3363 lines
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Entry
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- #603813 - HYPERCHOLESTEROLEMIA, FAMILIAL, 4; FHCL4
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- OMIM
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<p>
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<span class="h4">#603813</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/603813"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
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<a href="/phenotypicSeries/PS143890"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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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 role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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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 style="display: table-cell;">External Links</div>
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</a>
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</h4>
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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=" 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 in 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://clinicaltrials.gov/search?cond=HYPERCHOLESTEROLEMIA, FAMILIAL" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=22639&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK174884/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/8584" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/familial-hypercholesterolemia" 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=603813[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><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=391665" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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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/disease/DOID:0090105" 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="http://www.informatics.jax.org/disease/603813" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></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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</a>
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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:603813" 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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<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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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 391665<br />
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<strong>DO:</strong> 0090105<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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603813
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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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HYPERCHOLESTEROLEMIA, FAMILIAL, 4; FHCL4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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HYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE; ARH<br />
|
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HYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE, 1, FORMERLY; ARH1, FORMERLY<br />
|
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FHCB1, FORMERLY<br />
|
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HYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE, 2, FORMERLY; ARH2, FORMERLY<br />
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FHCB2, FORMERLY
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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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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene 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 table-hover 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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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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<tbody>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/301?start=-3&limit=10&highlight=301">
|
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1p36.11
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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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">
|
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<a href="/entry/603813"> 603813 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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LDLRAP1
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/605747"> 605747 </a>
|
|
</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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<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/603813" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
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<span class="caret"></span>
|
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<span class="sr-only">Toggle Dropdown</span>
|
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</button>
|
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</div>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS143890" class="btn btn-info" role="button"> Phenotypic Series </a>
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|
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
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<span class="sr-only">Toggle Dropdown</span>
|
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</button>
|
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</div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/603813" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/603813" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
|
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<p />
|
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</div>
|
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|
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
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<strong> INHERITANCE </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
|
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<span class="mim-font">
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- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
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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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<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
|
|
|
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|
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Xanthomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/75594004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">75594004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/63103006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">63103006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0302314&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0302314</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001114" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001114</a>]</span><br />
|
|
|
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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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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Hypertriglyceridemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302870006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302870006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/166848004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">166848004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020557&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020557</a>, <a href="https://bioportal.bioontology.org/search?q=C1522137&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1522137</a>, <a href="https://bioportal.bioontology.org/search?q=C0813230&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0813230</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002155" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002155</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002155" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002155</a>]</span><br /> -
|
|
Very high low-density lipoprotein (LDL) cholesterol (>400 mg/dL) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4692789&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4692789</a>]</span><br /> -
|
|
High total cholesterol (>600 mg/dL) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4692790&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4692790</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
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|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the low density lipoprotein receptor adaptor protein 1 gene (LDLRAP1, <a href="/entry/605747#0001">605747.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Hypercholesterolemia, familial
|
|
- <a href="/phenotypicSeries/PS143890">PS143890</a>
|
|
- 10 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<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">
|
|
<a href="/entry/603813"> Hypercholesterolemia, familial, 4 </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>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603813"> 603813 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605747"> LDLRAP1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605747"> 605747 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/646?start=-3&limit=10&highlight=646"> 1p32.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603776"> Hypercholesterolemia, familial, 3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603776"> 603776 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607786"> PCSK9 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607786"> 607786 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/646?start=-3&limit=10&highlight=646"> 1p32.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603776"> {Low density lipoprotein cholesterol level QTL 1} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603776"> 603776 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607786"> PCSK9 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607786"> 607786 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1346?start=-3&limit=10&highlight=1346"> 1q23.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/143890"> {Hypercholesterolemia, familial, modifier of} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <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>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/143890"> 143890 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/107670"> APOA2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
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<a href="/entry/107670"> 107670 </a>
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<a href="/entry/144010"> Hypercholesterolemia, familial, 2 </a>
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<a href="/entry/143890"> {Hypercholesterolemia, familial, modifier of} </a>
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<span class="mim-font">
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<a href="/entry/143890"> {Hypercholesterolemia, susceptibility to} </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<a href="/entry/143890"> 143890 </a>
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<a href="/entry/604088"> 604088 </a>
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<a href="/entry/143890"> {Hypercholesterolemia, familial, due to LDLR defect, modifier of} </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<a href="/entry/143890"> 143890 </a>
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<span class="mim-font">
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<a href="/entry/143890"> Hypercholesterolemia, familial, 1 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/143890"> 143890 </a>
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<a href="/entry/606945"> LDLR </a>
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<a href="/entry/606945"> 606945 </a>
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<a href="/entry/143890"> LDL cholesterol level QTL2 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/143890"> 143890 </a>
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<a href="/entry/606945"> LDLR </a>
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<a href="/entry/606945"> 606945 </a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because autosomal recessive familial hypercholesterolemia-4 (FHCL4) is caused by homozygous or compound heterozygous mutation in the ARH gene (LDLRAP1; <a href="/entry/605747">605747</a>) on chromosome 1p36.</p>
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<p>Autosomal recessive familial hypercholesterolemia-4 (FCHL4) is a rare monogenic disease characterized by very high levels of low-density lipoprotein (LDL) cholesterol (usually above 400 mg/dl) and increased risk of premature atherosclerotic cardiovascular disease (summary 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>). <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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<p><a href="#18" 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> described a consanguineous Sardinian family in which a brother and sister had a severe form of hypercholesterolemia with the clinical features of familial hypercholesterolemia (FH; <a href="/entry/143890">143890</a>) homozygotes, including severely elevated plasma low density lipoprotein (LDL) cholesterol, tuberous and tendon xanthomata, and premature atherosclerosis. However, LDL receptor (LDLR; <a href="/entry/606945">606945</a>) activity measured in skin fibroblasts was normal, as was LDL binding ability. Haplotype segregation analysis excluded involvement of the LDLR and apolipoprotein B (APOB; <a href="/entry/107730">107730</a>) genes in the pathogenesis of the disorder. Consanguinity, absence of vertical transmission, and bimodal distribution of plasma cholesterol levels in the kindred were consistent with autosomal recessive inheritance. Sitosterolemia (see <a href="/entry/210250">210250</a>) and pseudohomozygous hyperlipidemia (see <a href="/entry/144250">144250</a>) were ruled out. <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'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Zuliani, G., Arca, M., Signore, A., Bader, G., Fazio, S., Chianelli, M., Bellosta, S., Campagna, F., Montali, A., Maioli, M., Pacifico, A., Ricci, G., Fellin, R. <strong>Characterization of a new form of inherited hypercholesterolemia: familial recessive hypercholesterolemia.</strong> Arterioscler. Thromb. Vasc. Biol. 19: 802-809, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10073989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10073989</a>] [<a href="https://doi.org/10.1161/01.atv.19.3.802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10073989">Zuliani et al. (1999)</a> identified a second Sardinian kindred with similar characteristics. The probands showed severe hypercholesterolemia, whereas their parents and grandparents were normolipidemic. FH, familial defective apoB, sitosterolemia, and cholesteryl ester storage disease (<a href="/entry/278000">278000</a>) were excluded by in vitro studies. By LDL turnover studies, the authors found a marked reduction in the fractional catabolic rate and a significant increase in the production rate of LDL apoB in the probands compared with normolipidemic controls. The probands also showed a significant reduction in hepatic LDL uptake, similar to that observed in the FH homozygote studied in parallel. A reduced uptake of LDL by the kidney and spleen was also observed in all patients. These findings suggested that this recessive form of hypercholesterolemia is due to a marked reduction of in vivo LDL catabolism. This appeared to be caused by a selective reduction in hepatic LDL uptake. <a href="#17" class="mim-tip-reference" title="Zuliani, G., Arca, M., Signore, A., Bader, G., Fazio, S., Chianelli, M., Bellosta, S., Campagna, F., Montali, A., Maioli, M., Pacifico, A., Ricci, G., Fellin, R. <strong>Characterization of a new form of inherited hypercholesterolemia: familial recessive hypercholesterolemia.</strong> Arterioscler. Thromb. Vasc. Biol. 19: 802-809, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10073989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10073989</a>] [<a href="https://doi.org/10.1161/01.atv.19.3.802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10073989">Zuliani et al. (1999)</a> proposed that in this new lipid disorder, a recessive defect causes a selective impairment of LDLR function in the liver. In a note added in proof, <a href="#17" class="mim-tip-reference" title="Zuliani, G., Arca, M., Signore, A., Bader, G., Fazio, S., Chianelli, M., Bellosta, S., Campagna, F., Montali, A., Maioli, M., Pacifico, A., Ricci, G., Fellin, R. <strong>Characterization of a new form of inherited hypercholesterolemia: familial recessive hypercholesterolemia.</strong> Arterioscler. Thromb. Vasc. Biol. 19: 802-809, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10073989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10073989</a>] [<a href="https://doi.org/10.1161/01.atv.19.3.802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10073989">Zuliani et al. (1999)</a> stated that 4 'new' Sardinian families with the characteristics of familial recessive hypercholesterolemia had been identified. In all probands, the LDLR activities in fibroblasts as well as the binding ability of LDL to the LDLR were normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10073989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Schmidt, H. H.-J., Stuhrmann, M., Shamburek, R., Schewe, C. K., Ebhardt, M., Zech, L. A., Buttner, C., Wendt, M., Beisiegel, U., Brewer, H. B., Jr., Manns, M. P. <strong>Delayed low density lipoprotein (LDL) catabolism despite a functional intact LDL-apolipoprotein B particle and LDL-receptor in a subject with clinical homozygous familial hypercholesterolemia.</strong> J. Clin. Endocr. Metab. 83: 2167-2174, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9626156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9626156</a>] [<a href="https://doi.org/10.1210/jcem.83.6.4840" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9626156">Schmidt et al. (1998)</a> identified a 38-year-old male patient with the clinical expression of homozygous familial hypercholesterolemia presenting as severe coronary artery disease, tendon and skin xanthomas, arcus lipoides, and joint pain. They concluded that the disorder was autosomal recessive. Serum concentrations of cholesterol responded well to diet and statins. There was no evidence of an abnormal LDL-APOB particle, which was isolated from the patient by use of the U937 proliferation assay as a functional test of the LDL binding capacity. APOB-3500 and APOB-3531 defects were ruled out by PCR, and there was no evidence for a defect within the LDLR by skin fibroblast analysis, linkage analysis, SSCP, and Southern blot screening across the entire LDLR gene. The in vivo kinetics of radioiodinated LDL-APOB were evaluated in the proband and 3 normal controls. The LDL-APOB isolated from the patient showed normal catabolism, confirming an intact LDL particle. In contrast, the fractional catabolic rate of autologous LDL in the subject and normal controls revealed remarkably delayed catabolism of the patient's LDL. The elevation of LDL cholesterol in the patient resulted from an increased production rate with 22.8 mg/kg per day vs 12.7 to 15.7 mg/kg per day. The authors concluded that there is another catabolic defect beyond the APOB and LDLR genes causing familial hypercholesterolemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9626156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Norman, D., Sun, X.-M., Bourbon, M., Knight, B. L., Naoumova, R. P., Soutar, A. K. <strong>Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia.</strong> J. Clin. Invest. 104: 619-628, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10487776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10487776</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10487776[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/JCI6677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10487776">Norman et al. (1999)</a> identified apparently recessive familial hypercholesterolemia in 2 kindreds, one of Turkish origin and the other of Asian-Indian origin. The index patient of the Turkish family had a longstanding presumptive diagnosis of homozygous FH based on a raised plasma cholesterol concentration, the presence of extensive cutaneous xanthomata in the webs of her fingers and creases of her hands, and tendon xanthomata from an early age, as well as supravalvular aortic stenosis and premature coronary heart disease. The clinical characteristics of this woman were described in detail by <a href="#13" class="mim-tip-reference" title="Rallidis, L., Nihoyannopoulos, P., Thompson, G. R. <strong>Aortic stenosis in homozygous familial hypercholesterolaemia.</strong> Heart 76: 84-85, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8774336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8774336</a>] [<a href="https://doi.org/10.1136/hrt.76.1.84" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8774336">Rallidis et al. (1996)</a>. A sib and a double first cousin were also affected. The affected individuals were the offspring of a first-cousin marriage in each case. All 4 parents were apparently unaffected. In the Asian-Indian family, 2 sisters were affected. The parents of this family were also reported to be first cousins, but no additional members of the family were available for study. Cells from the patients in these families exhibited no measurable degradation of LDL in culture. Extensive analysis of DNA and mRNA revealed no defect in the LDL receptor gene, and alleles of the LDLR and apolipoprotein B (APOB; <a href="/entry/107730">107730</a>) genes did not cosegregate with hypercholesterolemia in these families. Fluorescence-activated cell sorting (FACS) analysis of binding and uptake of fluorescent LDL or anti-LDLR antibodies showed that LDL receptors were on the cell surface and bound LDL normally, but failed to be internalized, suggesting that some component of endocytosis through clathrin-coated pits was defective. Internalization of the transferrin receptor (<a href="/entry/190010">190010</a>) occurred normally, suggesting that the defective gene product may interact specifically with the LDL receptor internalization signal. <a href="#11" class="mim-tip-reference" title="Norman, D., Sun, X.-M., Bourbon, M., Knight, B. L., Naoumova, R. P., Soutar, A. K. <strong>Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia.</strong> J. Clin. Invest. 104: 619-628, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10487776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10487776</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10487776[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/JCI6677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10487776">Norman et al. (1999)</a> concluded that identification of the defective gene would aid genetic diagnosis of other hypercholesterolemic patients and elucidate the mechanism by which LDL receptors are internalized, thus suggesting perhaps more appropriate methods of treatment then those currently used for FH patients with known genetic defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10487776+8774336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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="Eden, E. R., Naoumova, R. P., Burden, J. J., McCarthy, M. I., Soutar, A. K. <strong>Use of homozygosity mapping to identify a region on chromosome 1 bearing a defective gene that causes autosomal recessive homozygous hypercholesterolemia in two unrelated families.</strong> Am. J. Hum. Genet. 68: 653-660, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179013</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11179013[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/318795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11179013">Eden et al. (2001)</a> performed a genomewide scan with polymorphic genetic markers in the 2 families reported by <a href="#11" class="mim-tip-reference" title="Norman, D., Sun, X.-M., Bourbon, M., Knight, B. L., Naoumova, R. P., Soutar, A. K. <strong>Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia.</strong> J. Clin. Invest. 104: 619-628, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10487776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10487776</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10487776[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/JCI6677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10487776">Norman et al. (1999)</a>. In both pedigrees, a single region of approximately 12 cM on 1p36-p35, designated FHCB2, fulfilled the criteria for homozygous inheritance of alleles in the affected offspring but not their unaffected sibs. The combined lod score was 5.3 in these unrelated families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11179013+10487776" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using 4 ARH families, including 2 previously studied by Zuliani et al. (<a href="#18" 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">1995</a>, <a href="#17" class="mim-tip-reference" title="Zuliani, G., Arca, M., Signore, A., Bader, G., Fazio, S., Chianelli, M., Bellosta, S., Campagna, F., Montali, A., Maioli, M., Pacifico, A., Ricci, G., Fellin, R. <strong>Characterization of a new form of inherited hypercholesterolemia: familial recessive hypercholesterolemia.</strong> Arterioscler. Thromb. Vasc. Biol. 19: 802-809, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10073989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10073989</a>] [<a href="https://doi.org/10.1161/01.atv.19.3.802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10073989">1999</a>), <a href="#6" 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 locus to a 1-cM interval on chromosome 1p35 extending from D1S1152 to D1S2885. <a href="#6" 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 6 mutations in a gene encoding a putative adaptor protein (LDLRAP1; <a href="/entry/605747">605747</a>) mapping to this region. They found no linkage to 15q25-q26, the locus that <a href="#4" class="mim-tip-reference" title="Ciccarese, M., Pacifico, A., Tonolo, G., Pintus, P., Nikoshkov, A., Zuliani, G., Fellin, R., Luthman, H., Maioli, M. <strong>A new locus for autosomal recessive hypercholesterolemia maps to human chromosome 15q25-q26.</strong> Am. J. Hum. Genet. 66: 453-460, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677305[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677305">Ciccarese et al. (2000)</a> had found to be associated with ARH using one of the same families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10073989+7628519+11326085+10677305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected individuals from 6 families with autosomal recessive hypercholesterolemia, including the 2 Sardinian families originally reported by <a href="#18" 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> and <a href="#17" class="mim-tip-reference" title="Zuliani, G., Arca, M., Signore, A., Bader, G., Fazio, S., Chianelli, M., Bellosta, S., Campagna, F., Montali, A., Maioli, M., Pacifico, A., Ricci, G., Fellin, R. <strong>Characterization of a new form of inherited hypercholesterolemia: familial recessive hypercholesterolemia.</strong> Arterioscler. Thromb. Vasc. Biol. 19: 802-809, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10073989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10073989</a>] [<a href="https://doi.org/10.1161/01.atv.19.3.802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10073989">Zuliani et al. (1999)</a> and a Lebanese family 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>, as well as another Lebanese family, an Iranian family, and an American family, <a href="#6" 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 homozygous mutations in the ARH gene (LDLRAP1; see <a href="/entry/605747#0001">605747.0001</a>-<a href="/entry/605747#0006">605747.0006</a>). The nonsense mutation (W22X; <a href="/entry/605747#0001">605747.0001</a>) and 1-bp insertion (<a href="/entry/605747#0002">605747.0002</a>) that were detected in the 2 original Sardinian families were also identified in homozygosity or compound heterozygosity in 10 additional unrelated Sardinian ARH probands, and neither mutation was found in 50 normolipidemic Sardinians. The authors suggested that the finding of 2 mutations accounting for ARH in 12 Sardinian families represented genetic drift on the island of Sardinia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10073989+7628519+11326085+4351242" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="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> screened the entire coding sequence of LDLRAP1 in 40 unrelated individuals from around the world who had hypercholesterolemia and at least 1 normocholesterolemic parent. They identified 4 Italian probands who were homozygous for the same 1-bp insertion (<a href="/entry/605747#0002">605747.0002</a>) that had previously been identified in Sardinian patients. No mutations were identified in the other 36 probands. <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>In a Syrian family with autosomal recessive hypercholesterolemia, <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 loci on 1p36.1-p35 and 13q22-q32 (see cholesterol-lowering factor, <a href="/entry/604595">604595</a>). They identified an intron 1 acceptor splice site mutation in the ARH gene (<a href="/entry/605747#0007">605747.0007</a>) in this family. <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 Japanese sibs with ARH, <a href="#8" 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 homozygosity for a 1-bp insertion in the LDLRAP1 gene (<a href="/entry/605747#0009">605747.0009</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'})"><span class="glyphicon glyphicon-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="#3" 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="/entry/605747#0008">605747.0008</a>), resulting in a mutant protein with an altered phosphotyrosine-binding (PTB) domain. Both parents and an unaffected sister were heterozygous for the mutation. <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><p><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> reviewed data from the Dyslipidemia Registry of the Spanish Atherosclerosis Society, from published reports of Spanish patients with hypercholesterolemia, and from all diagnostic genetic studies for familial hypercholesterolemia in Spain. They identified 7 Spanish patients with ARH and mutations in the LDLRAP1 gene, including 2 sibs who were previously reported by <a href="#12" class="mim-tip-reference" title="Quagliarini, F., Vallve, J.-C., Campagna, F., Alvaro, A., Fuentes-Jimenez, F. J., Sirinian, M. I., Meloni, F., Masana, L., Arca, M. <strong>Autosomal recessive hypercholesterolemia in Spanish kindred due to a large deletion in the ARH gene.</strong> Molec. Genet. Metab. 92: 243-248, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17686643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17686643</a>] [<a href="https://doi.org/10.1016/j.ymgme.2007.06.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17686643">Quagliarini et al. (2007)</a>. One patient, who was compound heterozygous for the missense mutations T218I (<a href="/entry/605747#0010">605747.0010</a>) and S288L (<a href="/entry/605747#0011">605747.0011</a>), exhibited a milder phenotype with much lower baseline LDL levels and later diagnosis than the other 6 patients, who were all homozygous for truncating mutations. <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> concluded that ARH is a very rare disease in Spain, with a prevalence of 1 case per 6.5 million people. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17686643+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><p><strong><em>Exclusion Studies</em></strong></p><p>
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Analysis of the gene defect in large cohorts of patients with a diagnosis of heterozygous FH provided evidence that inherited defects in genes other than those encoding LDLR and APOB can cause the hypercholesterolemia typical of FH. In several of these cohorts, exhaustive analysis of the LDLR gene failed to reveal a defect in about 15% of the patients, and in 2 such studies a family with a sufficiently large pedigree was available to determine that an allele of these genes did not segregate with hypercholesterolemia, suggesting that their defect lay elsewhere (<a href="#16" class="mim-tip-reference" title="Sun, X. M., Patel, D. D., Knight, B. L., Soutar, A. K. <strong>Comparison of the genetic defect with LDL-receptor activity in cultured cells from patients with a clinical diagnosis of heterozygous familial hypercholesterolemia.</strong> Arterioscler. Thromb. Vasc. Biol. 17: 3092-3101, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9409298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9409298</a>] [<a href="https://doi.org/10.1161/01.atv.17.11.3092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9409298">Sun et al., 1997</a>; <a href="#7" class="mim-tip-reference" title="Haddad, L., Day, I. N. M., Hunt, S., Williams, R. R., Humphries, S. E., Hopkins, P. N. <strong>Evidence for a third genetic locus causing familial hypercholesterolemia: a non-LDLR, non-APOB kindred.</strong> J. Lipid Res. 40: 1113-1122, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10357843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10357843</a>]" pmid="10357843">Haddad et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10357843+9409298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-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., 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 FH (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="#9" 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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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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[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://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'})">related citations</a>]
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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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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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Ciccarese, M., Pacifico, A., Tonolo, G., Pintus, P., Nikoshkov, A., Zuliani, G., Fellin, R., Luthman, H., Maioli, M.
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<strong>A new locus for autosomal recessive hypercholesterolemia maps to human chromosome 15q25-q26.</strong>
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Am. J. Hum. Genet. 66: 453-460, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677305[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=10677305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/302753" target="_blank">Full Text</a>]
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Eden, E. R., Naoumova, R. P., Burden, J. J., McCarthy, M. I., Soutar, A. K.
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<strong>Use of homozygosity mapping to identify a region on chromosome 1 bearing a defective gene that causes autosomal recessive homozygous hypercholesterolemia in two unrelated families.</strong>
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Am. J. Hum. Genet. 68: 653-660, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179013</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11179013[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=11179013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/318795" 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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Haddad, L., Day, I. N. M., Hunt, S., Williams, R. R., Humphries, S. E., Hopkins, P. N.
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<strong>Evidence for a third genetic locus causing familial hypercholesterolemia: a non-LDLR, non-APOB kindred.</strong>
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J. Lipid Res. 40: 1113-1122, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10357843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10357843</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10357843" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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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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J. Clin. Invest. 117: 165-174, 2007.
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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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<a id="Khachadurian1973" class="mim-anchor"></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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[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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Norman, D., Sun, X.-M., Bourbon, M., Knight, B. L., Naoumova, R. P., Soutar, A. K.
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<strong>Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10487776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10487776</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10487776[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=10487776" 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/JCI6677" target="_blank">Full Text</a>]
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Quagliarini, F., Vallve, J.-C., Campagna, F., Alvaro, A., Fuentes-Jimenez, F. J., Sirinian, M. I., Meloni, F., Masana, L., Arca, M.
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<strong>Autosomal recessive hypercholesterolemia in Spanish kindred due to a large deletion in the ARH gene.</strong>
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Molec. Genet. Metab. 92: 243-248, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17686643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17686643</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17686643" 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.ymgme.2007.06.012" target="_blank">Full Text</a>]
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Rallidis, L., Nihoyannopoulos, P., Thompson, G. R.
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<strong>Aortic stenosis in homozygous familial hypercholesterolaemia.</strong>
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Heart 76: 84-85, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8774336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8774336</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8774336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/hrt.76.1.84" target="_blank">Full Text</a>]
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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>
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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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Schmidt, H. H.-J., Stuhrmann, M., Shamburek, R., Schewe, C. K., Ebhardt, M., Zech, L. A., Buttner, C., Wendt, M., Beisiegel, U., Brewer, H. B., Jr., Manns, M. P.
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<strong>Delayed low density lipoprotein (LDL) catabolism despite a functional intact LDL-apolipoprotein B particle and LDL-receptor in a subject with clinical homozygous familial hypercholesterolemia.</strong>
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J. Clin. Endocr. Metab. 83: 2167-2174, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9626156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9626156</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9626156" 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/jcem.83.6.4840" target="_blank">Full Text</a>]
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Sun, X. M., Patel, D. D., Knight, B. L., Soutar, A. K.
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<strong>Comparison of the genetic defect with LDL-receptor activity in cultured cells from patients with a clinical diagnosis of heterozygous familial hypercholesterolemia.</strong>
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Arterioscler. Thromb. Vasc. Biol. 17: 3092-3101, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9409298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9409298</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9409298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Zuliani, G., Arca, M., Signore, A., Bader, G., Fazio, S., Chianelli, M., Bellosta, S., Campagna, F., Montali, A., Maioli, M., Pacifico, A., Ricci, G., Fellin, R.
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<strong>Characterization of a new form of inherited hypercholesterolemia: familial recessive hypercholesterolemia.</strong>
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Arterioscler. Thromb. Vasc. Biol. 19: 802-809, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10073989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10073989</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10073989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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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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Marla J. F. O'Neill - updated : 04/11/2018
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Marla J. F. O'Neill - updated : 11/15/2011<br>Marla J. F. O'Neill - updated : 3/30/2007<br>Marla J. F. O'Neill - updated : 3/29/2005<br>Marla J. F. O'Neill - updated : 3/11/2004<br>Ada Hamosh - updated : 6/7/2001<br>Victor A. McKusick - updated : 3/19/2001<br>Victor A. McKusick - updated : 4/6/2000<br>Victor A. McKusick - updated : 9/24/1999
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Victor A. McKusick : 5/17/1999
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carol : 11/19/2019
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carol : 06/19/2019<br>carol : 04/11/2018<br>carol : 11/16/2016<br>carol : 11/15/2011<br>terry : 11/15/2011<br>wwang : 4/17/2007<br>terry : 3/30/2007<br>wwang : 4/1/2005<br>wwang : 3/31/2005<br>terry : 3/29/2005<br>tkritzer : 3/11/2004<br>tkritzer : 3/11/2004<br>ckniffin : 6/5/2002<br>alopez : 6/11/2001<br>terry : 6/7/2001<br>mgross : 3/20/2001<br>mgross : 3/20/2001<br>terry : 3/19/2001<br>mgross : 4/10/2000<br>mgross : 4/7/2000<br>mgross : 4/6/2000<br>mgross : 4/6/2000<br>alopez : 11/15/1999<br>mgross : 10/1/1999<br>terry : 9/24/1999<br>terry : 6/9/1999<br>mgross : 5/19/1999
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<strong>#</strong> 603813
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HYPERCHOLESTEROLEMIA, FAMILIAL, 4; FHCL4
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HYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE; ARH<br />
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HYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE, 1, FORMERLY; ARH1, FORMERLY<br />
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FHCB1, FORMERLY<br />
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HYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE, 2, FORMERLY; ARH2, FORMERLY<br />
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FHCB2, FORMERLY
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</span>
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</h4>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>ORPHA:</strong> 391665;
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<strong>DO:</strong> 0090105;
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</span>
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</p>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene 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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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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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>
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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">
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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">
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603813
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<td>
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<span class="mim-font">
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LDLRAP1
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</span>
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</td>
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<td>
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<span class="mim-font">
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605747
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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<div>
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<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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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because autosomal recessive familial hypercholesterolemia-4 (FHCL4) is caused by homozygous or compound heterozygous mutation in the ARH gene (LDLRAP1; 605747) on chromosome 1p36.</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>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>Autosomal recessive familial hypercholesterolemia-4 (FCHL4) is a rare monogenic disease characterized by very high levels of low-density lipoprotein (LDL) cholesterol (usually above 400 mg/dl) and increased risk of premature atherosclerotic cardiovascular disease (summary by Sanchez-Hernandez et al., 2018). </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>Clinical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Zuliani et al. (1995) described a consanguineous Sardinian family in which a brother and sister had a severe form of hypercholesterolemia with the clinical features of familial hypercholesterolemia (FH; 143890) homozygotes, including severely elevated plasma low density lipoprotein (LDL) cholesterol, tuberous and tendon xanthomata, and premature atherosclerosis. However, LDL receptor (LDLR; 606945) activity measured in skin fibroblasts was normal, as was LDL binding ability. Haplotype segregation analysis excluded involvement of the LDLR and apolipoprotein B (APOB; 107730) genes in the pathogenesis of the disorder. Consanguinity, absence of vertical transmission, and bimodal distribution of plasma cholesterol levels in the kindred were consistent with autosomal recessive inheritance. Sitosterolemia (see 210250) and pseudohomozygous hyperlipidemia (see 144250) were ruled out. </p><p>Zuliani et al. (1999) identified a second Sardinian kindred with similar characteristics. The probands showed severe hypercholesterolemia, whereas their parents and grandparents were normolipidemic. FH, familial defective apoB, sitosterolemia, and cholesteryl ester storage disease (278000) were excluded by in vitro studies. By LDL turnover studies, the authors found a marked reduction in the fractional catabolic rate and a significant increase in the production rate of LDL apoB in the probands compared with normolipidemic controls. The probands also showed a significant reduction in hepatic LDL uptake, similar to that observed in the FH homozygote studied in parallel. A reduced uptake of LDL by the kidney and spleen was also observed in all patients. These findings suggested that this recessive form of hypercholesterolemia is due to a marked reduction of in vivo LDL catabolism. This appeared to be caused by a selective reduction in hepatic LDL uptake. Zuliani et al. (1999) proposed that in this new lipid disorder, a recessive defect causes a selective impairment of LDLR function in the liver. In a note added in proof, Zuliani et al. (1999) stated that 4 'new' Sardinian families with the characteristics of familial recessive hypercholesterolemia had been identified. In all probands, the LDLR activities in fibroblasts as well as the binding ability of LDL to the LDLR were normal. </p><p>Schmidt et al. (1998) identified a 38-year-old male patient with the clinical expression of homozygous familial hypercholesterolemia presenting as severe coronary artery disease, tendon and skin xanthomas, arcus lipoides, and joint pain. They concluded that the disorder was autosomal recessive. Serum concentrations of cholesterol responded well to diet and statins. There was no evidence of an abnormal LDL-APOB particle, which was isolated from the patient by use of the U937 proliferation assay as a functional test of the LDL binding capacity. APOB-3500 and APOB-3531 defects were ruled out by PCR, and there was no evidence for a defect within the LDLR by skin fibroblast analysis, linkage analysis, SSCP, and Southern blot screening across the entire LDLR gene. The in vivo kinetics of radioiodinated LDL-APOB were evaluated in the proband and 3 normal controls. The LDL-APOB isolated from the patient showed normal catabolism, confirming an intact LDL particle. In contrast, the fractional catabolic rate of autologous LDL in the subject and normal controls revealed remarkably delayed catabolism of the patient's LDL. The elevation of LDL cholesterol in the patient resulted from an increased production rate with 22.8 mg/kg per day vs 12.7 to 15.7 mg/kg per day. The authors concluded that there is another catabolic defect beyond the APOB and LDLR genes causing familial hypercholesterolemia. </p><p>Norman et al. (1999) identified apparently recessive familial hypercholesterolemia in 2 kindreds, one of Turkish origin and the other of Asian-Indian origin. The index patient of the Turkish family had a longstanding presumptive diagnosis of homozygous FH based on a raised plasma cholesterol concentration, the presence of extensive cutaneous xanthomata in the webs of her fingers and creases of her hands, and tendon xanthomata from an early age, as well as supravalvular aortic stenosis and premature coronary heart disease. The clinical characteristics of this woman were described in detail by Rallidis et al. (1996). A sib and a double first cousin were also affected. The affected individuals were the offspring of a first-cousin marriage in each case. All 4 parents were apparently unaffected. In the Asian-Indian family, 2 sisters were affected. The parents of this family were also reported to be first cousins, but no additional members of the family were available for study. Cells from the patients in these families exhibited no measurable degradation of LDL in culture. Extensive analysis of DNA and mRNA revealed no defect in the LDL receptor gene, and alleles of the LDLR and apolipoprotein B (APOB; 107730) genes did not cosegregate with hypercholesterolemia in these families. Fluorescence-activated cell sorting (FACS) analysis of binding and uptake of fluorescent LDL or anti-LDLR antibodies showed that LDL receptors were on the cell surface and bound LDL normally, but failed to be internalized, suggesting that some component of endocytosis through clathrin-coated pits was defective. Internalization of the transferrin receptor (190010) occurred normally, suggesting that the defective gene product may interact specifically with the LDL receptor internalization signal. Norman et al. (1999) concluded that identification of the defective gene would aid genetic diagnosis of other hypercholesterolemic patients and elucidate the mechanism by which LDL receptors are internalized, thus suggesting perhaps more appropriate methods of treatment then those currently used for FH patients with known genetic defects. </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>Eden et al. (2001) performed a genomewide scan with polymorphic genetic markers in the 2 families reported by Norman et al. (1999). In both pedigrees, a single region of approximately 12 cM on 1p36-p35, designated FHCB2, fulfilled the criteria for homozygous inheritance of alleles in the affected offspring but not their unaffected sibs. The combined lod score was 5.3 in these unrelated families. </p><p>Using 4 ARH families, including 2 previously studied by Zuliani et al. (1995, 1999), Garcia et al. (2001) mapped the ARH locus to a 1-cM interval on chromosome 1p35 extending from D1S1152 to D1S2885. Garcia et al. (2001) identified 6 mutations in a gene encoding a putative adaptor protein (LDLRAP1; 605747) mapping to this region. They found no linkage to 15q25-q26, the locus that Ciccarese et al. (2000) had found to be associated with ARH using one of the same families. </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">
|
|
<p>In affected individuals from 6 families with autosomal recessive hypercholesterolemia, including the 2 Sardinian families originally reported by Zuliani et al. (1995) and Zuliani et al. (1999) and a Lebanese family previously described by Khachadurian and Uthman (1973), as well as another Lebanese family, an Iranian family, and an American family, Garcia et al. (2001) identified homozygous mutations in the ARH gene (LDLRAP1; see 605747.0001-605747.0006). The nonsense mutation (W22X; 605747.0001) and 1-bp insertion (605747.0002) that were detected in the 2 original Sardinian families were also identified in homozygosity or compound heterozygosity in 10 additional unrelated Sardinian ARH probands, and neither mutation was found in 50 normolipidemic Sardinians. The authors suggested that the finding of 2 mutations accounting for ARH in 12 Sardinian families represented genetic drift on the island of Sardinia. </p><p>Arca et al. (2002) screened the entire coding sequence of LDLRAP1 in 40 unrelated individuals from around the world who had hypercholesterolemia and at least 1 normocholesterolemic parent. They identified 4 Italian probands who were homozygous for the same 1-bp insertion (605747.0002) that had previously been identified in Sardinian patients. No mutations were identified in the other 36 probands. </p><p>In a Syrian family with autosomal recessive hypercholesterolemia, Al-Kateb et al. (2002) found evidence for an interaction between loci on 1p36.1-p35 and 13q22-q32 (see cholesterol-lowering factor, 604595). They identified an intron 1 acceptor splice site mutation in the ARH gene (605747.0007) in this family. </p><p>In 2 Japanese sibs with ARH, Harada-Shiba et al. (2003) identified homozygosity for a 1-bp insertion in the LDLRAP1 gene (605747.0009). </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), resulting in a mutant protein with an altered phosphotyrosine-binding (PTB) domain. Both parents and an unaffected sister were heterozygous for the mutation. </p><p>Sanchez-Hernandez et al. (2018) reviewed data from the Dyslipidemia Registry of the Spanish Atherosclerosis Society, from published reports of Spanish patients with hypercholesterolemia, and from all diagnostic genetic studies for familial hypercholesterolemia in Spain. They identified 7 Spanish patients with ARH and mutations in the LDLRAP1 gene, including 2 sibs who were previously reported by Quagliarini et al. (2007). One patient, who was compound heterozygous for the missense mutations T218I (605747.0010) and S288L (605747.0011), exhibited a milder phenotype with much lower baseline LDL levels and later diagnosis than the other 6 patients, who were all homozygous for truncating mutations. Sanchez-Hernandez et al. (2018) concluded that ARH is a very rare disease in Spain, with a prevalence of 1 case per 6.5 million people. </p><p><strong><em>Exclusion Studies</em></strong></p><p>
|
|
Analysis of the gene defect in large cohorts of patients with a diagnosis of heterozygous FH provided evidence that inherited defects in genes other than those encoding LDLR and APOB can cause the hypercholesterolemia typical of FH. In several of these cohorts, exhaustive analysis of the LDLR gene failed to reveal a defect in about 15% of the patients, and in 2 such studies a family with a sufficiently large pedigree was available to determine that an allele of these genes did not segregate with hypercholesterolemia, suggesting that their defect lay elsewhere (Sun et al., 1997; Haddad et al., 1999). </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. (2007) examined the synthesis and catabolism of Vldl in mouse models of FH (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>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.
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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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[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">
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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: 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">
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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: 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">
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Ciccarese, M., Pacifico, A., Tonolo, G., Pintus, P., Nikoshkov, A., Zuliani, G., Fellin, R., Luthman, H., Maioli, M.
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<strong>A new locus for autosomal recessive hypercholesterolemia maps to human chromosome 15q25-q26.</strong>
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Am. J. Hum. Genet. 66: 453-460, 2000.
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[PubMed: 10677305]
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[Full Text: https://doi.org/10.1086/302753]
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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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Eden, E. R., Naoumova, R. P., Burden, J. J., McCarthy, M. I., Soutar, A. K.
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<strong>Use of homozygosity mapping to identify a region on chromosome 1 bearing a defective gene that causes autosomal recessive homozygous hypercholesterolemia in two unrelated families.</strong>
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Am. J. Hum. Genet. 68: 653-660, 2001.
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[PubMed: 11179013]
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[Full Text: https://doi.org/10.1086/318795]
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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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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: 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">
|
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Haddad, L., Day, I. N. M., Hunt, S., Williams, R. R., Humphries, S. E., Hopkins, P. N.
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<strong>Evidence for a third genetic locus causing familial hypercholesterolemia: a non-LDLR, non-APOB kindred.</strong>
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J. Lipid Res. 40: 1113-1122, 1999.
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[PubMed: 10357843]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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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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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">
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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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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">
|
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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>
|
|
Nutr. Metab. 15: 132-140, 1973.
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[PubMed: 4351242]
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[Full Text: https://doi.org/10.1159/000175431]
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Marla J. F. O'Neill - updated : 04/11/2018<br>Marla J. F. O'Neill - updated : 11/15/2011<br>Marla J. F. O'Neill - updated : 3/30/2007<br>Marla J. F. O'Neill - updated : 3/29/2005<br>Marla J. F. O'Neill - updated : 3/11/2004<br>Ada Hamosh - updated : 6/7/2001<br>Victor A. McKusick - updated : 3/19/2001<br>Victor A. McKusick - updated : 4/6/2000<br>Victor A. McKusick - updated : 9/24/1999
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