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Entry
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- *607786 - PROPROTEIN CONVERTASE, SUBTILISIN/KEXIN-TYPE, 9; PCSK9
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- OMIM
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<p>
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<span class="h4">*607786</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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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>
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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/607786">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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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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</li>
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</ul>
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</nav>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000169174;t=ENST00000302118" 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=255738" 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=607786" 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=ENSG00000169174;t=ENST00000302118" 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_001407240,NM_001407241,NM_001407242,NM_001407243,NM_001407244,NM_001407245,NM_001407246,NM_001407247,NM_174936,NR_110451,NR_176318,NR_176319,NR_176320,NR_176321,NR_176322,NR_176323,NR_176324" 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_174936" 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=607786" 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=07080&isoform_id=07080_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/PCSK9" 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/14134236,15422369,22761405,31317307,34530477,55925154,119627065,157649684,194375832,194387056,225131052,317373487,549802329,583072268,583197637,2245789806,2245789808,2245789832,2245789834,2245789848,2245789913,2245789959,2245790024,2462507512" 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/Q8NBP7" 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=255738" 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=ENSG00000169174;t=ENST00000302118" 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=PCSK9" 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=PCSK9" 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+255738" 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/PCSK9" 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:255738" 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/255738" 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=chr1&hgg_gene=ENST00000302118.5&hgg_start=55039548&hgg_end=55064852&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:20001" 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:20001" 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/pcsk9" 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=607786[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=607786[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/ENSG00000169174" 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=PCSK9" 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=PCSK9" 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=PCSK9" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.ucl.ac.uk/ldlr/LOVDv.1.1.0/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PCSK9&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/PA38617" 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:20001" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:2140260" 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/PCSK9#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:2140260" 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/255738/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/OMIA002329/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=255738" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-060927-1" 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:255738" 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=PCSK9&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> 441471003<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>
|
|
607786
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
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<span class="mim-font">
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PROPROTEIN CONVERTASE, SUBTILISIN/KEXIN-TYPE, 9; PCSK9
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
NEURAL APOPTOSIS-REGULATED CONVERTASE 1; NARC1
|
|
</span>
|
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</h4>
|
|
</div>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PCSK9" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PCSK9</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/1/646?start=-3&limit=10&highlight=646">1p32.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:55039548-55064852&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'})">1:55,039,548-55,064,852</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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|
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|
|
</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<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>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/646?start=-3&limit=10&highlight=646">
|
|
1p32.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Low density lipoprotein cholesterol level QTL 1}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/603776"> 603776 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
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|
|
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|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hypercholesterolemia, familial, 3
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/603776"> 603776 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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<p>PCSK9 is a serine protease that reduces both hepatic and extrahepatic low-density lipoprotein (LDL) receptor (LDLR; <a href="/entry/606945">606945</a>) levels and increases plasma LDL cholesterol (<a href="#18" class="mim-tip-reference" title="Schmidt, R. J., Beyer, T. P., Bensch, W. R., Qian, Y.-W., Lin, A., Kowala, M., Alborn, W. E., Konrad, R. J., Cao, G. <strong>Secreted proprotein convertase subtilisin/kexin type 9 reduces both hepatic and extrahepatic low-density lipoprotein receptors in vivo.</strong> Biochem. Biophys. Res. Commun. 370: 634-640, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18406350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18406350</a>] [<a href="https://doi.org/10.1016/j.bbrc.2008.04.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18406350">Schmidt et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18406350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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>To identify the gene mutant in the form of autosomal dominant familial hypercholesterolemia (see <a href="/entry/143890">143890</a>) that had been mapped to chromosome 1p32 (HCHOLA3; <a href="/entry/603776">603776</a>), <a href="#1" class="mim-tip-reference" title="Abifadel, M., Varret, M., Rabes, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derre, A., Villeger, L., and 14 others. <strong>Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.</strong> Nature Genet. 34: 154-156, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730697</a>] [<a href="https://doi.org/10.1038/ng1161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730697">Abifadel et al. (2003)</a> undertook positional cloning using the family in which linkage was originally identified (<a href="#24" class="mim-tip-reference" title="Varret, M., Rabes, J.-P., Saint-Jore, B., Cenarro, A., Marinoni, J.-C., Civeira, F., Devillers, M., Krempf, M., Coulon, M., Thiart, R., Kotze, M. J., Schmidt, H., and 9 others. <strong>A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32.</strong> Am. J. Hum. Genet. 64: 1378-1387, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10205269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10205269</a>] [<a href="https://doi.org/10.1086/302370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10205269">Varret et al., 1999</a>) and 23 French families in which a causative mutation in LDLR (<a href="/entry/606945">606945</a>) or APOB (<a href="/entry/107730">107730</a>) had been excluded. The critical linkage region contained 41 genes, including the PCSK9 gene. <a href="#1" class="mim-tip-reference" title="Abifadel, M., Varret, M., Rabes, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derre, A., Villeger, L., and 14 others. <strong>Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.</strong> Nature Genet. 34: 154-156, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730697</a>] [<a href="https://doi.org/10.1038/ng1161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730697">Abifadel et al. (2003)</a> found that the PCSK9 cDNA spans 3,617 basepairs and encodes a protein of 692 amino acids, known as NARC1. PCSK9 was expressed most abundantly in liver, small intestine, and kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12730697+10205269" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Kwon, H. J., Lagace, T. A., McNutt, M. C., Horton, J. D., Deisenhofer, J. <strong>Molecular basis for LDL receptor recognition by PCSK9.</strong> Proc. Nat. Acad. Sci. 105: 1820-1825, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18250299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18250299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18250299[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.0712064105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18250299">Kwon et al. (2008)</a> stated that PCSK9 contains an N-terminal signal peptide, followed by a prodomain, a subtilisin-like catalytic domain, and a C-terminal domain. The prodomain serves as a chaperone for folding and as an inhibitor of catalytic activity. Autocatalysis between gln152 and ser153 separates the prodomain from the catalytic domain, but the prodomain remains bound, occluding the catalytic site. The C-terminal domain is predicted to mediate protein-protein interactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18250299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Benjannet, S., Rhainds, D., Hamelin, J., Nassoury, N., Seidah, N. G. <strong>The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.</strong> J. Biol. Chem. 281: 30561-30572, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16912035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16912035</a>] [<a href="https://doi.org/10.1074/jbc.M606495200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16912035">Benjannet et al. (2006)</a> reported that PCSK9 is N-glycosylated at asn533 and that both the prosegment and the catalytic domain contain a sulfated tyrosine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16912035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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="#1" class="mim-tip-reference" title="Abifadel, M., Varret, M., Rabes, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derre, A., Villeger, L., and 14 others. <strong>Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.</strong> Nature Genet. 34: 154-156, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730697</a>] [<a href="https://doi.org/10.1038/ng1161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730697">Abifadel et al. (2003)</a> determined that the PCSK9 gene comprises 12 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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>By genomic sequence analysis, <a href="#1" class="mim-tip-reference" title="Abifadel, M., Varret, M., Rabes, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derre, A., Villeger, L., and 14 others. <strong>Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.</strong> Nature Genet. 34: 154-156, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730697</a>] [<a href="https://doi.org/10.1038/ng1161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730697">Abifadel et al. (2003)</a> mapped the PCSK9 gene to chromosome 1p32. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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="#10" class="mim-tip-reference" title="Kwon, H. J., Lagace, T. A., McNutt, M. C., Horton, J. D., Deisenhofer, J. <strong>Molecular basis for LDL receptor recognition by PCSK9.</strong> Proc. Nat. Acad. Sci. 105: 1820-1825, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18250299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18250299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18250299[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.0712064105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18250299">Kwon et al. (2008)</a> determined the crystal structure of PCSK9 in complex with the first EGF-like repeat (EGF-A) of LDLR to 2.4-angstrom resolution. They found that the N-terminal region of EGF-A bound to the surface of PCSK9 that is formed primarily by residues 367 to 381; residues 153 to 155 in the catalytic domain also contribute to the interface. Arg194 and phe379 within the catalytic domain were critical for EGF-A binding, since arg194 formed a salt bridge with EGF-A, and phe379 made several hydrophobic contacts. Mutation of either residue decreased PCSK9 binding by greater than 90%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18250299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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="#1" class="mim-tip-reference" title="Abifadel, M., Varret, M., Rabes, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derre, A., Villeger, L., and 14 others. <strong>Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.</strong> Nature Genet. 34: 154-156, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730697</a>] [<a href="https://doi.org/10.1038/ng1161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730697">Abifadel et al. (2003)</a> stated that the PCSK9 gene encodes NARC1, a novel putative proprotein convertase belonging to the subtilase subfamily (<a href="#19" class="mim-tip-reference" title="Seidah, N. G., Benjannet, S., Wickham, L., Marcinkiewicz, J., Jasmin, S. B., Stifani, S., Basak, A., Prat, A., Chretien, M. <strong>The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.</strong> Proc. Nat. Acad. Sci. 100: 928-933, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12552133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12552133</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12552133[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.0335507100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12552133">Seidah et al., 2003</a>). NARC1 is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. Prosegment cleavage is necessary for NARC1 to exit from the endoplasmic reticulum. A related protein is the subtilisin/kexin isoenzyme-1/site-1 protease (<a href="/entry/603355">603355</a>), which has a key role in cholesterol homeostasis through processing the sterol regulatory element-binding proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12730697+12552133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Maxwell, K. N., Fisher, E. A., Breslow, J. L. <strong>Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.</strong> Proc. Nat. Acad. Sci. 102: 2069-2074, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15677715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15677715</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15677715[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.0409736102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15677715">Maxwell et al. (2005)</a> found that overexpression of mouse Pcsk9 in a human hepatoma cell line caused a decrease in whole-cell and cell-surface LDLR levels. Overexpression had no effect on LDLR synthesis, but caused a dramatic increase in the degradation of the mature receptor and a lesser increase in the degradation of the LDLR precursor. In contrast, overexpression of a catalytically inactive Pcsk9 mutant prevented the degradation of the mature LDLR, but precursor degradation remained elevated. Pcsk9-induced LDLR degradation was not altered by inhibitors of the proteasome, lysosomal cysteine proteases, aspartic acid proteases, or metalloproteases, but required transport out of the endoplasmic reticulum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15677715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Benjannet, S., Rhainds, D., Hamelin, J., Nassoury, N., Seidah, N. G. <strong>The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.</strong> J. Biol. Chem. 281: 30561-30572, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16912035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16912035</a>] [<a href="https://doi.org/10.1074/jbc.M606495200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16912035">Benjannet et al. (2006)</a> found that the mature secreted 60-kD PCSK9 protein could be further processed by membrane-bound furin (<a href="/entry/136950">136950</a>) and, to a lesser extent, soluble PC5/6A (PCSK5; <a href="/entry/600488">600488</a>) into an approximately 53-kD form. Processing at the furin cleavage site led to disassociation of the inhibitory prosegment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16912035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Kwon, H. J., Lagace, T. A., McNutt, M. C., Horton, J. D., Deisenhofer, J. <strong>Molecular basis for LDL receptor recognition by PCSK9.</strong> Proc. Nat. Acad. Sci. 105: 1820-1825, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18250299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18250299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18250299[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.0712064105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18250299">Kwon et al. (2008)</a> stated that PCSK9 binds in a calcium-dependent manner to the EGF-A domain of the EGF-precursor homology domain of LDLR, but the catalytic domain of PCSK9 is not required for normal LDLR turnover. They found that deletion of the first 21 amino acids of the prodomain region of PCSK9 (called delta-53-PCSK9) increased the affinity of PCSK9 over 7-fold compared with full-length PCSK9. The affinity of both full-length PCSK9 and delta-53-PCSK9 increased about 3-fold when the pH was lowered from 7.0 to 6.0, suggesting that PCSK9 binds more avidly to LDLR in the lysosomal/endosomal compartment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18250299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Schmidt, R. J., Beyer, T. P., Bensch, W. R., Qian, Y.-W., Lin, A., Kowala, M., Alborn, W. E., Konrad, R. J., Cao, G. <strong>Secreted proprotein convertase subtilisin/kexin type 9 reduces both hepatic and extrahepatic low-density lipoprotein receptors in vivo.</strong> Biochem. Biophys. Res. Commun. 370: 634-640, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18406350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18406350</a>] [<a href="https://doi.org/10.1016/j.bbrc.2008.04.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18406350">Schmidt et al. (2008)</a> showed that recombinant human PCSK9, when intravenously injected in mice or expressed in mouse liver, reduced Ldlr levels in multiple extrahepatic tissues, including lung, adipose, and kidney, with more dramatic reduction in liver. Wildtype PCSK9 and a catalytically inactive PCSK9 mutant showed similar reductions in hepatic Ldlr levels, indicating that the catalytic activity of secreted PCSK9 is not necessary to reduce LDLR levels in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18406350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Familial Hypercholesterolemia 3, Autosomal Dominant</em></strong></p><p>
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By sequencing the 12 exons of PCSK9 in a French family (HC92) with hypercholesterolemia (FHCL3; <a href="/entry/603776">603776</a>), <a href="#1" class="mim-tip-reference" title="Abifadel, M., Varret, M., Rabes, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derre, A., Villeger, L., and 14 others. <strong>Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.</strong> Nature Genet. 34: 154-156, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730697</a>] [<a href="https://doi.org/10.1038/ng1161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730697">Abifadel et al. (2003)</a> identified a 625T-A transversion in exon 2 of the PCSK9 gene, predicting a ser127-to-arg (S127R) amino acid change (<a href="#0001">607786.0001</a>). They found the mutation in 12 affected family members and in 1 family member whose total cholesterol level was in the 90th percentile when compared with other French individuals matched by age and sex. Thus, the penetrance in the family was estimated at 0.94. The authors also found the same mutation in another affected French family. The S127R mutation is located between the primary and putative secondary zymogen processing sites of the NARC1 propeptide. In another affected French family, <a href="#1" class="mim-tip-reference" title="Abifadel, M., Varret, M., Rabes, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derre, A., Villeger, L., and 14 others. <strong>Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.</strong> Nature Genet. 34: 154-156, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730697</a>] [<a href="https://doi.org/10.1038/ng1161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730697">Abifadel et al. (2003)</a> found another missense mutation in the PCSK9 gene (F216L; <a href="#0002">607786.0002</a>), which was located close to the active site at his226. The molecular mechanisms that underlie the dominance of the trait caused by these missense mutations was unclear. That only missense mutations had been identified favors a gain-of-function or dominant-negative mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By mutation screening of genes in the chromosome 1p32 region in patients with familial hypercholesterolemia from the Utah pedigree (K1173) studied by <a href="#5" class="mim-tip-reference" title="Haddad, L., Day, I. N. M., Hunt, S., Williams, R. R., Humphries, S. E., Hopkins, P. N. <strong>Evidence for a third genetic locus causing familial hypercholesterolemia: a non-LDLR, non-APOB kindred.</strong> J. Lipid Res. 40: 1113-1122, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10357843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10357843</a>]" pmid="10357843">Haddad et al. (1999)</a> and <a href="#6" class="mim-tip-reference" title="Hunt, S. C., Hopkins, P. N., Bulka, K., McDermott, M. T., Thorne, T. L., Wardell, B. B., Bowen, B. R., Ballinger, D. G., Skolnick, M. H., Samuels, M. E. <strong>Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred.</strong> Arterioscler. Thromb. Vasc. Biol. 20: 1089-1093, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10764678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10764678</a>] [<a href="https://doi.org/10.1161/01.atv.20.4.1089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10764678">Hunt et al. (2000)</a>, <a href="#23" class="mim-tip-reference" title="Timms, K. M., Wagner, S., Samuels, M. E., Forbey, K., Goldfine, H., Jammulapati, S., Skolnick, M. H., Hopkins, P. N., Hunt, S. C., Shattuck, D. M. <strong>A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree.</strong> Hum. Genet. 114: 349-353, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14727179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14727179</a>] [<a href="https://doi.org/10.1007/s00439-003-1071-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14727179">Timms et al. (2004)</a> identified a heterozygous missense mutation (D374Y; <a href="#0003">607786.0003</a>) in the PCSK9 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14727179+10357843+10764678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Sun, X.-M., Eden, E. R., Tosi, I., Neuwirth, C. K., Wile, D., Naoumova, R. P., Soutar, A. K. <strong>Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia.</strong> Hum. Molec. Genet. 14: 1161-1169, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15772090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15772090</a>] [<a href="https://doi.org/10.1093/hmg/ddi128" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15772090">Sun et al. (2005)</a> identified the D374Y mutation in 3 families of English origin with hypercholesterolemia; all 12 affected individuals had unusually severe hypercholesterolaemia and required more stringent treatment than FH patients with heterozygous LDLR mutations. In stably transfected rat hepatoma cells, both mutant and wildtype PCSK9 colocalized with protein disulfide isomerase in the ER. Expression of D374Y-mutant PCSK9 increased secretion of apolipoprotein B100 (<a href="/entry/107730">107730</a>)-containing lipoproteins by 2- to 4-fold compared to wildtype, but no significant difference in LDLR content was observed in any transfected cell line. <a href="#21" class="mim-tip-reference" title="Sun, X.-M., Eden, E. R., Tosi, I., Neuwirth, C. K., Wile, D., Naoumova, R. P., Soutar, A. K. <strong>Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia.</strong> Hum. Molec. Genet. 14: 1161-1169, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15772090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15772090</a>] [<a href="https://doi.org/10.1093/hmg/ddi128" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15772090">Sun et al. (2005)</a> suggested that pathogenic variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15772090" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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>Low Density Lipoprotein cholesterol level Quantitative Trait Locus 1</em></strong></p><p>
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In a 1,793-person cohort representing the general population of Japan, <a href="#20" class="mim-tip-reference" title="Shioji, K., Mannami, T., Kokubo, Y., Inamoto, N., Takagi, S., Goto, Y., Nonogi, H., Iwai, N. <strong>Genetic variants in PCSK9 affect the cholesterol level in Japanese.</strong> J. Hum. Genet. 49: 109-114, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14727156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14727156</a>] [<a href="https://doi.org/10.1007/s10038-003-0114-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14727156">Shioji et al. (2004)</a> directly sequenced the PCSK9 gene and identified 21 polymorphisms, 2 of which were significantly associated with lower levels of total cholesterol and low density lipoprotein (LDL) cholesterol (LDLCQ1; see <a href="/entry/603776">603776</a>): a -161C-T transition in intron 1 and an ile474-to-val (I474V) change in exon 9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14727156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>As indicated, mutations in PCSK9 causing hypercholesterolemia are probably gain-of-function mutations; overexpression of PCSK9 in the liver of mice produces hypercholesterolemia by reducing LDLR number (<a href="#12" class="mim-tip-reference" title="Maxwell, K. N., Breslow, J. L. <strong>Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype.</strong> Proc. Nat. Acad. Sci. 101: 7100-7105, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15118091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15118091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15118091[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.0402133101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15118091">Maxwell and Breslow, 2004</a>; <a href="#16" class="mim-tip-reference" title="Park, S. W., Moon, Y.-A., Horton, J. D. <strong>Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver.</strong> J. Biol. Chem. 279: 50630-50638, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385538</a>] [<a href="https://doi.org/10.1074/jbc.M410077200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15385538">Park et al., 2004</a>). To test whether loss-of-function mutations in PCSK9 have the opposite effect, <a href="#4" class="mim-tip-reference" title="Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., Hobbs, H. H. <strong>Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.</strong> Nature Genet. 37: 161-165, 2005. Note: Erratum: Nature Genet. 37: 328 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15654334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15654334</a>] [<a href="https://doi.org/10.1038/ng1509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15654334">Cohen et al. (2005)</a> sequenced the coding region of PCSK9 in 128 subjects (50% African American) with low plasma levels of LDL cholesterol and found 2 nonsense mutations: Y142X (<a href="#0004">607786.0004</a>) and C679X (<a href="#0005">607786.0005</a>). These mutations were common in African Americans (combined frequency, 2%) but rare in European Americans (less than 0.1%) and were associated with a 40% reduction in plasma levels of LDL cholesterol (LDLCQ1; see <a href="/entry/603776">603776</a>). The data indicated that common sequence variations have large effects on plasma cholesterol levels in selected populations. The high frequency of these 2 ancient nonsense mutations in individuals of African ancestry suggested that positive selection pressure may have maintained these alleles in the population. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15118091+15654334+15385538" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Selected missense mutations in the PCSK9 gene cause autosomal dominant hypercholesterolemia (e.g., <a href="#0001">607786.0001</a>), whereas nonsense mutations in the same gene are associated with low plasma levels of low density lipoprotein cholesterol (LDL-C) (e.g., <a href="#0004">607786.0004</a>). <a href="#9" class="mim-tip-reference" title="Kotowski, I. K., Pertsemlidis, A., Luke, A., Cooper, R. S., Vega, G. L., Cohen, J. C., Hobbs, H. H. <strong>A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol.</strong> Am. J. Hum. Genet. 78: 410-422, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16465619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16465619</a>] [<a href="https://doi.org/10.1086/500615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16465619">Kotowski et al. (2006)</a> used DNA sequencing and chip-based oligonucleotide hybridization to determine whether other sequence variations in PCSK9 contribute to differences in LDL-C levels. The coding regions of PCSK9 were sequenced in the blacks and whites from the Dallas Heart Study (n = 3,543) who had the lowest (less than 5th percentile) and highest (more than 95th percentile) plasma levels of LDL-C. Of the 17 missense variants identified, R46L (<a href="#0006">607786.0006</a>; <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11591147;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11591147</a>), L253F, and A443T were significantly and reproducibly associated with lower plasma levels of LDL-C (reductions ranging from 3.5 to 30%). None of the low LDL-C variants was associated with increased hepatic triglyceride content, as measured by proton magnetic resonance spectroscopy. This finding was considered most consistent with the reduction in LDL-C being caused primarily by accelerating LDL clearance, rather than by reduced lipoprotein production. Association studies with 93 noncoding single-nucleotide polymorphisms (SNPs) at the PCSK9 locus identified 3 SNPs associated with modest differences in plasma LDL-C levels. Thus, a spectrum of sequence variations ranging in frequency (from 0.2 to 34%) and magnitude of effect (from a 3% increase to a 49% decrease) contributed to interindividual differences in LDL-C levels. These findings revealed that PCSK9 activity is a major determinant of plasma levels of LDL-C in humans and made it an attractive therapeutic target for LDL-C lowering. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16465619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Cohen, J. C., Boerwinkle, E., Mosley, T. H., Jr., Hobbs, H. H. <strong>Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.</strong> New Eng. J. Med. 354: 1264-1272, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16554528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16554528</a>] [<a href="https://doi.org/10.1056/NEJMoa054013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16554528">Cohen et al. (2006)</a> examined the effect of DNA sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population. Of the 3,363 black subjects examined, 2.6% had nonsense mutations in PCSK9; these mutations were associated with a 28% reduction in mean LDL cholesterol and an 88% reduction in the risk of coronary heart disease (CHD), including myocardial infarction, fatal CHD, or coronary revascularization, over a 15-year period. Of the 9,524 white subjects examined, 3.2% had a sequence variation in PCSK9 that was associated with a 15% reduction in LDL cholesterol and a 47% reduction in the risk of CHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16554528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="#25" class="mim-tip-reference" title="Zhao, Z., Tuakli-Wosornu, Y., Lagace, T. A., Kinch, L., Grishin, N. V., Horton, J. D., Cohen, J. C., Hobbs, H. H. <strong>Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.</strong> Am. J. Hum. Genet. 79: 514-523, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16909389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16909389</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16909389[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/10.1086/507488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16909389">Zhao et al. (2006)</a> showed that 4 severe loss-of-function mutations prevent the secretion of PCSK9 by disrupting synthesis or trafficking of the protein. In contrast to recombinant wildtype PCSK9, which was secreted from cells into the medium within 2 hours, the severe loss-of-function mutations in PCSK9 largely abolished PCSK9 secretion. This finding predicted that circulating levels of PCSK9 would be lower in individuals with the loss-of-function mutations. Immunoprecipitation and immunoblotting of plasma for PCSK9 provided direct evidence that the serine protease is present in the serum and identified the first known individual who had no immunodetectable circulating PCSK9. This healthy, fertile college graduate, who was a compound heterozygote for 2 inactivating mutations in PCSK9 (<a href="#0007">607786.0007</a>, <a href="#0008">607786.0008</a>) had a strikingly low plasma level of LDL cholesterol (14 mg/dL). The very low plasma level of LDL cholesterol and apparent good health of this individual demonstrates that PCSK9 plays a major role in determining plasma levels of LDL cholesterol and provides an attractive target for LDL-lowering therapy. Findings in this patient recapitulate those found in mice with no PCSK9, which show accelerated LDL clearance (<a href="#17" class="mim-tip-reference" title="Rashid, S., Curtis, D. E., Garuti, R., Anderson, N. N., Bashmakov, Y., Ho, Y. K., Hammer, R. E., Moon, Y.-A., Horton, J. D. <strong>Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.</strong> Proc. Nat. Acad. Sci. 102: 5374-5379, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805190</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15805190[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.0501652102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805190">Rashid et al., 2005</a>). Evidence suggests that PCSK9 acts to limit the number of LDL receptors at the cell surface. Thus, the PCSK9 mutations associated with hypercholesterolemia are presumably gain-of-function mutations, whereas those reported by <a href="#25" class="mim-tip-reference" title="Zhao, Z., Tuakli-Wosornu, Y., Lagace, T. A., Kinch, L., Grishin, N. V., Horton, J. D., Cohen, J. C., Hobbs, H. H. <strong>Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.</strong> Am. J. Hum. Genet. 79: 514-523, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16909389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16909389</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16909389[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/10.1086/507488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16909389">Zhao et al. (2006)</a> are loss-of-function mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16909389+15805190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="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, including <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11591147;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11591147</a> of PCSK9, had previously been associated with elevated LDL or lower HDL. <a href="#7" 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 each SNP 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="#14" class="mim-tip-reference" title="Mayne, J., Raymond, A., Chaplin, A., Cousins, M., Kaefer, N., Gyamera-Acheampong, C., Seidah, N. G., Mbikay, M., Chretien, M., Ooi, T. C. <strong>Plasma PCSK9 levels correlate with cholesterol in men but not in women.</strong> Biochem. Biophys. Res. Commun. 361: 451-456, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17645871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17645871</a>] [<a href="https://doi.org/10.1016/j.bbrc.2007.07.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17645871">Mayne et al. (2007)</a> examined the relationship between plasma PCSK9 levels and lipoprotein parameters in 182 normolipidemic individuals and found a correlation between plasma PCSK9 and total cholesterol, LDL cholesterol, and the total cholesterol/HDL cholesterol ratio in men but not in women. Analysis of the PCSK9 gene in 3 individuals with total and LDL cholesterol levels below the fifth percentile revealed compound heterozygosity for known PCSK9 mutations; analysis of family members of 1 proband showed that the ratio of plasma PCSK9/LDLC was increased in men, but not women, carrying loss of function PCSK9 variants. <a href="#14" class="mim-tip-reference" title="Mayne, J., Raymond, A., Chaplin, A., Cousins, M., Kaefer, N., Gyamera-Acheampong, C., Seidah, N. G., Mbikay, M., Chretien, M., Ooi, T. C. <strong>Plasma PCSK9 levels correlate with cholesterol in men but not in women.</strong> Biochem. Biophys. Res. Commun. 361: 451-456, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17645871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17645871</a>] [<a href="https://doi.org/10.1016/j.bbrc.2007.07.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17645871">Mayne et al. (2007)</a> suggested that there is a gender difference in PCSK9 regulation and function, with PCSK9 correlated to total and LDL cholesterol in men but not women. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17645871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="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> performed a genomewide association study for plasma lipids in more than 100,000 individuals of European ancestry and reported 95 significantly associated loci (P = less than 5 x 10(-8)), with 59 showing genomewide significant association with lipid traits for the first time. The newly reported associations included SNPs near known lipid regulators as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contributed not only to normal variation in lipid traits but also to extreme lipid phenotypes and had an impact on lipid traits in 3 non-European populations (East Asians, South Asians, and African Americans). <a href="#22" 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 <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2479409;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2479409</a> near the PCSK9 gene as implicated in LDL cholesterol concentrations with an effect size of +2.01 mg per deciliter and a P value of 2 x 10(-28). <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>
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<p><a href="#2" class="mim-tip-reference" title="Benjannet, S., Rhainds, D., Hamelin, J., Nassoury, N., Seidah, N. G. <strong>The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.</strong> J. Biol. Chem. 281: 30561-30572, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16912035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16912035</a>] [<a href="https://doi.org/10.1074/jbc.M606495200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16912035">Benjannet et al. (2006)</a> found that the hypercholesterolemia-associated gain-of-function PCSK9 mutations R218S, F216L, and D374Y resulted in total or partial loss of processing of mature PCSK9 at the furin cleavage motif RFHR. In contrast, the hypocholesterolemia-associated loss-of-function PCSK9 mutations A443T and C679X resulted in abnormal subcellular localization and enhanced susceptibility to furin cleavage (A443T) or to the inability of PCSK9 to exit the endoplasmic reticulum (C679X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16912035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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>To study the function of Pcsk9 in mice, <a href="#12" class="mim-tip-reference" title="Maxwell, K. N., Breslow, J. L. <strong>Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype.</strong> Proc. Nat. Acad. Sci. 101: 7100-7105, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15118091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15118091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15118091[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.0402133101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15118091">Maxwell and Breslow (2004)</a> used an adenovirus constitutively expressing murine Pcsk9 (Pcsk9-Ad). Pcsk9 overexpression in wildtype mice caused a 2-fold increase in plasma total cholesterol and a 5-fold increase in non-high density lipoprotein (HDL) cholesterol, with no increase in HDL cholesterol, as compared with mice infected with a control adenovirus. The increase in non-HDL cholesterol was shown to be due to an increase in low density lipoprotein (LDL) cholesterol. This effect appeared to depend on the LDL receptor (LDLR; <a href="/entry/606945">606945</a>) because Ldlr knockout mice infected with Pcsk9-Ad showed no change in plasma cholesterol levels as compared with knockout mice infected with a control adenovirus. Furthermore, whereas overexpression of Pcsk9 had no effect on Ldlr mRNA levels, there was a near absence of Ldlr protein in animals overexpressing Pcsk9. These and other results indicated that overexpression of PCSK9 interferes with LDLR-mediated LDL cholesterol uptake. Because PCSK9 and LDLR are coordinately regulated by cholesterol, <a href="#12" class="mim-tip-reference" title="Maxwell, K. N., Breslow, J. L. <strong>Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype.</strong> Proc. Nat. Acad. Sci. 101: 7100-7105, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15118091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15118091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15118091[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.0402133101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15118091">Maxwell and Breslow (2004)</a> suggested that PCSK9 may be involved in a novel mechanism to modulate LDLR function by an alternative pathway than classic cholesterol inhibition of sterol regulatory element binding protein-mediated transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15118091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="#17" class="mim-tip-reference" title="Rashid, S., Curtis, D. E., Garuti, R., Anderson, N. N., Bashmakov, Y., Ho, Y. K., Hammer, R. E., Moon, Y.-A., Horton, J. D. <strong>Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.</strong> Proc. Nat. Acad. Sci. 102: 5374-5379, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805190</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15805190[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.0501652102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805190">Rashid et al. (2005)</a> found that the livers of mice lacking Pcsk9 showed increased LDLR protein but not mRNA. Increased LDLR led to increased clearance of circulating lipoproteins and decreased plasma cholesterol levels. Administration of a statin-class drug to Pcsk9-null mice produced an exaggerated increase in LDLRs in liver and enhanced LDL clearance from plasma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15805190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Lambert, G., Jarnoux, A.-L., Pineau, T., Pape, O., Chetiveaux, M., Laboisse, C., Krempf, M., Costet, P. <strong>Fasting induces hyperlipidemia in mice overexpressing proprotein convertase subtilisin kexin type 9: lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor.</strong> Endocrinology 147: 4985-4995, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16794006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16794006</a>] [<a href="https://doi.org/10.1210/en.2006-0098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16794006">Lambert et al. (2006)</a> showed that upon dietary challenge, downregulation of Ldlr in mice is a key mechanism whereby Pcsk9 modulates hepatic production of Apob-containing lipoproteins. Overexpression of Pcsk9 in mice promoted hypercholesterolemia and massive hypertriglyceridemia following a 24-hour fast due to dramatically increased hepatic output of very low density lipoprotein (VLDL) and Apob, and both processes required Ldlr. Increased VLDL production was associated with a concomitant reduction of intrahepatic lipid stores and absence of Ppara (<a href="/entry/170998">170998</a>) downregulation. Experiments with a Ppara agonist confirmed that hepatic expression of Pcsk9 was negatively regulated by Ppara. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16794006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>8 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607786[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28942111 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28942111;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=rs28942111" 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=rs28942111" 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=RCV000003007 OR RCV000505185" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003007, RCV000505185" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003007...</a>
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<p>In 2 French families with autosomal dominant hypercholesterolemia-3 (FCHL3; <a href="/entry/603776">603776</a>), <a href="#1" class="mim-tip-reference" title="Abifadel, M., Varret, M., Rabes, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derre, A., Villeger, L., and 14 others. <strong>Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.</strong> Nature Genet. 34: 154-156, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730697</a>] [<a href="https://doi.org/10.1038/ng1161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730697">Abifadel et al. (2003)</a> identified a 625T-A transversion in exon 2 of the PCSK9 gene, resulting in a ser127-to-arg (S127R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Kwon, H. J., Lagace, T. A., McNutt, M. C., Horton, J. D., Deisenhofer, J. <strong>Molecular basis for LDL receptor recognition by PCSK9.</strong> Proc. Nat. Acad. Sci. 105: 1820-1825, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18250299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18250299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18250299[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.0712064105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18250299">Kwon et al. (2008)</a> stated that PCSK9 processing and secretion were reduced in PCSK9 containing the S127R mutation, but the affinity of PCSK9 for LDLR was only modestly affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18250299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="#15" class="mim-tip-reference" title="Ouguerram, K., Chetiveaux, M., Zair, Y., Costet, P., Abifadel, M., Varret, M., Boileau, C., Magot, T., Krempf, M. <strong>Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9.</strong> Arterioscler. Thromb. Vasc. Biol. 24: 1448-1453, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15166014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15166014</a>] [<a href="https://doi.org/10.1161/01.ATV.0000133684.77013.88" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15166014">Ouguerram et al. (2004)</a> found that the S127R mutation in 2 related individuals with hypercholesterolemia was associated with increased production of APOB (3-fold) related to overproduction of VLDL (3-fold), intermediate density lipoprotein (IDL) (3-fold), and LDL (5-fold) compared with controls. The 2 individuals also showed a decrease in VLDL and IDL conversion (10 to 30% of controls), and their LDL fractional catabolic rate was slightly decreased (by 30%) compared with controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15166014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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">rs28942112 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28942112;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=rs28942112" 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=rs28942112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In the proband of a family with autosomal dominant hypercholesterolemia-3 (FHCL3; <a href="/entry/603776">603776</a>) who died from myocardial infarction at 49 years of age, <a href="#1" class="mim-tip-reference" title="Abifadel, M., Varret, M., Rabes, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derre, A., Villeger, L., and 14 others. <strong>Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.</strong> Nature Genet. 34: 154-156, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730697</a>] [<a href="https://doi.org/10.1038/ng1161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730697">Abifadel et al. (2003)</a> identified an 890T-C transition in exon 4 of the PCSK9 gene, resulting in a phe216-to-leu (F216L) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Kwon, H. J., Lagace, T. A., McNutt, M. C., Horton, J. D., Deisenhofer, J. <strong>Molecular basis for LDL receptor recognition by PCSK9.</strong> Proc. Nat. Acad. Sci. 105: 1820-1825, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18250299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18250299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18250299[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.0712064105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18250299">Kwon et al. (2008)</a> stated that phe216 is located within a disordered loop in PCSK9 and that the F216L mutation reduces proteolytic processing of PCSK9 after arg218. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18250299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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> rs137852912 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852912;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/rs137852912?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=rs137852912" 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=rs137852912" 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=RCV000003009 OR RCV000505195 OR RCV004017221 OR RCV004018541" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003009, RCV000505195, RCV004017221, RCV004018541" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003009...</a>
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<p>In a large Utah pedigree (K1173) segregating hypercholesterolemia (FHCL3; <a href="/entry/603776">603776</a>), originally described by <a href="#5" class="mim-tip-reference" title="Haddad, L., Day, I. N. M., Hunt, S., Williams, R. R., Humphries, S. E., Hopkins, P. N. <strong>Evidence for a third genetic locus causing familial hypercholesterolemia: a non-LDLR, non-APOB kindred.</strong> J. Lipid Res. 40: 1113-1122, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10357843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10357843</a>]" pmid="10357843">Haddad et al. (1999)</a>, <a href="#6" class="mim-tip-reference" title="Hunt, S. C., Hopkins, P. N., Bulka, K., McDermott, M. T., Thorne, T. L., Wardell, B. B., Bowen, B. R., Ballinger, D. G., Skolnick, M. H., Samuels, M. E. <strong>Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred.</strong> Arterioscler. Thromb. Vasc. Biol. 20: 1089-1093, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10764678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10764678</a>] [<a href="https://doi.org/10.1161/01.atv.20.4.1089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10764678">Hunt et al. (2000)</a> found linkage of the disorder to chromosome 1p32. By mutation screening of genes in this region, <a href="#23" class="mim-tip-reference" title="Timms, K. M., Wagner, S., Samuels, M. E., Forbey, K., Goldfine, H., Jammulapati, S., Skolnick, M. H., Hopkins, P. N., Hunt, S. C., Shattuck, D. M. <strong>A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree.</strong> Hum. Genet. 114: 349-353, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14727179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14727179</a>] [<a href="https://doi.org/10.1007/s00439-003-1071-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14727179">Timms et al. (2004)</a> identified a G-to-T transversion in the PCSK9 gene, resulting in an asp374-to-tyr (D374Y) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14727179+10357843+10764678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Sun, X.-M., Eden, E. R., Tosi, I., Neuwirth, C. K., Wile, D., Naoumova, R. P., Soutar, A. K. <strong>Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia.</strong> Hum. Molec. Genet. 14: 1161-1169, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15772090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15772090</a>] [<a href="https://doi.org/10.1093/hmg/ddi128" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15772090">Sun et al. (2005)</a> identified the D374Y mutation in 3 families of English origin with hypercholesterolemia; all 12 affected individuals had unusually severe hypercholesterolaemia and required more stringent treatment than FH patients with heterozygous LDLR mutations. In stably transfected rat hepatoma cells, both mutant and wildtype PCSK9 colocalized with protein disulfide isomerase in the ER. Expression of D374Y-mutant PCSK9 increased secretion of apolipoprotein B100 (<a href="/entry/107730">107730</a>)-containing lipoproteins by 2- to 4-fold compared to wildtype, but no significant difference in LDLR content was observed in any transfected cell line. <a href="#21" class="mim-tip-reference" title="Sun, X.-M., Eden, E. R., Tosi, I., Neuwirth, C. K., Wile, D., Naoumova, R. P., Soutar, A. K. <strong>Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia.</strong> Hum. Molec. Genet. 14: 1161-1169, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15772090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15772090</a>] [<a href="https://doi.org/10.1093/hmg/ddi128" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15772090">Sun et al. (2005)</a> suggested that pathogenic variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15772090" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Kwon, H. J., Lagace, T. A., McNutt, M. C., Horton, J. D., Deisenhofer, J. <strong>Molecular basis for LDL receptor recognition by PCSK9.</strong> Proc. Nat. Acad. Sci. 105: 1820-1825, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18250299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18250299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18250299[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.0712064105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18250299">Kwon et al. (2008)</a> found that the D374Y mutation increased the affinity of mutant PCSK9 for LDLR compared with wildtype PCSK9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18250299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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> rs67608943 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs67608943;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/rs67608943?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=rs67608943" 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=rs67608943" 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=RCV000003010 OR RCV000588335 OR RCV001097394 OR RCV001191121 OR RCV001731276 OR RCV004658956" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003010, RCV000588335, RCV001097394, RCV001191121, RCV001731276, RCV004658956" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003010...</a>
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<p>In 3 of 64 African American subjects with low plasma levels of low density lipoprotein cholesterol (LDLCQ1; see <a href="/entry/603776">603776</a>), <a href="#4" class="mim-tip-reference" title="Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., Hobbs, H. H. <strong>Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.</strong> Nature Genet. 37: 161-165, 2005. Note: Erratum: Nature Genet. 37: 328 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15654334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15654334</a>] [<a href="https://doi.org/10.1038/ng1509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15654334">Cohen et al. (2005)</a> identified a 426C-G transversion in exon 3 of the PCSK9 gene, resulting in a tyr142-to-ter mutation (Y142X). This mutation was predicted to delete the last four-fifths of the protein. The authors hypothesized that the Y142X mutation would induce nonsense-mediated mRNA decay. This is one of the sequence variations found by <a href="#3" class="mim-tip-reference" title="Cohen, J. C., Boerwinkle, E., Mosley, T. H., Jr., Hobbs, H. H. <strong>Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.</strong> New Eng. J. Med. 354: 1264-1272, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16554528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16554528</a>] [<a href="https://doi.org/10.1056/NEJMoa054013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16554528">Cohen et al. (2006)</a> to be associated with protection against coronary heart disease in black participants in a longitudinal study. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15654334+16554528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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> rs28362286 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28362286;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/rs28362286?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=rs28362286" 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=rs28362286" 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=RCV000003011 OR RCV000508694 OR RCV000531428 OR RCV000771132 OR RCV001508868 OR RCV001731277 OR RCV004649062 OR RCV004734496" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003011, RCV000508694, RCV000531428, RCV000771132, RCV001508868, RCV001731277, RCV004649062, RCV004734496" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003011...</a>
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<p>In 4 of 64 African American subjects with low plasma levels of LDL cholesterol (LDLCQ1; see <a href="/entry/603776">603776</a>), <a href="#4" class="mim-tip-reference" title="Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., Hobbs, H. H. <strong>Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.</strong> Nature Genet. 37: 161-165, 2005. Note: Erratum: Nature Genet. 37: 328 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15654334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15654334</a>] [<a href="https://doi.org/10.1038/ng1509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15654334">Cohen et al. (2005)</a> found a 2037C-A transversion in the PCSK9 gene that was predicted to truncate the protein by 14 amino acids (cys679 to ter; C679X). Among 549 Nigerians from a Yoruba-speaking rural community, they found a frequency of the 2037A allele of 1.4%, which was similar to the frequencies observed in 2 African American populations. This is one of the sequence variations found by <a href="#3" class="mim-tip-reference" title="Cohen, J. C., Boerwinkle, E., Mosley, T. H., Jr., Hobbs, H. H. <strong>Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.</strong> New Eng. J. Med. 354: 1264-1272, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16554528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16554528</a>] [<a href="https://doi.org/10.1056/NEJMoa054013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16554528">Cohen et al. (2006)</a> to be associated with protection against coronary heart disease in black participants in a longitudinal study. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15654334+16554528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 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> rs11591147 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11591147;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/rs11591147?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=rs11591147" 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=rs11591147" 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=RCV000003012 OR RCV000203182 OR RCV000256313 OR RCV000508774 OR RCV000605465 OR RCV000985896 OR RCV001099060 OR RCV001523785 OR RCV002381236" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003012, RCV000203182, RCV000256313, RCV000508774, RCV000605465, RCV000985896, RCV001099060, RCV001523785, RCV002381236" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003012...</a>
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<p><a href="#3" class="mim-tip-reference" title="Cohen, J. C., Boerwinkle, E., Mosley, T. H., Jr., Hobbs, H. H. <strong>Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.</strong> New Eng. J. Med. 354: 1264-1272, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16554528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16554528</a>] [<a href="https://doi.org/10.1056/NEJMoa054013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16554528">Cohen et al. (2006)</a> found that the arg46-to-leu (R46L) substitution (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11591147;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11591147</a>) in white subjects in a longitudinal study was associated with significant reduction in plasma levels of total cholesterol (9%) and LDL cholesterol (15%) (see <a href="/entry/603776">603776</a>). <a href="#3" class="mim-tip-reference" title="Cohen, J. C., Boerwinkle, E., Mosley, T. H., Jr., Hobbs, H. H. <strong>Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.</strong> New Eng. J. Med. 354: 1264-1272, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16554528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16554528</a>] [<a href="https://doi.org/10.1056/NEJMoa054013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16554528">Cohen et al. (2006)</a> found that persons who were heterozygous or homozygous for PCSK9(46L) had a 47% reduction in the rate of coronary events (6.3% vs 11.8%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16554528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="#8" class="mim-tip-reference" title="Kathiresan, S. <strong>A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. (Letter)</strong> New Eng. J. Med. 358: 2299-2300, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18499582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18499582</a>] [<a href="https://doi.org/10.1056/NEJMc0707445" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18499582">Kathiresan (2008)</a> reported a significant association between the R46L variant and decreased risk of early-onset myocardial infarction in a study of 1,454 patients from 5 different study sites (metaanalysis odds ratio of 0.40; p = 2.0 x 10(-5)). The R46L allele frequency in 1,617 controls was 2.4%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18499582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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 LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 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> rs67608943 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs67608943;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/rs67608943?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=rs67608943" 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=rs67608943" 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=RCV000003010 OR RCV000588335 OR RCV001097394 OR RCV001191121 OR RCV001731276 OR RCV004658956" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003010, RCV000588335, RCV001097394, RCV001191121, RCV001731276, RCV004658956" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003010...</a>
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<p><a href="#25" class="mim-tip-reference" title="Zhao, Z., Tuakli-Wosornu, Y., Lagace, T. A., Kinch, L., Grishin, N. V., Horton, J. D., Cohen, J. C., Hobbs, H. H. <strong>Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.</strong> Am. J. Hum. Genet. 79: 514-523, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16909389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16909389</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16909389[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/10.1086/507488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16909389">Zhao et al. (2006)</a> identified the first known individual with no immunodetectable circulating PCSK9. This healthy, fertile college graduate was found to be a compound heterozygote for 2 inactivating mutations in PCSK9, a tyr142-to-stop substitution on the maternal allele (Y142X) that disrupted synthesis of the protein, and a 3-bp deletion on the paternal allele (<a href="#0008">607786.0008</a>). She had a strikingly low plasma level of LDL cholesterol (14 mg/dL) (see <a href="/entry/603776">603776</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16909389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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">rs587776545 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776545;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=rs587776545" 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=rs587776545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>A patient with no immunodetectable circulating PCSK9 reported by <a href="#25" class="mim-tip-reference" title="Zhao, Z., Tuakli-Wosornu, Y., Lagace, T. A., Kinch, L., Grishin, N. V., Horton, J. D., Cohen, J. C., Hobbs, H. H. <strong>Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.</strong> Am. J. Hum. Genet. 79: 514-523, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16909389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16909389</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16909389[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/10.1086/507488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16909389">Zhao et al. (2006)</a> carried a 3-bp deletion (290_292delGCC) on the paternal allele of her PCSK9 gene that removed an arginine at codon 97 (see <a href="/entry/603776">603776</a>). Expression of the mutant protein in HEK293 cells demonstrated that the mutation prevents autocatalytic cleavage and secretion of PCSK9. The maternal allele carried a premature termination mutation (<a href="#0007">607786.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16909389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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Abifadel, M., Varret, M., Rabes, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derre, A., Villeger, L., and 14 others.
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<strong>Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.</strong>
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Nature Genet. 34: 154-156, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730697</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730697" 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/ng1161" target="_blank">Full Text</a>]
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Benjannet, S., Rhainds, D., Hamelin, J., Nassoury, N., Seidah, N. G.
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<strong>The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.</strong>
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J. Biol. Chem. 281: 30561-30572, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16912035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16912035</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16912035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Cohen, J. C., Boerwinkle, E., Mosley, T. H., Jr., Hobbs, H. H.
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<strong>Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.</strong>
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New Eng. J. Med. 354: 1264-1272, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16554528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16554528</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16554528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa054013" target="_blank">Full Text</a>]
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Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., Hobbs, H. H.
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<strong>Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.</strong>
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Nature Genet. 37: 161-165, 2005. Note: Erratum: Nature Genet. 37: 328 only, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15654334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15654334</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15654334" 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/ng1509" target="_blank">Full Text</a>]
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Haddad, L., Day, I. N. M., Hunt, S., Williams, R. R., Humphries, S. E., Hopkins, P. N.
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<strong>Evidence for a third genetic locus causing familial hypercholesterolemia: a non-LDLR, non-APOB kindred.</strong>
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J. Lipid Res. 40: 1113-1122, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10357843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10357843</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10357843" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Hunt, S. C., Hopkins, P. N., Bulka, K., McDermott, M. T., Thorne, T. L., Wardell, B. B., Bowen, B. R., Ballinger, D. G., Skolnick, M. H., Samuels, M. E.
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<strong>Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred.</strong>
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Arterioscler. Thromb. Vasc. Biol. 20: 1089-1093, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10764678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10764678</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10764678" 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/10.1161/01.atv.20.4.1089" target="_blank">Full Text</a>]
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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.
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<strong>Polymorphisms associated with cholesterol and risk of cardiovascular events.</strong>
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New Eng. J. Med. 358: 1240-1249, 2008.
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa0706728" target="_blank">Full Text</a>]
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<a id="Kathiresan2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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<strong>A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. (Letter)</strong>
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[<a href="https://doi.org/10.1056/NEJMc0707445" target="_blank">Full Text</a>]
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<a id="Kotowski2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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<strong>A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol.</strong>
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[<a href="https://doi.org/10.1086/500615" target="_blank">Full Text</a>]
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<a id="Kwon2008" class="mim-anchor"></a>
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<div class="">
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<strong>Molecular basis for LDL receptor recognition by PCSK9.</strong>
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[<a href="https://doi.org/10.1073/pnas.0712064105" target="_blank">Full Text</a>]
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<div class="">
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<strong>Fasting induces hyperlipidemia in mice overexpressing proprotein convertase subtilisin kexin type 9: lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor.</strong>
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[<a href="https://doi.org/10.1210/en.2006-0098" target="_blank">Full Text</a>]
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<strong>Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype.</strong>
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[<a href="https://doi.org/10.1073/pnas.0402133101" target="_blank">Full Text</a>]
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<strong>Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.</strong>
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[<a href="https://doi.org/10.1073/pnas.0409736102" target="_blank">Full Text</a>]
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<a id="Mayne2007" class="mim-anchor"></a>
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<div class="">
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[<a href="https://doi.org/10.1016/j.bbrc.2007.07.029" target="_blank">Full Text</a>]
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<a id="Ouguerram2004" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1161/01.ATV.0000133684.77013.88" target="_blank">Full Text</a>]
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<a id="Park2004" class="mim-anchor"></a>
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<strong>Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver.</strong>
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[<a href="https://doi.org/10.1074/jbc.M410077200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0501652102" target="_blank">Full Text</a>]
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<a id="Schmidt2008" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1016/j.bbrc.2008.04.004" target="_blank">Full Text</a>]
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<a id="Seidah2003" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1073/pnas.0335507100" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10038-003-0114-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature09270" target="_blank">Full Text</a>]
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Timms, K. M., Wagner, S., Samuels, M. E., Forbey, K., Goldfine, H., Jammulapati, S., Skolnick, M. H., Hopkins, P. N., Hunt, S. C., Shattuck, D. M.
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<strong>A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree.</strong>
|
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Hum. Genet. 114: 349-353, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14727179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14727179</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14727179" 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/s00439-003-1071-9" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Varret1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Varret, M., Rabes, J.-P., Saint-Jore, B., Cenarro, A., Marinoni, J.-C., Civeira, F., Devillers, M., Krempf, M., Coulon, M., Thiart, R., Kotze, M. J., Schmidt, H., and 9 others.
|
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<strong>A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32.</strong>
|
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Am. J. Hum. Genet. 64: 1378-1387, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10205269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10205269</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10205269" 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/10.1086/302370" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Zhao2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhao, Z., Tuakli-Wosornu, Y., Lagace, T. A., Kinch, L., Grishin, N. V., Horton, J. D., Cohen, J. C., Hobbs, H. H.
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<strong>Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.</strong>
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Am. J. Hum. Genet. 79: 514-523, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16909389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16909389</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16909389[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=16909389" 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/10.1086/507488" target="_blank">Full Text</a>]
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</p>
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</ol>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 9/27/2010
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 12/31/2008<br>Marla J. F. O'Neill - updated : 12/23/2008<br>Patricia A. Hartz - updated : 8/18/2008<br>Cassandra L. Kniffin - updated : 5/23/2008<br>George E. Tiller - updated : 5/19/2008<br>Ada Hamosh - updated : 4/1/2008<br>Victor A. McKusick - updated : 8/23/2006<br>Victor A. McKusick - updated : 3/29/2006<br>Victor A. McKusick - updated : 2/21/2006<br>Patricia A. Hartz - updated : 6/30/2005<br>Patricia A. Hartz - updated : 6/8/2005<br>Victor A. McKusick - updated : 2/4/2005<br>Victor A. McKusick - updated : 5/18/2004<br>Victor A. McKusick - updated : 4/2/2004<br>Marla J. F. O'Neill - updated : 3/16/2004
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 5/14/2003
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 01/30/2020
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/20/2019<br>carol : 06/20/2019<br>carol : 06/19/2019<br>alopez : 07/24/2013<br>carol : 2/15/2012<br>wwang : 9/27/2010<br>alopez : 9/27/2010<br>mgross : 1/9/2009<br>terry : 12/31/2008<br>carol : 12/24/2008<br>terry : 12/23/2008<br>wwang : 8/22/2008<br>terry : 8/18/2008<br>wwang : 5/27/2008<br>ckniffin : 5/23/2008<br>wwang : 5/21/2008<br>terry : 5/19/2008<br>carol : 4/2/2008<br>carol : 4/1/2008<br>alopez : 8/24/2006<br>terry : 8/23/2006<br>alopez : 3/30/2006<br>terry : 3/29/2006<br>alopez : 2/28/2006<br>terry : 2/21/2006<br>wwang : 7/21/2005<br>terry : 6/30/2005<br>wwang : 6/17/2005<br>wwang : 6/9/2005<br>terry : 6/8/2005<br>alopez : 3/4/2005<br>alopez : 2/9/2005<br>alopez : 2/9/2005<br>terry : 2/4/2005<br>tkritzer : 5/20/2004<br>terry : 5/18/2004<br>tkritzer : 4/7/2004<br>terry : 4/2/2004<br>tkritzer : 3/16/2004<br>carol : 8/13/2003<br>alopez : 6/3/2003<br>alopez : 5/29/2003<br>alopez : 5/14/2003
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</span>
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</div>
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</div>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 607786
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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PROPROTEIN CONVERTASE, SUBTILISIN/KEXIN-TYPE, 9; PCSK9
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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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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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NEURAL APOPTOSIS-REGULATED CONVERTASE 1; NARC1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PCSK9</em></strong>
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</span>
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</p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 441471003;
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</span>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 1p32.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:55,039,548-55,064,852 </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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</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>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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1p32.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Low density lipoprotein cholesterol level QTL 1}
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</span>
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</td>
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<td>
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<span class="mim-font">
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603776
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<tr>
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<td>
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<span class="mim-font">
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Hypercholesterolemia, familial, 3
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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603776
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>PCSK9 is a serine protease that reduces both hepatic and extrahepatic low-density lipoprotein (LDL) receptor (LDLR; 606945) levels and increases plasma LDL cholesterol (Schmidt et al., 2008). </p>
|
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
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|
<p>To identify the gene mutant in the form of autosomal dominant familial hypercholesterolemia (see 143890) that had been mapped to chromosome 1p32 (HCHOLA3; 603776), Abifadel et al. (2003) undertook positional cloning using the family in which linkage was originally identified (Varret et al., 1999) and 23 French families in which a causative mutation in LDLR (606945) or APOB (107730) had been excluded. The critical linkage region contained 41 genes, including the PCSK9 gene. Abifadel et al. (2003) found that the PCSK9 cDNA spans 3,617 basepairs and encodes a protein of 692 amino acids, known as NARC1. PCSK9 was expressed most abundantly in liver, small intestine, and kidney. </p><p>Kwon et al. (2008) stated that PCSK9 contains an N-terminal signal peptide, followed by a prodomain, a subtilisin-like catalytic domain, and a C-terminal domain. The prodomain serves as a chaperone for folding and as an inhibitor of catalytic activity. Autocatalysis between gln152 and ser153 separates the prodomain from the catalytic domain, but the prodomain remains bound, occluding the catalytic site. The C-terminal domain is predicted to mediate protein-protein interactions. </p><p>Benjannet et al. (2006) reported that PCSK9 is N-glycosylated at asn533 and that both the prosegment and the catalytic domain contain a sulfated tyrosine. </p>
|
|
</span>
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<div>
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<br />
|
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
|
<p>Abifadel et al. (2003) determined that the PCSK9 gene comprises 12 exons. </p>
|
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</span>
|
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<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>By genomic sequence analysis, Abifadel et al. (2003) mapped the PCSK9 gene to chromosome 1p32. </p>
|
|
</span>
|
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<div>
|
|
<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
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</h4>
|
|
</div>
|
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|
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<span class="mim-text-font">
|
|
<p><strong><em>Crystal Structure</em></strong></p><p>
|
|
Kwon et al. (2008) determined the crystal structure of PCSK9 in complex with the first EGF-like repeat (EGF-A) of LDLR to 2.4-angstrom resolution. They found that the N-terminal region of EGF-A bound to the surface of PCSK9 that is formed primarily by residues 367 to 381; residues 153 to 155 in the catalytic domain also contribute to the interface. Arg194 and phe379 within the catalytic domain were critical for EGF-A binding, since arg194 formed a salt bridge with EGF-A, and phe379 made several hydrophobic contacts. Mutation of either residue decreased PCSK9 binding by greater than 90%. </p>
|
|
</span>
|
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<div>
|
|
<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<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>Abifadel et al. (2003) stated that the PCSK9 gene encodes NARC1, a novel putative proprotein convertase belonging to the subtilase subfamily (Seidah et al., 2003). NARC1 is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. Prosegment cleavage is necessary for NARC1 to exit from the endoplasmic reticulum. A related protein is the subtilisin/kexin isoenzyme-1/site-1 protease (603355), which has a key role in cholesterol homeostasis through processing the sterol regulatory element-binding proteins. </p><p>Maxwell et al. (2005) found that overexpression of mouse Pcsk9 in a human hepatoma cell line caused a decrease in whole-cell and cell-surface LDLR levels. Overexpression had no effect on LDLR synthesis, but caused a dramatic increase in the degradation of the mature receptor and a lesser increase in the degradation of the LDLR precursor. In contrast, overexpression of a catalytically inactive Pcsk9 mutant prevented the degradation of the mature LDLR, but precursor degradation remained elevated. Pcsk9-induced LDLR degradation was not altered by inhibitors of the proteasome, lysosomal cysteine proteases, aspartic acid proteases, or metalloproteases, but required transport out of the endoplasmic reticulum. </p><p>Benjannet et al. (2006) found that the mature secreted 60-kD PCSK9 protein could be further processed by membrane-bound furin (136950) and, to a lesser extent, soluble PC5/6A (PCSK5; 600488) into an approximately 53-kD form. Processing at the furin cleavage site led to disassociation of the inhibitory prosegment. </p><p>Kwon et al. (2008) stated that PCSK9 binds in a calcium-dependent manner to the EGF-A domain of the EGF-precursor homology domain of LDLR, but the catalytic domain of PCSK9 is not required for normal LDLR turnover. They found that deletion of the first 21 amino acids of the prodomain region of PCSK9 (called delta-53-PCSK9) increased the affinity of PCSK9 over 7-fold compared with full-length PCSK9. The affinity of both full-length PCSK9 and delta-53-PCSK9 increased about 3-fold when the pH was lowered from 7.0 to 6.0, suggesting that PCSK9 binds more avidly to LDLR in the lysosomal/endosomal compartment. </p><p>Schmidt et al. (2008) showed that recombinant human PCSK9, when intravenously injected in mice or expressed in mouse liver, reduced Ldlr levels in multiple extrahepatic tissues, including lung, adipose, and kidney, with more dramatic reduction in liver. Wildtype PCSK9 and a catalytically inactive PCSK9 mutant showed similar reductions in hepatic Ldlr levels, indicating that the catalytic activity of secreted PCSK9 is not necessary to reduce LDLR levels in vivo. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Familial Hypercholesterolemia 3, Autosomal Dominant</em></strong></p><p>
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By sequencing the 12 exons of PCSK9 in a French family (HC92) with hypercholesterolemia (FHCL3; 603776), Abifadel et al. (2003) identified a 625T-A transversion in exon 2 of the PCSK9 gene, predicting a ser127-to-arg (S127R) amino acid change (607786.0001). They found the mutation in 12 affected family members and in 1 family member whose total cholesterol level was in the 90th percentile when compared with other French individuals matched by age and sex. Thus, the penetrance in the family was estimated at 0.94. The authors also found the same mutation in another affected French family. The S127R mutation is located between the primary and putative secondary zymogen processing sites of the NARC1 propeptide. In another affected French family, Abifadel et al. (2003) found another missense mutation in the PCSK9 gene (F216L; 607786.0002), which was located close to the active site at his226. The molecular mechanisms that underlie the dominance of the trait caused by these missense mutations was unclear. That only missense mutations had been identified favors a gain-of-function or dominant-negative mechanism. </p><p>By mutation screening of genes in the chromosome 1p32 region in patients with familial hypercholesterolemia from the Utah pedigree (K1173) studied by Haddad et al. (1999) and Hunt et al. (2000), Timms et al. (2004) identified a heterozygous missense mutation (D374Y; 607786.0003) in the PCSK9 gene. </p><p>Sun et al. (2005) identified the D374Y mutation in 3 families of English origin with hypercholesterolemia; all 12 affected individuals had unusually severe hypercholesterolaemia and required more stringent treatment than FH patients with heterozygous LDLR mutations. In stably transfected rat hepatoma cells, both mutant and wildtype PCSK9 colocalized with protein disulfide isomerase in the ER. Expression of D374Y-mutant PCSK9 increased secretion of apolipoprotein B100 (107730)-containing lipoproteins by 2- to 4-fold compared to wildtype, but no significant difference in LDLR content was observed in any transfected cell line. Sun et al. (2005) suggested that pathogenic variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers. </p><p><strong><em>Low Density Lipoprotein cholesterol level Quantitative Trait Locus 1</em></strong></p><p>
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In a 1,793-person cohort representing the general population of Japan, Shioji et al. (2004) directly sequenced the PCSK9 gene and identified 21 polymorphisms, 2 of which were significantly associated with lower levels of total cholesterol and low density lipoprotein (LDL) cholesterol (LDLCQ1; see 603776): a -161C-T transition in intron 1 and an ile474-to-val (I474V) change in exon 9. </p><p>As indicated, mutations in PCSK9 causing hypercholesterolemia are probably gain-of-function mutations; overexpression of PCSK9 in the liver of mice produces hypercholesterolemia by reducing LDLR number (Maxwell and Breslow, 2004; Park et al., 2004). To test whether loss-of-function mutations in PCSK9 have the opposite effect, Cohen et al. (2005) sequenced the coding region of PCSK9 in 128 subjects (50% African American) with low plasma levels of LDL cholesterol and found 2 nonsense mutations: Y142X (607786.0004) and C679X (607786.0005). These mutations were common in African Americans (combined frequency, 2%) but rare in European Americans (less than 0.1%) and were associated with a 40% reduction in plasma levels of LDL cholesterol (LDLCQ1; see 603776). The data indicated that common sequence variations have large effects on plasma cholesterol levels in selected populations. The high frequency of these 2 ancient nonsense mutations in individuals of African ancestry suggested that positive selection pressure may have maintained these alleles in the population. </p><p>Selected missense mutations in the PCSK9 gene cause autosomal dominant hypercholesterolemia (e.g., 607786.0001), whereas nonsense mutations in the same gene are associated with low plasma levels of low density lipoprotein cholesterol (LDL-C) (e.g., 607786.0004). Kotowski et al. (2006) used DNA sequencing and chip-based oligonucleotide hybridization to determine whether other sequence variations in PCSK9 contribute to differences in LDL-C levels. The coding regions of PCSK9 were sequenced in the blacks and whites from the Dallas Heart Study (n = 3,543) who had the lowest (less than 5th percentile) and highest (more than 95th percentile) plasma levels of LDL-C. Of the 17 missense variants identified, R46L (607786.0006; rs11591147), L253F, and A443T were significantly and reproducibly associated with lower plasma levels of LDL-C (reductions ranging from 3.5 to 30%). None of the low LDL-C variants was associated with increased hepatic triglyceride content, as measured by proton magnetic resonance spectroscopy. This finding was considered most consistent with the reduction in LDL-C being caused primarily by accelerating LDL clearance, rather than by reduced lipoprotein production. Association studies with 93 noncoding single-nucleotide polymorphisms (SNPs) at the PCSK9 locus identified 3 SNPs associated with modest differences in plasma LDL-C levels. Thus, a spectrum of sequence variations ranging in frequency (from 0.2 to 34%) and magnitude of effect (from a 3% increase to a 49% decrease) contributed to interindividual differences in LDL-C levels. These findings revealed that PCSK9 activity is a major determinant of plasma levels of LDL-C in humans and made it an attractive therapeutic target for LDL-C lowering. </p><p>Cohen et al. (2006) examined the effect of DNA sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population. Of the 3,363 black subjects examined, 2.6% had nonsense mutations in PCSK9; these mutations were associated with a 28% reduction in mean LDL cholesterol and an 88% reduction in the risk of coronary heart disease (CHD), including myocardial infarction, fatal CHD, or coronary revascularization, over a 15-year period. Of the 9,524 white subjects examined, 3.2% had a sequence variation in PCSK9 that was associated with a 15% reduction in LDL cholesterol and a 47% reduction in the risk of CHD. </p><p>Zhao et al. (2006) showed that 4 severe loss-of-function mutations prevent the secretion of PCSK9 by disrupting synthesis or trafficking of the protein. In contrast to recombinant wildtype PCSK9, which was secreted from cells into the medium within 2 hours, the severe loss-of-function mutations in PCSK9 largely abolished PCSK9 secretion. This finding predicted that circulating levels of PCSK9 would be lower in individuals with the loss-of-function mutations. Immunoprecipitation and immunoblotting of plasma for PCSK9 provided direct evidence that the serine protease is present in the serum and identified the first known individual who had no immunodetectable circulating PCSK9. This healthy, fertile college graduate, who was a compound heterozygote for 2 inactivating mutations in PCSK9 (607786.0007, 607786.0008) had a strikingly low plasma level of LDL cholesterol (14 mg/dL). The very low plasma level of LDL cholesterol and apparent good health of this individual demonstrates that PCSK9 plays a major role in determining plasma levels of LDL cholesterol and provides an attractive target for LDL-lowering therapy. Findings in this patient recapitulate those found in mice with no PCSK9, which show accelerated LDL clearance (Rashid et al., 2005). Evidence suggests that PCSK9 acts to limit the number of LDL receptors at the cell surface. Thus, the PCSK9 mutations associated with hypercholesterolemia are presumably gain-of-function mutations, whereas those reported by Zhao et al. (2006) are loss-of-function mutations. </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, including rs11591147 of PCSK9, had previously been associated with elevated LDL or lower HDL. Kathiresan et al. (2008) replicated the associations with each SNP 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>Mayne et al. (2007) examined the relationship between plasma PCSK9 levels and lipoprotein parameters in 182 normolipidemic individuals and found a correlation between plasma PCSK9 and total cholesterol, LDL cholesterol, and the total cholesterol/HDL cholesterol ratio in men but not in women. Analysis of the PCSK9 gene in 3 individuals with total and LDL cholesterol levels below the fifth percentile revealed compound heterozygosity for known PCSK9 mutations; analysis of family members of 1 proband showed that the ratio of plasma PCSK9/LDLC was increased in men, but not women, carrying loss of function PCSK9 variants. Mayne et al. (2007) suggested that there is a gender difference in PCSK9 regulation and function, with PCSK9 correlated to total and LDL cholesterol in men but not women. </p><p>Teslovich et al. (2010) performed a genomewide association study for plasma lipids in more than 100,000 individuals of European ancestry and reported 95 significantly associated loci (P = less than 5 x 10(-8)), with 59 showing genomewide significant association with lipid traits for the first time. The newly reported associations included SNPs near known lipid regulators as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contributed not only to normal variation in lipid traits but also to extreme lipid phenotypes and had an impact on lipid traits in 3 non-European populations (East Asians, South Asians, and African Americans). Teslovich et al. (2010) identified rs2479409 near the PCSK9 gene as implicated in LDL cholesterol concentrations with an effect size of +2.01 mg per deciliter and a P value of 2 x 10(-28). </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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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</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>Benjannet et al. (2006) found that the hypercholesterolemia-associated gain-of-function PCSK9 mutations R218S, F216L, and D374Y resulted in total or partial loss of processing of mature PCSK9 at the furin cleavage motif RFHR. In contrast, the hypocholesterolemia-associated loss-of-function PCSK9 mutations A443T and C679X resulted in abnormal subcellular localization and enhanced susceptibility to furin cleavage (A443T) or to the inability of PCSK9 to exit the endoplasmic reticulum (C679X). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>To study the function of Pcsk9 in mice, Maxwell and Breslow (2004) used an adenovirus constitutively expressing murine Pcsk9 (Pcsk9-Ad). Pcsk9 overexpression in wildtype mice caused a 2-fold increase in plasma total cholesterol and a 5-fold increase in non-high density lipoprotein (HDL) cholesterol, with no increase in HDL cholesterol, as compared with mice infected with a control adenovirus. The increase in non-HDL cholesterol was shown to be due to an increase in low density lipoprotein (LDL) cholesterol. This effect appeared to depend on the LDL receptor (LDLR; 606945) because Ldlr knockout mice infected with Pcsk9-Ad showed no change in plasma cholesterol levels as compared with knockout mice infected with a control adenovirus. Furthermore, whereas overexpression of Pcsk9 had no effect on Ldlr mRNA levels, there was a near absence of Ldlr protein in animals overexpressing Pcsk9. These and other results indicated that overexpression of PCSK9 interferes with LDLR-mediated LDL cholesterol uptake. Because PCSK9 and LDLR are coordinately regulated by cholesterol, Maxwell and Breslow (2004) suggested that PCSK9 may be involved in a novel mechanism to modulate LDLR function by an alternative pathway than classic cholesterol inhibition of sterol regulatory element binding protein-mediated transcription. </p><p>Rashid et al. (2005) found that the livers of mice lacking Pcsk9 showed increased LDLR protein but not mRNA. Increased LDLR led to increased clearance of circulating lipoproteins and decreased plasma cholesterol levels. Administration of a statin-class drug to Pcsk9-null mice produced an exaggerated increase in LDLRs in liver and enhanced LDL clearance from plasma. </p><p>Lambert et al. (2006) showed that upon dietary challenge, downregulation of Ldlr in mice is a key mechanism whereby Pcsk9 modulates hepatic production of Apob-containing lipoproteins. Overexpression of Pcsk9 in mice promoted hypercholesterolemia and massive hypertriglyceridemia following a 24-hour fast due to dramatically increased hepatic output of very low density lipoprotein (VLDL) and Apob, and both processes required Ldlr. Increased VLDL production was associated with a concomitant reduction of intrahepatic lipid stores and absence of Ppara (170998) downregulation. Experiments with a Ppara agonist confirmed that hepatic expression of Pcsk9 was negatively regulated by Ppara. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>8 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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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 HYPERCHOLESTEROLEMIA, FAMILIAL, 3</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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PCSK9, SER127ARG
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<br />
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SNP: rs28942111,
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ClinVar: RCV000003007, RCV000505185
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 French families with autosomal dominant hypercholesterolemia-3 (FCHL3; 603776), Abifadel et al. (2003) identified a 625T-A transversion in exon 2 of the PCSK9 gene, resulting in a ser127-to-arg (S127R) substitution. </p><p>Kwon et al. (2008) stated that PCSK9 processing and secretion were reduced in PCSK9 containing the S127R mutation, but the affinity of PCSK9 for LDLR was only modestly affected. </p><p>Ouguerram et al. (2004) found that the S127R mutation in 2 related individuals with hypercholesterolemia was associated with increased production of APOB (3-fold) related to overproduction of VLDL (3-fold), intermediate density lipoprotein (IDL) (3-fold), and LDL (5-fold) compared with controls. The 2 individuals also showed a decrease in VLDL and IDL conversion (10 to 30% of controls), and their LDL fractional catabolic rate was slightly decreased (by 30%) compared with controls. </p>
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</span>
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</div>
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<div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 HYPERCHOLESTEROLEMIA, FAMILIAL, 3</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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PCSK9, PHE216LEU
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<br />
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SNP: rs28942112,
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ClinVar: RCV000003008
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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 proband of a family with autosomal dominant hypercholesterolemia-3 (FHCL3; 603776) who died from myocardial infarction at 49 years of age, Abifadel et al. (2003) identified an 890T-C transition in exon 4 of the PCSK9 gene, resulting in a phe216-to-leu (F216L) substitution. </p><p>Kwon et al. (2008) stated that phe216 is located within a disordered loop in PCSK9 and that the F216L mutation reduces proteolytic processing of PCSK9 after arg218. </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>.0003 HYPERCHOLESTEROLEMIA, FAMILIAL, 3</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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PCSK9, ASP374TYR
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<br />
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SNP: rs137852912,
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gnomAD: rs137852912,
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ClinVar: RCV000003009, RCV000505195, RCV004017221, RCV004018541
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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 large Utah pedigree (K1173) segregating hypercholesterolemia (FHCL3; 603776), originally described by Haddad et al. (1999), Hunt et al. (2000) found linkage of the disorder to chromosome 1p32. By mutation screening of genes in this region, Timms et al. (2004) identified a G-to-T transversion in the PCSK9 gene, resulting in an asp374-to-tyr (D374Y) substitution. </p><p>Sun et al. (2005) identified the D374Y mutation in 3 families of English origin with hypercholesterolemia; all 12 affected individuals had unusually severe hypercholesterolaemia and required more stringent treatment than FH patients with heterozygous LDLR mutations. In stably transfected rat hepatoma cells, both mutant and wildtype PCSK9 colocalized with protein disulfide isomerase in the ER. Expression of D374Y-mutant PCSK9 increased secretion of apolipoprotein B100 (107730)-containing lipoproteins by 2- to 4-fold compared to wildtype, but no significant difference in LDLR content was observed in any transfected cell line. Sun et al. (2005) suggested that pathogenic variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers. </p><p>Kwon et al. (2008) found that the D374Y mutation increased the affinity of mutant PCSK9 for LDLR compared with wildtype PCSK9. </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>.0004 LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 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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PCSK9, TYR142TER
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<br />
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SNP: rs67608943,
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gnomAD: rs67608943,
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ClinVar: RCV000003010, RCV000588335, RCV001097394, RCV001191121, RCV001731276, RCV004658956
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 of 64 African American subjects with low plasma levels of low density lipoprotein cholesterol (LDLCQ1; see 603776), Cohen et al. (2005) identified a 426C-G transversion in exon 3 of the PCSK9 gene, resulting in a tyr142-to-ter mutation (Y142X). This mutation was predicted to delete the last four-fifths of the protein. The authors hypothesized that the Y142X mutation would induce nonsense-mediated mRNA decay. This is one of the sequence variations found by Cohen et al. (2006) to be associated with protection against coronary heart disease in black participants in a longitudinal study. </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>.0005 LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 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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PCSK9, CYS679TER
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<br />
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SNP: rs28362286,
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gnomAD: rs28362286,
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ClinVar: RCV000003011, RCV000508694, RCV000531428, RCV000771132, RCV001508868, RCV001731277, RCV004649062, RCV004734496
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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 4 of 64 African American subjects with low plasma levels of LDL cholesterol (LDLCQ1; see 603776), Cohen et al. (2005) found a 2037C-A transversion in the PCSK9 gene that was predicted to truncate the protein by 14 amino acids (cys679 to ter; C679X). Among 549 Nigerians from a Yoruba-speaking rural community, they found a frequency of the 2037A allele of 1.4%, which was similar to the frequencies observed in 2 African American populations. This is one of the sequence variations found by Cohen et al. (2006) to be associated with protection against coronary heart disease in black participants in a longitudinal study. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 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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PCSK9, ARG46LEU ({dbSNP rs11591147})
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<br />
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SNP: rs11591147,
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gnomAD: rs11591147,
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ClinVar: RCV000003012, RCV000203182, RCV000256313, RCV000508774, RCV000605465, RCV000985896, RCV001099060, RCV001523785, RCV002381236
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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>Cohen et al. (2006) found that the arg46-to-leu (R46L) substitution (rs11591147) in white subjects in a longitudinal study was associated with significant reduction in plasma levels of total cholesterol (9%) and LDL cholesterol (15%) (see 603776). Cohen et al. (2006) found that persons who were heterozygous or homozygous for PCSK9(46L) had a 47% reduction in the rate of coronary events (6.3% vs 11.8%). </p><p>Kathiresan (2008) reported a significant association between the R46L variant and decreased risk of early-onset myocardial infarction in a study of 1,454 patients from 5 different study sites (metaanalysis odds ratio of 0.40; p = 2.0 x 10(-5)). The R46L allele frequency in 1,617 controls was 2.4%. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 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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PCSK9, TYR142TER
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<br />
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SNP: rs67608943,
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gnomAD: rs67608943,
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ClinVar: RCV000003010, RCV000588335, RCV001097394, RCV001191121, RCV001731276, RCV004658956
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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>Zhao et al. (2006) identified the first known individual with no immunodetectable circulating PCSK9. This healthy, fertile college graduate was found to be a compound heterozygote for 2 inactivating mutations in PCSK9, a tyr142-to-stop substitution on the maternal allele (Y142X) that disrupted synthesis of the protein, and a 3-bp deletion on the paternal allele (607786.0008). She had a strikingly low plasma level of LDL cholesterol (14 mg/dL) (see 603776). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0008 LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 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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PCSK9, 3-BP DEL, 290GCC
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<br />
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SNP: rs587776545,
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ClinVar: RCV000003014, RCV003996076
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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 patient with no immunodetectable circulating PCSK9 reported by Zhao et al. (2006) carried a 3-bp deletion (290_292delGCC) on the paternal allele of her PCSK9 gene that removed an arginine at codon 97 (see 603776). Expression of the mutant protein in HEK293 cells demonstrated that the mutation prevents autocatalytic cleavage and secretion of PCSK9. The maternal allele carried a premature termination mutation (607786.0007). </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>REFERENCES</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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<ol>
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<li>
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<p class="mim-text-font">
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Abifadel, M., Varret, M., Rabes, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., Derre, A., Villeger, L., and 14 others.
|
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<strong>Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.</strong>
|
|
Nature Genet. 34: 154-156, 2003.
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[PubMed: 12730697]
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[Full Text: https://doi.org/10.1038/ng1161]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Benjannet, S., Rhainds, D., Hamelin, J., Nassoury, N., Seidah, N. G.
|
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<strong>The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.</strong>
|
|
J. Biol. Chem. 281: 30561-30572, 2006.
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[PubMed: 16912035]
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[Full Text: https://doi.org/10.1074/jbc.M606495200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cohen, J. C., Boerwinkle, E., Mosley, T. H., Jr., Hobbs, H. H.
|
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<strong>Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.</strong>
|
|
New Eng. J. Med. 354: 1264-1272, 2006.
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[PubMed: 16554528]
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[Full Text: https://doi.org/10.1056/NEJMoa054013]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., Hobbs, H. H.
|
|
<strong>Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.</strong>
|
|
Nature Genet. 37: 161-165, 2005. Note: Erratum: Nature Genet. 37: 328 only, 2005.
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[PubMed: 15654334]
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[Full Text: https://doi.org/10.1038/ng1509]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Haddad, L., Day, I. N. M., Hunt, S., Williams, R. R., Humphries, S. E., Hopkins, P. N.
|
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<strong>Evidence for a third genetic locus causing familial hypercholesterolemia: a non-LDLR, non-APOB kindred.</strong>
|
|
J. Lipid Res. 40: 1113-1122, 1999.
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[PubMed: 10357843]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hunt, S. C., Hopkins, P. N., Bulka, K., McDermott, M. T., Thorne, T. L., Wardell, B. B., Bowen, B. R., Ballinger, D. G., Skolnick, M. H., Samuels, M. E.
|
|
<strong>Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred.</strong>
|
|
Arterioscler. Thromb. Vasc. Biol. 20: 1089-1093, 2000.
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[PubMed: 10764678]
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[Full Text: https://doi.org/10.1161/01.atv.20.4.1089]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
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.
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|
|
[PubMed: 18354102]
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[Full Text: https://doi.org/10.1056/NEJMoa0706728]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kathiresan, S.
|
|
<strong>A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. (Letter)</strong>
|
|
New Eng. J. Med. 358: 2299-2300, 2008.
|
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[PubMed: 18499582]
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[Full Text: https://doi.org/10.1056/NEJMc0707445]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kotowski, I. K., Pertsemlidis, A., Luke, A., Cooper, R. S., Vega, G. L., Cohen, J. C., Hobbs, H. H.
|
|
<strong>A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol.</strong>
|
|
Am. J. Hum. Genet. 78: 410-422, 2006.
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|
|
[PubMed: 16465619]
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[Full Text: https://doi.org/10.1086/500615]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kwon, H. J., Lagace, T. A., McNutt, M. C., Horton, J. D., Deisenhofer, J.
|
|
<strong>Molecular basis for LDL receptor recognition by PCSK9.</strong>
|
|
Proc. Nat. Acad. Sci. 105: 1820-1825, 2008.
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|
[PubMed: 18250299]
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[Full Text: https://doi.org/10.1073/pnas.0712064105]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lambert, G., Jarnoux, A.-L., Pineau, T., Pape, O., Chetiveaux, M., Laboisse, C., Krempf, M., Costet, P.
|
|
<strong>Fasting induces hyperlipidemia in mice overexpressing proprotein convertase subtilisin kexin type 9: lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor.</strong>
|
|
Endocrinology 147: 4985-4995, 2006.
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|
|
[PubMed: 16794006]
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[Full Text: https://doi.org/10.1210/en.2006-0098]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Maxwell, K. N., Breslow, J. L.
|
|
<strong>Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype.</strong>
|
|
Proc. Nat. Acad. Sci. 101: 7100-7105, 2004.
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[PubMed: 15118091]
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[Full Text: https://doi.org/10.1073/pnas.0402133101]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Maxwell, K. N., Fisher, E. A., Breslow, J. L.
|
|
<strong>Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.</strong>
|
|
Proc. Nat. Acad. Sci. 102: 2069-2074, 2005.
|
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|
|
[PubMed: 15677715]
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[Full Text: https://doi.org/10.1073/pnas.0409736102]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Mayne, J., Raymond, A., Chaplin, A., Cousins, M., Kaefer, N., Gyamera-Acheampong, C., Seidah, N. G., Mbikay, M., Chretien, M., Ooi, T. C.
|
|
<strong>Plasma PCSK9 levels correlate with cholesterol in men but not in women.</strong>
|
|
Biochem. Biophys. Res. Commun. 361: 451-456, 2007.
|
|
|
|
|
|
[PubMed: 17645871]
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[Full Text: https://doi.org/10.1016/j.bbrc.2007.07.029]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ouguerram, K., Chetiveaux, M., Zair, Y., Costet, P., Abifadel, M., Varret, M., Boileau, C., Magot, T., Krempf, M.
|
|
<strong>Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9.</strong>
|
|
Arterioscler. Thromb. Vasc. Biol. 24: 1448-1453, 2004.
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|
|
[PubMed: 15166014]
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|
[Full Text: https://doi.org/10.1161/01.ATV.0000133684.77013.88]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Park, S. W., Moon, Y.-A., Horton, J. D.
|
|
<strong>Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver.</strong>
|
|
J. Biol. Chem. 279: 50630-50638, 2004.
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|
|
[PubMed: 15385538]
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[Full Text: https://doi.org/10.1074/jbc.M410077200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Rashid, S., Curtis, D. E., Garuti, R., Anderson, N. N., Bashmakov, Y., Ho, Y. K., Hammer, R. E., Moon, Y.-A., Horton, J. D.
|
|
<strong>Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.</strong>
|
|
Proc. Nat. Acad. Sci. 102: 5374-5379, 2005.
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|
|
[PubMed: 15805190]
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[Full Text: https://doi.org/10.1073/pnas.0501652102]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Schmidt, R. J., Beyer, T. P., Bensch, W. R., Qian, Y.-W., Lin, A., Kowala, M., Alborn, W. E., Konrad, R. J., Cao, G.
|
|
<strong>Secreted proprotein convertase subtilisin/kexin type 9 reduces both hepatic and extrahepatic low-density lipoprotein receptors in vivo.</strong>
|
|
Biochem. Biophys. Res. Commun. 370: 634-640, 2008.
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|
|
[PubMed: 18406350]
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[Full Text: https://doi.org/10.1016/j.bbrc.2008.04.004]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Seidah, N. G., Benjannet, S., Wickham, L., Marcinkiewicz, J., Jasmin, S. B., Stifani, S., Basak, A., Prat, A., Chretien, M.
|
|
<strong>The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.</strong>
|
|
Proc. Nat. Acad. Sci. 100: 928-933, 2003.
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|
[PubMed: 12552133]
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[Full Text: https://doi.org/10.1073/pnas.0335507100]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Shioji, K., Mannami, T., Kokubo, Y., Inamoto, N., Takagi, S., Goto, Y., Nonogi, H., Iwai, N.
|
|
<strong>Genetic variants in PCSK9 affect the cholesterol level in Japanese.</strong>
|
|
J. Hum. Genet. 49: 109-114, 2004.
|
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|
|
|
[PubMed: 14727156]
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|
|
[Full Text: https://doi.org/10.1007/s10038-003-0114-3]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Sun, X.-M., Eden, E. R., Tosi, I., Neuwirth, C. K., Wile, D., Naoumova, R. P., Soutar, A. K.
|
|
<strong>Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia.</strong>
|
|
Hum. Molec. Genet. 14: 1161-1169, 2005.
|
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|
|
[PubMed: 15772090]
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[Full Text: https://doi.org/10.1093/hmg/ddi128]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
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.
|
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|
|
[PubMed: 20686565]
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[Full Text: https://doi.org/10.1038/nature09270]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Timms, K. M., Wagner, S., Samuels, M. E., Forbey, K., Goldfine, H., Jammulapati, S., Skolnick, M. H., Hopkins, P. N., Hunt, S. C., Shattuck, D. M.
|
|
<strong>A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree.</strong>
|
|
Hum. Genet. 114: 349-353, 2004.
|
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|
|
[PubMed: 14727179]
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[Full Text: https://doi.org/10.1007/s00439-003-1071-9]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
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Varret, M., Rabes, J.-P., Saint-Jore, B., Cenarro, A., Marinoni, J.-C., Civeira, F., Devillers, M., Krempf, M., Coulon, M., Thiart, R., Kotze, M. J., Schmidt, H., and 9 others.
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<strong>A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32.</strong>
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Am. J. Hum. Genet. 64: 1378-1387, 1999.
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[PubMed: 10205269]
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[Full Text: https://doi.org/10.1086/302370]
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Zhao, Z., Tuakli-Wosornu, Y., Lagace, T. A., Kinch, L., Grishin, N. V., Horton, J. D., Cohen, J. C., Hobbs, H. H.
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<strong>Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.</strong>
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Am. J. Hum. Genet. 79: 514-523, 2006.
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[PubMed: 16909389]
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[Full Text: https://doi.org/10.1086/507488]
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Ada Hamosh - updated : 9/27/2010<br>Patricia A. Hartz - updated : 12/31/2008<br>Marla J. F. O'Neill - updated : 12/23/2008<br>Patricia A. Hartz - updated : 8/18/2008<br>Cassandra L. Kniffin - updated : 5/23/2008<br>George E. Tiller - updated : 5/19/2008<br>Ada Hamosh - updated : 4/1/2008<br>Victor A. McKusick - updated : 8/23/2006<br>Victor A. McKusick - updated : 3/29/2006<br>Victor A. McKusick - updated : 2/21/2006<br>Patricia A. Hartz - updated : 6/30/2005<br>Patricia A. Hartz - updated : 6/8/2005<br>Victor A. McKusick - updated : 2/4/2005<br>Victor A. McKusick - updated : 5/18/2004<br>Victor A. McKusick - updated : 4/2/2004<br>Marla J. F. O'Neill - updated : 3/16/2004
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Victor A. McKusick : 5/14/2003
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