4131 lines
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Entry
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- *605747 - LOW DENSITY LIPOPROTEIN RECEPTOR ADAPTOR PROTEIN 1; LDLRAP1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*605747</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</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="#geneFunction">Gene Function</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="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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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/605747">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000157978;t=ENST00000374338" 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=26119" 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=605747" 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=ENSG00000157978;t=ENST00000374338" 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_015627,XM_006710559,XM_006710560,XM_006710561,XM_011541209,XM_011541210,XM_011541211,XM_011541212,XM_017000994,XM_017000995,XM_024446315,XM_047417473,XM_047417482,XM_047417497,XR_007058621,XR_946603" 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_015627" 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=605747" 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=05765&isoform_id=05765_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/LDLRAP1" 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/10436776,37256045,57997045,116241254,119628277,119628278,119628279,119628280,127796563,132626790,193787103,578798896,578798898,578798900,767903666,767903670,767903673,767903676,1034557621,1034557632,1370452769,2217266359,2217266362,2217266372,2462507718,2462507720,2462507722,2462507724,2462507726,2462507729,2462507731,2462507733,2462507735,2462507737,2462507739,2462507741,2462507744" 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/Q5SW96" 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=26119" 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=ENSG00000157978;t=ENST00000374338" 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=LDLRAP1" 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=LDLRAP1" 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+26119" 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/LDLRAP1" 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:26119" 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/26119" 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=ENST00000374338.5&hgg_start=25543606&hgg_end=25590400&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/genes/HGNC:18640" 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/ldlrap1" 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=605747[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=605747[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/ENSG00000157978" 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=LDLRAP1" 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=LDLRAP1" 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=LDLRAP1" 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/Current/index.php?select_db=LDLRAP1" 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=LDLRAP1&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/PA128394641" 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:18640" 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:2140175" 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/LDLRAP1#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:2140175" 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/26119/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://www.orthodb.org/?ncbi=26119" 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-030328-13" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:605747" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:26119" 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=LDLRAP1&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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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
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605747
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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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LOW DENSITY LIPOPROTEIN RECEPTOR ADAPTOR PROTEIN 1; LDLRAP1
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
LDLR ADAPTOR PROTEIN 1<br />
|
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ARH GENE; ARH
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=LDLRAP1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">LDLRAP1</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/1/301?start=-3&limit=10&highlight=301">1p36.11</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:25543606-25590400&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'})">1:25,543,606-25,590,400</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</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>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/301?start=-3&limit=10&highlight=301">
|
|
1p36.11
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Hypercholesterolemia, familial, 4
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/603813"> 603813 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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>
|
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</td>
|
|
|
|
|
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</tr>
|
|
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|
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</tbody>
|
|
</table>
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<p>LDLRAP1 is an adaptor protein that interacts with the cytoplasmic tail of low density lipoprotein receptor (LDLR; <a href="/entry/606945">606945</a>), phospholipids, and components of the clathrin (see CLTC; <a href="/entry/118955">118955</a>) endocytic machinery (<a href="#6" class="mim-tip-reference" title="Garuti, R., Jones, C., Li, W.-P., Michaely, P., Herz, J., Gerard, R. D., Cohen, J. C., Hobbs, H. H. <strong>The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits.</strong> J. Biol. Chem. 280: 40996-41004, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16179341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16179341</a>] [<a href="https://doi.org/10.1074/jbc.M509394200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16179341">Garuti et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16179341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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="#5" class="mim-tip-reference" title="Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong> Science 292: 1394-1398, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326085</a>] [<a href="https://doi.org/10.1126/science.1060458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11326085">Garcia et al. (2001)</a> cloned the ARH gene after performing linkage analysis in families suffering from autosomal recessive hypercholesterolemia (ARH; <a href="/entry/603813">603813</a>) that mapped the ARH locus to a 1-cM interval on chromosome 1p35. The gene encodes a 308-amino acid protein containing a 170-amino acid phosphotyrosine-binding (PTB) domain, which shares considerable sequence similarity with the PTB domains of many adaptor proteins. PTB domains bind the consensus sequence NPXY, which is present in the cytoplasmic domains of several cell surface receptors, including LDLR. The integrity of the NPXY sequence in the cytoplasmic tail of LDLR is absolutely required for internalization, and LDLR has been shown in vitro to bind other proteins containing PTB domains. The human ARH protein shares 89% sequence identity with orthologous proteins in mouse and Xenopus. By Northern blot analysis, <a href="#5" class="mim-tip-reference" title="Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong> Science 292: 1394-1398, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326085</a>] [<a href="https://doi.org/10.1126/science.1060458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11326085">Garcia et al. (2001)</a> found that ARH is normally expressed at high levels in the kidney, liver, and placenta, with lower levels detectable in brain, heart, muscle, colon, spleen, intestine, lung, and leukocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11326085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Nagai, M., Meerloo, T., Takeda, T., Farquhar, M. G. <strong>The adaptor protein ARH escorts megalin to and through endosomes.</strong> Molec. Biol. Cell 14: 4984-4996, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14528014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14528014</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14528014[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1091/mbc.e03-06-0385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14528014">Nagai et al. (2003)</a> reported that the N-terminal half of human, rat, and mouse ARH contains the PTB domain, and the C-terminal half contains a clathrin box (LLDLE), a beta-2 adaptin (AP2B1; <a href="/entry/601025">601025</a>)-binding site, and a C-terminal PDZ-binding motif. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14528014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using yeast 2-hybrid, pull-down, and coimmunoprecipitation assays, <a href="#13" class="mim-tip-reference" title="Nagai, M., Meerloo, T., Takeda, T., Farquhar, M. G. <strong>The adaptor protein ARH escorts megalin to and through endosomes.</strong> Molec. Biol. Cell 14: 4984-4996, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14528014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14528014</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14528014[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1091/mbc.e03-06-0385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14528014">Nagai et al. (2003)</a> found that rat Arh bound the first FxNPxY motif of megalin (LRP2; <a href="/entry/600073">600073</a>). Arh colocalized with megalin in clathrin-coated pits and in recycling endosomes in the Golgi region of rat L2 cells. Upon internalization of megalin, megalin and Arh colocalized in clathrin-coated pits, followed by their colocalization in early endosomes and tubular recycling endosomes in the pericentriolar region, and then by their reappearance at the cell surface. Expression of Arh in canine kidney cells expressing megalin minireceptors enhanced megalin-mediated uptake of lactoferrin (LTF; <a href="/entry/150210">150210</a>), a megalin ligand. <a href="#13" class="mim-tip-reference" title="Nagai, M., Meerloo, T., Takeda, T., Farquhar, M. G. <strong>The adaptor protein ARH escorts megalin to and through endosomes.</strong> Molec. Biol. Cell 14: 4984-4996, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14528014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14528014</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14528014[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1091/mbc.e03-06-0385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14528014">Nagai et al. (2003)</a> concluded that ARH facilitates endocytosis of megalin and escorts megalin along its endocytic route. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14528014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 biochemical assays and electron microscopy, <a href="#11" class="mim-tip-reference" title="Michaely, P., Li, W.-P., Anderson, R. G. W., Cohen, J. C., Hobbs, H. H. <strong>The molecular adaptor protein ARH is required for low density lipoprotein (LDL) binding and internalization but not for LDL receptor clustering in coated pits.</strong> J. Biol. Chem. 279: 34023-34031, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15166224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15166224</a>] [<a href="https://doi.org/10.1074/jbc.M405242200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15166224">Michaely et al. (2004)</a> found that lymphocytes from patients with ARH deficiency had over 20-fold more LDLR on the cell surface and about 27-fold excess of LDLR outside of coated pits. However, despite the increase in cell surface receptors, LDL binding was only 2-fold higher in ARH-deficient lymphocytes. <a href="#11" class="mim-tip-reference" title="Michaely, P., Li, W.-P., Anderson, R. G. W., Cohen, J. C., Hobbs, H. H. <strong>The molecular adaptor protein ARH is required for low density lipoprotein (LDL) binding and internalization but not for LDL receptor clustering in coated pits.</strong> J. Biol. Chem. 279: 34023-34031, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15166224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15166224</a>] [<a href="https://doi.org/10.1074/jbc.M405242200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15166224">Michaely et al. (2004)</a> concluded that ARH is not only required for internalization of the LDL-LDLR complex, but also for efficient binding of LDL to the receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15166224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 analysis, <a href="#6" class="mim-tip-reference" title="Garuti, R., Jones, C., Li, W.-P., Michaely, P., Herz, J., Gerard, R. D., Cohen, J. C., Hobbs, H. H. <strong>The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits.</strong> J. Biol. Chem. 280: 40996-41004, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16179341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16179341</a>] [<a href="https://doi.org/10.1074/jbc.M509394200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16179341">Garuti et al. (2005)</a> found that integrity of the FDNPVY sequence in LDLR was required for ARH-associated LDLR clustering into clathrin-coated pits in polarized hepatocytes. The phosphotyrosine-binding domain of ARH plus either the clathrin box or the AP2-binding region was required for LDLR clustering and internalization. These findings were confirmed in vivo by expressing the same ARH mutants in livers of Arh -/- mice. <a href="#6" class="mim-tip-reference" title="Garuti, R., Jones, C., Li, W.-P., Michaely, P., Herz, J., Gerard, R. D., Cohen, J. C., Hobbs, H. H. <strong>The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits.</strong> J. Biol. Chem. 280: 40996-41004, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16179341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16179341</a>] [<a href="https://doi.org/10.1074/jbc.M509394200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16179341">Garuti et al. (2005)</a> concluded that ARH must bind the LDLR tail and either clathrin or AP2 to promote receptor clustering and internalization of LDL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16179341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Sirinian, M. I., Belleudi, F., Campagna, F., Ceridono, M., Garofalo, T., Quagliarini, F., Verna, R., Calandra, S., Bertolini, S., Sorice, M., Torrisi, M. R., Arca, M. <strong>Adaptor protein ARH is recruited to the plasma membrane by low density lipoprotein (LDL) binding and modulates endocytosis of the LDL/LDL receptor complex in hepatocytes.</strong> J. Biol. Chem. 280: 38416-38423, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16129683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16129683</a>] [<a href="https://doi.org/10.1074/jbc.M504343200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16129683">Sirinian et al. (2005)</a> found that ARH codistributed with LDLR on the basolateral surface of polarized confluent HepG2 cells. Activation of LDLR-mediated endocytosis, but not binding of LDL to LDLR, promoted colocalization of ARH with the LDL-LDLR complex. Depletion of ARH by more than 70% by RNA interference caused an 80% reduction in LDL internalization. Coimmunoprecipitation analysis of LDL-stimulated polarized HepG2 cells showed that ARH interacted with other components of the endocytic machinery, including beta-adaptin, DAB2 (<a href="/entry/601236">601236</a>), and the small GTPase RAB4 (<a href="/entry/179511">179511</a>). <a href="#15" class="mim-tip-reference" title="Sirinian, M. I., Belleudi, F., Campagna, F., Ceridono, M., Garofalo, T., Quagliarini, F., Verna, R., Calandra, S., Bertolini, S., Sorice, M., Torrisi, M. R., Arca, M. <strong>Adaptor protein ARH is recruited to the plasma membrane by low density lipoprotein (LDL) binding and modulates endocytosis of the LDL/LDL receptor complex in hepatocytes.</strong> J. Biol. Chem. 280: 38416-38423, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16129683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16129683</a>] [<a href="https://doi.org/10.1074/jbc.M504343200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16129683">Sirinian et al. (2005)</a> concluded that ARH is not constitutively associated with LDLR at the plasma membrane, but is recruited to the membrane after LDL binding, thus facilitating endocytosis of the LDL-LDLR complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16129683" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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="#5" class="mim-tip-reference" title="Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong> Science 292: 1394-1398, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326085</a>] [<a href="https://doi.org/10.1126/science.1060458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11326085">Garcia et al. (2001)</a> determined that the ARH gene spans 25 kb and contains 9 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11326085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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="#5" class="mim-tip-reference" title="Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong> Science 292: 1394-1398, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326085</a>] [<a href="https://doi.org/10.1126/science.1060458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11326085">Garcia et al. (2001)</a> mapped the ARH gene to chromosome 1p35. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11326085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 6 families with autosomal recessive hypercholesterolemia-4 (FCHL4; <a href="/entry/603813">603813</a>), including 2 Sardinian, 2 Lebanese, 1 Iranian, and 1 American family, <a href="#5" class="mim-tip-reference" title="Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong> Science 292: 1394-1398, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326085</a>] [<a href="https://doi.org/10.1126/science.1060458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11326085">Garcia et al. (2001)</a> identified homozygosity for 6 different mutations in the LDLRAP1 gene (<a href="#0001">605747.0001</a>-<a href="#0006">605747.0006</a>). A nonsense mutation (Q136X; <a href="#0003">605747.0003</a>) was identified in 1 of the Lebanese families; only trace amounts of ARH mRNA was detected in cultured fibroblasts from patients with this mutation. The other Lebanese family was homozygous for a missense mutation (P202H; <a href="#0004">605747.0004</a>) that was associated with a normal level of ARH mRNA in cultured fibroblasts. <a href="#5" class="mim-tip-reference" title="Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong> Science 292: 1394-1398, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326085</a>] [<a href="https://doi.org/10.1126/science.1060458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11326085">Garcia et al. (2001)</a> found that the defect in LDLR function in ARH patients appeared to be not only receptor-specific, but also tissue-specific. They were not able to identify a consistent defect in LDLR function (binding, uptake, or internalization) in cultured fibroblasts from ARH patients. It is possible that another PTB domain protein compensates for the absence of ARH in cultured fibroblasts, or that adaptor molecules are not required for receptor-mediated endocytosis of LDL in fibroblasts and possibly other extrahepatic cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11326085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Arca, M., Zuliani, G., Wilund, K., Campagna, F., Fellin, R., Bertolini, S., Calandra, S., Ricci, G., Glorioso, N., Maioli, M., Pintus, P., Carru, C., Cossu, F., Cohen, J., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis.</strong> Lancet 359: 841-847, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11897284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11897284</a>] [<a href="https://doi.org/10.1016/S0140-6736(02)07955-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11897284">Arca et al. (2002)</a> performed extensive clinical and molecular genetic studies in 28 Sardinians with autosomal recessive hypercholesterolemia from 17 unrelated families. They sequenced the coding regions and consensus splice sites of the ARH gene in probands from these families, and from 40 individuals of non-Sardinian origin who had an autosomal recessive form of hypercholesterolemia of unknown cause. In all 17 unrelated Sardinian families, 2 ARH mutations were present, 432insA in exon 4 (<a href="#0002">605747.0002</a>), referred to as ARH1 by them, and a nonsense mutation, 65G-A in exon 1 (trp22 to ter; <a href="#0001">605747.0001</a>), referred to as ARH2 by them. Three of the ARH alleles in the Sardinian patients contained both mutations, as a result of an ancient recombination between ARH1 and ARH2. No regional clustering of the 3 mutant alleles was apparent. Furthermore, 4 Italians from the mainland with autosomal recessive hypercholesterolemia were homozygous for ARH1. The small number, high frequency, and dispersed distribution of ARH mutations on Sardinia were consistent with these mutations being ancient and maintained in the Sardinian population because of geographic isolation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11897284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Mishra, S. K., Watkins, S. C., Traub, L. M. <strong>The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery.</strong> Proc. Nat. Acad. Sci. 99: 16099-16104, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12451172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12451172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12451172[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.252630799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12451172">Mishra et al. (2002)</a> showed that the ARH protein is a component of the endocytic machinery, with mutations of the ARH gene contributing to the LDL-uptake-disease phenotype of ARH patients. PTB domains of the ARH protein bind to the internalization motif of the LDL receptor. The authors showed that in addition, ARH binds directly to soluble clathrin trimers and to clathrin adaptors. At steady state, ARH colocalizes with endocytic proteins in HeLa cells, and the LDL receptor fluxes through peripheral ARH-positive sites before delivery to early endosomes. Their findings suggested that in ARH patients, defective sorting adaptor function in hepatocytes leads to faulty LDL receptor traffic and hypercholesterolemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12451172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To define the molecular mechanism underlying autosomal recessive hypercholesterolemia, <a href="#16" class="mim-tip-reference" title="Wilund, K. R., Yi, M., Campagna, F., Arca, M., Zuliani, G., Fellin, R., Ho, Y.-K., Garcia, J. V., Hobbs, H. H., Cohen, J. C. <strong>Molecular mechanisms of autosomal recessive hypercholesterolemia.</strong> Hum. Molec. Genet. 11: 3019-3030, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417523</a>] [<a href="https://doi.org/10.1093/hmg/11.24.3019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12417523">Wilund et al. (2002)</a> examined ARH mRNA and protein in fibroblasts and lymphocytes from 6 hypercholesterolemic patients with different ARH mutations. Five probands were homozygous for mutations that introduced premature termination codons; the sixth patient was homozygous for a 2.6-kb insertion in intron 1 which was associated with no detectable ARH mRNA. None of the probands had detectable full-length ARH protein in fibroblasts or lymphoblasts. No relationship was apparent between the site of the mutation in ARH and the amount of mRNA. Radiolabeled LDL degradation was normal in ARH fibroblasts, but LDLR function was markedly reduced in ARH lymphoblasts, despite a 2-fold increase in LDL cell surface binding in these cells. <a href="#16" class="mim-tip-reference" title="Wilund, K. R., Yi, M., Campagna, F., Arca, M., Zuliani, G., Fellin, R., Ho, Y.-K., Garcia, J. V., Hobbs, H. H., Cohen, J. C. <strong>Molecular mechanisms of autosomal recessive hypercholesterolemia.</strong> Hum. Molec. Genet. 11: 3019-3030, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417523</a>] [<a href="https://doi.org/10.1093/hmg/11.24.3019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12417523">Wilund et al. (2002)</a> concluded that ARH is required for normal LDLR function in lymphocytes and hepatocytes, but not in fibroblasts, and that residual LDLR function in cells that do not require ARH may explain why ARH patients have lower plasma LDL levels than do patients with homozygous familial hypercholesterolemia (<a href="/entry/144010">144010</a>) who have no functional LDLRs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12417523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Al-Kateb, H., Bahring, S., Hoffmann, K., Strauch, K., Busjahn, A., Nurnberg, G., Jouma, M., Bautz, E. K. F., Dresel, H. A., Luft, F. C. <strong>Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.</strong> Circ. Res. 90: 951-958, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12016260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12016260</a>] [<a href="https://doi.org/10.1161/01.res.0000018002.43041.08" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12016260">Al-Kateb et al. (2002)</a> studied a Syrian family in which 3 sibs had elevated LDL levels; 3 other sibs and both parents had normal LDL levels, suggesting an autosomal recessive mode of inheritance. A genomewide scan using 427 markers showed support for linkage on both chromosomes 1 and 13, with significant lod scores at 1p36.1-p35 and 13q22-q32 (see cholesterol-lowering factor, <a href="/entry/604595">604595</a>). <a href="#1" class="mim-tip-reference" title="Al-Kateb, H., Bahring, S., Hoffmann, K., Strauch, K., Busjahn, A., Nurnberg, G., Jouma, M., Bautz, E. K. F., Dresel, H. A., Luft, F. C. <strong>Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.</strong> Circ. Res. 90: 951-958, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12016260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12016260</a>] [<a href="https://doi.org/10.1161/01.res.0000018002.43041.08" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12016260">Al-Kateb et al. (2002)</a> found evidence for an interaction between these loci. They identified an intron 1 acceptor splice site mutation in the ARH gene (<a href="#0007">605747.0007</a>) in homozygous state in the affected sibs and in heterozygous state in the parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12016260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 affected sibs from a nonconsanguineous Mexican family with autosomal recessive hypercholesterolemia, <a href="#4" class="mim-tip-reference" title="Canizales-Quinteros, S., Aguilar-Salinas, C. A., Huertas-Vasquez, A., Ordonez-Sanchez, M. L., Rodriguez-Torres, M., Venturas-Gallegos, J. L., Riba, L., Ramirez-Jimenez, S., Salas-Montiel, R., Medina-Palacios, G., Robles-Osorio, L., Miliar-Garcia, A., Rosales-Leon, L., Ruiz-Ordaz, B. H., Zentella-Dehesa, A., Ferre-D'Amare, A., Gomez-Perez, F. J., Tusie-Luna, M. T. <strong>A novel ARH splice site mutation in a Mexican kindred with autosomal recessive hypercholesterolemia.</strong> Hum. Genet. 116: 114-120, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15599766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15599766</a>] [<a href="https://doi.org/10.1007/s00439-004-1192-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15599766">Canizales-Quinteros et al. (2005)</a> identified homozygosity for a donor splice site mutation in intron 4 of the ARH gene (<a href="#0008">605747.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15599766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Jones, C., Hammer, R. E., Li, W.-P., Cohen, J. C., Hobbs, H. H., Herz, J. <strong>Normal sorting but defective endocytosis of the low density lipoprotein receptor in mice with autosomal recessive hypercholesterolemia.</strong> J. Biol. Chem. 278: 29024-29030, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12746448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12746448</a>] [<a href="https://doi.org/10.1074/jbc.M304855200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12746448">Jones et al. (2003)</a> generated Arh-deficient mice and found that the fractional clearance rate of radiolabeled Ldl in these mice was lower than that in Ldlr -/- mice. By immunolocalization studies, they demonstrated that Ldl receptors are sorted normally to the sinusoidal surface in Arh -/- mouse livers. <a href="#9" class="mim-tip-reference" title="Jones, C., Hammer, R. E., Li, W.-P., Cohen, J. C., Hobbs, H. H., Herz, J. <strong>Normal sorting but defective endocytosis of the low density lipoprotein receptor in mice with autosomal recessive hypercholesterolemia.</strong> J. Biol. Chem. 278: 29024-29030, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12746448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12746448</a>] [<a href="https://doi.org/10.1074/jbc.M304855200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12746448">Jones et al. (2003)</a> concluded that the Ldl internalization defect in Arh-deficient mice is caused by the inability of the receptors to enter the endocytic cycle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12746448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Jones, C., Garuti, R., Michaely, P., Li, W.-P., Maeda, N., Cohen, J. C., Herz, J., Hobbs, H. H. <strong>Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia.</strong> J. Clin. Invest. 117: 165-174, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200716</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200716[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI29415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200716">Jones et al. (2007)</a> examined the synthesis and catabolism of Vldl in mouse models of autosomal dominant familial hypercholesterolemia (Ldlr -/-) and ARH (Arh -/-). Despite similar rates of Vldl secretion in response to a high-sucrose diet, the rate of Vldl clearance was significantly higher in Arh-null mice than in Ldlr-null mice, suggesting that LDLR-dependent uptake of VLDL is maintained in the absence of ARH. Hepatocytes from Arh-null mice, but not Ldlr-null mice, internalized beta-Vldl, demonstrating that ARH is not required for LDLR-dependent uptake of VLDL by the liver. <a href="#8" class="mim-tip-reference" title="Jones, C., Garuti, R., Michaely, P., Li, W.-P., Maeda, N., Cohen, J. C., Herz, J., Hobbs, H. H. <strong>Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia.</strong> J. Clin. Invest. 117: 165-174, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200716</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200716[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI29415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200716">Jones et al. (2007)</a> concluded that the preservation of VLDL remnant clearance attenuates the phenotype of ARH and likely contributes to greater responsiveness to statins in ARH compared with FH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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> rs121908324 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908324;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/rs121908324?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=rs121908324" 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=rs121908324" 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=RCV000005039" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005039" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005039</a>
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<p>In a Sardinian family with autosomal recessive hypercholesterolemia (FHCL4; <a href="/entry/603813">603813</a>), <a href="#5" class="mim-tip-reference" title="Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong> Science 292: 1394-1398, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326085</a>] [<a href="https://doi.org/10.1126/science.1060458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11326085">Garcia et al. (2001)</a> found all affected individuals to be homozygous for a c.65G-A transition in exon 1 of the ARH gene, resulting in a trp22-to-ter (W22X) substitution. Three additional Sardinian patients were homozygous for this nonsense mutation, and 3 other unrelated probands were compound heterozygotes for this mutation and a frameshift mutation (<a href="#0002">605747.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11326085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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>.0002 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</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">rs1557703339 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1557703339;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=rs1557703339" 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=rs1557703339" 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=RCV000005040" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005040" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005040</a>
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<p>In 2 affected sibs from a consanguineous Sardinian family (ARH1) with autosomal recessive hypercholesterolemia (FHCL4; <a href="/entry/603813">603813</a>), originally reported by <a href="#17" class="mim-tip-reference" title="Zuliani, G., Vigna, G. B., Corsini, A., Maioli, M., Romagnoni, F., Fellin, R. <strong>Severe hypercholesterolaemia: unusual inheritance in an Italian pedigree.</strong> Europ. J. Clin. Invest. 25: 322-331, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7628519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7628519</a>] [<a href="https://doi.org/10.1111/j.1365-2362.1995.tb01709.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7628519">Zuliani et al. (1995)</a>, <a href="#5" class="mim-tip-reference" title="Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong> Science 292: 1394-1398, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326085</a>] [<a href="https://doi.org/10.1126/science.1060458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11326085">Garcia et al. (2001)</a> identified homozygosity for a 1-bp insertion (c.432insA) in exon 4 of the LDLRAP1 gene, causing a frameshift predicted to result in a premature termination codon at residue 170, within the terminal portion of the PTB domain. The plasma LDL level was about 460 mg/dl in a proband from this family. Coronary artery disease was prevalent in this family, with 8 relatives dying at less than 33 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7628519+11326085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 Italian probands who had hypercholesterolemia and at least 1 normocholesterolemic parent, <a href="#3" class="mim-tip-reference" title="Arca, M., Zuliani, G., Wilund, K., Campagna, F., Fellin, R., Bertolini, S., Calandra, S., Ricci, G., Glorioso, N., Maioli, M., Pintus, P., Carru, C., Cossu, F., Cohen, J., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis.</strong> Lancet 359: 841-847, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11897284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11897284</a>] [<a href="https://doi.org/10.1016/S0140-6736(02)07955-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11897284">Arca et al. (2002)</a> identified homozygosity for the c.432insA mutation in the LDLRAP1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11897284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</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">rs121908325 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908325;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=rs121908325" 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=rs121908325" 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=RCV000005041 OR RCV001826419 OR RCV002321472" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005041, RCV001826419, RCV002321472" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005041...</a>
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<p>In 4 affected sibs from a consanguineous Lebanese family (ARH3) with autosomal recessive hypercholesterolemia (FHCL4; <a href="/entry/603813">603813</a>), previously described by <a href="#10" class="mim-tip-reference" title="Khachadurian, A. K., Uthman, S. M. <strong>Experiences with the homozygous cases of familial hypercholesterolemia: a report of 52 patients.</strong> Nutr. Metab. 15: 132-140, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4351242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4351242</a>] [<a href="https://doi.org/10.1159/000175431" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4351242">Khachadurian and Uthman (1973)</a>, <a href="#5" class="mim-tip-reference" title="Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong> Science 292: 1394-1398, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326085</a>] [<a href="https://doi.org/10.1126/science.1060458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11326085">Garcia et al. (2001)</a> identified homozygosity for a c.406C-T transition in the LDLRAP1 gene, resulting in a gln136-to-ter (Q136X) substitution. Plasma total cholesterol in this family ranged from 440 to 580 mg/dl, and LDL receptor (see <a href="/entry/606945">606945</a>) activity was 60 to 70% of normal in fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4351242+11326085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</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> rs121908326 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908326;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/rs121908326?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=rs121908326" 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=rs121908326" 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=RCV000005042 OR RCV001275174 OR RCV004585986" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005042, RCV001275174, RCV004585986" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005042...</a>
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<p>In a Lebanese family (ARH4) with autosomal recessive hypercholesterolemia (FHCL4; <a href="/entry/603813">603813</a>), <a href="#5" class="mim-tip-reference" title="Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong> Science 292: 1394-1398, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326085</a>] [<a href="https://doi.org/10.1126/science.1060458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11326085">Garcia et al. (2001)</a> found that all affected individuals were homozygous for a C-to-A transversion at nucleotide 605 of the ARH gene, resulting in a pro-to-his substitution at codon 202 (P202H). Family members had plasma total cholesterol of 520 to 610 mg/dl, with LDL cholesterol ranging from 392 to 520 dl. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11326085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</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">rs1553170279 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553170279;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=rs1553170279" 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=rs1553170279" 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=RCV000005043" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005043" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005043</a>
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<p>In an Iranian family (ARH5) with autosomal recessive hypercholesterolemia (FHCL4; <a href="/entry/603813">603813</a>), <a href="#5" class="mim-tip-reference" title="Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong> Science 292: 1394-1398, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326085</a>] [<a href="https://doi.org/10.1126/science.1060458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11326085">Garcia et al. (2001)</a> identified a frameshift at nucleotide 72 of the ARH gene, resulting in a premature termination codon at residue 33. The 10-year-old proband had a plasma total cholesterol of 637 mg/dl. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11326085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</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">rs1201229554 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1201229554;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=rs1201229554" 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=rs1201229554" 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=RCV000560474 OR RCV000993947 OR RCV001829587" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000560474, RCV000993947, RCV001829587" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000560474...</a>
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<p>In a family (ARH6) with autosomal recessive hypercholesterolemia (FHCL4; <a href="/entry/603813">603813</a>) from the United States, <a href="#5" class="mim-tip-reference" title="Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H. <strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong> Science 292: 1394-1398, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326085</a>] [<a href="https://doi.org/10.1126/science.1060458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11326085">Garcia et al. (2001)</a> identified a single basepair deletion at nucleotide 71 of the ARH gene, resulting in a premature termination codon at residue 55. The patient was homozygous for this mutation and had a plasma total cholesterol of 800 mg/dl at the age of 15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11326085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</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> rs755104973 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs755104973;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/rs755104973?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=rs755104973" 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=rs755104973" 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=RCV000005045 OR RCV001826420" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005045, RCV001826420" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005045...</a>
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<p>In a Syrian family with autosomal recessive hypercholesterolemia (FHCL4; <a href="/entry/603813">603813</a>), <a href="#1" class="mim-tip-reference" title="Al-Kateb, H., Bahring, S., Hoffmann, K., Strauch, K., Busjahn, A., Nurnberg, G., Jouma, M., Bautz, E. K. F., Dresel, H. A., Luft, F. C. <strong>Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.</strong> Circ. Res. 90: 951-958, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12016260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12016260</a>] [<a href="https://doi.org/10.1161/01.res.0000018002.43041.08" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12016260">Al-Kateb et al. (2002)</a> identified a G-to-C transversion in the acceptor splice site of intron 1 of the ARH gene. <a href="#2" class="mim-tip-reference" title="Al-Kateb, H., Bautz, E. K. F., Luft, F. C., Bahring, S. <strong>A splice mutation in a Syrian autosomal recessive hypercholesterolemia family causes a two-nucleotide deletion of mRNA. (Letter)</strong> Circ. Res. 93: E49-E50, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12958143/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12958143</a>] [<a href="https://doi.org/10.1161/01.RES.0000089508.53350.70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12958143">Al-Kateb et al. (2003)</a> found that the mutation caused the deletion of 2 bp from the start of exon 2, resulting in a frameshift and a truncated protein due to a premature stop codon (TGA) 2 codons later. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12016260+12958143" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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>.0008 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</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> rs1461905374 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1461905374;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/rs1461905374?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=rs1461905374" 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=rs1461905374" 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=RCV000005046 OR RCV002223751" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005046, RCV002223751" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005046...</a>
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<p>In 2 affected sibs from a nonconsanguineous Mexican family with autosomal recessive hypercholesterolemia (FHCL4; <a href="/entry/603813">603813</a>), <a href="#4" class="mim-tip-reference" title="Canizales-Quinteros, S., Aguilar-Salinas, C. A., Huertas-Vasquez, A., Ordonez-Sanchez, M. L., Rodriguez-Torres, M., Venturas-Gallegos, J. L., Riba, L., Ramirez-Jimenez, S., Salas-Montiel, R., Medina-Palacios, G., Robles-Osorio, L., Miliar-Garcia, A., Rosales-Leon, L., Ruiz-Ordaz, B. H., Zentella-Dehesa, A., Ferre-D'Amare, A., Gomez-Perez, F. J., Tusie-Luna, M. T. <strong>A novel ARH splice site mutation in a Mexican kindred with autosomal recessive hypercholesterolemia.</strong> Hum. Genet. 116: 114-120, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15599766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15599766</a>] [<a href="https://doi.org/10.1007/s00439-004-1192-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15599766">Canizales-Quinteros et al. (2005)</a> identified homozygosity for a +2T-G transversion in intron 4 of the ARH gene, resulting in the activation of a cryptic splice site and the expression of a mutant protein lacking 26 amino acids involving the beta-6 and beta-7 strands of the phosphotyrosine-binding (PTB) domain. The authors stated that this was the first case of an ARH mutation causing an altered PTB domain. Both parents and an unaffected sister were heterozygous for the mutation, which was not found in 41 unrelated normolipidemic Mexican individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15599766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</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> rs781585299 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs781585299;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/rs781585299?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=rs781585299" 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=rs781585299" 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=RCV000005047 OR RCV001277156 OR RCV002223752" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005047, RCV001277156, RCV002223752" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005047...</a>
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<p>In 2 Japanese sibs with autosomal recessive hypercholesterolemia (FHCL4; <a href="/entry/603813">603813</a>), <a href="#7" class="mim-tip-reference" title="Harada-Shiba, M., Takagi, A., Miyamoto, Y., Tsushima, M., Ikeda, Y., Yokoyama, S., Yamamoto, A. <strong>Clinical features and genetic analysis of autosomal recessive hypercholesterolemia.</strong> J. Clin. Endocr. Metab. 88: 2541-2547, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788851</a>] [<a href="https://doi.org/10.1210/jc.2002-021487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12788851">Harada-Shiba et al. (2003)</a> identified a novel insertion in the ARH gene of a cytosine in the tract of 8 cytosines at positions 599 through 606 in exon 6, resulting in a sequence of 9 cytosines and generating an early stop codon at 657-659. The mother was heterozygous for this mutation. Neither transcription product nor protein of ARH was detected in the fibroblasts of the homozygous patients. Both sibs exhibited fatty liver, which may also be related to this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12788851" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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>.0010 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</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> rs114583297 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs114583297;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/rs114583297?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=rs114583297" 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=rs114583297" 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=RCV000623146 OR RCV001777171 OR RCV001834972" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000623146, RCV001777171, RCV001834972" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000623146...</a>
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<p>In a Spanish man with autosomal recessive hypercholesterolemia (FHCL4; <a href="/entry/603813">603813</a>), <a href="#14" class="mim-tip-reference" title="Sanchez-Hernandez, R. M., Prieto-Matos, P., Civeira, F., Lafuente, E. E., Vargas, M. F., Real, J. T., Goicoechea, F. G., Fuentes, F. J., Pocovi, M., Boronat, M., Wagner, A. M., Masana, L. <strong>Autosomal recessive hypercholesterolemia in Spain.</strong> Atherosclerosis 269: 1-5, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29245109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29245109</a>] [<a href="https://doi.org/10.1016/j.atherosclerosis.2017.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29245109">Sanchez-Hernandez et al. (2018)</a> identified compound heterozygosity for missense mutations in the LDLRAP1 gene: a c.653C-T transition, resulting in a thr218-to-ile (T218I) substitution, and a c.863C-T transition, resulting in a ser288-to-leu (S288L; <a href="#0011">605747.0011</a>) substitution. The authors noted that this patient presented a milder phenotype than patients with homozygous truncating mutations in LDLRAP1, with much lower baseline low density lipoprotein cholesterol levels and later diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29245109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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>.0011 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</strong>
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LDLRAP1, SER288LEU
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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> rs753151497 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs753151497;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/rs753151497?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=rs753151497" 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=rs753151497" 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=RCV000623682" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000623682" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000623682</a>
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<p>For discussion of the c.863C-T transition in the LDLRAP1 gene, resulting in a ser288-to-leu (S288L) substitution, that was found in compound heterozygous state in a Spanish man with autosomal recessive hypercholesterolemia (FHCL4; <a href="/entry/603813">603813</a>) by <a href="#14" class="mim-tip-reference" title="Sanchez-Hernandez, R. M., Prieto-Matos, P., Civeira, F., Lafuente, E. E., Vargas, M. F., Real, J. T., Goicoechea, F. G., Fuentes, F. J., Pocovi, M., Boronat, M., Wagner, A. M., Masana, L. <strong>Autosomal recessive hypercholesterolemia in Spain.</strong> Atherosclerosis 269: 1-5, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29245109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29245109</a>] [<a href="https://doi.org/10.1016/j.atherosclerosis.2017.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29245109">Sanchez-Hernandez et al. (2018)</a>, see <a href="#0010">605747.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29245109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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>REFERENCES</strong>
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<a id="Al-Kateb2002" class="mim-anchor"></a>
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Al-Kateb, H., Bahring, S., Hoffmann, K., Strauch, K., Busjahn, A., Nurnberg, G., Jouma, M., Bautz, E. K. F., Dresel, H. A., Luft, F. C.
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<strong>Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.</strong>
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Circ. Res. 90: 951-958, 2002.
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[<a href="https://doi.org/10.1161/01.res.0000018002.43041.08" target="_blank">Full Text</a>]
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Al-Kateb, H., Bautz, E. K. F., Luft, F. C., Bahring, S.
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<strong>A splice mutation in a Syrian autosomal recessive hypercholesterolemia family causes a two-nucleotide deletion of mRNA. (Letter)</strong>
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Circ. Res. 93: E49-E50, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12958143/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12958143</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12958143" 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.RES.0000089508.53350.70" target="_blank">Full Text</a>]
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Arca, M., Zuliani, G., Wilund, K., Campagna, F., Fellin, R., Bertolini, S., Calandra, S., Ricci, G., Glorioso, N., Maioli, M., Pintus, P., Carru, C., Cossu, F., Cohen, J., Hobbs, H. H.
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<strong>Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis.</strong>
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Lancet 359: 841-847, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11897284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11897284</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11897284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(02)07955-2" target="_blank">Full Text</a>]
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Canizales-Quinteros, S., Aguilar-Salinas, C. A., Huertas-Vasquez, A., Ordonez-Sanchez, M. L., Rodriguez-Torres, M., Venturas-Gallegos, J. L., Riba, L., Ramirez-Jimenez, S., Salas-Montiel, R., Medina-Palacios, G., Robles-Osorio, L., Miliar-Garcia, A., Rosales-Leon, L., Ruiz-Ordaz, B. H., Zentella-Dehesa, A., Ferre-D'Amare, A., Gomez-Perez, F. J., Tusie-Luna, M. T.
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<strong>A novel ARH splice site mutation in a Mexican kindred with autosomal recessive hypercholesterolemia.</strong>
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Hum. Genet. 116: 114-120, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15599766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15599766</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15599766" 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/s00439-004-1192-9" target="_blank">Full Text</a>]
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Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H.
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<strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong>
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Science 292: 1394-1398, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326085</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11326085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1060458" target="_blank">Full Text</a>]
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Garuti, R., Jones, C., Li, W.-P., Michaely, P., Herz, J., Gerard, R. D., Cohen, J. C., Hobbs, H. H.
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<strong>The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits.</strong>
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J. Biol. Chem. 280: 40996-41004, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16179341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16179341</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16179341" 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/10.1074/jbc.M509394200" target="_blank">Full Text</a>]
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Harada-Shiba, M., Takagi, A., Miyamoto, Y., Tsushima, M., Ikeda, Y., Yokoyama, S., Yamamoto, A.
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<strong>Clinical features and genetic analysis of autosomal recessive hypercholesterolemia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12788851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12788851</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12788851" 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/10.1210/jc.2002-021487" target="_blank">Full Text</a>]
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Jones, C., Garuti, R., Michaely, P., Li, W.-P., Maeda, N., Cohen, J. C., Herz, J., Hobbs, H. H.
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<strong>Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200716</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200716[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=17200716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI29415" target="_blank">Full Text</a>]
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Jones, C., Hammer, R. E., Li, W.-P., Cohen, J. C., Hobbs, H. H., Herz, J.
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<strong>Normal sorting but defective endocytosis of the low density lipoprotein receptor in mice with autosomal recessive hypercholesterolemia.</strong>
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[<a href="https://doi.org/10.1074/jbc.M304855200" target="_blank">Full Text</a>]
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Khachadurian, A. K., Uthman, S. M.
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<strong>Experiences with the homozygous cases of familial hypercholesterolemia: a report of 52 patients.</strong>
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Nutr. Metab. 15: 132-140, 1973.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4351242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4351242</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4351242" 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/10.1159/000175431" target="_blank">Full Text</a>]
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Michaely, P., Li, W.-P., Anderson, R. G. W., Cohen, J. C., Hobbs, H. H.
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<strong>The molecular adaptor protein ARH is required for low density lipoprotein (LDL) binding and internalization but not for LDL receptor clustering in coated pits.</strong>
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J. Biol. Chem. 279: 34023-34031, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15166224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15166224</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15166224" 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/10.1074/jbc.M405242200" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Mishra2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Mishra, S. K., Watkins, S. C., Traub, L. M.
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<strong>The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery.</strong>
|
|
Proc. Nat. Acad. Sci. 99: 16099-16104, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12451172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12451172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12451172[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=12451172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.252630799" target="_blank">Full Text</a>]
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</p>
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</div>
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<a id="13" class="mim-anchor"></a>
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<a id="Nagai2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nagai, M., Meerloo, T., Takeda, T., Farquhar, M. G.
|
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<strong>The adaptor protein ARH escorts megalin to and through endosomes.</strong>
|
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Molec. Biol. Cell 14: 4984-4996, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14528014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14528014</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14528014[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=14528014" 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/10.1091/mbc.e03-06-0385" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Sanchez-Hernandez2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sanchez-Hernandez, R. M., Prieto-Matos, P., Civeira, F., Lafuente, E. E., Vargas, M. F., Real, J. T., Goicoechea, F. G., Fuentes, F. J., Pocovi, M., Boronat, M., Wagner, A. M., Masana, L.
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<strong>Autosomal recessive hypercholesterolemia in Spain.</strong>
|
|
Atherosclerosis 269: 1-5, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29245109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29245109</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29245109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.atherosclerosis.2017.12.006" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Sirinian2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sirinian, M. I., Belleudi, F., Campagna, F., Ceridono, M., Garofalo, T., Quagliarini, F., Verna, R., Calandra, S., Bertolini, S., Sorice, M., Torrisi, M. R., Arca, M.
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<strong>Adaptor protein ARH is recruited to the plasma membrane by low density lipoprotein (LDL) binding and modulates endocytosis of the LDL/LDL receptor complex in hepatocytes.</strong>
|
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J. Biol. Chem. 280: 38416-38423, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16129683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16129683</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16129683" 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/10.1074/jbc.M504343200" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Wilund2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wilund, K. R., Yi, M., Campagna, F., Arca, M., Zuliani, G., Fellin, R., Ho, Y.-K., Garcia, J. V., Hobbs, H. H., Cohen, J. C.
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<strong>Molecular mechanisms of autosomal recessive hypercholesterolemia.</strong>
|
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Hum. Molec. Genet. 11: 3019-3030, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417523</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12417523" 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/10.1093/hmg/11.24.3019" 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="17" class="mim-anchor"></a>
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<a id="Zuliani1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zuliani, G., Vigna, G. B., Corsini, A., Maioli, M., Romagnoni, F., Fellin, R.
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<strong>Severe hypercholesterolaemia: unusual inheritance in an Italian pedigree.</strong>
|
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Europ. J. Clin. Invest. 25: 322-331, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7628519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7628519</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7628519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2362.1995.tb01709.x" target="_blank">Full Text</a>]
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</p>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 04/11/2018
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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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Marla J. F. O'Neill - updated : 3/30/2007<br>Patricia A. Hartz - updated : 11/2/2006<br>John A. Phillips, III - updated : 6/29/2005<br>Marla J. F. O'Neill - updated : 3/29/2005<br>Marla J. F. O'Neill - updated : 3/11/2004<br>Victor A. McKusick - updated : 1/15/2003<br>Victor A. McKusick - updated : 6/26/2002<br>Ada Hamosh - updated : 6/11/2001
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 3/20/2001
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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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carol : 06/19/2019
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 04/16/2018<br>carol : 04/12/2018<br>carol : 04/11/2018<br>joanna : 03/10/2014<br>carol : 11/15/2011<br>wwang : 4/17/2007<br>terry : 3/30/2007<br>mgross : 12/5/2006<br>terry : 11/2/2006<br>alopez : 6/29/2005<br>wwang : 4/1/2005<br>wwang : 3/31/2005<br>terry : 3/29/2005<br>tkritzer : 8/23/2004<br>carol : 6/21/2004<br>carol : 6/21/2004<br>tkritzer : 3/22/2004<br>tkritzer : 3/11/2004<br>tkritzer : 3/11/2004<br>joanna : 3/4/2004<br>cwells : 1/16/2003<br>terry : 1/15/2003<br>cwells : 7/10/2002<br>terry : 6/26/2002<br>ckniffin : 6/5/2002<br>alopez : 6/12/2001<br>alopez : 6/12/2001<br>alopez : 6/11/2001<br>alopez : 6/11/2001<br>mgross : 3/20/2001
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 605747
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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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LOW DENSITY LIPOPROTEIN RECEPTOR ADAPTOR PROTEIN 1; LDLRAP1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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LDLR ADAPTOR PROTEIN 1<br />
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ARH GENE; ARH
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: LDLRAP1</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 1p36.11
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:25,543,606-25,590,400 </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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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene-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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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
|
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<span class="mim-font">
|
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1p36.11
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Hypercholesterolemia, familial, 4
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
603813
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>TEXT</strong>
|
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</span>
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</h4>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<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>LDLRAP1 is an adaptor protein that interacts with the cytoplasmic tail of low density lipoprotein receptor (LDLR; 606945), phospholipids, and components of the clathrin (see CLTC; 118955) endocytic machinery (Garuti et al., 2005). </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>Garcia et al. (2001) cloned the ARH gene after performing linkage analysis in families suffering from autosomal recessive hypercholesterolemia (ARH; 603813) that mapped the ARH locus to a 1-cM interval on chromosome 1p35. The gene encodes a 308-amino acid protein containing a 170-amino acid phosphotyrosine-binding (PTB) domain, which shares considerable sequence similarity with the PTB domains of many adaptor proteins. PTB domains bind the consensus sequence NPXY, which is present in the cytoplasmic domains of several cell surface receptors, including LDLR. The integrity of the NPXY sequence in the cytoplasmic tail of LDLR is absolutely required for internalization, and LDLR has been shown in vitro to bind other proteins containing PTB domains. The human ARH protein shares 89% sequence identity with orthologous proteins in mouse and Xenopus. By Northern blot analysis, Garcia et al. (2001) found that ARH is normally expressed at high levels in the kidney, liver, and placenta, with lower levels detectable in brain, heart, muscle, colon, spleen, intestine, lung, and leukocytes. </p><p>Nagai et al. (2003) reported that the N-terminal half of human, rat, and mouse ARH contains the PTB domain, and the C-terminal half contains a clathrin box (LLDLE), a beta-2 adaptin (AP2B1; 601025)-binding site, and a C-terminal PDZ-binding motif. </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>
|
|
<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>Using yeast 2-hybrid, pull-down, and coimmunoprecipitation assays, Nagai et al. (2003) found that rat Arh bound the first FxNPxY motif of megalin (LRP2; 600073). Arh colocalized with megalin in clathrin-coated pits and in recycling endosomes in the Golgi region of rat L2 cells. Upon internalization of megalin, megalin and Arh colocalized in clathrin-coated pits, followed by their colocalization in early endosomes and tubular recycling endosomes in the pericentriolar region, and then by their reappearance at the cell surface. Expression of Arh in canine kidney cells expressing megalin minireceptors enhanced megalin-mediated uptake of lactoferrin (LTF; 150210), a megalin ligand. Nagai et al. (2003) concluded that ARH facilitates endocytosis of megalin and escorts megalin along its endocytic route. </p><p>By biochemical assays and electron microscopy, Michaely et al. (2004) found that lymphocytes from patients with ARH deficiency had over 20-fold more LDLR on the cell surface and about 27-fold excess of LDLR outside of coated pits. However, despite the increase in cell surface receptors, LDL binding was only 2-fold higher in ARH-deficient lymphocytes. Michaely et al. (2004) concluded that ARH is not only required for internalization of the LDL-LDLR complex, but also for efficient binding of LDL to the receptor. </p><p>By mutation analysis, Garuti et al. (2005) found that integrity of the FDNPVY sequence in LDLR was required for ARH-associated LDLR clustering into clathrin-coated pits in polarized hepatocytes. The phosphotyrosine-binding domain of ARH plus either the clathrin box or the AP2-binding region was required for LDLR clustering and internalization. These findings were confirmed in vivo by expressing the same ARH mutants in livers of Arh -/- mice. Garuti et al. (2005) concluded that ARH must bind the LDLR tail and either clathrin or AP2 to promote receptor clustering and internalization of LDL. </p><p>Sirinian et al. (2005) found that ARH codistributed with LDLR on the basolateral surface of polarized confluent HepG2 cells. Activation of LDLR-mediated endocytosis, but not binding of LDL to LDLR, promoted colocalization of ARH with the LDL-LDLR complex. Depletion of ARH by more than 70% by RNA interference caused an 80% reduction in LDL internalization. Coimmunoprecipitation analysis of LDL-stimulated polarized HepG2 cells showed that ARH interacted with other components of the endocytic machinery, including beta-adaptin, DAB2 (601236), and the small GTPase RAB4 (179511). Sirinian et al. (2005) concluded that ARH is not constitutively associated with LDLR at the plasma membrane, but is recruited to the membrane after LDL binding, thus facilitating endocytosis of the LDL-LDLR complex. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Garcia et al. (2001) determined that the ARH gene spans 25 kb and contains 9 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Garcia et al. (2001) mapped the ARH gene to chromosome 1p35. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 6 families with autosomal recessive hypercholesterolemia-4 (FCHL4; 603813), including 2 Sardinian, 2 Lebanese, 1 Iranian, and 1 American family, Garcia et al. (2001) identified homozygosity for 6 different mutations in the LDLRAP1 gene (605747.0001-605747.0006). A nonsense mutation (Q136X; 605747.0003) was identified in 1 of the Lebanese families; only trace amounts of ARH mRNA was detected in cultured fibroblasts from patients with this mutation. The other Lebanese family was homozygous for a missense mutation (P202H; 605747.0004) that was associated with a normal level of ARH mRNA in cultured fibroblasts. Garcia et al. (2001) found that the defect in LDLR function in ARH patients appeared to be not only receptor-specific, but also tissue-specific. They were not able to identify a consistent defect in LDLR function (binding, uptake, or internalization) in cultured fibroblasts from ARH patients. It is possible that another PTB domain protein compensates for the absence of ARH in cultured fibroblasts, or that adaptor molecules are not required for receptor-mediated endocytosis of LDL in fibroblasts and possibly other extrahepatic cells. </p><p>Arca et al. (2002) performed extensive clinical and molecular genetic studies in 28 Sardinians with autosomal recessive hypercholesterolemia from 17 unrelated families. They sequenced the coding regions and consensus splice sites of the ARH gene in probands from these families, and from 40 individuals of non-Sardinian origin who had an autosomal recessive form of hypercholesterolemia of unknown cause. In all 17 unrelated Sardinian families, 2 ARH mutations were present, 432insA in exon 4 (605747.0002), referred to as ARH1 by them, and a nonsense mutation, 65G-A in exon 1 (trp22 to ter; 605747.0001), referred to as ARH2 by them. Three of the ARH alleles in the Sardinian patients contained both mutations, as a result of an ancient recombination between ARH1 and ARH2. No regional clustering of the 3 mutant alleles was apparent. Furthermore, 4 Italians from the mainland with autosomal recessive hypercholesterolemia were homozygous for ARH1. The small number, high frequency, and dispersed distribution of ARH mutations on Sardinia were consistent with these mutations being ancient and maintained in the Sardinian population because of geographic isolation. </p><p>Mishra et al. (2002) showed that the ARH protein is a component of the endocytic machinery, with mutations of the ARH gene contributing to the LDL-uptake-disease phenotype of ARH patients. PTB domains of the ARH protein bind to the internalization motif of the LDL receptor. The authors showed that in addition, ARH binds directly to soluble clathrin trimers and to clathrin adaptors. At steady state, ARH colocalizes with endocytic proteins in HeLa cells, and the LDL receptor fluxes through peripheral ARH-positive sites before delivery to early endosomes. Their findings suggested that in ARH patients, defective sorting adaptor function in hepatocytes leads to faulty LDL receptor traffic and hypercholesterolemia. </p><p>To define the molecular mechanism underlying autosomal recessive hypercholesterolemia, Wilund et al. (2002) examined ARH mRNA and protein in fibroblasts and lymphocytes from 6 hypercholesterolemic patients with different ARH mutations. Five probands were homozygous for mutations that introduced premature termination codons; the sixth patient was homozygous for a 2.6-kb insertion in intron 1 which was associated with no detectable ARH mRNA. None of the probands had detectable full-length ARH protein in fibroblasts or lymphoblasts. No relationship was apparent between the site of the mutation in ARH and the amount of mRNA. Radiolabeled LDL degradation was normal in ARH fibroblasts, but LDLR function was markedly reduced in ARH lymphoblasts, despite a 2-fold increase in LDL cell surface binding in these cells. Wilund et al. (2002) concluded that ARH is required for normal LDLR function in lymphocytes and hepatocytes, but not in fibroblasts, and that residual LDLR function in cells that do not require ARH may explain why ARH patients have lower plasma LDL levels than do patients with homozygous familial hypercholesterolemia (144010) who have no functional LDLRs. </p><p>Al-Kateb et al. (2002) studied a Syrian family in which 3 sibs had elevated LDL levels; 3 other sibs and both parents had normal LDL levels, suggesting an autosomal recessive mode of inheritance. A genomewide scan using 427 markers showed support for linkage on both chromosomes 1 and 13, with significant lod scores at 1p36.1-p35 and 13q22-q32 (see cholesterol-lowering factor, 604595). Al-Kateb et al. (2002) found evidence for an interaction between these loci. They identified an intron 1 acceptor splice site mutation in the ARH gene (605747.0007) in homozygous state in the affected sibs and in heterozygous state in the parents. </p><p>In 2 affected sibs from a nonconsanguineous Mexican family with autosomal recessive hypercholesterolemia, Canizales-Quinteros et al. (2005) identified homozygosity for a donor splice site mutation in intron 4 of the ARH gene (605747.0008). </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>Jones et al. (2003) generated Arh-deficient mice and found that the fractional clearance rate of radiolabeled Ldl in these mice was lower than that in Ldlr -/- mice. By immunolocalization studies, they demonstrated that Ldl receptors are sorted normally to the sinusoidal surface in Arh -/- mouse livers. Jones et al. (2003) concluded that the Ldl internalization defect in Arh-deficient mice is caused by the inability of the receptors to enter the endocytic cycle. </p><p>Jones et al. (2007) examined the synthesis and catabolism of Vldl in mouse models of autosomal dominant familial hypercholesterolemia (Ldlr -/-) and ARH (Arh -/-). Despite similar rates of Vldl secretion in response to a high-sucrose diet, the rate of Vldl clearance was significantly higher in Arh-null mice than in Ldlr-null mice, suggesting that LDLR-dependent uptake of VLDL is maintained in the absence of ARH. Hepatocytes from Arh-null mice, but not Ldlr-null mice, internalized beta-Vldl, demonstrating that ARH is not required for LDLR-dependent uptake of VLDL by the liver. Jones et al. (2007) concluded that the preservation of VLDL remnant clearance attenuates the phenotype of ARH and likely contributes to greater responsiveness to statins in ARH compared with FH. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<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>11 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>
|
|
<span class="mim-font">
|
|
<strong>.0001 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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LDLRAP1, TRP22TER
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<br />
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SNP: rs121908324,
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gnomAD: rs121908324,
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|
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ClinVar: RCV000005039
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a Sardinian family with autosomal recessive hypercholesterolemia (FHCL4; 603813), Garcia et al. (2001) found all affected individuals to be homozygous for a c.65G-A transition in exon 1 of the ARH gene, resulting in a trp22-to-ter (W22X) substitution. Three additional Sardinian patients were homozygous for this nonsense mutation, and 3 other unrelated probands were compound heterozygotes for this mutation and a frameshift mutation (605747.0002). </p>
|
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</span>
|
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</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
LDLRAP1, 1-BP INS, 432A
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<br />
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|
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SNP: rs1557703339,
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|
|
ClinVar: RCV000005040
|
|
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</span>
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</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In 2 affected sibs from a consanguineous Sardinian family (ARH1) with autosomal recessive hypercholesterolemia (FHCL4; 603813), originally reported by Zuliani et al. (1995), Garcia et al. (2001) identified homozygosity for a 1-bp insertion (c.432insA) in exon 4 of the LDLRAP1 gene, causing a frameshift predicted to result in a premature termination codon at residue 170, within the terminal portion of the PTB domain. The plasma LDL level was about 460 mg/dl in a proband from this family. Coronary artery disease was prevalent in this family, with 8 relatives dying at less than 33 years of age. </p><p>In 4 Italian probands who had hypercholesterolemia and at least 1 normocholesterolemic parent, Arca et al. (2002) identified homozygosity for the c.432insA mutation in the LDLRAP1 gene. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLRAP1, GLN136TER
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|
|
<br />
|
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|
|
SNP: rs121908325,
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|
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|
|
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|
|
ClinVar: RCV000005041, RCV001826419, RCV002321472
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 affected sibs from a consanguineous Lebanese family (ARH3) with autosomal recessive hypercholesterolemia (FHCL4; 603813), previously described by Khachadurian and Uthman (1973), Garcia et al. (2001) identified homozygosity for a c.406C-T transition in the LDLRAP1 gene, resulting in a gln136-to-ter (Q136X) substitution. Plasma total cholesterol in this family ranged from 440 to 580 mg/dl, and LDL receptor (see 606945) activity was 60 to 70% of normal in fibroblasts. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLRAP1, PRO202HIS
|
|
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|
|
|
<br />
|
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|
|
SNP: rs121908326,
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|
|
|
|
|
gnomAD: rs121908326,
|
|
|
|
|
|
ClinVar: RCV000005042, RCV001275174, RCV004585986
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Lebanese family (ARH4) with autosomal recessive hypercholesterolemia (FHCL4; 603813), Garcia et al. (2001) found that all affected individuals were homozygous for a C-to-A transversion at nucleotide 605 of the ARH gene, resulting in a pro-to-his substitution at codon 202 (P202H). Family members had plasma total cholesterol of 520 to 610 mg/dl, with LDL cholesterol ranging from 392 to 520 dl. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLRAP1, 1-BP INS, 72G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1553170279,
|
|
|
|
|
|
|
|
ClinVar: RCV000005043
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Iranian family (ARH5) with autosomal recessive hypercholesterolemia (FHCL4; 603813), Garcia et al. (2001) identified a frameshift at nucleotide 72 of the ARH gene, resulting in a premature termination codon at residue 33. The 10-year-old proband had a plasma total cholesterol of 637 mg/dl. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLRAP1, 1-BP DEL, 71G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1201229554,
|
|
|
|
|
|
|
|
ClinVar: RCV000560474, RCV000993947, RCV001829587
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family (ARH6) with autosomal recessive hypercholesterolemia (FHCL4; 603813) from the United States, Garcia et al. (2001) identified a single basepair deletion at nucleotide 71 of the ARH gene, resulting in a premature termination codon at residue 55. The patient was homozygous for this mutation and had a plasma total cholesterol of 800 mg/dl at the age of 15. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
LDLRAP1, IVS1AS, G-C, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs755104973,
|
|
|
|
|
|
gnomAD: rs755104973,
|
|
|
|
|
|
ClinVar: RCV000005045, RCV001826420
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Syrian family with autosomal recessive hypercholesterolemia (FHCL4; 603813), Al-Kateb et al. (2002) identified a G-to-C transversion in the acceptor splice site of intron 1 of the ARH gene. Al-Kateb et al. (2003) found that the mutation caused the deletion of 2 bp from the start of exon 2, resulting in a frameshift and a truncated protein due to a premature stop codon (TGA) 2 codons later. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
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|
LDLRAP1, IVS4DS, T-G, +2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1461905374,
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|
|
|
|
|
gnomAD: rs1461905374,
|
|
|
|
|
|
ClinVar: RCV000005046, RCV002223751
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected sibs from a nonconsanguineous Mexican family with autosomal recessive hypercholesterolemia (FHCL4; 603813), Canizales-Quinteros et al. (2005) identified homozygosity for a +2T-G transversion in intron 4 of the ARH gene, resulting in the activation of a cryptic splice site and the expression of a mutant protein lacking 26 amino acids involving the beta-6 and beta-7 strands of the phosphotyrosine-binding (PTB) domain. The authors stated that this was the first case of an ARH mutation causing an altered PTB domain. Both parents and an unaffected sister were heterozygous for the mutation, which was not found in 41 unrelated normolipidemic Mexican individuals. </p>
|
|
</span>
|
|
</div>
|
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</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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LDLRAP1, 1-BP INS, 599C
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<br />
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SNP: rs781585299,
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gnomAD: rs781585299,
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ClinVar: RCV000005047, RCV001277156, RCV002223752
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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 Japanese sibs with autosomal recessive hypercholesterolemia (FHCL4; 603813), Harada-Shiba et al. (2003) identified a novel insertion in the ARH gene of a cytosine in the tract of 8 cytosines at positions 599 through 606 in exon 6, resulting in a sequence of 9 cytosines and generating an early stop codon at 657-659. The mother was heterozygous for this mutation. Neither transcription product nor protein of ARH was detected in the fibroblasts of the homozygous patients. Both sibs exhibited fatty liver, which may also be related to this mutation. </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>.0010 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</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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LDLRAP1, THR218ILE
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<br />
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SNP: rs114583297,
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gnomAD: rs114583297,
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ClinVar: RCV000623146, RCV001777171, RCV001834972
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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 Spanish man with autosomal recessive hypercholesterolemia (FHCL4; 603813), Sanchez-Hernandez et al. (2018) identified compound heterozygosity for missense mutations in the LDLRAP1 gene: a c.653C-T transition, resulting in a thr218-to-ile (T218I) substitution, and a c.863C-T transition, resulting in a ser288-to-leu (S288L; 605747.0011) substitution. The authors noted that this patient presented a milder phenotype than patients with homozygous truncating mutations in LDLRAP1, with much lower baseline low density lipoprotein cholesterol levels and later diagnosis. </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>.0011 HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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LDLRAP1, SER288LEU
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<br />
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SNP: rs753151497,
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gnomAD: rs753151497,
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ClinVar: RCV000623682
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.863C-T transition in the LDLRAP1 gene, resulting in a ser288-to-leu (S288L) substitution, that was found in compound heterozygous state in a Spanish man with autosomal recessive hypercholesterolemia (FHCL4; 603813) by Sanchez-Hernandez et al. (2018), see 605747.0010. </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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Al-Kateb, H., Bahring, S., Hoffmann, K., Strauch, K., Busjahn, A., Nurnberg, G., Jouma, M., Bautz, E. K. F., Dresel, H. A., Luft, F. C.
|
|
<strong>Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.</strong>
|
|
Circ. Res. 90: 951-958, 2002.
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[PubMed: 12016260]
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[Full Text: https://doi.org/10.1161/01.res.0000018002.43041.08]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Al-Kateb, H., Bautz, E. K. F., Luft, F. C., Bahring, S.
|
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<strong>A splice mutation in a Syrian autosomal recessive hypercholesterolemia family causes a two-nucleotide deletion of mRNA. (Letter)</strong>
|
|
Circ. Res. 93: E49-E50, 2003.
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|
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[PubMed: 12958143]
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[Full Text: https://doi.org/10.1161/01.RES.0000089508.53350.70]
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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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Arca, M., Zuliani, G., Wilund, K., Campagna, F., Fellin, R., Bertolini, S., Calandra, S., Ricci, G., Glorioso, N., Maioli, M., Pintus, P., Carru, C., Cossu, F., Cohen, J., Hobbs, H. H.
|
|
<strong>Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis.</strong>
|
|
Lancet 359: 841-847, 2002.
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|
|
[PubMed: 11897284]
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[Full Text: https://doi.org/10.1016/S0140-6736(02)07955-2]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Canizales-Quinteros, S., Aguilar-Salinas, C. A., Huertas-Vasquez, A., Ordonez-Sanchez, M. L., Rodriguez-Torres, M., Venturas-Gallegos, J. L., Riba, L., Ramirez-Jimenez, S., Salas-Montiel, R., Medina-Palacios, G., Robles-Osorio, L., Miliar-Garcia, A., Rosales-Leon, L., Ruiz-Ordaz, B. H., Zentella-Dehesa, A., Ferre-D'Amare, A., Gomez-Perez, F. J., Tusie-Luna, M. T.
|
|
<strong>A novel ARH splice site mutation in a Mexican kindred with autosomal recessive hypercholesterolemia.</strong>
|
|
Hum. Genet. 116: 114-120, 2005.
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|
|
[PubMed: 15599766]
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[Full Text: https://doi.org/10.1007/s00439-004-1192-9]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., Hobbs, H. H.
|
|
<strong>Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.</strong>
|
|
Science 292: 1394-1398, 2001.
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[PubMed: 11326085]
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[Full Text: https://doi.org/10.1126/science.1060458]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Garuti, R., Jones, C., Li, W.-P., Michaely, P., Herz, J., Gerard, R. D., Cohen, J. C., Hobbs, H. H.
|
|
<strong>The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits.</strong>
|
|
J. Biol. Chem. 280: 40996-41004, 2005.
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|
|
[PubMed: 16179341]
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[Full Text: https://doi.org/10.1074/jbc.M509394200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Harada-Shiba, M., Takagi, A., Miyamoto, Y., Tsushima, M., Ikeda, Y., Yokoyama, S., Yamamoto, A.
|
|
<strong>Clinical features and genetic analysis of autosomal recessive hypercholesterolemia.</strong>
|
|
J. Clin. Endocr. Metab. 88: 2541-2547, 2003.
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|
|
[PubMed: 12788851]
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[Full Text: https://doi.org/10.1210/jc.2002-021487]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Jones, C., Garuti, R., Michaely, P., Li, W.-P., Maeda, N., Cohen, J. C., Herz, J., Hobbs, H. H.
|
|
<strong>Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia.</strong>
|
|
J. Clin. Invest. 117: 165-174, 2007.
|
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|
|
[PubMed: 17200716]
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[Full Text: https://doi.org/10.1172/JCI29415]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Jones, C., Hammer, R. E., Li, W.-P., Cohen, J. C., Hobbs, H. H., Herz, J.
|
|
<strong>Normal sorting but defective endocytosis of the low density lipoprotein receptor in mice with autosomal recessive hypercholesterolemia.</strong>
|
|
J. Biol. Chem. 278: 29024-29030, 2003.
|
|
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|
|
[PubMed: 12746448]
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[Full Text: https://doi.org/10.1074/jbc.M304855200]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Khachadurian, A. K., Uthman, S. M.
|
|
<strong>Experiences with the homozygous cases of familial hypercholesterolemia: a report of 52 patients.</strong>
|
|
Nutr. Metab. 15: 132-140, 1973.
|
|
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|
|
|
[PubMed: 4351242]
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|
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[Full Text: https://doi.org/10.1159/000175431]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Michaely, P., Li, W.-P., Anderson, R. G. W., Cohen, J. C., Hobbs, H. H.
|
|
<strong>The molecular adaptor protein ARH is required for low density lipoprotein (LDL) binding and internalization but not for LDL receptor clustering in coated pits.</strong>
|
|
J. Biol. Chem. 279: 34023-34031, 2004.
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|
|
[PubMed: 15166224]
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[Full Text: https://doi.org/10.1074/jbc.M405242200]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Mishra, S. K., Watkins, S. C., Traub, L. M.
|
|
<strong>The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery.</strong>
|
|
Proc. Nat. Acad. Sci. 99: 16099-16104, 2002.
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|
|
[PubMed: 12451172]
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[Full Text: https://doi.org/10.1073/pnas.252630799]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Nagai, M., Meerloo, T., Takeda, T., Farquhar, M. G.
|
|
<strong>The adaptor protein ARH escorts megalin to and through endosomes.</strong>
|
|
Molec. Biol. Cell 14: 4984-4996, 2003.
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|
|
[PubMed: 14528014]
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|
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[Full Text: https://doi.org/10.1091/mbc.e03-06-0385]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Sanchez-Hernandez, R. M., Prieto-Matos, P., Civeira, F., Lafuente, E. E., Vargas, M. F., Real, J. T., Goicoechea, F. G., Fuentes, F. J., Pocovi, M., Boronat, M., Wagner, A. M., Masana, L.
|
|
<strong>Autosomal recessive hypercholesterolemia in Spain.</strong>
|
|
Atherosclerosis 269: 1-5, 2018.
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|
|
[PubMed: 29245109]
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[Full Text: https://doi.org/10.1016/j.atherosclerosis.2017.12.006]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Sirinian, M. I., Belleudi, F., Campagna, F., Ceridono, M., Garofalo, T., Quagliarini, F., Verna, R., Calandra, S., Bertolini, S., Sorice, M., Torrisi, M. R., Arca, M.
|
|
<strong>Adaptor protein ARH is recruited to the plasma membrane by low density lipoprotein (LDL) binding and modulates endocytosis of the LDL/LDL receptor complex in hepatocytes.</strong>
|
|
J. Biol. Chem. 280: 38416-38423, 2005.
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|
[PubMed: 16129683]
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[Full Text: https://doi.org/10.1074/jbc.M504343200]
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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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Wilund, K. R., Yi, M., Campagna, F., Arca, M., Zuliani, G., Fellin, R., Ho, Y.-K., Garcia, J. V., Hobbs, H. H., Cohen, J. C.
|
|
<strong>Molecular mechanisms of autosomal recessive hypercholesterolemia.</strong>
|
|
Hum. Molec. Genet. 11: 3019-3030, 2002.
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|
|
[PubMed: 12417523]
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[Full Text: https://doi.org/10.1093/hmg/11.24.3019]
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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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Zuliani, G., Vigna, G. B., Corsini, A., Maioli, M., Romagnoni, F., Fellin, R.
|
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<strong>Severe hypercholesterolaemia: unusual inheritance in an Italian pedigree.</strong>
|
|
Europ. J. Clin. Invest. 25: 322-331, 1995.
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[PubMed: 7628519]
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[Full Text: https://doi.org/10.1111/j.1365-2362.1995.tb01709.x]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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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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Marla J. F. O'Neill - updated : 04/11/2018<br>Marla J. F. O'Neill - updated : 3/30/2007<br>Patricia A. Hartz - updated : 11/2/2006<br>John A. Phillips, III - updated : 6/29/2005<br>Marla J. F. O'Neill - updated : 3/29/2005<br>Marla J. F. O'Neill - updated : 3/11/2004<br>Victor A. McKusick - updated : 1/15/2003<br>Victor A. McKusick - updated : 6/26/2002<br>Ada Hamosh - updated : 6/11/2001
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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 class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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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 : 3/20/2001
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</span>
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</div>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Edit History:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/19/2019<br>carol : 04/16/2018<br>carol : 04/12/2018<br>carol : 04/11/2018<br>joanna : 03/10/2014<br>carol : 11/15/2011<br>wwang : 4/17/2007<br>terry : 3/30/2007<br>mgross : 12/5/2006<br>terry : 11/2/2006<br>alopez : 6/29/2005<br>wwang : 4/1/2005<br>wwang : 3/31/2005<br>terry : 3/29/2005<br>tkritzer : 8/23/2004<br>carol : 6/21/2004<br>carol : 6/21/2004<br>tkritzer : 3/22/2004<br>tkritzer : 3/11/2004<br>tkritzer : 3/11/2004<br>joanna : 3/4/2004<br>cwells : 1/16/2003<br>terry : 1/15/2003<br>cwells : 7/10/2002<br>terry : 6/26/2002<br>ckniffin : 6/5/2002<br>alopez : 6/12/2001<br>alopez : 6/12/2001<br>alopez : 6/11/2001<br>alopez : 6/11/2001<br>mgross : 3/20/2001
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