperm: experimental design considerations.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2568090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2568090</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2568090" 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)1096-8628(19961016)65:2<149::AID-AJMG14>3.0.CO;2-Q" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.81.9.2826" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0888-7543(89)90037-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199201023260118" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.4001923" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1439789" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.72.3.1092" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI107332" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00206073" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.atv.13.1.56" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)10:1<36::AID-HUMU5>3.0.CO;2-K" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00273653" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198709173171204" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.82.22.7651" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI113402" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI114212" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1146/annurev.ge.24.120190.001025" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1432-1033.1987.tb10995.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.24.3.144" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00295672" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.21258" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:5<437::AID-HUMU10>3.0.CO;2-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1017/S0003480099007800" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.atv.8.2.187" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa0706728" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9343(64)90196-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.81.17.5454" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1432-1033.1989.tb14602.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302704" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(01)00371-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00451446" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1168974" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Carol A. Bocchini - updated : 08/19/2019
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Ada Hamosh - updated : 05/10/2019<br>Ada Hamosh - updated : 3/11/2015<br>Marla J. F. O'Neill - updated : 10/14/2013<br>Marla J. F. O'Neill - updated : 2/9/2012<br>Ada Hamosh - updated : 10/12/2010<br>Paul J. Converse - updated : 8/5/2010<br>Ada Hamosh - updated : 1/21/2010<br>Marla J. F. O'Neill - updated : 12/9/2009<br>Ada Hamosh - updated : 8/14/2009<br>Marla J. F. O'Neill - updated : 5/7/2009<br>Ada Hamosh - updated : 4/1/2008<br>Ada Hamosh - updated : 6/18/2007<br>Cassandra L. Kniffin - updated : 10/5/2005<br>Victor A. McKusick - updated : 4/15/2005<br>Cassandra L. Kniffin - updated : 3/1/2005<br>Victor A. McKusick - updated : 2/25/2004<br>Victor A. McKusick - updated : 12/4/2003<br>Ada Hamosh - updated : 4/3/2003<br>Victor A. McKusick - updated : 2/10/2003<br>Victor A. McKusick - updated : 8/27/2002
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carol : 08/19/2019<br>carol : 06/20/2019<br>carol : 06/19/2019<br>carol : 06/04/2019<br>alopez : 05/10/2019<br>carol : 11/28/2017<br>carol : 07/15/2016<br>carol : 7/14/2016<br>alopez : 3/11/2015<br>carol : 2/21/2014<br>carol : 10/14/2013<br>carol : 10/14/2013<br>carol : 6/7/2013<br>joanna : 5/4/2012<br>carol : 2/15/2012<br>carol : 2/13/2012<br>terry : 2/9/2012<br>terry : 10/26/2011<br>terry : 10/26/2011<br>carol : 5/23/2011<br>carol : 4/8/2011<br>alopez : 10/12/2010<br>wwang : 9/27/2010<br>alopez : 8/6/2010<br>terry : 8/5/2010<br>joanna : 4/27/2010<br>carol : 4/5/2010<br>alopez : 1/21/2010<br>wwang : 12/11/2009<br>terry : 12/9/2009<br>alopez : 8/17/2009<br>terry : 8/14/2009<br>wwang : 7/20/2009<br>wwang : 5/18/2009<br>terry : 5/7/2009<br>terry : 4/3/2009<br>carol : 10/21/2008<br>carol : 10/9/2008<br>wwang : 4/23/2008<br>carol : 4/16/2008<br>carol : 4/2/2008<br>carol : 4/1/2008<br>alopez : 6/18/2007<br>wwang : 10/18/2005<br>wwang : 10/12/2005<br>ckniffin : 10/5/2005<br>tkritzer : 4/15/2005<br>terry : 4/15/2005<br>tkritzer : 3/9/2005<br>ckniffin : 3/1/2005<br>tkritzer : 3/1/2004<br>terry : 2/25/2004<br>alopez : 12/10/2003<br>terry : 12/4/2003<br>alopez : 4/3/2003<br>terry : 4/3/2003<br>carol : 2/19/2003<br>tkritzer : 2/14/2003<br>terry : 2/10/2003<br>tkritzer : 12/10/2002<br>tkritzer : 12/3/2002<br>terry : 11/27/2002<br>carol : 11/13/2002<br>tkritzer : 8/30/2002<br>terry : 8/27/2002<br>carol : 6/5/2002<br>ckniffin : 6/5/2002<br>ckniffin : 6/3/2002<br>ckniffin : 5/17/2002
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606945
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</h3>
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<h3>
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<span class="mim-font">
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LOW DENSITY LIPOPROTEIN RECEPTOR; LDLR
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</h3>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: LDLR</em></strong>
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</span>
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</p>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 397915002, 441665004;
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<strong>ICD10CM:</strong> E78.00;
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<p>
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<strong>
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<em>
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Cytogenetic location: 19p13.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:11,089,463-11,133,820 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<th>
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Location
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<th>
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Phenotype
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</th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<td rowspan="2">
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<span class="mim-font">
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19p13.2
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<td>
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<span class="mim-font">
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Hypercholesterolemia, familial, 1
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</td>
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<span class="mim-font">
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143890
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<span class="mim-font">
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Autosomal dominant; Autosomal recessive
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<span class="mim-font">
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3
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<span class="mim-font">
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LDL cholesterol level QTL2
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<span class="mim-font">
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143890
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Autosomal dominant; Autosomal recessive
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<td>
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<span class="mim-font">
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3
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</table>
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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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</h4>
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</div>
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<span class="mim-text-font">
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<p>The low density lipoprotein receptor is a cell surface receptor that plays an important role in cholesterol homeostasis.</p>
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<h4>
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<strong>Cloning and Expression</strong>
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</h4>
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<p>The low density lipoprotein receptor is synthesized as a 120-kD glycoprotein precursor that undergoes change to a 160-kD mature glycoprotein through the covalent addition of a 40-kD protein (Tolleshaug et al., 1982). </p><p>Yamamoto et al. (1984) reported that the human LDL receptor is an 839-amino acid protein rich in cysteine, with multiple copies of the Alu family of repetitive DNAs. Russell et al. (1984) demonstrated DNA sequence homology of the LDL receptor with the epidermal growth factor receptor (EGF; 131530). </p><p>Sudhof et al. (1985) found that 13 of the 18 exons of the gene encode protein sequences that are homologous to sequences in other proteins: 5 encode a sequence similar to one in C9 component of complement (120940); 3 encode a sequence similar to a repeat sequence in the precursor for EGF and in 3 proteins of the blood clotting system--factor IX (300746), factor X (613872), and protein C (612283), and 5 other exons encode nonrepeated sequences that are shared only with the EGF precursor. Since the LDL receptor is a mosaic protein built up of exons shared with different proteins, it is a member of several supergene families. Gilbert (1985) commented on the relevance of these findings to understanding the significance of 'split genes' and 'exon shuffling' during evolution. </p>
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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>Francke et al. (1984) assigned the LDL receptor to chromosome 19 on the basis of expression studies in hamster-human somatic cell hybrids. The LDLR gene was regionalized to 19p13.1-p13.3 by in situ hybridization (Lindgren et al., 1985). </p><p>Frank et al. (1989) identified RFLPs of the mouse LDL receptor gene and used them to map the gene, designated Ldlr, to the proximal region of chromosome 9. Using interspecific backcrosses, they established the order and interval distances for this and several other loci on mouse chromosome 9, namely, Apoa4 (107690), which is on chromosome 11 in man, and mannosephosphate isomerase (154550), which is on chromosome 15 in man. </p>
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</span>
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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>Brown and Goldstein (1974) described LDL binding to cultured fibroblasts in a manner consistent with a receptor, and found that this binding resulted in suppression of cholesterol synthesis by the cell via repression of HMG CoA reductase. In a review article, Brown and Goldstein (1979) described the mechanism of receptor-mediated endocytosis using the LDL receptor as the prototypic example, thus further describing its role in cholesterol metabolism. Normally, LDL is bound at the cell membrane and taken into the cell ending up in lysosomes where the protein is degraded and the cholesterol is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. </p><p>Lo et al. (2007) observed that inhibition of lymphotoxin (see 153440) and LIGHT (TNFSF14; 604520) signaling with a soluble lymphotoxin B receptor (LTBR; 600979) decoy protein attenuated the dyslipidemia in LDL receptor-deficient mice, which lack the ability to control lipid levels in the blood. The authors concluded that the immune system directly influences lipid metabolism and that lymphotoxin modulating agents may represent a novel therapeutic route for the treatment of dyslipidemia. </p><p><strong><em>LDL Receptor as a Viral Receptor</em></strong></p><p>
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Hepatitis C virus (HCV), the principal viral cause of chronic hepatitis, is not readily replicated in cell culture systems, making it difficult to ascertain information on cell receptors for the virus. However, several observations from studies on the role of HCV in mixed cryoglobulinemia provided some insight into HCV entry into cells. Evidence indicated that HCV and other viruses enter cells through the mediation of LDL receptors: by the demonstration that endocytosis of these viruses correlates with LDL receptor activity, by complete inhibition of detectable endocytosis by anti-LDL receptor antibody, by inhibition with anti-apolipoprotein E and anti-apolipoprotein B antibodies, by chemical methods abrogating lipoprotein/LDL receptor interactions, and by inhibition with the endocytosis inhibitor phenylarsine oxide. Agnello et al. (1999) provided confirmatory evidence by the lack of detectable LDL receptor on cells known to be resistant to infection by one of these viruses, bovine viral diarrheal virus (BVDV). Endocytosis via the LDL receptor was shown to be mediated by complexing of the virus to very low density lipoprotein (VLDL) or LDL, but not high density lipoprotein (HDL). Studies using LDL receptor-deficient cells or a cytolytic BVDV system indicated that the LDL receptor may be the main but not exclusive means of cell entry of these viruses. </p><p>Atherogenic lipoprotein phenotype (108725) shows close linkage to the LDLR locus; indeed, the mutation(s) responsible for this phenotype may reside in the LDLR gene rather than in a separate, closely situated gene.</p><p>Zelcer et al. (2009) demonstrated that the sterol-responsive nuclear liver X receptor (LXR) (see 600380) helps maintain cholesterol homeostasis, not only through promotion of cholesterol efflux but also through suppression of LDL uptake. LXR inhibits the LDLR pathway through the transcriptional induction of IDOL (MYLIP; 610082), an E3 ubiquitin ligase that triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby targeting it for degradation. LXR ligand reduced, whereas LXR knockout increased, LDLR protein levels in vivo in a tissue-selective manner. IDOL knockdown in hepatocytes increased LDLR protein levels and promoted LDL uptake. Conversely, Zelcer et al. (2009) found that adenovirus-mediated expression of IDOL in mouse liver promoted LDLR degradation and elevated plasma LDL levels. Zelcer et al. (2009) concluded that the LXR-IDOL-LDLR axis defines a complementary pathway to sterol response element-binding proteins for sterol regulation of cholesterol uptake. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</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>Crystal Structure</em></strong></p><p>
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Rudenko et al. (2002) described the crystal structure of the LDL receptor extracellular domain at endosomal pH. The ligand-binding domain (modules R2 to R7) folds back as an arc over the epidermal growth factor precursor homology domain (the modules A, B, beta propeller, and C). The modules R4 and R5, which are critical for lipoprotein binding, associate with the beta propeller via their calcium-binding loop. Rudenko et al. (2002) proposed a mechanism for lipoprotein release in the endosome whereby the beta propeller functions as an alternate substrate for the ligand-binding domain, binding in a calcium-dependent way and promoting lipoprotein release. </p>
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</span>
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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>Brown and Goldstein (1976) found that one of the LDLR mutations in a patient (J.D.) with familial hypercholesterolemia (FHCL1; 143890) was able to bind LDL normally, but internalization of the receptor-bound protein failed to occur. The internalization defect was a tyr807-to-cys (Y207C; 606945.0019) substitution inherited from his father; he also had binding defect (null allele) inherited from his mother (Davis et al., 1986). Lehrman et al. (1985) had previously identified a nonsense and a frameshift mutation in the LDLR gene that truncated the cytoplasmic domain, resulting in internalization-defective LDL receptors. </p><p>In a patient with homozygous familial hypercholesterolemia-1, Hobbs et al. (1986) described an LDL receptor mutant in which 1 of the 7 repeating units constituting the ligand-binding domain had been deleted. The deletion arose by homologous recombination by repetitive Alu sequences in intron 4 and intron 5 of the gene. The deletion removed exon 5, which normally encodes the sixth repeat of the ligand binding domain. In the resultant mRNA, exon 4 was found to be spliced to exon 6, preserving the reading frame. The resulting shortened protein reaches the cell surface and reacts with antireceptor antibodies but does not bind LDL. It does, however, bind VLDL, a lipoprotein that contains apoprotein E as well as apoprotein B-100. The findings in this instructive case supported the hypothesis that the 7 repeated sequences in the receptor constitute the LDL-binding domain, that the sixth repeat is required for binding of LDL but not of VLDL, and that deletion of a single repeat can alter the binding specificity of the LDL receptor. </p><p>Horsthemke et al. (1987) analyzed DNA from 70 patients in the UK with heterozygous familial hypercholesterolemia. In most, the restriction fragment pattern of the LDLR gene was indistinguishable from normal; however, 3 patients were found to have a deletion of about 1 kb in the central portion of the gene. In 2 patients, the deletion included all or part of exon 5 (606945.0027); in the third, the deletion included exon 7 (606945.0033). Including a previously described patient with a deletion in the 3-prime part of the gene, these results indicated that 4 out of 70 patients, or 6%, have deletions. </p><p>Langlois et al. (1988) screened 234 unrelated heterozygotes for FH to detect major rearrangements in the LDLR gene. Total genomic DNA was analyzed by Southern blot hybridization to probes encompassing exons 1 to 18 of the LDLR gene. Six different mutations were detected and characterized by use of exon-specific probes and detailed restriction mapping. The frequency of deletions in the Langlois et al. (1988) study was 2.5% (6 out of 234 patients). An illustration of previously mapped deletions and the deletions identified in this study (a total of 16) suggested that particular areas in the LDLR gene are susceptible to deletion. </p><p>In a Japanese subject with homozygous hypercholesterolemia, Lehrman et al. (1987) found a 7.8-kb deletion in LDLR (606945.0029). The deletion joined intron 15 to the middle of exon 18, which encodes the 3-prime untranslated region, thereby removing all 3-prime splice acceptor sites distal to intron 15. The mRNA should produce a truncated receptor that lacks the normal membrane-COOH terminus. The truncated protein was such that more than 90% of the receptor was secreted from the cell, and the receptors remaining on the surface showed defective internalization. The deletion resulted from recombination between 2 repetitive sequences of the Alu family, one in intron 15 and the other in exon 18. Lehrman et al. (1987) stated that Alu sequences had been found at the deletion joints of all 4 gross deletions that had been characterized in LDLR. Because of these and similar findings in connection with deletions in the gamma-delta-beta-globin cluster, recombination between Alu sequences appears to be a frequent cause of deletions in the human genome (see EVOLUTION). </p><p>Horsthemke et al. (1987) suggested that unequal crossing-over between 2 Alu-repetitive DNA sequences was responsible for an intragenic deletion of the LDLR gene leading to familial hypercholesterolemia. A 4-kb deletion had occurred between an Alu-repetitive sequence in intron 12 and a sequence in intron 14. The deletion eliminated exons 13 and 14 and changed the reading frame of the resulting spliced mRNA such that a stop codon was created in the following exon (606945.0032). The truncated receptor protein appeared to be rapidly degraded. The deletion was presumably caused by an unequal crossover event between 2 homologous chromosomes at meiosis. </p><p>Hobbs et al. (1988) found that 16 of 132 cell strains (12%) from persons with the clinical syndrome of homozygous familial hypercholesterolemia synthesized no immunodetectable LDL receptor protein, indicating the presence of 2 mutant genes that failed to produce crossreacting material (CRM-negative mutants). DNA and mRNA from all but one of these CRM-negative patients were available for study. Haplotype analysis based on 10 RFLPs suggested that the 30 CRM-negative genes represented by these 15 individuals had included 13 different mutant alleles. Four of the alleles produced no mRNA; 3 of these 4 had large deletions ranging from 6 to 20 kb that eliminated the promoter region of the gene. The reason for the lack of mRNA in the fourth allele was not apparent. Three alleles encoded mRNAs of abnormal size. One of the abnormal mRNAs was produced by a gene harboring a deletion, and another was produced by a gene with a complex rearrangement. The third abnormal-sized mRNA (3.1 kb larger than normal) was produced by an allele that had no detectable alteration as judged by Southern blotting. The other 6 mRNA-positive alleles appeared normal by Southern blotting and produced normal-sized mRNA but no receptor protein. </p><p>Among 20 mutant LDL receptor genes, Yamakawa et al. (1989) found 4 different deletion mutations (20%). None of these had been reported previously in Caucasians. Three of them were novel and one was similar to a previously described Japanese mutation. In 3 of the 4 deletions, the rearrangements were related to intron 15 in which there are many Alu sequences. </p><p>Rudiger et al. (1991) reviewed previously described deletions in the LDLR gene in cases of familial hypercholesterolemia and reported the finding of a deletion in 3 of 25 unrelated patients with FH. Two of these were equivalent to previously described LDLR alterations, thus supporting a notion of recombination hotspots which involve Alu sequences. In at least 4 cases (FH626, PO, JA, and FH-DK3), a deletion of exon 5 of the LDLR gene has been found as the defect responsible for FH. The FH626 mutation was characterized by Hobbs et al. (1986) and found to involve Alu repeat sequences in introns 4 and 5. Rudiger et al. (1991) characterized FH-DK3 and likewise found involvement of 2 Alu repeated sequences present in introns 4 and 5. The crossover breakpoints involve sequences similar to those reported for FH626 but not at identical positions in the 5-prime end. By use of denaturing gradient gel electrophoresis (DGGE) in combination with PCR, Top et al. (1992) found no evidence of a promoter mutation in the LDLR gene in 350 heterozygotes for FH. Hobbs et al. (1992) reviewed 71 mutations in the LDL receptor gene that had been characterized at the molecular level and added 79 additional mutations. Furthermore, they reviewed the insight that all 150 mutations provided into the structure/function relationship of the receptor protein and the clinical manifestations of FH. </p><p>Feussner et al. (1996) described a 20-year-old man with a combination of heterozygous FH caused by splice mutation (606945.0054) and type III hyperlipoproteinemia (107741). </p><p>Lee et al. (1998) studied 80 unrelated individuals with FH from the West of Scotland. Microsatellite analysis using D19S394 was informative in 20 of 23 families studied. In these families, there was no inconsistency with segregation of the FH phenotype with the LDLR locus. Using SSCP, Lee et al. (1998) also detected mutations in exon 4 of the LDLR gene in 15 of 80 of these individuals; 7 of 15 had the same cys163-to-tyr mutation (606945.0058). Lee et al. (1998) concluded that microsatellite analysis using D19S394 is useful in tracking the LDLR gene in families and could be used in conjunction with LDL cholesterol levels to diagnose FH, especially in children and young adults, in whom phenotypic diagnosis can be difficult. </p><p>Jensen et al. (1999) studied 17 families with mutations in the LDLR gene as a model in which to test formally for linkage directly between an atherogenic genotype and ischemic heart disease or aortocoronary calcified atherosclerosis. The aortocoronary calcification was significantly associated with age and plasma cholesterol. Sex, hypertension, body mass index, and smoking were not associated with the aortocoronary calcification. Nonparametric analysis indicated significant linkage of the LDLR locus to aortic (p less than 0.00005) and to aortocoronary calcified atherosclerosis (p less than 0.00001). Assuming a dominant mode of inheritance, significant linkage was detected for aortic (lod = 3.89) and aortocoronary calcified atherosclerosis (lod = 4.10). Jensen et al. (1999) suggested that the atherogenicity of variations in other genes could be assessed by a similar approach. </p><p>Yamakawa et al. (1988) described a TaqI polymorphism in the LDLR gene which should be useful in the study of FH. Leitersdorf et al. (1989) used 10 different RFLPs to construct 123 differing haplotypes from 20 pedigrees. The 5 most common haplotypes accounted for 67.5% of the sample. Heterozygosity and polymorphism information content (PIC) for each site were determined. </p><p>Kathiresan et al. (2008) studied SNPs in 9 genes in 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. All 9 SNPs had been associated with elevated LDL or lowered HDL. One of the SNPs, rs1529729 in the SMARCA4 gene, was highly correlated with variants in LDLR. Kathiresan et al. (2008) replicated the associations with the 9 SNPs and created a genotype score on the basis of the number of unfavorable alleles. With increasing genotype scores, the level of LDL cholesterol increased, whereas the level of HDL cholesterol decreased. At 10-year follow-up, the genotype score was found to be an independent risk factor for incident cardiovascular disease (myocardial infarction, ischemic stroke, or death from coronary heart disease); the score did not improve risk discrimination but modestly improved clinical risk reclassification for individual subjects beyond standard clinical factors. </p><p>Aulchenko et al. (2009) reported a genomewide association (GWA) study of loci affecting total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. This study included a total of 17,797 to 22,562 individuals aged 18 to 104 years from geographic regions spanning from the Nordic countries to Southern Europe. Aulchenko et al. (2009) established 22 loci associated with serum lipid levels at a genomewide significance level (P less than 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. Association of the LDLR gene region identified by rs2228671 was found with total cholesterol levels (P = 9.3 x 10(-24)). </p><p>In a patient diagnosed with probable heterozygous FH, Bourbon et al. (2007) analyzed the LDLR gene and identified a novel variant initially assumed to be a silent polymorphism (R385R; 606945.0065); however, analysis of mRNA from the patient's cells showed that the mutation introduces a new 5-prime acceptor splice site that causes a 31-bp deletion predicted to result in premature termination. The variant was subsequently also found in a Chinese homozygous FH patient. </p><p>Defesche et al. (2008) analyzed the LDLR gene in 1,350 patients clinically diagnosed with familial hypercholesterolemia who were negative for functional DNA variation in the LDLR, APOB (107730), and PCSK9 (607786) genes. The authors examined the effects of 128 seemingly neutral exonic and intronic DNA variants and identified the R385R variant in 2 Chinese families and a G186G (606945.0066) variant that clearly affected a donor splice site and segregated with hypercholesterolemia in 35 unrelated Dutch families. </p><p>In a metaanalysis of plasma lipid concentrations in greater than 100,000 individuals of European descent, Teslovich et al. (2010) identified SNP rs6511720 near the LDLR gene as having an effect on LDL cholesterol concentrations with an effect size of -6.99 mg per deciliter and a P value of 4 x 10(-117). This variant was also found to affect coronary artery disease risk. </p><p>Kulseth et al. (2010) performed RNA analysis in 30 unrelated patients with clinically defined hypercholesterolemia but without any LDLR mutations detected by standard DNA analysis; sequencing of RT-PCR products from an index patient revealed that the major product contained an insertion of 81 bp from the 5-prime end of intron 14 of LDLR. DNA sequencing of exons 13 and 14 detected an intronic mutation (606945.0067) that segregated in heterozygosity with elevated cholesterol in the proband's family. Kulseth et al. (2010) analyzed an additional 550 index patients and identified the same splice site mutation in 3 more probands. </p><p>Noting that large-scale genetic cascade screening for familial hypercholesterolemia showed that 15% of LDLR or APOB mutation carriers had LDLC levels below the 75th percentile, Huijgen et al. (2010) proposed 3 criteria for determining pathogenicity of such mutations: mean LDLC greater than the 75th percentile, higher mean LDLC level in untreated than in treated carriers, and higher percentage of medication users in carriers than in noncarriers at screening. Applying these criteria to 46 mutations found in more than 50 untreated adults, 3 of the mutations were determined to be nonpathogenic: 1 in LDLR and 2 in APOB. Nonpathogenicity of the 3 variants was confirmed by segregation analysis. Huijgen et al. (2010) emphasized that novel sequence changes in LDLR and APOB should be interpreted with caution before being incorporated into a cascade screening program. </p><p>Do et al. (2015) sequenced the protein-coding regions of 9,793 genomes from patients with myocardial infarction (MI) at an early age (50 years or younger in males and 60 years or younger in females) along with MI-free controls. They identified 2 genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exomewide significance: LDLR and APOA5 (606368). Carriers of rare nonsynonymous mutations in LDLR were at 4.2-fold increased risk for MI, while carriers of null alleles in LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbor a rare, damaging mutation in LDLR; this estimate is similar to one made by Goldstein et al. (1973) using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol greater than 190 mg/dl. Carriers of rare nonsynonymous mutations in APOA5 were at 2.2-fold increased risk for MI. When compared with noncarriers, LDLR mutation carriers had higher plasma LDL cholesterol (see 143890), whereas APOA5 mutation carriers had higher plasma triglycerides (see 145750). Evidence has connected MI risk with coding-sequence mutations at 2 genes functionally related to APOA5, namely lipoprotein lipase (LPL; 609708) and apolipoprotein C-III (APOC3; 107720). Do et al. (2015) concluded that LDL cholesterol as well as disordered metabolism of triglyceride-rich lipoproteins contributes to myocardial infarction risk. </p><p><strong><em>LDLR Mutation Databases</em></strong></p><p>
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Varret et al. (1997) described a database of LDLR genes and provided a listing of the 210 mutations it contained as of the fall of 1996. Wilson et al. (1998) described an online database of LDLR mutations. </p><p>Leigh et al. (2017) updated the University College of London (UCL) LDLR variant database according to the guidelines of the Association of Clinical Genetic Scientists. Of the 2,925 curated variants, representing 1,707 independent events, all 129 nonsense variants, 337 small frameshift variants, and 117/118 large rearrangements were classified as likely or clearly pathogenic. Of the 795 missense variants, 115 were clearly not or unlikely pathogenic, 605 were likely pathogenic, and 75 were variants of unknown significance; 111/181 intronic variants, 4/35 synonymous variants, and 14/37 promoter variants were likely or clearly pathogenic. Overall, 112 (7%) of reported variants were variants of unknown significance. </p><p><strong><em>Modifiers</em></strong></p><p>
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Vergopoulos et al. (1997) presented findings suggesting the existence of a xanthomatosis susceptibility gene in a consanguineous Syrian kindred containing 6 individuals with homozygous FH (see 602247). Half of the homozygotes had giant xanthomas, while half did not, even though their LDL cholesterol concentrations were elevated to similar degrees (more than 14 mmol/l). Heterozygous FH individuals in this family were also clearly distinguishable with respect to xanthoma size. By DNA analysis they identified a hitherto undescribed mutation in the LDLR gene in this family: a T-to-C transition at nucleotide 1999 in codon 646 of exon 14, resulting in an arginine for cysteine substitution. Segregation analysis suggested that a separate susceptibility gene may explain the formation of giant xanthomas. </p><p>In a 13-year-old girl with severe hypercholesterolemia, Ekstrom et al. (1999) demonstrated compound heterozygosity for a cys240-to-phe mutation (606945.0059) and a tyr167-to-ter mutation (606945.0045) in the LDLR gene. Her 2 heterozygous sibs also carried the C240F mutation, but only one of them was hypercholesterolemic. The authors concluded that there may be cholesterol-lowering mechanisms that are activated by mutations in other genes (see 143890). </p><p>Knoblauch et al. (2000) studied an Arab family that carried the tyr807-to-cys substitution (606945.0019). In this family, some heterozygous persons had normal LDL levels, while some homozygous individuals had LDL levels similar to those persons with heterozygous FH. The authors presented evidence for the existence of a cholesterol-lowering gene on 13q (604595). </p><p>Based on the finding from bioinformatic analysis that Alu repeats represent 85% of LDLR intronic sequences outside exon-intron junctions, Amsellem et al. (2002) designed a strategy to improve the exploration of genomic regions in the vicinity of exons in 110 FH subjects from an admixed population. In the first group of 42 patients found negative for mutations by former screening strategies, approximately half (22) were carriers of at least 1 heterozygous mutation. Among a second group of 68 patients recruited to correct for ascertainment bias toward exonic mutations, 37 (27%) mutation carriers had a splicing regulatory mutation. Of the 54 mutations identified, 13 were intronic and 18 were novel, nearly half of which were intronic. Amsellem et al. (2002) stated that their strategy of detecting the most likely disease-causing LDLR mutations outside of Alu-rich genomic regions revealed that intronic mutations may have a greater impact on the molecular basis of FH than previously reported. </p>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Seftel et al. (1980) pointed to a high frequency of hypercholesterolemic homozygotes in South Africa. In a 7-year period, 34 homozygotes were seen in one clinic in Johannesburg. All were Afrikaners and most lived in Transvaal Province. The authors calculated the frequency of heterozygotes and homozygotes to be 1 in 100 and 1 in 30,000, respectively. The oldest of their patients was a 46-year-old woman. Of the 34, six were age 30 or older. The authors concluded that the high frequency of the gene is attributable to founder effect, as in the case of porphyria variegata (176200), lipoid proteinosis (247100), and sclerosteosis (269500). Torrington and Botha (1981) found that 20 of 26 families with FHC (77%) belonged to the Gereformeerde Kerk, whereas according to the 1970 census only 5% of the Afrikaans-speaking white population of South Africa belonged to this religious group. Again, the data were consistent with a founder effect. Using the LDLR activity of lymphocytes, Steyn et al. (1989) calculated the prevalence of heterozygous FHC in the permanent residents of a predominantly Afrikaans-speaking community in South Africa to be 1 in 71--the highest prevalence reported to date. </p><p>Hobbs et al. (1987) found a large deletion (more than 10 kb) in the LDLR gene in 63% of French Canadians with heterozygous FH. The deletion also occurred in homozygous form in 4 of 7 French Canadian homozygotes. The deletion removed the promoter and first exon of the gene and abolished the production of mRNA for LDL receptor. The high frequency of the mutation was interpreted as representing founder effect; 8,000 ancestors account for present-day French Canadians and there has been relatively little outbreeding. The deletion has not been observed in any other ethnic group. It can be detected by analysis of genomic DNA from blood leukocytes, thus allowing direct diagnosis of FH in most affected French Canadians. Ma et al. (1989) identified a second 'French Canadian' LDLR gene deletion which was found in 4 of 80 heterozygotes (5%). The mutation consisted of a 5-kb deletion removing exons 2 and 3 of the LDLR gene, which corresponded to the first 2 repeats of the LDLR-binding domain (606945.0026). </p><p>Leitersdorf et al. (1990) analyzed the LDL receptor genes of 11 French Canadian FH homozygotes. Only 3 different LDLR haplotypes were identified, and the coding region of the allele associated with each was sequenced. Three different missense mutations were found. Assays developed to detect each of these directly were applied to 130 FH heterozygotes from the greater Montreal area. The common deletion (606945.0025) responsible for about 60% of cases (Hobbs et al., 1987) and the smaller deletion (606945.0026) identified by Ma et al. (1989) and found in about 5% of French Canadians were also sought. They were able to detect LDL receptor mutations in 76% of the subjects and 14% had 1 of the 3 missense mutations. In the Saguenay-Lac-Saint-Jean region of Quebec province, De Braekeleer (1991) estimated the prevalence of familial hypercholesterolemia as 1/122, compared to the usually estimated frequency of 1/500 for European populations. </p><p>Like the French Canadians, the South Afrikaners appear to have a unique form of mutation in the LDLR gene consistent with founder effect (Brink et al., 1987). Because of the presumed role of founder effect on the high frequency of familial hypercholesterolemia in South Africa, it is not surprising that Kotze et al. (1987) found a predominance of 2 haplotypes in 27 informative families with FH. In a study of homozygotes from the Afrikaner population in South Africa, Leitersdorf et al. (1989) found that 2 mutations account for more than 95% of the mutant LDL receptor genes. Both mutations were basepair substitutions that resulted in a single amino acid change and both could be detected readily with PCR and restriction analysis. The findings were considered consistent with the high frequency of FH being due to founder effect. Graadt van Roggen et al. (1991) studied the prevalence and distribution of the 3 common mutations in South Africa in 27 unrelated homozygous and 79 unrelated heterozygous FH Afrikaner patients from 2 regions of South Africa, the Transvaal and Cape Provinces. The 3 mutations were FH Afrikaner-1 (606945.0006), FH Afrikaner-2 (606945.0009), and FH Afrikaner-3 (606945.0044). The relative distribution of each of the 3 mutations was similar in the 2 regions, with frequencies of 66, 27, and 7%, respectively. Defects other than the 3 common mutations were more frequent in the Cape than in the Transvaal; thus, the 3 known mutations accounted for 98% of FH alleles in the Transvaal and only 74% in the Cape Province. None of the patients carried the familial apolipoprotein B-100 mutation. </p><p>Schuster et al. (1995) identified yet another homozygote for the val408-to-met mutation (606945.0009), a 12-year-old Greek boy living in Germany. The mutation was present in both his parents, his brother, grandmother, uncle, and cousin. The haplotype, using 6 RFLPs of the LDL receptor gene, was different from the one reported earlier in Afrikaner and Dutch FH patients. Schuster et al. (1995) concluded that the mutation in the Greek boy probably occurred independently. Furthermore, they speculated that, because the parents were from different areas in Greece, the mutation may be common in Greeks. </p><p>Deletion of gly197 (606945.0005) is the most prevalent LDL receptor mutation causing familial hypercholesterolemia in Ashkenazi Jewish individuals. Studying index cases from Israel, South Africa, Russia, the Netherlands, and the United States, Durst et al. (2001) found that all traced their ancestry to Lithuania. A highly conserved haplotype was identified in chromosomes carrying this deletion, suggesting a common founder. When 2 methods were used for analysis of linkage disequilibrium between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the deletion was found to be 20 +/- 7 generations, so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 14th century. This corresponds with the founding of the Jewish community of Lithuania (1338 A.D.), as well as with the great demographic expansion of Ashkenazi Jewish individuals in eastern Europe, which followed this settlement. Durst et al. (2001) could find no evidence supporting a selective evolutionary metabolic advantage. Therefore, the founder effect in a rapidly expanding population from a limited number of families remains a simple, parsimonious hypothesis explaining the spread of this mutation in Ashkenazi Jewish individuals. </p><p>Defesche and Kastelein (1998) stated that more than 350 different mutations had been found in patients with familial hypercholesterolemia. They tabulated the preferential geographic distribution that has been demonstrated for some of the LDL receptor mutations. For example, in the West of Scotland about half of the index cases of FH were found to have the cys163-to-tyr mutation (606945.0058). Defesche and Kastelein (1998) commented on the geographic associations of LDL receptor mutations within the Netherlands. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Evolution</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>Alu sequences are widely scattered in the genome, being present in 300,000 to 500,000 copies. They have been described, for example, in the genes for alpha-globin (see 141800), gastrin (137250), gamma crystallin (123660), insulin-like growth factor II (147470), and soluble thymidine kinase. Each is about 300 bp long; thus Alu sequences represent about 3% of the total DNA. On the basis of structural similarity, the origin of Alu elements can be traced to the gene for 7SL RNA (Ullu and Tschudi, 1984). The abundant cytoplasmic 7SL RNA functions in protein secretion as a component of the signal-recognition particle. This particle, consisting of 6 different polypeptides and 1 molecule of 7SL RNA, mediates the translocation of secretory proteins across the cytoplasmic reticulum. Although the 7SL RNA has a well-defined biologic function, that of the related Alu repeat remains unknown. Thus, the 7SL RNA gene may be a progenitor of a processed pseudogene, the Alu element, that has 'recently' spread to different locations in the human genome. The average Alu family member probably integrated into its present genomic location about 15-30 Myr ago. The Alu family is specific to primates, suggesting that these repeats were not present as little as 65 Myr ago. </p><p>According to the Alu family copy number, one would, on the average, expect to find 1 such repeat every 3 to 5 kb in the human genome if they are randomly distributed. However, studies of the albumin/alpha-fetoprotein family by Ruffner et al. (1987) and of the thymidine kinase (188300) and beta-tubulin (191130) genes by Slagel et al. (1987) indicate clustering of Alu repeats in some parts of the genome. For example, the beta-tubulin gene has 10 of these repeats in less than 5 kb of a single intron and the thymidine kinase has 13 members within its introns in a region of about 10 kb. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>History</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>Some early studies of somatic hybrid cells suggested that the gene(s) for low density lipoprotein receptor may be on chromosome 5 or 21 or both (Maartmann-Moe et al., 1982).</p><p>Li et al. (1988) worked out a PCR method for analyzing DNA sequences in individual diploid cells and human sperm. They showed that 2 genetic loci could be coamplified from a single sperm, and proposed its use for genetic linkage studies. They analyzed the genotype of single sperm derived from an individual heterozygous at the LDLR locus and the HLA-DQ(alpha) locus and could show independent assortment. Individual sperm were drawn into a fine plastic needle under microscopic observation and delivered to a tube for lysis and amplification. Eighty individual sperm were analyzed for the study of independent assortment of LDLR and DQA. The method has great promise for fine mapping. Boehnke et al. (1989) described the experimental design and issues of sample size to be considered in the application of the method to the generation of fine-structure human genetic maps. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</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>Using Ldlr -/- mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) transgene under control of the insulin promoter, which functions as a mouse model in which type 1 diabetes (125853) can be induced at will, Johansson et al. (2008) administered a high-fat diet for 16 weeks to induce the development of advanced atherosclerotic lesions before inducing diabetes. After the onset of diabetes, there was increased intraplaque hemorrhage and plaque disruption, regardless of lesion size, in mice fed low- or high-fat diets for an additional 14 weeks. Furthermore, diabetes resulted in increased accumulation of monocytic cells positive for S100A9 (123886), a proinflammatory biomarker for cardiovascular events, and for a macrophage marker protein, without increasing lesion macrophage content, and S100A9 immunoreactivity correlated with intraplaque hemorrhage. Hyperglycemia was not sufficient to induce plaque disruption: aggressive lipid lowering, primarily of triglyceride-rich lipoproteins, prevented both plaque disruption and the increased S100A9 in diabetic atherosclerotic lesions. Conversely, oleate promoted macrophage differentiation into an S100A9-positive population in vitro, thereby mimicking the effects of diabetes. Johansson et al. (2008) concluded that diabetes increases plaque disruption independently of effects on plaque initiation, through a mechanism that requires triglyceride-rich lipoproteins and is associated with an increased accumulation of S100A9-positive monocytic cells, and that this represents an important link between diabetes, plaque disruption, and the innate immune system. </p><p>Lewis et al. (2009) generated mice lacking C1qa (120550) and/or serum IgM (147020) as well as Ldlr and studied them on both low- and high-fat semisynthetic diets. On both diets, serum IgM/Ldlr -/- mice developed substantially larger and more complex en face and aortic root atherosclerotic lesions, with accelerated cholesterol crystal formation and increased smooth muscle content in aortic root lesions. TUNEL analysis revealed increased apoptosis in both C1qa/Ldlr -/- and serum IgM/Ldlr -/- mice. Overall lesions were larger in mice lacking IgM rather than C1q, suggesting that IgM protective mechanisms are partially independent of classic complement pathway activation and apoptotic cell clearance. Lewis et al. (2009) concluded that IgM antibodies play a central role in protection against atherosclerosis. </p><p>Childs et al. (2016) used transgenic and pharmacologic approaches to eliminate senescent cells in atherosclerosis-prone Ldlr-deficient mice and showed that these cells are detrimental throughout disease pathogenesis. Childs et al. (2016) found that foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis, where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines. In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease production. Childs et al. (2016) concluded that their results demonstrated that senescent cells are key drivers of atheroma formation and maturation. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>67 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 FH TURKEY</strong>
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</span>
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</h4>
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LDLR, GLN12TER
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<br />
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SNP: rs121908024,
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gnomAD: rs121908024,
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ClinVar: RCV000003868, RCV000786350, RCV001034691, RCV002381238
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<span class="mim-text-font">
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<p>In a homozygote with familial hypercholesterolemia (FHCL1; 143890) of Turkish ancestry, Leitersdorf and Hobbs (1990) identified a CAG-to-TAG change in codon 12 converting glutamine to a stop codon.</p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 FH CAPE TOWN 1</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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LDLR, ASP26/GLY27DEL
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<br />
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SNP: rs387906301,
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ClinVar: RCV000237855
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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 South African black with FH (FHCL1; 143890), Leitersdorf et al. (1988) demonstrated deletion of aspartic acid-26 and glycine-27 due to deletion of the 6 nucleotides of codons 26 and 27: GCGATG. </p><p>Thiart et al. (2000) found this mutation in 28% of mutant alleles in 56 South African black patients. </p>
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</span>
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 FH FRENCH CANADIAN 4</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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LDLR, TRP66GLY
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<br />
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SNP: rs121908025,
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gnomAD: rs121908025,
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ClinVar: RCV000003870, RCV000622852, RCV000776466, RCV000844748, RCV002426484
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This change in exon 3 is a class 3 binding-defective mutation (Leitersdorf et al., 1990). In the French Canadian population of a province in Quebec, Moorjani et al. (1993) compared the clinical features of homozygous FH (FHCL1; 143890) because of the relatively high frequency of a small number of mutations. In a comparison of 10 subjects who had the trp66-to-gly (W66G) mutation in exon 3 with 11 subjects who were homozygous for the 'greater than 10 kb' deletion of the promoter region in exon 1 (606945.0025), they found the following: mean plasma cholesterol concentration was higher in the subjects with the deletion and there was no overlap in values in the 2 groups. Although the frequency of coronary heart disease was similar in the 2 groups, age of onset was earlier in subjects with the deletion; in addition, coronary deaths were more frequent and occurred at an earlier age in the deletion subjects. </p><p>Grossman et al. (1994) reported a 29-year-old woman with FH and a homozygous W66G mutation who underwent hepatocyte-directed ex vivo gene therapy with LDLR-expressing retroviruses. She tolerated the procedures well, liver biopsy after 4 months showed engraftment of the transgene, and there was no clinical or pathologic evidence for autoimmune hepatitis. The patient showed an improvement in serum lipids up to 18 months after the treatment. </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>.0004 FH PUERTO RICO</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, SER156LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908026,
|
|
|
|
|
|
gnomAD: rs121908026,
|
|
|
|
|
|
ClinVar: RCV000003871, RCV000161958, RCV000588687, RCV002345224
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
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<span class="mim-text-font">
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|
<p>Hobbs et al. (1989) found this missense mutation in a Puerto Rican kindred that appeared to have an independently segregating mutation that suppressed the hypercholesterolemia phenotype in some heterozygotes (see 144020). The same mutation was identified in a German family by Schuster et al. (1993). </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 FH PISCATAWAY</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">
|
|
FH LITHUANIA
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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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|
LDLR, GLY197DEL
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|
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|
<br />
|
|
|
|
SNP: rs121908027,
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|
|
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|
|
ClinVar: RCV000211647, RCV000489033, RCV000589051, RCV002363056, RCV004017502
|
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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>Meiner et al. (1991) found that the mutation was responsible for 35% of 71 Ashkenazi-Jewish FH (FHCL1; 143890) families in Israel. Of the 25 Ashkenazi patients who carried the mutant allele, 16 were of Lithuanian origin. The mutation was not found in 47 non-Ashkenazi FH families. The mutation was found in 8 of 10 FH cases in the Jewish community in South Africa, which originated mainly from Lithuania. PCR amplification of a DNA fragment that includes the mutation in heterozygous individuals results in the formation of a heteroduplex that can be demonstrated by PAGE and used for molecular diagnosis. </p><p>Mandelshtam et al. (1998) found this mutation in one-third (7 of 23) of familial hypercholesterolemia cases in St. Petersburg (Russia) Jews and in no patients of Russian descent. The mutation has also been called FH St. Petersburg. </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>.0006 FH AFRIKANER 1</strong>
|
|
</span>
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
FH MAINE
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, ASP206GLU
|
|
|
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|
<br />
|
|
|
|
SNP: rs121908028,
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|
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|
|
gnomAD: rs121908028,
|
|
|
|
|
|
ClinVar: RCV000003876, RCV000771320, RCV001823092, RCV002362555
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Kotze et al. (1990) demonstrated a cytosine-to-guanine base substitution at nucleotide 681 resulting in an amino acid change from aspartic acid to glutamic acid at residue 206 (D206E) in the cysteine-rich ligand-binding domain of the LDL receptor. The mutation gives rise to an additional DdeI restriction site; segregation of the mutation with the disease was confirmed in 5 large Afrikaner FH (FHCL1; 143890) families. Kotze et al. (1990) predicted that 65% of affected South African Afrikaners carry this particular base substitution which can be diagnosed by PCR amplification of genomic DNA followed by restriction enzyme analysis. Indeed, from analysis of 138 chromosomes of Afrikaner FH patients, Kotze et al. (1991) found this mutation in 91 (68.4%). Komuro et al. (1987) described a homozygote for defective internalization of the LDL receptor who survived to age 57. Leitersdorf and Hobbs (1990) found the same mutation in an English American living in Maine. </p><p>Vergotine et al. (2001) demonstrated the feasibility of prenatal diagnosis of homozygous familial hypercholesterolemia in an Afrikaner family with the D206E mutation. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 FH MEXICO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
FH FRENCH CANADIAN 3
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, GLU207LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908029,
|
|
|
|
|
|
gnomAD: rs121908029,
|
|
|
|
|
|
ClinVar: RCV000003878, RCV000623885, RCV000735406, RCV000775232, RCV000844738, RCV002362556
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Codon 207 (GAG) is changed to AAG (Leitersdorf and Hobbs, 1990). The same mutation was found in French Canadians with FHCL1 (143890) (Leitersdorf et al., 1990). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 FH DENVER 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, ASP283ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908030,
|
|
|
|
|
|
gnomAD: rs121908030,
|
|
|
|
|
|
ClinVar: RCV000003880, RCV000791377, RCV000826215, RCV000985772, RCV002051612, RCV002371758, RCV004724728
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an African American patient with FHCL1 (143890), Leitersdorf and Hobbs (1990) found a change of aspartic acid-283 (GAC) to asparagine (AAC).</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 FH AFRIKANER 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, VAL408MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28942078,
|
|
|
|
|
|
gnomAD: rs28942078,
|
|
|
|
|
|
ClinVar: RCV000003882, RCV000775062, RCV000786355, RCV002381239, RCV004017225, RCV004745143
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This and the asp206-to-glu mutation (see 606945.0006) are frequent among Afrikaners with FHCL1 (143890). A GTG-to-ATG mutation is responsible (Leitersdorf et al., 1989). In a study of 138 chromosomes of Afrikaner FH patients, Kotze et al. (1991) found that 31 (23.3%) had this mutation. Schuster et al. (1993) found the same mutation in a German family and showed that it existed on the same 7-RFLP haplotype as did the mutation described in South Africa and in the Netherlands, suggesting a common European origin. Similarly, Defesche et al. (1993) found the val408-to-met mutation in 19 (1.5%) of 1,268 FH patients of Dutch descent. In 9 of the patients carrying this mutation on one allele, the LDLR DNA haplotype was that observed in a South African FH patient homozygous for the same mutation. The remaining 10 Dutch FH patients all shared a common haplotype, partly identical to the Afrikaner haplotype, which could have arisen from a single recombinational event. With the exception of the family reported by Schuster et al. (1993), this mutation has been described only in persons of Dutch ancestry. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 FH ALGERIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, ALA410THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28942079,
|
|
|
|
|
|
gnomAD: rs28942079,
|
|
|
|
|
|
ClinVar: RCV000003883, RCV000806811, RCV000985760, RCV002381240, RCV004017226
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>A GCT-to-ACT change is responsible for this variant (Zuliani and Hobbs, 1990).</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 FH KUWAIT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, VAL502MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28942080,
|
|
|
|
|
|
gnomAD: rs28942080,
|
|
|
|
|
|
ClinVar: RCV000003884, RCV000161992, RCV000587718, RCV000825622, RCV002399309
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>A GTG-to-ATG mutation is responsible for this variant (Zuliani and Hobbs, 1990).</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 FH SAINT OMER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, GLY525ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28942081,
|
|
|
|
|
|
|
|
ClinVar: RCV000003885, RCV001175478
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>A GGC-to-GAC mutation is responsible for this variant (Leitersdorf and Hobbs, 1990).</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 FH GENOA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, GLY528ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28941776,
|
|
|
|
|
|
gnomAD: rs28941776,
|
|
|
|
|
|
ClinVar: RCV000003886, RCV000161997, RCV000587938, RCV002390088
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>A GGT-to-GAT mutation is responsible for this variant (Leitersdorf and Hobbs, 1990).</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 FH NAPLES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, GLY544VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28942082,
|
|
|
|
|
|
|
|
ClinVar: RCV000003874, RCV000791454, RCV001195593, RCV002399308
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Esser and Russell (1988) found a GGC-to-GTC mutation as the basis of this variant. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 FH FRENCH CANADIAN 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, CYS646TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28942083,
|
|
|
|
|
|
gnomAD: rs28942083,
|
|
|
|
|
|
ClinVar: RCV000030131, RCV000313287, RCV000775084, RCV002415393
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Leitersdorf et al. (1990) found a TGT-to-TAT mutation in exon 14 as the basis of this variant. See 606945.0003, 606945.0007, 606945.0025, and 606945.0026 for other French Canadian mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 FH LEBANESE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, CYS660TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908031,
|
|
|
|
|
|
gnomAD: rs121908031,
|
|
|
|
|
|
ClinVar: RCV000003887, RCV000481771, RCV000590806, RCV000844750, RCV002415394, RCV004584310
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Lehrman et al. (1987) analyzed the nature of the LDLR mutation present in high frequency in Lebanon; the frequency of homozygotes is more than 10 times higher than in other parts of the world. It was on the basis of studies in Lebanon that Khachadurian (1964) first established the existence of homozygous FHCL1 (143890). Lehrman et al. (1987) demonstrated that the mutation involves a shortened receptor protein containing 3 domains: the region of clustered O-linked carbohydrates, the membrane-spanning region, and the cytoplasmic tail. The defect was attributable to a single nucleotide substitution that creates a premature termination codon at amino acid 660, eliminating 180 residues from the mature protein. The termination codon occurred in the middle of a cysteine-rich sequence that is part of the domain homologous to epidermal growth factor precursor. The truncated protein retains only 2 domains: a complete ligand-binding region (residues 1-292) and a partial epidermal growth factor precursor homology region (residues 293-659). The mutant gene lacks the portions that code for the membrane-spanning region and the cytoplasmic tail. After synthesis, most of the mutant receptor remains within the cell. The mutation creates a new restriction site for the enzyme HinfI, thus permitting diagnosis by Southern blotting of genomic DNA. Lehrman et al. (1987) studied 4 unrelated Arab patients with homozygous familial hypercholesterolemia, 3 from Lebanon and 1 from Syria. They referred to this mutation as the Lebanese allele. In 5 Christian-Arab kindreds in Israel, Oppenheim et al. (1991) found the 'Lebanese' allele in correlation with hypercholesterolemia. In addition, their results suggested the possible existence of an independent factor contributing to elevated LDL cholesterol levels. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0017 FH ZAMBIA</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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LDLR, PRO664LEU
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<br />
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|
|
SNP: rs28942084,
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gnomAD: rs28942084,
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|
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ClinVar: RCV000003891, RCV000162007, RCV000775085, RCV000844731, RCV002415395, RCV004745144
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|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In an Asiatic Indian with FHCL1 (143890), Knight et al. (1989) and Soutar et al. (1989) found a CCG-to-CTG mutation changing proline-664 to leucine. Knight et al. (1989) found that the precursor form of the mutant receptor is converted more slowly than normal, and the mature form on the cell surface binds LDL less well than normal. Soutar et al. (1991) identified this mutation in a large Asian-Indian kindred containing 22 heterozygotes and 3 homozygotes. All the heterozygotes had a raised level of plasma total cholesterol and low density lipoprotein cholesterol, but were remarkably free from premature coronary disease. No correlation could be found between the apo(a) phenotype (152200) and the presence or absence of the LDLR mutation. There was, however, evidence for an inherited trait that markedly increased Lp(a) concentration, which did not segregate with either apo(a) or the defective LDLR allele. FH Zambia was found in a patient with familial hypercholesterolemia who was of Indian origin residing in Zambia. Rubinsztein et al. (1992) found the same mutation in 4 South African families of Muslim religion who traced their origin to the vicinity of Surat in the Gujerat province of India. Functional studies suggested that the FH in these subjects was due to low steady-state levels of receptor molecules that are functionally normal but exhibit accelerated turnover. </p><p>Among 915 consecutive patients with FH and of Dutch descent, Defesche et al. (1992) found 7 persons with the C-to-T transition at nucleotide 2054 in exon 14. All the patients shared the same haplotype. Contrary to previous reports, no difference was found in plasma levels of Lp(a) between family members with the mutation in exon 14 and unaffected persons. </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>.0018 FH BAHRAIN</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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LDLR, TRP792TER
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<br />
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SNP: rs121908032,
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ClinVar: RCV000003892
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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 Bahraini patient with FH (FHCL1; 143890), Lehrman et al. (1985) found a change in the tryptophan-792 codon to a stop codon as the basis of this variant. Truncation of the cytoplasmic domain of the LDLR protein results in defective internalization. Recurrence of this mutation was observed by Loux et al. (1991) in the course of a survey of 139 unrelated French FH subjects. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0019 FH BARI</strong>
|
|
</span>
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
FH SYRIA
|
|
</span>
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</div>
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<div>
|
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<span class="mim-text-font">
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LDLR, TYR807CYS
|
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<br />
|
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|
|
SNP: rs28942085,
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|
|
ClinVar: RCV000003893, RCV000162025, RCV002426485, RCV002512729
|
|
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|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In an Italian patient with FH (FHCL1; 143890), Davis et al. (1986) found a TAT-to-TGT mutation in this internalization-defective allele. </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>.0020 FH NASHVILLE</strong>
|
|
</span>
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
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LDLR, 4-BP INS, EX8
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|
|
<br />
|
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|
|
SNP: rs875989916,
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|
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|
|
|
|
ClinVar: RCV000211651, RCV000588024, RCV000825618, RCV002284377, RCV002433922
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an American patient with FH (FHCL1; 143890), Leitersdorf and Hobbs (1990) found insertion of 4 nucleotides in exon 8 causing frameshift and premature termination as the basis of this null allele.</p>
|
|
</span>
|
|
</div>
|
|
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|
|
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|
<div>
|
|
<br />
|
|
</div>
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</div>
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|
|
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<div>
|
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 FH PARIS 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, 4-BP INS, EX17
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906302,
|
|
|
|
|
|
|
|
ClinVar: RCV000003895, RCV001256974
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French patient with FH (FHCL1; 143890), Lehrman et al. (1985) found insertion of 4 nucleotides in exon 17 causing frameshift and premature termination as the basis of this internalization-defective allele. Benlian et al. (1990) found the same duplication of 4 bases in exon 17 as the basis of familial hypercholesterolemia in a homozygous offspring of consanguineous French parents and in heterozygous relatives. The same mutation was not found in any normal individuals or in 158 other individuals with hypercholesterolemia type IIa. The duplication involved the third nucleotide of codon 796 and the 3 nucleotides of codon 797, resulting in a frameshift and a stop codon 20 basepairs downstream. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 FH PORTUGAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, ASP203ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906303,
|
|
|
|
|
|
|
|
ClinVar: RCV000003896, RCV001851629, RCV002362557
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Portuguese patients with FH (FHCL1; 143890), Hobbs et al. (1992) identified a G-A transition in exon 4 of the LDLR gene, resulting in an asp203-to-asn (D203N) substitution. The mutation was not found in over 200 non-FH alleles. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 FH ST. LOUIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX2-8DUP
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000237421
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an American child homozygous for FH (FHCL1; 143890), Lehrman et al. (1987) found that the LDL receptor precursor was unusually long due to a duplication of 7 exons. Unequal crossing-over between homologous repetitive elements (Alu sequences) in intron 1 and intron 8 was the basis of the duplication. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 FH PARIS 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX2-5DUP
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000237716
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French patient with FH (FHCL1; 143890), Leitersdorf and Hobbs (1990) found this mutation.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 FH FRENCH CANADIAN 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
FH DENVER
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, PROMOTER/EX1 DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003899
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Deletion of the promoter and exon 1 of the LDLR gene resulting in a null allele is the mutation found in about 60% of French Canadian cases of FH (FHCL1; 143890) in Quebec (Hobbs et al., 1987; Leitersdorf et al., 1990). Leitersdorf et al. (1990) quoted work indicating that all persons with the 'French Canadian deletion' trace their ancestry to a small town northeast of Montreal called Kamouraska, thus illustrating founder effect. Founder effect was suggested as well by the fact that the mutation was also found in France where it was, however, rare (Fumeron et al., 1992). The same mutation was found in a non-French Canadian Caucasian in Denver, Colorado (Hobbs et al., 1988). Betard et al. (1992) found that the 10-kb deletion had the same haplotype, called the B haplotype. They identified 15 different haplotypes for the normal allele in heterozygotes. Thus, founder effect is again supported. </p><p>(It is more accurate to state that Kamouraska is northeast of Quebec City on the south side of the St. Lawrence River. See 609313 for a unique form of erythrokeratodermia variabilis, designated the Kamouraska type and symbolized EKV3, that has been identified in families living in the same region of Quebec.)</p><p>Simard et al. (2004) identified the breakpoint of the more than 15-kb deletion involving the promoter and exon 1 of the LDLR gene, as well as the breakpoint of the 5-kb deletion of exons 2 and 3 (606945.0026), which accounts for 5% of French Canadian FH cases. Both deletions appeared to be the result of homologous recombination by unequal crossing over between the left arms of Alu repeats. Simard et al. (2004) determined that 55% of the LDLR gene is composed of Alu elements; thus, it is not surprising that most LDLR rearrangements involve at least 1 Alu. They developed a rapid PCR-based assay for these 2 'French Canadian' deletions. Screening of a representative population sample of 943 French Canadian youths whose LDL cholesterol levels were above the 50th percentile allowed Simard et al. (2004) to estimate the prevalence of the more than 15-kb allele as 0.11% (95% confidence interval, 0.03 to 0.38). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 FH FRENCH CANADIAN 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
FH TONAMI 2<br />
|
|
FH TSUKUBA 1
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX2-3DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003901
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ma et al. (1989) found deletion of exons 2 and 3 in a French Canadian patient with FH (FHCL1; 143890). The same mutation was found in 2 Japanese patients with homozygous FH and called FH Tonami-2 (Kajinami et al., 1989) and FH Tsukuba-1 (Yamakawa et al., 1989). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 FH PARIS 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX5DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555803632,
|
|
|
|
|
|
|
|
ClinVar: RCV000237282
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French patient with FH (FHCL1; 143890), Hobbs et al. (1986) found deletion of exon 5 of the LDLR gene. Horsthemke et al. (1987) found the same mutation in 2 English patients. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 FH CAPE TOWN 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
FH LEUVEN<br />
|
|
FH LEIDEN 1
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX7-8DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003889, RCV000575461
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In South African patients with FH (FHCL1; 143890), Henderson et al. (1988) detected a hitherto undescribed 2.5-kb deletion in the central region of the LDLR gene, most likely including all of exons 7 and 8. The same mutation was present in a Dutch patient in Leuven (Russell et al., 1986). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 FH ROCHESTER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
FH OSAKA 1<br />
|
|
FH HELSINKI
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX16-18DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003905
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an American patient with FH (FHCL1; 143890), Lehrman et al. (1985) found deletion of exons 16, 17, and part of 18, due apparently to Alu-Alu recombination. The same mutation was found in Japanese by Lehrman et al. (1987) and in many Finns by Aalto-Setala et al. (1989). A 9.5-kb deletion extended from intron 15 to exon 18. Because of loss of the domains encoded by exons 16, 17, and 18, the carboxy-terminal portion of the normal receptor, comprising amino acids 750-839, has been replaced by an unrelated stretch of 55 amino acids. This particular mutation was found in 23 of 46 unrelated Finnish FH patients with an established functional defect of LDLR. In cultured fibroblasts, both receptor-mediated binding and internalization of LDL were reduced on the average by 25 and 50%, respectively. Aalto-Setala et al. (1989) referred to the mutation as FH-Helsinki. Rodningen et al. (1992) found the same mutation in 3 out of 181 (1.7%) unrelated Norwegian FH subjects. All 3 showed the same haplotype. Aalto-Setala et al. (1992) found that the FH-Helsinki mutation was present in 75 (38%) of 199 unrelated Finnish patients with hypercholesterolemia. The prevalence ranged from 26 to 58% in different areas of Finland, with the striking exception of the North Karelia region where only 1 of 26 (4%) FH patients carried the FH-Helsinki allele. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 FH VANCOUVER 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
FH VANCOUVER 5
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX2-6DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003907
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Langlois et al. (1988) found 2 instances of deletion of exons 2-6. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 FH VANCOUVER 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX3-8DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003909
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Langlois et al. (1988) found an instance of deletion of exons 3-8. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 FH LONDON 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
FH ITALY 1<br />
|
|
FH VANCOUVER 1
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX13-14DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000238262
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an English patient with FH (FHCL1; 143890), Horsthemke et al. (1987) found deletion of exons 13 and 14. Hobbs et al. (1988) found the same mutation in an Italian patient and Langlois et al. (1988) found it in Vancouver. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 FH LONDON 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX7DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003913
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an English patient with FH (FHCL1; 143890), Horsthemke et al. (1987) found deletion of exon 7. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 FH OSAKA 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX7-14DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003914
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with FH (FHCL1; 143890), Miyake et al. (1989) found deletion of exons 7 to 14. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 FH VANCOUVER 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX17DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000238491
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Langlois (1989) found deletion of exon 17 in a patient in Vancouver, B.C.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0036 FH VANCOUVER 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX4-6DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000238046, RCV000509511
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Langlois et al. (1988) found deletion of exons 4 to 6. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0037 FH REYKJAVIK</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX9-10DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000237483
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the Icelandic population, Taylor et al. (1989) found this deletion in patients with familial hypercholesterolemia (FHCL1; 143890). However, in 17 unrelated families from Iceland, Taylor et al. (1989) identified at least 4 different haplotypes, indicating that FH is a heterogeneous disease even in this small, geographically isolated population. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0038 FH TONAMI 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX15DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000237642
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Kajinami et al. (1988) found deletion of exon 15 in a Japanese patient. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0039 FH TSUKUBA 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX16-17DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000237703
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Yamakawa et al. (1989) found deletion of exons 16 and 17 in a Japanese patient with FH (FHCL1; 143890). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0040 FH BALTIMORE-1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX17-18DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003920
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an American Caucasian with FH (FHCL1; 143890), Hobbs et al. (1990) found a deletion from intron 16 to the 3-prime flanking region of the LDLR gene, resulting in the deletion of exons 17 and 18. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0041 FH LEIDEN 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX16DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003921
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Dutch patients with FH (FHCL1; 143890), Top et al. (1990) found that deletion of the 5-prime part of exon 16 was a frequent mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0042 FH POTENZA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX13-15DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003922
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian patient with FH (FHCL1; 143890), Lehrman et al. (1986) found deletion of exons 14 and 15 and part of 13. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0043 FH BOLOGNA 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, EX13-15DUP
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000238544
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a survey of Italian patients with FH (FHCL1; 143890), Lelli et al. (1991) identified a heterozygous patient with an insertion in the LDLR gene that represented a duplication of exons 13, 14, and 15. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0044 FH AFRIKANER 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, ASP154ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908033,
|
|
|
|
|
|
gnomAD: rs121908033,
|
|
|
|
|
|
ClinVar: RCV000003924, RCV000775043, RCV001090451, RCV002336075
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Graadt van Roggen et al. (1991) found a G-to-A transition in codon 154 resulting in substitution of asparagine for aspartic acid. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0045 FH DRUZE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, TYR167TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908034,
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|
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gnomAD: rs121908034,
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ClinVar: RCV000003925, RCV001186871, RCV002345225, RCV004017227
|
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|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In FH (FHCL1; 143890) families from 2 distinct Druze villages from the Golan Heights in northern Israel, Landsberger et al. (1992) found a TAC-to-TAG substitution in codon 167, changing the sense from tyrosine to stop. The mutation was in exon 4, which encodes the fourth repeat of the binding domain of the mature receptor. Landsberger et al. (1992) presented demographic data concerning the Druze. </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>.0046 FH PAVIA</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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|
|
LDLR, EX2-12DEL
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<br />
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|
|
ClinVar: RCV000237383, RCV000505253
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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>Bertolini et al. (1992) found a large rearrangement of the LDLR gene in 3 apparently unrelated families segregating for FH (FHCL1; 143890) living in northern Italy. Southern blot analysis demonstrated heterozygosity for a 25-kb deletion eliminating exons 2-12. The affected subjects possessed 2 LDL receptor mRNA species: one of normal size (5.3 kb) and one of smaller size (3.5 kb). In the latter mRNA, the coding sequence of exon 1 was joined to the coding sequence of exon 13, causing a change in the reading frame and thereby giving rise to a premature stop codon. The predicted receptor protein, a short polypeptide of 29 amino acids, would be expected to be devoid of any function. Bertolini et al. (1992) found a common ancestor for the 3 families who had lived in the 17th century in a region called Lomellina in southwest Lombardy, near Pavia. </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>.0047 FH NORTH KARELIA</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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LDLR, 7-BP DEL, EX6
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<br />
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|
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SNP: rs387906304,
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|
|
ClinVar: RCV000003927, RCV000810136, RCV004791195
|
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|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>Koivisto et al. (1992) identified a mutation found in many Finnish patients with heterozygous FH (FHCL1; 143890). The mutation, designated FH North Karelia (FH-NK) , deleted 7 nucleotides from exon 6 of the LDLR gene, caused a translational frameshift, and was predicted to result in a truncated receptor protein. The mutation was found in 69 (34%) of 201 unrelated Finnish FH patients and was especially frequent (prevalence 79%) in patients from eastern Finland. FH Helsinki (606945.0029) and FH North Karelia together account for about two-thirds of FH mutations in Finland. </p><p>In Finnish North Karelia, with a population of about 180,000, Vuorio et al. (1997) found that the FH-NK mutation accounts for 84% (340 of 407) of FH cases, while the FH-Helsinki allele was found in 4% (18 cases). The minimum prevalence of FH in North Karelia was estimated to be 1 in 441 inhabitants; in 1 commune, a frequency of 1 in 143 was found. By use of parish and tax records, they identified a common ancestor for most of the North Karelian FH-NK persons in the village of Puso, located within an area where the FH prevalence is the highest. DNA analysis indicated that 2% of subjects aged 1 to 25 years would have been diagnosed as false-negative and 7% as false-positive FH patients on the basis of LDL cholesterol determinations alone. Coronary heart disease (CHD) was present in 65 (30%) of the 179 FH gene carriers aged 25 years or more, and 19 individuals had a previous history of acute myocardial infarction. The average age at onset of CHD was 42 years for males and 48 years for females. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0048 FH LONDON 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
LDLR, CYS210TER
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<br />
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|
|
SNP: rs121908035,
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|
|
ClinVar: RCV000003928, RCV000775046, RCV002362558
|
|
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|
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Irish subject with familial hypercholesterolemia (FHCL1; 143890), 1 of 200 patients attending lipid clinics in the London area, Gudnason et al. (1993) found a GCG-to-GAG transversion changing cys210 to a stop codon. </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>.0049 FH LONDON 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, 2-BP DEL, 694AC
|
|
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|
|
<br />
|
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|
|
SNP: rs387906305,
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|
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|
|
|
gnomAD: rs387906305,
|
|
|
|
|
|
ClinVar: RCV000003929, RCV000517763, RCV000844736, RCV001201362, RCV002362559
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 patients of British extraction with familial hypercholesterolemia (FHCL1; 143890), Gudnason et al. (1993) found deletion of the last 2 bases (694 and 695) of codon 206 (GAC). </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0050 FH OSAKA 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, ASP412HIS
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs121908036,
|
|
|
|
|
|
|
|
ClinVar: RCV000003930, RCV001851630
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with homozygous familial hypercholesterolemia (FHCL1; 143890), Miyake et al. (1992) identified a G-to-C transversion in exon 9 which was predicted to change asp412 to his. The amino acid change occurred in the epidermal growth factor precursor homology domain of the LDL receptor. Both in the fibroblasts of the patient and in transfected COS-1 cells, the mutant protein showed impaired processing and rapid degradation. Members of the family carrying the mutant gene in heterozygous state showed higher serum cholesterol levels than the others; however, cholesterol levels were also influenced by the apolipoprotein E phenotype. The mutant LDLR reported by Miyake et al. (1992) is designated here FH Osaka-3. </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>.0051 FH AFRIKANER 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, 18-BP DUP
|
|
|
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|
|
<br />
|
|
|
|
SNP: rs387906306,
|
|
|
|
|
|
|
|
ClinVar: RCV000003931, RCV001201377, RCV003457636
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Kotze et al. (1995) identified a de novo duplication in the LDLR gene in the course of screening hypercholesterolemics who did not have 1 of the 3 known mutations responsible for the high frequency of FH (FHCL1; 143890) (more than 1/100) in South African Afrikaners. The de novo duplication of 18 basepairs in exon 4 occurred after nucleotide 678 (or 681) of their sequence. The authors suggested that the resultant change is severe, because the corresponding duplicated amino acids 200-205 (or 201-206) are highly conserved in E/apo B binding repeat 5 of LDLC. One of the daughters of the index patient inherited the defective LDLR gene, which was absent in both grandparents. Kotze et al. (1995) suggested that this was the first report of a molecularly characterized de novo mutation associated with FH. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0052 FH TURKU</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, GLY823ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908037,
|
|
|
|
|
|
|
|
ClinVar: RCV000003932, RCV001523922
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Two deletions, designated FH-Helsinki (606945.0029) and FH-North Karelia (606945.0047), account for the mutations present in approximately 60 to 70% of all heterozygous FH (143890) probands in Finland. Koivisto et al. (1995) screened the DNA samples from a cohort representing the remaining 30% of heterozygous patients by amplifying all 18 exons of the LDLR gene by PCR and searching for DNA variations with the SSCP technique. Ten novel mutations were identified, comprising 2 nonsense and 7 missense mutations, as well as 1 frameshift mutation caused by a 13-bp deletion. Koivisto et al. (1995) found a single nucleotide change, substituting adenine for guanine at position 2533 of their sequence and resulting in a gly823-to-asp amino acid change, in DNA samples from 14 unrelated FH probands (FHCL1; 143890). The mutation, designated FH-Turku, affected the sequence encoding the putative basolateral sorting signal of the LDL receptor protein. The FH-Turku gene and another point mutation, FH-Pori (leu380 to his; 606945.0053), accounted for approximately 8% of the FH-causing gene alterations in Finland and were found to be particularly common among FH patients from the southwestern part of the country. The FH-Turku missense mutation was the one closest to the C terminus of LDLR identified to date. </p><p>Koivisto et al. (2001) showed that the FH-Turku mutant receptor is mistargeted to the apical surface in both Madin-Darby canine kidney (MDCK) cells and hepatic epithelial cells, resulting in reduced endocytosis of LDL from the basolateral/sinusoidal surface. Consequently, virally encoded mutant receptor fails to mediate cholesterol clearance in LDL receptor-deficient mice, suggesting that a defect in polarized LDL receptor expression in hepatocytes underlies the hypercholesterolemia in patients harboring this allele. This evidence directly links the pathogenesis of a human disease to defects in basolateral targeting signals, providing a genetic confirmation of these signals in maintaining epithelial cell polarity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0053 FH PORI</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, LEU380HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908038,
|
|
|
|
|
|
|
|
ClinVar: RCV000003933, RCV001220262, RCV002345226, RCV004794323
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 606945.0052 and Koivisto et al. (1995). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0054 FH ELVERUM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, IVS3, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003934, RCV000058917, RCV000791438, RCV000844753, RCV002321469, RCV003944798, RCV004584311
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In Norway, Leren et al. (1994) identified a splice mutation, a G-to-A change of the first base of intron 3 destroying the conserved GT splice donor site of intron 3 of the LDLR gene. The same mutation was reported in patients with FH (FHCL1; 143890) in England (Sun et al., 1995) and Germany (Feussner et al., 1996). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0055 FH AARHUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, ASN543HIS AND 9-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003935, RCV000211626, RCV000211657, RCV000825620, RCV001034619, RCV001034620, RCV001176084, RCV001529505, RCV001553637, RCV001553638, RCV001699069, RCV002408915, RCV002444850
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>During a survey of mutations of the LDL receptor gene in Danish patients with familial hypercholesterolemia (FHCL1; 143890), using SSCP analysis, Jensen et al. (1997) observed different patterns in exons 11 and 17 from 2 apparently unrelated FH index cases indicating the presence of 2 different mutations. No other mutations were identified by analysis of the remaining 16 exons and the promoter region. The mutation in exon 11 was found to be a 1690A-C transversion, causing an N543H amino acid substitution. In exon 17, they identified a 9-bp deletion of nucleotides 2393-2405 (2393del9). This sequence contains a 4-bp repeat of the nucleotides TCCT at the end. It was therefore likely that the 9-bp deletion had occurred due to 'slipped mispairing mutagenesis,' involving mispairing of the 4-bp repeat during replication. The deletion did not cause a frameshift, and the mutant allele coded, therefore, for an LDL receptor protein lacking 3 amino acids in the membrane-spanning domain: leu778, val779, and phe780. The 2 mutations were in the same allele of the LDLR gene. Each of these mutations alone had little or no effect on receptor function in transfected COS cells, but when both mutations were present simultaneously, receptor function, as assessed by flow cytometric measurement of fluorescent LDL uptake in cells, was reduced by 75%. Immunostainable receptors on the cell surface were decreased by 80% as measured by flow cytometry. The 2 mutations therefore acted in synergy to affect receptor function, possibly during intracellular receptor transport, since Northern blot analysis suggested that mRNA levels were unaffected. Jensen et al. (1997) noted that double mutations had been reported in several clinically relevant genes, such as the HEXA gene (606869.0036) and the CFTR gene (602421) (Savov et al., 1995). In most of these disorders, one mutation was found to be causative, and the other modified the onset or severity of the disease. The common methionine-valine polymorphism in the PRNP gene (176640.0005) modifies both qualitatively and quantitatively the phenotypic expression of the pathogenic D178N mutation (176640.0010) resulting in 2 different disorders: fatal familial insomnia and familial Creutzfeldt-Jakob disease (Goldfarb et al., 1992). Jensen et al. (1997) stated that in the case of the LDLR double mutant, there appeared to be a true synergistic action. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0056 FH ICELAND</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, IVS4, T-C, +2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs200238879,
|
|
|
|
|
|
|
|
ClinVar: RCV000003936, RCV001201185, RCV002362560
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Gudnason et al. (1997) stated that haplotype analysis in 18 apparently unrelated families with FH (FHCL1; 143890) in Iceland has identified at least 5 different chromosomes cosegregating with hypercholesterolemia. The most common haplotype was identified in 11 of the 18 families, indicating a founder mutation. By using SSCP analysis and direct sequencing of amplified DNA, Gudnason et al. (1997) identified a T-to-C transition in the second nucleotide in the 5-prime part of intron 4 of the LDLR gene. This mutation was present in 10 of the 18 families. In half of the cases, these families could be traced to a common ancestor by going back no further than the 18th century. The mutation was predicted to affect correct splicing of exon 4, and analysis at the cellular level demonstrated an abnormal mRNA containing intron 4 sequence in lymphoblastoid cells from a patient carrying the mutation. Translation of the mRNA would lead to a premature stop codon and a truncated nonfunctional protein of 285 amino acids. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0057 MOVED TO 606945.0005</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0058 FH GLASCO</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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LDLR, CYS163TYR
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<br />
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SNP: rs121908039,
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|
gnomAD: rs121908039,
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|
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ClinVar: RCV000003937, RCV000587146, RCV000826197, RCV001535532, RCV002345227
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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>Lee et al. (1998) reported that in the West of Scotland, in the Glasco area, about half of the index cases of familial hypercholesterolemia (FHCL1; 143890) were found to have the cys163-to-tyr mutation of the LDLR gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0059 HYPERCHOLESTEROLEMIA, FAMILIAL, 1</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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LDLR, CYS240PHE
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<br />
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SNP: rs121908040,
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|
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gnomAD: rs121908040,
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ClinVar: RCV000003938, RCV000776469, RCV000825593, RCV002051613, RCV002408448, RCV004998074
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|
|
</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
<p>In a 13-year-old girl with severe hypercholesterolemia (FHCL1; 143890), Ekstrom et al. (1999) demonstrated compound heterozygosity for a cys240-to-phe mutation and a tyr167-to-ter mutation (606945.0045) in the LDLR gene. Fibroblasts from the patient showed very low cholesterol esterification rate, LDL uptake, and degradation as compared to normal fibroblasts. Her 2 heterozygous sibs also carried the C240F mutation, but only one of them was hypercholesterolemic. Ekstrom et al. (1999) expressed the C240F mutant in LDLR-deficient CHOldlA7 cells. The transfected cells produced a detectable protein but were unable to mediate uptake or degradation of LDL. The authors concluded that there may be cholesterol-lowering mechanisms that can be activated, perhaps by mutations in known or hitherto unknown genes. </p>
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</span>
|
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</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0060 HYPERCHOLESTEROLEMIA, FAMILIAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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LDLR, TRP23TER
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|
<br />
|
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SNP: rs267607213,
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|
|
ClinVar: RCV000003939, RCV000775022, RCV000786354, RCV000844726, RCV002381241
|
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|
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In patients with familial hypercholesterolemia (FHCL1; 143890), Hobbs et al. (1992) identified a trp23-to-ter mutation in the LDLR gene. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
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|
</div>
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</div>
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|
<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0061 HYPERCHOLESTEROLEMIA, FAMILIAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
LDLR, CYS25SER
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|
|
|
<br />
|
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|
|
SNP: rs121908041,
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|
|
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|
|
|
|
ClinVar: RCV000003940
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with familial hypercholesterolemia (FHCL1; 143890), Takahashi et al. (2001) identified a G-to-C transversion at nucleotide 137 of the LDLR gene, resulting in a cys25-to-ser (C25S) amino acid substitution in the ligand-binding site (mutation class 2B: slow transport and processing). The patient first noticed xanthomas on both elbows at the age of 5 years. These continued to increase in number and size. At age 40 years, xanthomas were present on elbows, palms, knees, and feet. Clinical manifestations of myocardial ischemia developed at age 41. Selective LDL filtration was initiated after plasma apheresis through a macromolecular exclusion filter. With bimonthly treatments, her LDL cholesterol decreased by approximately 50% and the xanthomas regressed markedly, almost disappearing with 5 years of treatment. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
|
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</div>
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</div>
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<div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0062 HYPERCHOLESTEROLEMIA, FAMILIAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
LDLR, CYS88SER
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|
<br />
|
|
|
|
SNP: rs121908042,
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|
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|
|
|
gnomAD: rs121908042,
|
|
|
|
|
|
ClinVar: RCV000003941
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Pisciotta et al. (2002) identified a de novo LDLR mutation in a 47-year-old white male who at the age of 43 had suffered a myocardial infarction. He was heterozygous for a G-to-C transversion in exon 4, which resulted in a serine for cysteine substitution at position 88 (C88S) of the receptor protein. The mutation was not found in his parents (nonpaternity was excluded), but it was present in his 9-year-old son, who had familial hypercholesterolemia (FHCL1; 143890). Haplotype analysis indicated that this de novo mutation occurred in the paternal germline. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0063 HYPERCHOLESTEROLEMIA, FAMILIAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, IVS14, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs145787161,
|
|
|
|
|
|
|
|
ClinVar: RCV000003942, RCV000775089, RCV001787369, RCV002426486, RCV003398438
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Takada et al. (2002) described a novel splice site mutation in the LDLR gene, IVS14+1G-A, which genealogic research confirmed was shared by 14 of 1,135 members of an American Caucasian pedigree descended from a common ancestor and affected with familial hypercholesterolemia (FHCL1; 143890). The mutation resulted in an abruptly truncated LDLR protein, reducing functional LDLR activity by half in heterozygous carriers of the mutant allele. Takada et al. (2002) stated this was the largest familial hypercholesterolemia kindred described, and of 208 members screened for this LDLR mutation, 94 carriers and 114 noncarriers were identified. Strikingly lower total cholesterol and LDL cholesterol values were observed among most of the LDLR mutation carriers who were simultaneously homozygous for the -265C allele of the -265C-T polymorphism of the APOA2 gene (107670.0002). In vitro transfection assays showed that transcriptional activity of the APOA2 promoter was reduced by 30% in the -265C allele as compared with the -265T allele. The variant of the APOA2 gene was associated with reduced plasma LDL cholesterol only in familial hypercholesterolemia patients. </p><p>In the same large family reported by Takada et al. (2002), Takada et al. (2003) found that a SNP in the growth hormone receptor gene (GHR), resulting in a L526I (600946.0028) substitution, influenced plasma levels of high density lipoprotein (HDL) cholesterol in affected family members with the LDLR mutation. The lowest levels of plasma HDL were observed among leu/leu homozygotes, highest levels among ile/ile homozygotes, and intermediate levels among leu/ile heterozygotes. No such effect was observed among noncarriers of the LDLR mutation. </p><p>In the pedigree reported by Takada et al. (2002), Sato et al. (2004) demonstrated a significant modification of the phenotype of familial hypercholesterolemia resulting from the IVS14+1G-A mutation by the arg287 variation in the EPHX2 gene (132811.0001). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0064 FH PYRGOS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, -45T DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906307,
|
|
|
|
|
|
|
|
ClinVar: RCV000003943, RCV002512730
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with familial hypercholesterolemia (FHCL1; 143890), Dedoussis et al. (2003) identified a novel mutation in repeat 3 of the LDLR gene promoter, -45delT. Analysis of a neutral polymorphism in LDLR mRNA from the patient's white blood cells showed that the expression of 1 allele was significantly reduced, and cells had only 24% of LDLR activity by binding and uptake of iodine-labeled LDL. Transient transfection studies using a luciferase gene reporter revealed that the -45delT mutation considerably reduced the transcriptional activity of the LDLR promoter and strongly suggested that the mutation was the cause of the familial hypercholesterolemia phenotype. The proband was a female in her late thirties; her father was reported to have elevated cholesterol levels and had undergone bypass surgery at the age of 70. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0065 HYPERCHOLESTEROLEMIA, FAMILIAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, ARG385ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908043,
|
|
|
|
|
|
gnomAD: rs121908043,
|
|
|
|
|
|
ClinVar: RCV000003944, RCV000588218, RCV002354146
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient diagnosed with probable heterozygous familial hypercholesterolemia (FHCL1; 143890), who had tendinous xanthomas and angina since the age of 29 years, Bourbon et al. (2007) identified heterozygosity for a 1216C-A transversion in exon 9 of the LDLR gene, resulting in a synonymous arg385-to-arg (R385R) change. However, analysis of mRNA from the patient's cells showed that the mutation introduces a new 5-prime acceptor splice site that is used to the exclusion of the natural splice site and causes a 31-bp deletion predicted to result in premature termination 4 codons beyond the change. Review of previous LDLR gene sequencing data revealed that the same base substitution was present in a Chinese homozygous FH patient in whom no other mutation in LDLR had been found. The authors stated that the difference in origins of the 2 patients suggested that the mutation was very unlikely to have been inherited from a common ancestor and that it might be present in other populations as well. </p><p>Defesche et al. (2008) analyzed the LDLR gene in 1,350 patients clinically diagnosed with familial hypercholesterolemia who were negative for functional DNA variation in known hypercholesterolemia genes and identified the R385R variant in 2 probands, both of Chinese origin, and their family members. In view of the faint band representing the aberrantly spliced mRNA on gel electrophoresis, the authors suggested that this DNA variant likely leads to nonsense-mediated mRNA decay. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0066 HYPERCHOLESTEROLEMIA, FAMILIAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, GLY186GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908044,
|
|
|
|
|
|
|
|
ClinVar: RCV000003945, RCV001389663, RCV002254902, RCV002362561
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 35 unrelated Dutch patients clinically diagnosed with familial hypercholesterolemia who were negative for functional DNA variation in known hypercholesterolemia genes, Defesche et al. (2008) identified a 621C-T transition in exon 4 of the LDLR gene, resulting in a synonymous gly186-to-gly (G186G) change, that introduces a 3-prime splice donor site with a higher 'probability score' than the naturally occurring 3-prime splice site 75 bp downstream. Analysis of cDNA synthesized from total RNA revealed that the aberrant splicing results in a 75-bp in-frame deletion and a stable mRNA, predicted to produce an LDLR protein lacking a 25-amino acid fragment (gly186 to cys210). The variant was found in homozygosity in 2 of the probands, who had LDL cholesterol levels of 14.8 and 10.5 mmol/L, respectively, and who both suffered myocardial infarctions before the age of 20 years. The variant was also identified in 62 first-degree relatives of the index cases. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0067 HYPERCHOLESTEROLEMIA, FAMILIAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLR, IVS14, C-G, +86
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776886,
|
|
|
|
|
|
gnomAD: rs587776886,
|
|
|
|
|
|
ClinVar: RCV000023602
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a proband with clinically defined hypercholesterolemia (FHCL1; 143890), Kulseth et al. (2010) identified heterozygosity for a splice site mutation (2140+86C-G) in intron 14 of the LDLR gene, activating a cryptic splice site that results in aberrantly spliced mRNA containing an 81-bp insertion. Twelve of 23 family members tested were heterozygous for the mutation, and carriers had significantly increased total cholesterol levels compared to noncarriers. The 2140+86C-G mutation was found in 3 additional probands with hypercholesterolemia, and in 1 proband's family the mutation was found in 6 of 7 tested family members, who all had LDL cholesterol levels above the 97th percentile. RT-PCR analysis in 1 affected individual from that family showed that the mutant allele mainly gave rise to aberrantly spliced mRNA, but contributed 21% normal transcripts. Transfection studies in CHO cells demonstrated retention of mutant LDLR in the endoplasmic reticulum, presumably due to protein misfolding. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
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|
|
</div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Allen et al. (1980); Elston et al. (1976); Goldstein et al. (1977);
|
|
Goldstein et al. (1975); Hobbs et al. (1985); Horsthemke et al.
|
|
(1987); Horsthemke et al. (1985); Kingsley and Krieger (1984);
|
|
Lehrman et al. (1987); Lehrman et al. (1985); Sudhof et al. (1985)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
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<div>
|
|
<ol>
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
Aalto-Setala, K., Helve, E., Kovanen, P. T., Kontula, K.
|
|
<strong>Finnish type of low density lipoprotein receptor gene mutation (FH-Helsinki) deletes exons encoding the carboxy-terminal part of the receptor and creates an internalization-defective phenotype.</strong>
|
|
J. Clin. Invest. 84: 499-505, 1989.
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|
[PubMed: 2760198]
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[Full Text: https://doi.org/10.1172/JCI114192]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Aalto-Setala, K., Koivisto, U.-M., Miettinen, T. A., Gylling, H., Kesaniemi, Y. A., Savolainen, M., Pyorala, K., Ebeling, T., Mononen, I., Turtola, H., Viikari, J., Kontula, K.
|
|
<strong>Prevalence and geographical distribution of major LDL receptor gene rearrangements in Finland.</strong>
|
|
J. Intern. Med. 231: 227-234, 1992.
|
|
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|
|
[PubMed: 1372927]
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|
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|
|
[Full Text: https://doi.org/10.1111/j.1365-2796.1992.tb00528.x]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Agnello, V., Abel, G., Elfahal, M., Knight, G. B., Zhang, Q.-X.
|
|
<strong>Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor.</strong>
|
|
Proc. Nat. Acad. Sci. 96: 12766-12771, 1999.
|
|
|
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|
|
[PubMed: 10535997]
|
|
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|
[Full Text: https://doi.org/10.1073/pnas.96.22.12766]
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</p>
|
|
</li>
|
|
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|
<li>
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Carol A. Bocchini - updated : 08/19/2019<br>Ada Hamosh - updated : 05/10/2019<br>Ada Hamosh - updated : 3/11/2015<br>Marla J. F. O'Neill - updated : 10/14/2013<br>Marla J. F. O'Neill - updated : 2/9/2012<br>Ada Hamosh - updated : 10/12/2010<br>Paul J. Converse - updated : 8/5/2010<br>Ada Hamosh - updated : 1/21/2010<br>Marla J. F. O'Neill - updated : 12/9/2009<br>Ada Hamosh - updated : 8/14/2009<br>Marla J. F. O'Neill - updated : 5/7/2009<br>Ada Hamosh - updated : 4/1/2008<br>Ada Hamosh - updated : 6/18/2007<br>Cassandra L. Kniffin - updated : 10/5/2005<br>Victor A. McKusick - updated : 4/15/2005<br>Cassandra L. Kniffin - updated : 3/1/2005<br>Victor A. McKusick - updated : 2/25/2004<br>Victor A. McKusick - updated : 12/4/2003<br>Ada Hamosh - updated : 4/3/2003<br>Victor A. McKusick - updated : 2/10/2003<br>Victor A. McKusick - updated : 8/27/2002
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