4199 lines
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Entry
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- *192977 - VERY LOW DENSITY LIPOPROTEIN RECEPTOR; VLDLR
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*192977</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/192977">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li 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 id="mimFloatingLinksMenu">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000147852;t=ENST00000382100" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=7436" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=192977" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000147852;t=ENST00000382100" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001018056,NM_001322225,NM_001322226,NM_003383,XM_047423848" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_003383" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=192977" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=01895&isoform_id=01895_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/VLDLR" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/391734,391736,407221,409426,437387,688371,1730111,21750962,62087224,65301164,65301167,66394594,119579208,119579209,119579210,119579211,119579212,148744344,158260077,187950383,193788224,219521548,1016080525,1016080540,2217378525,2462626327" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P98155" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=7436" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000147852;t=ENST00000382100" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=VLDLR" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=VLDLR" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+7436" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/VLDLR" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:7436" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/7436" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr9&hgg_gene=ENST00000382100.8&hgg_start=2621787&hgg_end=2660056&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:12698" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:12698" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/vldlr" 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=192977[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=192977[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/VLDLR/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000147852" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=VLDLR" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=VLDLR" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=VLDLR" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=VLDLR&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA37317" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:12698" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0051092.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:98935" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/VLDLR#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:98935" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/7436/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/results?search_type=advanced&omia_id=000865,001947" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=7436" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00020481;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-803" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7436" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=VLDLR&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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192977
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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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VERY LOW DENSITY LIPOPROTEIN RECEPTOR; VLDLR
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=VLDLR" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">VLDLR</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/9/15?start=-3&limit=10&highlight=15">9p24.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:2621787-2660056&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">9:2,621,787-2,660,056</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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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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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/9/15?start=-3&limit=10&highlight=15">
|
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9p24.2
|
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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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Cerebellar hypoplasia, impaired intellectual development, and dysequilibrium syndrome 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/224050"> 224050 </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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</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">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/192977" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/192977" 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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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<p>On isolating and characterizing cDNAs encoding human very low density lipoprotein (VLDL) receptor, <a href="#17" class="mim-tip-reference" title="Sakai, J., Hoshino, A., Takahashi, S., Miura, Y., Ishii, H., Suzuki, H., Kawarabayasi, Y., Yamamoto, T. <strong>Structure, chromosome location, and expression of the human very low density lipoprotein receptor gene.</strong> J. Biol. Chem. 269: 2173-2182, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8294473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8294473</a>]" pmid="8294473">Sakai et al. (1994)</a> found 2 isoforms, one consisting of 5 domains that resembles the low density lipoprotein receptor (<a href="/entry/606945">606945</a>), and a variant form lacking an O-linked sugar domain. The 5-prime untranslated region of the receptor mRNA contains a polymorphic triplet repeat that is also found in the FMR1 gene (<a href="/entry/309550">309550</a>) in the fragile X syndrome (<a href="/entry/300624">300624</a>). The VLDL receptor has a ligand specificity and tissue distribution different from those of the LDL receptor (LDLR; <a href="/entry/606945">606945</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8294473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>VLDLR, like LDLR, consists of 5 domains: an N-terminal 328 amino acids composed of 8 cysteine-rich repeats homologous to the ligand-binding domain of LDLR; a 396-amino acid region homologous to the epidermal growth factor precursor that mediates the acid-dependent dissociation of the ligand in the LDLR; a 46-amino acid domain homologous to the clustered O-linked sugars of the LDLR; a 22-amino acid transmembrane domain; and a 54-amino acid cytoplasmic domain including an NPXY sequence that is required for clustering of the receptor into coated pits. The gene for the VLDL receptor is highly expressed in heart, muscle, and adipose tissues, which are active in fatty acid metabolism; essentially no expression is found in liver. VLDLR appears to play a crucial role in triglyceride metabolism. <a href="#13" class="mim-tip-reference" title="Oka, K., Tzung, K.-W., Sullivan, M., Lindsay, E., Baldini, A., Chan, L. <strong>Human very-low-density lipoprotein receptor complementary DNA and deduced amino acid sequence and localization of its gene (VLDLR) to chromosome band 9q24 by fluorescence in situ hybridization.</strong> Genomics 20: 298-300, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8020981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8020981</a>] [<a href="https://doi.org/10.1006/geno.1994.1171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8020981">Oka et al. (1994)</a> cloned a cDNA for VLDLR from a human heart cDNA library. A mature protein of 846 amino acids, preceded by a 27-residue signal peptide, shares 97% amino acid sequence identity with rabbit VLDLR. A tetrapeptide NPVY that potentially serves as a signal for clustering of the VLDLR on coated pits was present in the cytoplasmic domain, which is 100% conserved between human and rabbit. <a href="#6" class="mim-tip-reference" title="Gafvels, M. E., Paavola, L. G., Boyd, C. O., Nolan, P. M., Wittmaack, F., Chawla, A., Lazar, M. A., Bucan, M., Angelin, B., Strauss, J. F., III. <strong>Cloning of a complementary deoxyribonucleic acid encoding the murine homolog of the very low density lipoprotein/apolipoprotein-E receptor: expression pattern and assignment of the gene to mouse chromosome 19.</strong> Endocrinology 135: 387-394, 1994. Note: Erratum: Endocrinology 136: 795 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8013374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8013374</a>] [<a href="https://doi.org/10.1210/endo.135.1.8013374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8013374">Gafvels et al. (1994)</a> cloned cDNA for the mouse homolog of VLDLR, deduced the amino acid sequence of the protein, and by Northern hybridization demonstrated that the VLDLR mRNA is most abundant in skeletal muscle, heart, kidney, and brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8020981+8013374" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#17" class="mim-tip-reference" title="Sakai, J., Hoshino, A., Takahashi, S., Miura, Y., Ishii, H., Suzuki, H., Kawarabayasi, Y., Yamamoto, T. <strong>Structure, chromosome location, and expression of the human very low density lipoprotein receptor gene.</strong> J. Biol. Chem. 269: 2173-2182, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8294473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8294473</a>]" pmid="8294473">Sakai et al. (1994)</a> determined that the VLDLR gene contains 19 exons spanning approximately 40 kb. The exon-intron organization of the gene is almost identical to that of the LDLR gene, except for an extra exon that encodes an additional repeat in the ligand binding domain of the VLDL receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8294473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By PCR analysis of DNA from human-rodent hybrid cells, <a href="#17" class="mim-tip-reference" title="Sakai, J., Hoshino, A., Takahashi, S., Miura, Y., Ishii, H., Suzuki, H., Kawarabayasi, Y., Yamamoto, T. <strong>Structure, chromosome location, and expression of the human very low density lipoprotein receptor gene.</strong> J. Biol. Chem. 269: 2173-2182, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8294473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8294473</a>]" pmid="8294473">Sakai et al. (1994)</a> mapped the VLDLR gene to chromosome 9. By fluorescence in situ hybridization using the cloned cDNA as a hybridization probe, <a href="#13" class="mim-tip-reference" title="Oka, K., Tzung, K.-W., Sullivan, M., Lindsay, E., Baldini, A., Chan, L. <strong>Human very-low-density lipoprotein receptor complementary DNA and deduced amino acid sequence and localization of its gene (VLDLR) to chromosome band 9q24 by fluorescence in situ hybridization.</strong> Genomics 20: 298-300, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8020981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8020981</a>] [<a href="https://doi.org/10.1006/geno.1994.1171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8020981">Oka et al. (1994)</a> localized the VLDLR gene to 9p23. <a href="#12" class="mim-tip-reference" title="Naggert, J. K., Mu, J.-L. <strong>The mouse very low density lipoprotein receptor (Vldlr) gene maps to chromosome 19.</strong> Mammalian Genome 5: 453-455, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7919660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7919660</a>] [<a href="https://doi.org/10.1007/BF00357008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7919660">Naggert and Mu (1994)</a> showed that the mouse Vldlr gene maps to chromosome 19. By interspecific backcross linkage analysis, <a href="#16" class="mim-tip-reference" title="Pilz, A., Woodward, K., Povey, S., Abbott, C. <strong>Comparative mapping of 50 human chromosome 9 loci in the laboratory mouse.</strong> Genomics 25: 139-149, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7774911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7774911</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80119-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7774911">Pilz et al. (1995)</a> mapped the Vldlr gene to mouse chromosome 19. The assignment of Snf2l2 to the same chromosome defined a new region of synteny between mouse chromosome 19 and the proximal portion of human 9p. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8020981+7919660+7774911+8294473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using in vitro binding experiments, <a href="#9" class="mim-tip-reference" title="Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A., Mumby, M. C., Cooper, J. A., Herz, J. <strong>Direct binding of reelin to VLDL receptor and apoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation.</strong> Neuron 24: 481-489, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10571241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10571241</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80861-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10571241">Hiesberger et al. (1999)</a> showed that Reln (<a href="/entry/600514">600514</a>) binds directly and specifically to the extracellular domains of Vldlr and ApoER2 (<a href="/entry/602600">602600</a>). Blockade of Vldlr and ApoER2 ligand binding correlated with loss of Reelin-induced Dab1 (<a href="/entry/603448">603448</a>) tyrosine phosphorylation. With Western blot analysis, they demonstrated that mice lacking either Reln or Vldlr and ApoER2 (<a href="#21" class="mim-tip-reference" title="Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A., Herz, J. <strong>Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2.</strong> Cell 97: 689-701, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10380922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10380922</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80782-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10380922">Trommsdorff et al., 1999</a>) exhibit a dramatic increase in the phosphorylation level of the microtubule-stabilizing protein tau (MAPT; <a href="/entry/157140">157140</a>). <a href="#9" class="mim-tip-reference" title="Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A., Mumby, M. C., Cooper, J. A., Herz, J. <strong>Direct binding of reelin to VLDL receptor and apoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation.</strong> Neuron 24: 481-489, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10571241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10571241</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80861-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10571241">Hiesberger et al. (1999)</a> concluded that Reln acts via Vldlr and ApoER2 to regulate Dab1 tyrosine phosphorylation and microtubule function in neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10571241+10380922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR), a coordinated series of cellular events that increases the capacity of the ER to process the unfolded proteins and reduce the protein loads. Using microarray analysis, <a href="#5" class="mim-tip-reference" title="Dombroski, B. A., Nayak, R. R., Ewens, K. G., Ankener, W., Cheung, V. G., Spielman, R. S. <strong>Gene expression and genetic variation in response to endoplasmic reticulum stress in human cells.</strong> Am. J. Hum. Genet. 86: 719-729, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20398888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20398888</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20398888[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/10.1016/j.ajhg.2010.03.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20398888">Dombroski et al. (2010)</a> found that VLDLR and INHBE (<a href="/entry/612031">612031</a>) were among hundreds of genes upregulated by ER stress in immortalized human B cell lines. Their expression was also induced by ER stress in primary human fibroblasts, and the expression of VLDLR was induced by ER stress in keratinocytes, which do not express INHBE. The expression of many genes showed individual variation; however, both INHBE and VLDLR were consistently upregulated by ER stress in all 60 immortalized B cell lines examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20398888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Senturk, A., Pfennig, S., Weiss, A., Burk, K., Acker-Palmer, A. <strong>Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration.</strong> Nature 472: 356-360, 2011. Note: Erratum: Nature 478: 274 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21460838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21460838</a>] [<a href="https://doi.org/10.1038/nature09874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21460838">Senturk et al. (2011)</a> showed that the neuronal guidance cues ephrin B proteins are essential for Reelin signaling during the development of laminated structures in the brain. They showed that ephrin Bs genetically interact with Reelin. Notably, compound mouse mutants (Reln heterozygotes null for either Efnb2 (<a href="/entry/600527">600527</a>) or Efnb3 (<a href="/entry/602297">602297</a>)) and triple Efnb1 (<a href="/entry/300035">300035</a>)/Efnb2/Efnb3 knockouts showed neuronal migration defects that recapitulated the ones observed in the neocortex, hippocampus, and cerebellum of the reeler mouse. Mechanistically, <a href="#18" class="mim-tip-reference" title="Senturk, A., Pfennig, S., Weiss, A., Burk, K., Acker-Palmer, A. <strong>Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration.</strong> Nature 472: 356-360, 2011. Note: Erratum: Nature 478: 274 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21460838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21460838</a>] [<a href="https://doi.org/10.1038/nature09874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21460838">Senturk et al. (2011)</a> showed that Reelin binds to the extracellular domain of ephrin Bs, which associate at the membrane with VLDLR and ApoER2 in neurons. Clustering of ephrin Bs leads to the recruitment and phosphorylation of Dab1, which is necessary for Reelin signaling. Conversely, loss of function of ephrin Bs severely impairs Reelin-induced Dab1 phosphorylation. Importantly, activation of ephrin Bs can rescue the reeler neuronal migration defects in the absence of Reelin protein. <a href="#18" class="mim-tip-reference" title="Senturk, A., Pfennig, S., Weiss, A., Burk, K., Acker-Palmer, A. <strong>Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration.</strong> Nature 472: 356-360, 2011. Note: Erratum: Nature 478: 274 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21460838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21460838</a>] [<a href="https://doi.org/10.1038/nature09874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21460838">Senturk et al. (2011)</a> concluded that their results identified ephrin Bs as essential components of the Reelin receptor/signaling pathway to control neuronal migration during the development of the nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21460838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Cerebellar Ataxia, Impaired Intellectual Development, and Dysequilibrium Syndrome 1</em></strong></p><p>
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An autosomal recessive syndrome of nonprogressive cerebellar ataxia and impaired intellectual development is associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification in the Hutterite population (CAMRQ1; <a href="/entry/224050">224050</a>). <a href="#2" class="mim-tip-reference" title="Boycott, K. M., Flavelle, S., Bureau, A., Glass, H. C., Fujiwara, T. M., Wirrell, E., Davey, K., Chudley, A. E., Scott, J. N., McLeod, D. R., Parboosingh, J. S. <strong>Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification.</strong> Am. J. Hum. Genet. 77: 477-483, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16080122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16080122</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16080122[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/10.1086/444400" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16080122">Boycott et al. (2005)</a> used an identity-by-descent mapping approach in 8 patients from 3 interrelated Hutterite families and localized the gene for this syndrome to 9p24. Haplotype analysis identified familial and ancestral recombination events and refined the minimal region to a 2-Mb interval between markers D9S129 and D9S1871. Within this interval, <a href="#2" class="mim-tip-reference" title="Boycott, K. M., Flavelle, S., Bureau, A., Glass, H. C., Fujiwara, T. M., Wirrell, E., Davey, K., Chudley, A. E., Scott, J. N., McLeod, D. R., Parboosingh, J. S. <strong>Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification.</strong> Am. J. Hum. Genet. 77: 477-483, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16080122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16080122</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16080122[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/10.1086/444400" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16080122">Boycott et al. (2005)</a> found a 199-kb homozygous deletion encompassing the entire VLDLR gene (<a href="#0001">192977.0001</a>) in all affected individuals. VLDLR is part of the reelin (RELN; <a href="/entry/600514">600514</a>) signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. <a href="#2" class="mim-tip-reference" title="Boycott, K. M., Flavelle, S., Bureau, A., Glass, H. C., Fujiwara, T. M., Wirrell, E., Davey, K., Chudley, A. E., Scott, J. N., McLeod, D. R., Parboosingh, J. S. <strong>Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification.</strong> Am. J. Hum. Genet. 77: 477-483, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16080122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16080122</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16080122[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/10.1086/444400" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16080122">Boycott et al. (2005)</a> proposed that this Hutterite disorder should be referred to as VLDLR-associated cerebellar hypoplasia. It appeared to represent the first human lipoprotein receptor malformation syndrome and the second human disease associated with a reelin pathway defect, the other being the form of lissencephaly syndrome (<a href="/entry/257320">257320</a>) due to mutations in the RELN gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16080122" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 2 unrelated Turkish families with cerebellar hypoplasia, impaired intellectual development, and quadrupedal locomotion, previously reported by <a href="#20" class="mim-tip-reference" title="Tan, U. <strong>Unertan syndrome: review and report of four new cases.</strong> Int. J. Neurosci. 118: 211-225, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18205078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18205078</a>] [<a href="https://doi.org/10.1080/00207450701667808" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18205078">Tan, 2008</a> and <a href="#19" class="mim-tip-reference" title="Tan, U., Karaca, S., Tan, M., Yillmaz, B., Bagci, N. K., Ozkur, A., Pence, S. <strong>Unertan syndrome: a case series demonstrating human devolution.</strong> Int. J. Neurosci. 118: 1-25, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18041603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18041603</a>] [<a href="https://doi.org/10.1080/00207450701667857" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18041603">Tan et al., 2008</a>, respectively, <a href="#15" class="mim-tip-reference" title="Ozcelik, T., Akarsu, N., Uz, E., Caglayan, S., Gulsuner, S., Onat, O. E., Tan, M., Tan, U. <strong>Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans.</strong> Proc. Nat. Acad. Sci. 105: 4232-4236, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18326629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18326629</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18326629[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0710010105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18326629">Ozcelik et al. (2008)</a> identified 2 different homozygous mutations in the VLDLR gene (<a href="#0002">192977.0002</a> and <a href="#0003">192977.0003</a>, respectively). The findings suggested that reelin and VLDLR are important for proper cerebellar development, which plays a large role in gait. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18205078+18041603+18326629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#23" class="mim-tip-reference" title="Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M. A., Mayer, M., Rodriguez, D., Burglen, L. <strong>RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.</strong> Clin. Genet. 90: 545-549, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27000652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27000652</a>] [<a href="https://doi.org/10.1111/cge.12779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27000652">Valence et al. (2016)</a> identified homozygous or compound heterozygous mutations in the VLDLR gene (<a href="#0007">192977.0007</a>-<a href="#0011">192977.0011</a>) in 4 patients from 3 families with CAMRQ1. <a href="#23" class="mim-tip-reference" title="Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M. A., Mayer, M., Rodriguez, D., Burglen, L. <strong>RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.</strong> Clin. Genet. 90: 545-549, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27000652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27000652</a>] [<a href="https://doi.org/10.1111/cge.12779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27000652">Valence et al. (2016)</a> noted that the combination of an extremely hypoplastic vermis with absent folia and cortical anomalies was strongly suggestive of a defect in the reelin pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27000652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Associations Pending Confirmation</em></strong></p><p>
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A specific isoform of apolipoprotein E (<a href="/entry/107741">107741</a>), encoded by the APOE4 allele, is associated with the accelerated rate of disease expression of sporadic Alzheimer disease (AD) and late-onset familial AD. <a href="#14" class="mim-tip-reference" title="Okuizumi, K., Onodera, O., Namba, Y., Ikeda, K., Yamamoto, T., Seki, K., Ueki, A., Nanko, S., Tanaka, H., Takahashi, H., Oyanagi, K., Mizusawa, H., Kanazawa, I., Tsuji, S. <strong>Genetic association of the very low density lipoprotein (VLDL) receptor gene with sporadic Alzheimer's disease.</strong> Nature Genet. 11: 207-209, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550352</a>] [<a href="https://doi.org/10.1038/ng1095-207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550352">Okuizumi et al. (1995)</a> noted that, in patients who carry the APOE4 allele, an earlier age of onset has also been demonstrated in patients who also have mutations in the amyloid precursor protein gene (<a href="/entry/104760">104760</a>) involving codon 717 (<a href="/entry/104760#0002">104760.0002</a>) and codons 670 and 671 (<a href="/entry/104760#0008">104760.0008</a>). On the other hand, the presence of the APOE4 allele makes no difference in familial AD patients with APP692 (<a href="/entry/104760#0005">104760.0005</a>) or APP693 mutations, nor does it make a difference in chromosome 14-linked familial AD patients (AD3; <a href="/entry/607822">607822</a>). Hypothesizing that receptors for APOE-containing lipoproteins act as a potential risk factor for AD, <a href="#14" class="mim-tip-reference" title="Okuizumi, K., Onodera, O., Namba, Y., Ikeda, K., Yamamoto, T., Seki, K., Ueki, A., Nanko, S., Tanaka, H., Takahashi, H., Oyanagi, K., Mizusawa, H., Kanazawa, I., Tsuji, S. <strong>Genetic association of the very low density lipoprotein (VLDL) receptor gene with sporadic Alzheimer's disease.</strong> Nature Genet. 11: 207-209, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550352</a>] [<a href="https://doi.org/10.1038/ng1095-207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550352">Okuizumi et al. (1995)</a> performed an association study using a polymorphic triplet (CGG) repeat in the VLDLR gene. The frequency of the 5-repeat allele was significantly higher in all Japanese sporadic AD patients (P less than 0.02) than in Japanese controls. Moreover, the odds ratio (OR) was significantly increased in the AD patients homozygous for the 5-repeat allele; OR = 2.1, 95% confidence interval = 1.1-4.2. Multiple logistic regression analysis showed that the relative risk conferred by the presence of 2 copies of the 5-repeat allele and at least 1 copy of the APOE4 allele is 8.7; 95% CI = 2.9-25.8. <a href="#14" class="mim-tip-reference" title="Okuizumi, K., Onodera, O., Namba, Y., Ikeda, K., Yamamoto, T., Seki, K., Ueki, A., Nanko, S., Tanaka, H., Takahashi, H., Oyanagi, K., Mizusawa, H., Kanazawa, I., Tsuji, S. <strong>Genetic association of the very low density lipoprotein (VLDL) receptor gene with sporadic Alzheimer's disease.</strong> Nature Genet. 11: 207-209, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550352</a>] [<a href="https://doi.org/10.1038/ng1095-207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550352">Okuizumi et al. (1995)</a> concluded that VLDLR is a susceptibility gene for AD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550352" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 population study of 221 subjects with dementia compared with 249 controls, <a href="#8" class="mim-tip-reference" title="Helbecque, N., Berr, C., Cottel, D., Fromentin-David, I., Sazdovitch, V., Ricolfi, F., Ducimetiere, P., Di Menza, C., Amouyel, P. <strong>VLDL receptor polymorphism, cognitive impairment, and dementia.</strong> Neurology 56: 1183-1188, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11342683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11342683</a>] [<a href="https://doi.org/10.1212/wnl.56.9.1183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11342683">Helbecque et al. (2001)</a> found that the presence of the VLDLR 5-repeat allele was associated with an increased relative risk of dementia (OR = 1.9). The risk was more pronounced in individuals who also had cardiovascular problems (OR = 2.5) or who carried the APOE4 allele (OR = 8.4). In a clinical study of 124 patients with dementia compared with 179 neuropathologically defined controls, the OR of developing dementia when bearing at least 1 VLDLR 5-repeat allele was 8.1, and was more pronounced in subjects with mixed or vascular dementia than in patients with AD. APOE4 conferred a higher risk of AD than of vascular or mixed dementia. <a href="#8" class="mim-tip-reference" title="Helbecque, N., Berr, C., Cottel, D., Fromentin-David, I., Sazdovitch, V., Ricolfi, F., Ducimetiere, P., Di Menza, C., Amouyel, P. <strong>VLDL receptor polymorphism, cognitive impairment, and dementia.</strong> Neurology 56: 1183-1188, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11342683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11342683</a>] [<a href="https://doi.org/10.1212/wnl.56.9.1183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11342683">Helbecque et al. (2001)</a> concluded that carrying a VLDLR 5-repeat allele is a risk factor for vascular dementia in individuals with a history of vascular disease, whereas carrying the APOE4 allele is associated with dementia in others. In general, the results suggested the influence of vascular risk factors in the occurrence of dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11342683" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Layering of neurons in the cerebral cortex and cerebellum requires reelin (RELN; <a href="/entry/600514">600514</a>), an extracellular matrix protein, and mammalian disabled (DAB1; <a href="/entry/603448">603448</a>), a cytosolic protein that activates tyrosine kinases. By targeted disruption experiments in mice, <a href="#21" class="mim-tip-reference" title="Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A., Herz, J. <strong>Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2.</strong> Cell 97: 689-701, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10380922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10380922</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80782-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10380922">Trommsdorff et al. (1999)</a> showed that 2 cell surface receptors, VLDLR and apolipoprotein E receptor-2 (APOER2; <a href="/entry/602600">602600</a>), are also required. Both receptors bound Dab1 on their cytoplasmic tails and were expressed in cortical and cerebellar layers adjacent to layers expressing Reln. Dab1 expression was upregulated in knockout mice lacking both the Vldlr and Apoer2 genes. Inversion of cortical layers, absence of cerebellar foliation, and the migration of Purkinje cells in these animals precisely mimicked the phenotype of mice lacking Reln or Dab1. These findings established novel signaling functions for the LDL receptor gene family and suggested that VLDLR and APOER2 participate in transmitting the extracellular RELN signal to intracellular signaling processes initiated by DAB1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10380922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Li, C., Huang, Z., Kingsley, R., Zhou, X., Li, F., Parke, D. W., II, Cao, W. <strong>Biochemical alterations in the retinas of very low-density lipoprotein receptor knockout mice: an animal model of retinal angiomatous proliferation.</strong> Arch. Ophthal. 125: 795-803, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17562991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17562991</a>] [<a href="https://doi.org/10.1001/archopht.125.6.795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17562991">Li et al. (2007)</a> characterized biochemical alterations in the retinas of Vldlr knockout mice in an animal model of retinal angiomatous proliferation. Expression of the angiogenic factors vascular endothelial growth factor (VEGF; <a href="/entry/192240">192240</a>) and basic fibroblast growth factor (BFGF; <a href="/entry/134920">134920</a>) was significantly greater in the area of retinal neovascularization. Mueller cells around the lesion were activated, as indicated by increased expression of glial fibrillary acidic protein (GFAP; <a href="/entry/137780">137780</a>). Expression of the proinflammatory cytokine IL18 (<a href="/entry/600953">600953</a>) and the inflammation mediator intercellular adhesion molecule-1 (ICAM1; <a href="/entry/147840">147840</a>) was increased before significant intraretinal neovascularization. Furthermore, phosphorylation of Akt (<a href="/entry/164730">164730</a>) and mitogen-activated protein kinase (see <a href="/entry/176948">176948</a>) and translocalization of nuclear factor kappa-B (see <a href="/entry/164011">164011</a>) were greater in Vldlr knockout mouse retinas. Thus, <a href="#10" class="mim-tip-reference" title="Li, C., Huang, Z., Kingsley, R., Zhou, X., Li, F., Parke, D. W., II, Cao, W. <strong>Biochemical alterations in the retinas of very low-density lipoprotein receptor knockout mice: an animal model of retinal angiomatous proliferation.</strong> Arch. Ophthal. 125: 795-803, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17562991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17562991</a>] [<a href="https://doi.org/10.1001/archopht.125.6.795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17562991">Li et al. (2007)</a> concluded that an inflammatory process was involved in the development of neovascularization in the Vldlr knockout mouse retina. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17562991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012984" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012984" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012984</a>
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<p><a href="#2" class="mim-tip-reference" title="Boycott, K. M., Flavelle, S., Bureau, A., Glass, H. C., Fujiwara, T. M., Wirrell, E., Davey, K., Chudley, A. E., Scott, J. N., McLeod, D. R., Parboosingh, J. S. <strong>Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification.</strong> Am. J. Hum. Genet. 77: 477-483, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16080122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16080122</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16080122[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/10.1086/444400" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16080122">Boycott et al. (2005)</a> found that the autosomal recessive syndrome of nonprogressive ataxia and impaired intellectual development associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification occurring in the Hutterite population (CAMRQ1; <a href="/entry/224050">224050</a>) is due to deletion of the VLDLR gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16080122" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80338907 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338907;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80338907?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80338907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80338907" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a Turkish family with cerebellar hypoplasia, impaired intellectual development, and quadrupedal locomotion-1 (CAMRQ1; <a href="/entry/224050">224050</a>), <a href="#15" class="mim-tip-reference" title="Ozcelik, T., Akarsu, N., Uz, E., Caglayan, S., Gulsuner, S., Onat, O. E., Tan, M., Tan, U. <strong>Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans.</strong> Proc. Nat. Acad. Sci. 105: 4232-4236, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18326629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18326629</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18326629[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0710010105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18326629">Ozcelik et al. (2008)</a> identified a homozygous 769C-T transition in exon 5 of the VLDLR gene, resulting in an arg257-to-ter (R257X) substitution in the ligand-binding domain. Because the mutation is located in the extracellular region, the protein cannot be inserted into the cell membrane to function as a receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18326629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338906 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338906;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80338906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80338906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 affected members of a Turkish family with cerebellar hypoplasia, impaired intellectual development, and quadrupedal locomotion-1 (CAMRQ1; <a href="/entry/224050">224050</a>), <a href="#15" class="mim-tip-reference" title="Ozcelik, T., Akarsu, N., Uz, E., Caglayan, S., Gulsuner, S., Onat, O. E., Tan, M., Tan, U. <strong>Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans.</strong> Proc. Nat. Acad. Sci. 105: 4232-4236, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18326629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18326629</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18326629[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0710010105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18326629">Ozcelik et al. (2008)</a> identified a homozygous 1-bp deletion (2339delT) in exon 17 of the VLDLR gene, resulting in a frameshift and premature termination in the O-linked sugar domain of the protein. Because the mutation is located in the extracellular region, the protein could not be inserted into the cell membrane to function as a receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18326629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Turkmen, S., Hoffmann, K., Demirhan, O., Aruoba, D., Humphrey, N., Mundlos, S. <strong>Cerebellar hypoplasia, with quadrupedal locomotion, caused by mutations in the very low-density lipoprotein receptor gene.</strong> Europ. J. Hum. Genet. 16: 1070-1074, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18364738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18364738</a>] [<a href="https://doi.org/10.1038/ejhg.2008.73" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18364738">Turkmen et al. (2008)</a> identified homozygosity for the 2339delT deletion in 3 affected members of another Turkish family with cerebellar hypoplasia and impaired intellectual development with quadrupedal locomotion. <a href="#22" class="mim-tip-reference" title="Turkmen, S., Hoffmann, K., Demirhan, O., Aruoba, D., Humphrey, N., Mundlos, S. <strong>Cerebellar hypoplasia, with quadrupedal locomotion, caused by mutations in the very low-density lipoprotein receptor gene.</strong> Europ. J. Hum. Genet. 16: 1070-1074, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18364738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18364738</a>] [<a href="https://doi.org/10.1038/ejhg.2008.73" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18364738">Turkmen et al. (2008)</a> postulated nonsense-mediated mRNA decay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18364738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80338905 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338905;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80338905?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80338905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80338905" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a consanguineous Iranian family with congenital cerebellar ataxia and impaired intellectual development (CAMRQ1; <a href="/entry/224050">224050</a>), <a href="#11" class="mim-tip-reference" title="Moheb, L. A., Tzschach, A., Garshasbi, M., Kahrizi, K., Darvish, H., Heshmati, Y., Kordi, A., Najmabadi, H., Ropers, H. H., Kuss, A. W. <strong>Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome.</strong> Europ. J. Hum. Genet. 16: 270-273, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18043714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18043714</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18043714">Moheb et al. (2008)</a> identified a homozygous 1342C-T transition in exon 10 of the VLDLR gene, resulting in an arg448-to-ter (R448X) substitution affecting both isoforms. Affected individuals had either no speech at all or spoke only a few words, and none could walk independently. Brain imaging was not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18043714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122380 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122380;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs398122380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs398122380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000049269" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049269" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049269</a>
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<p>In 2 sibs, born of consanguineous Turkish parents, with congenital cerebellar ataxia and impaired intellectual development (CAMRQ1; <a href="/entry/224050">224050</a>), <a href="#4" class="mim-tip-reference" title="Dixon-Salazar, T. J., Silhavy, J. L., Udpa, N., Schroth, J., Bielas, S., Schaffer, A. E., Olvera, J., Bafna, V., Zaki, M. S., Abdel-Salam, G. H., Mansour, L. A., Selim, L., and 17 others. <strong>Exome sequencing can improve diagnosis and alter patient management.</strong> Sci. Transl. Med. 4: 138ra78, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22700954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22700954</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22700954[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/scitranslmed.3003544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22700954">Dixon-Salazar et al. (2012)</a> identified a homozygous 7-bp deletion in the VLDLR gene (c.1247_53delGTTACAA), resulting in a frameshift and premature termination (Tyr417fsTer434). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in 200 controls. The patients had microcephaly, nystagmus, mild spasticity, arachnodactyly, and pontocerebellar hypoplasia on brain imaging. The patients were initially reported as having pontocerebellar hypoplasia (<a href="#3" class="mim-tip-reference" title="Dilber, E., Aynaci, F. M., Ahmetoglu, A. <strong>Pontocerebellar hypoplasia in two siblings with dysmorphic features.</strong> J. Child Neurol. 17: 64-66, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11913577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11913577</a>] [<a href="https://doi.org/10.1177/088307380201700119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11913577">Dilber et al., 2002</a>), but exome sequencing yielded the correct diagnosis. (<a href="#7" class="mim-tip-reference" title="Gleeson, J. <strong>Personal Communication.</strong> San Diego, Ca. 1/16/2014."None>Gleeson (2014)</a> provided the correct protein change caused by this mutation, which was erroneously stated in the article by <a href="#4" class="mim-tip-reference" title="Dixon-Salazar, T. J., Silhavy, J. L., Udpa, N., Schroth, J., Bielas, S., Schaffer, A. E., Olvera, J., Bafna, V., Zaki, M. S., Abdel-Salam, G. H., Mansour, L. A., Selim, L., and 17 others. <strong>Exome sequencing can improve diagnosis and alter patient management.</strong> Sci. Transl. Med. 4: 138ra78, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22700954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22700954</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22700954[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/scitranslmed.3003544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22700954">Dixon-Salazar et al. (2012)</a> as p.G1246fsX1305.) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11913577+22700954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514750 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514750;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397514750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397514750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000054559 OR RCV004798764" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000054559, RCV004798764" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000054559...</a>
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<p>In 5 patients from 2 Omani families with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; <a href="/entry/224050">224050</a>), <a href="#1" class="mim-tip-reference" title="Ali, B. R., Silhavy, J. L., Gleeson, M. J., Gleeson, J. G., Al-Gazali, L. <strong>A missense founder mutation in VLDLR is associated with dysequilibrium syndrome without quadrupedal locomotion.</strong> BMC Med. Genet. 13: 80, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22973972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22973972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22973972[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/10.1186/1471-2350-13-80" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22973972">Ali et al. (2012)</a> identified a homozygous c.2117G-T transversion in exon 15 of the VLDLR gene, resulting in a cys706-to-phe (C706F) substitution at a highly conserved residue in the extracellular EGF-like-3 domain that is predicted to be involved in a cysteine bond. <a href="#1" class="mim-tip-reference" title="Ali, B. R., Silhavy, J. L., Gleeson, M. J., Gleeson, J. G., Al-Gazali, L. <strong>A missense founder mutation in VLDLR is associated with dysequilibrium syndrome without quadrupedal locomotion.</strong> BMC Med. Genet. 13: 80, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22973972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22973972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22973972[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/10.1186/1471-2350-13-80" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22973972">Ali et al. (2012)</a> suggested that the mutation would result in protein misfolding, possible degradation, and loss of function. The mutation was not found in over 1,000 ethnically matched control exomes or in a control database. Haplotype analysis indicated a founder effect. The patients had classic features of the disorder, including delayed psychomotor development, hypotonia, mental retardation, lack of speech development, gait and truncal ataxia, cerebellar hypoplasia, and simplified cortical gyri. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22973972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003325251 OR RCV003561303" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003325251, RCV003561303" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003325251...</a>
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<p>In 2 sibs (patients 2 and 3) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; <a href="/entry/224050">224050</a>), <a href="#23" class="mim-tip-reference" title="Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M. A., Mayer, M., Rodriguez, D., Burglen, L. <strong>RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.</strong> Clin. Genet. 90: 545-549, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27000652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27000652</a>] [<a href="https://doi.org/10.1111/cge.12779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27000652">Valence et al. (2016)</a> identified compound heterozygous mutations in the VLDLR gene: an arg301-to-ter (R301X) substitution on one allele and a c.820+1G-A (<a href="#0008">192977.0008</a>) mutation, predicted to result in abnormal splicing of exon 54, on the other allele. The splice mutation was found in cis with an arg301-to-gln (R301Q) variant, the pathogenicity of which was unknown. Each parent was heterozygous for one of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27000652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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VLDLR, c.820+1G-A
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002722922 OR RCV003325245" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002722922, RCV003325245" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002722922...</a>
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<p>For discussion of the c.820+1G-A mutation in the VLDLR gene, predicted to result in abnormal splicing of exon 54, that was identified in compound heterozygous state in 2 sibs (patients 2 and 3) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; <a href="/entry/224050">224050</a>) by <a href="#23" class="mim-tip-reference" title="Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M. A., Mayer, M., Rodriguez, D., Burglen, L. <strong>RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.</strong> Clin. Genet. 90: 545-549, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27000652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27000652</a>] [<a href="https://doi.org/10.1111/cge.12779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27000652">Valence et al. (2016)</a>, see <a href="#0007">192977.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27000652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003325252" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003325252" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003325252</a>
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<p>In a patient (patient 4) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; <a href="/entry/224050">224050</a>), <a href="#23" class="mim-tip-reference" title="Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M. A., Mayer, M., Rodriguez, D., Burglen, L. <strong>RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.</strong> Clin. Genet. 90: 545-549, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27000652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27000652</a>] [<a href="https://doi.org/10.1111/cge.12779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27000652">Valence et al. (2016)</a> identified compound heterozygous mutations in the VLDLR gene: a trp50-to-ter (W50X) substitution and a glu654-to-gly (E654G; <a href="#0010">192977.0010</a>) substitution. The mutations were identified by sequencing of the VLDLR gene; the parents were not tested for the mutations. The D654G mutation was not present in the dbSNP, ExAC, and ESP variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27000652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003325253" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003325253" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003325253</a>
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<p>For discussion of the glu654-to-gly (E654G) substitution in the VLDLR gene that was identified in compound heterozygous state in a patient (patient 4) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; <a href="/entry/224050">224050</a>) by <a href="#23" class="mim-tip-reference" title="Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M. A., Mayer, M., Rodriguez, D., Burglen, L. <strong>RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.</strong> Clin. Genet. 90: 545-549, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27000652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27000652</a>] [<a href="https://doi.org/10.1111/cge.12779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27000652">Valence et al. (2016)</a>, see <a href="#0009">192977.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27000652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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VLDLR, TRP575TER
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003325254" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003325254" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003325254</a>
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<p>In a patient (patient 5) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; <a href="/entry/224050">224050</a>), <a href="#23" class="mim-tip-reference" title="Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M. A., Mayer, M., Rodriguez, D., Burglen, L. <strong>RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.</strong> Clin. Genet. 90: 545-549, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27000652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27000652</a>] [<a href="https://doi.org/10.1111/cge.12779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27000652">Valence et al. (2016)</a> identified homozygosity for a trp575-to-ter (W575X) mutation in the VLDLR gene. The mutation, which was identified by sequencing of the VLDLR gene, was present in heterozygous state in the parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27000652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<div class="">
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<strong>A missense founder mutation in VLDLR is associated with dysequilibrium syndrome without quadrupedal locomotion.</strong>
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[<a href="https://doi.org/10.1186/1471-2350-13-80" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16080122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16080122</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16080122[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=16080122" 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/10.1086/444400" target="_blank">Full Text</a>]
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<a id="Dilber2002" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1177/088307380201700119" target="_blank">Full Text</a>]
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Dixon-Salazar, T. J., Silhavy, J. L., Udpa, N., Schroth, J., Bielas, S., Schaffer, A. E., Olvera, J., Bafna, V., Zaki, M. S., Abdel-Salam, G. H., Mansour, L. A., Selim, L., and 17 others.
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<strong>Exome sequencing can improve diagnosis and alter patient management.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22700954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22700954</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22700954[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=22700954" 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/scitranslmed.3003544" target="_blank">Full Text</a>]
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<a id="Dombroski2010" class="mim-anchor"></a>
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Dombroski, B. A., Nayak, R. R., Ewens, K. G., Ankener, W., Cheung, V. G., Spielman, R. S.
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<strong>Gene expression and genetic variation in response to endoplasmic reticulum stress in human cells.</strong>
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<a id="Gafvels1994" class="mim-anchor"></a>
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Gafvels, M. E., Paavola, L. G., Boyd, C. O., Nolan, P. M., Wittmaack, F., Chawla, A., Lazar, M. A., Bucan, M., Angelin, B., Strauss, J. F., III.
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<strong>Cloning of a complementary deoxyribonucleic acid encoding the murine homolog of the very low density lipoprotein/apolipoprotein-E receptor: expression pattern and assignment of the gene to mouse chromosome 19.</strong>
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[<a href="https://doi.org/10.1210/endo.135.1.8013374" target="_blank">Full Text</a>]
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Gleeson, J.
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<strong>Personal Communication.</strong>
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San Diego, Ca. 1/16/2014.
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[<a href="https://doi.org/10.1016/s0896-6273(00)80861-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archopht.125.6.795" target="_blank">Full Text</a>]
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<a id="Moheb2008" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1038/sj.ejhg.5201967" target="_blank">Full Text</a>]
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<a id="Naggert1994" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1007/BF00357008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1994.1171" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1095-207" target="_blank">Full Text</a>]
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Ozcelik2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ozcelik, T., Akarsu, N., Uz, E., Caglayan, S., Gulsuner, S., Onat, O. E., Tan, M., Tan, U.
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<strong>Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18326629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18326629</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18326629[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=18326629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0710010105" target="_blank">Full Text</a>]
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</p>
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</div>
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<a id="16" class="mim-anchor"></a>
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<a id="Pilz1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pilz, A., Woodward, K., Povey, S., Abbott, C.
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<strong>Comparative mapping of 50 human chromosome 9 loci in the laboratory mouse.</strong>
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Genomics 25: 139-149, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7774911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7774911</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7774911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(95)80119-7" target="_blank">Full Text</a>]
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Sakai1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sakai, J., Hoshino, A., Takahashi, S., Miura, Y., Ishii, H., Suzuki, H., Kawarabayasi, Y., Yamamoto, T.
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<strong>Structure, chromosome location, and expression of the human very low density lipoprotein receptor gene.</strong>
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J. Biol. Chem. 269: 2173-2182, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8294473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8294473</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8294473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Senturk2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Senturk, A., Pfennig, S., Weiss, A., Burk, K., Acker-Palmer, A.
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<strong>Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration.</strong>
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Nature 472: 356-360, 2011. Note: Erratum: Nature 478: 274 only, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21460838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21460838</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21460838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature09874" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Tan2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tan, U., Karaca, S., Tan, M., Yillmaz, B., Bagci, N. K., Ozkur, A., Pence, S.
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<strong>Unertan syndrome: a case series demonstrating human devolution.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18041603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18041603</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18041603" 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/10.1080/00207450701667857" target="_blank">Full Text</a>]
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Tan2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tan, U.
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<strong>Unertan syndrome: review and report of four new cases.</strong>
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Int. J. Neurosci. 118: 211-225, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18205078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18205078</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18205078" 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/10.1080/00207450701667808" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Trommsdorff1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A., Herz, J.
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<strong>Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2.</strong>
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Cell 97: 689-701, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10380922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10380922</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10380922" 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/s0092-8674(00)80782-5" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Turkmen2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Turkmen, S., Hoffmann, K., Demirhan, O., Aruoba, D., Humphrey, N., Mundlos, S.
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<strong>Cerebellar hypoplasia, with quadrupedal locomotion, caused by mutations in the very low-density lipoprotein receptor gene.</strong>
|
|
Europ. J. Hum. Genet. 16: 1070-1074, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18364738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18364738</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18364738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ejhg.2008.73" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Valence2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M. A., Mayer, M., Rodriguez, D., Burglen, L.
|
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<strong>RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.</strong>
|
|
Clin. Genet. 90: 545-549, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27000652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27000652</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27000652" 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/cge.12779" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 08/29/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 8/28/2013<br>Cassandra L. Kniffin - updated : 7/1/2013<br>Ada Hamosh - updated : 7/8/2011<br>Patricia A. Hartz - updated : 6/4/2010<br>Cassandra L. Kniffin - updated : 2/3/2010<br>Cassandra L. Kniffin - updated : 1/8/2009<br>Cassandra L. Kniffin - updated : 6/19/2008<br>Jane Kelly - updated : 12/6/2007<br>Victor A. McKusick - updated : 9/1/2005<br>Cassandra L. Kniffin - updated : 2/3/2003<br>Dawn Watkins-Chow - updated : 11/25/2001<br>Stylianos E. Antonarakis - updated : 7/8/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 8/26/1994
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/29/2023
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</span>
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</div>
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</div>
|
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 12/28/2022<br>carol : 12/25/2022<br>carol : 12/21/2022<br>carol : 01/17/2014<br>carol : 12/9/2013<br>carol : 9/17/2013<br>carol : 8/30/2013<br>tpirozzi : 8/30/2013<br>ckniffin : 8/28/2013<br>carol : 7/9/2013<br>ckniffin : 7/1/2013<br>terry : 3/28/2013<br>alopez : 11/29/2011<br>alopez : 7/12/2011<br>terry : 7/8/2011<br>alopez : 6/4/2010<br>carol : 2/4/2010<br>carol : 2/4/2010<br>ckniffin : 2/3/2010<br>wwang : 1/21/2009<br>ckniffin : 1/8/2009<br>joanna : 9/8/2008<br>ckniffin : 9/3/2008<br>wwang : 7/16/2008<br>ckniffin : 7/15/2008<br>ckniffin : 6/19/2008<br>alopez : 12/6/2007<br>carol : 1/31/2007<br>carol : 11/27/2006<br>alopez : 9/8/2005<br>terry : 9/1/2005<br>ckniffin : 5/28/2003<br>carol : 2/14/2003<br>ckniffin : 2/3/2003<br>ckniffin : 6/5/2002<br>carol : 11/25/2001<br>mgross : 7/8/1999<br>mgross : 7/8/1999<br>mgross : 7/8/1999<br>mark : 1/8/1996<br>mark : 10/10/1995<br>carol : 2/7/1995<br>terry : 8/26/1994
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 192977
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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VERY LOW DENSITY LIPOPROTEIN RECEPTOR; VLDLR
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: VLDLR</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: 9p24.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:2,621,787-2,660,056 </span>
|
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</em>
|
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</strong>
|
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<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
|
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
|
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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9p24.2
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Cerebellar hypoplasia, impaired intellectual development, and dysequilibrium syndrome 1
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
224050
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>On isolating and characterizing cDNAs encoding human very low density lipoprotein (VLDL) receptor, Sakai et al. (1994) found 2 isoforms, one consisting of 5 domains that resembles the low density lipoprotein receptor (606945), and a variant form lacking an O-linked sugar domain. The 5-prime untranslated region of the receptor mRNA contains a polymorphic triplet repeat that is also found in the FMR1 gene (309550) in the fragile X syndrome (300624). The VLDL receptor has a ligand specificity and tissue distribution different from those of the LDL receptor (LDLR; 606945). </p><p>VLDLR, like LDLR, consists of 5 domains: an N-terminal 328 amino acids composed of 8 cysteine-rich repeats homologous to the ligand-binding domain of LDLR; a 396-amino acid region homologous to the epidermal growth factor precursor that mediates the acid-dependent dissociation of the ligand in the LDLR; a 46-amino acid domain homologous to the clustered O-linked sugars of the LDLR; a 22-amino acid transmembrane domain; and a 54-amino acid cytoplasmic domain including an NPXY sequence that is required for clustering of the receptor into coated pits. The gene for the VLDL receptor is highly expressed in heart, muscle, and adipose tissues, which are active in fatty acid metabolism; essentially no expression is found in liver. VLDLR appears to play a crucial role in triglyceride metabolism. Oka et al. (1994) cloned a cDNA for VLDLR from a human heart cDNA library. A mature protein of 846 amino acids, preceded by a 27-residue signal peptide, shares 97% amino acid sequence identity with rabbit VLDLR. A tetrapeptide NPVY that potentially serves as a signal for clustering of the VLDLR on coated pits was present in the cytoplasmic domain, which is 100% conserved between human and rabbit. Gafvels et al. (1994) cloned cDNA for the mouse homolog of VLDLR, deduced the amino acid sequence of the protein, and by Northern hybridization demonstrated that the VLDLR mRNA is most abundant in skeletal muscle, heart, kidney, and brain. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</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>Sakai et al. (1994) determined that the VLDLR gene contains 19 exons spanning approximately 40 kb. The exon-intron organization of the gene is almost identical to that of the LDLR gene, except for an extra exon that encodes an additional repeat in the ligand binding domain of the VLDL receptor. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By PCR analysis of DNA from human-rodent hybrid cells, Sakai et al. (1994) mapped the VLDLR gene to chromosome 9. By fluorescence in situ hybridization using the cloned cDNA as a hybridization probe, Oka et al. (1994) localized the VLDLR gene to 9p23. Naggert and Mu (1994) showed that the mouse Vldlr gene maps to chromosome 19. By interspecific backcross linkage analysis, Pilz et al. (1995) mapped the Vldlr gene to mouse chromosome 19. The assignment of Snf2l2 to the same chromosome defined a new region of synteny between mouse chromosome 19 and the proximal portion of human 9p. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using in vitro binding experiments, Hiesberger et al. (1999) showed that Reln (600514) binds directly and specifically to the extracellular domains of Vldlr and ApoER2 (602600). Blockade of Vldlr and ApoER2 ligand binding correlated with loss of Reelin-induced Dab1 (603448) tyrosine phosphorylation. With Western blot analysis, they demonstrated that mice lacking either Reln or Vldlr and ApoER2 (Trommsdorff et al., 1999) exhibit a dramatic increase in the phosphorylation level of the microtubule-stabilizing protein tau (MAPT; 157140). Hiesberger et al. (1999) concluded that Reln acts via Vldlr and ApoER2 to regulate Dab1 tyrosine phosphorylation and microtubule function in neurons. </p><p>The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR), a coordinated series of cellular events that increases the capacity of the ER to process the unfolded proteins and reduce the protein loads. Using microarray analysis, Dombroski et al. (2010) found that VLDLR and INHBE (612031) were among hundreds of genes upregulated by ER stress in immortalized human B cell lines. Their expression was also induced by ER stress in primary human fibroblasts, and the expression of VLDLR was induced by ER stress in keratinocytes, which do not express INHBE. The expression of many genes showed individual variation; however, both INHBE and VLDLR were consistently upregulated by ER stress in all 60 immortalized B cell lines examined. </p><p>Senturk et al. (2011) showed that the neuronal guidance cues ephrin B proteins are essential for Reelin signaling during the development of laminated structures in the brain. They showed that ephrin Bs genetically interact with Reelin. Notably, compound mouse mutants (Reln heterozygotes null for either Efnb2 (600527) or Efnb3 (602297)) and triple Efnb1 (300035)/Efnb2/Efnb3 knockouts showed neuronal migration defects that recapitulated the ones observed in the neocortex, hippocampus, and cerebellum of the reeler mouse. Mechanistically, Senturk et al. (2011) showed that Reelin binds to the extracellular domain of ephrin Bs, which associate at the membrane with VLDLR and ApoER2 in neurons. Clustering of ephrin Bs leads to the recruitment and phosphorylation of Dab1, which is necessary for Reelin signaling. Conversely, loss of function of ephrin Bs severely impairs Reelin-induced Dab1 phosphorylation. Importantly, activation of ephrin Bs can rescue the reeler neuronal migration defects in the absence of Reelin protein. Senturk et al. (2011) concluded that their results identified ephrin Bs as essential components of the Reelin receptor/signaling pathway to control neuronal migration during the development of the nervous system. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Cerebellar Ataxia, Impaired Intellectual Development, and Dysequilibrium Syndrome 1</em></strong></p><p>
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An autosomal recessive syndrome of nonprogressive cerebellar ataxia and impaired intellectual development is associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification in the Hutterite population (CAMRQ1; 224050). Boycott et al. (2005) used an identity-by-descent mapping approach in 8 patients from 3 interrelated Hutterite families and localized the gene for this syndrome to 9p24. Haplotype analysis identified familial and ancestral recombination events and refined the minimal region to a 2-Mb interval between markers D9S129 and D9S1871. Within this interval, Boycott et al. (2005) found a 199-kb homozygous deletion encompassing the entire VLDLR gene (192977.0001) in all affected individuals. VLDLR is part of the reelin (RELN; 600514) signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. Boycott et al. (2005) proposed that this Hutterite disorder should be referred to as VLDLR-associated cerebellar hypoplasia. It appeared to represent the first human lipoprotein receptor malformation syndrome and the second human disease associated with a reelin pathway defect, the other being the form of lissencephaly syndrome (257320) due to mutations in the RELN gene. </p><p>In affected members of 2 unrelated Turkish families with cerebellar hypoplasia, impaired intellectual development, and quadrupedal locomotion, previously reported by Tan, 2008 and Tan et al., 2008, respectively, Ozcelik et al. (2008) identified 2 different homozygous mutations in the VLDLR gene (192977.0002 and 192977.0003, respectively). The findings suggested that reelin and VLDLR are important for proper cerebellar development, which plays a large role in gait. </p><p>Valence et al. (2016) identified homozygous or compound heterozygous mutations in the VLDLR gene (192977.0007-192977.0011) in 4 patients from 3 families with CAMRQ1. Valence et al. (2016) noted that the combination of an extremely hypoplastic vermis with absent folia and cortical anomalies was strongly suggestive of a defect in the reelin pathway. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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A specific isoform of apolipoprotein E (107741), encoded by the APOE4 allele, is associated with the accelerated rate of disease expression of sporadic Alzheimer disease (AD) and late-onset familial AD. Okuizumi et al. (1995) noted that, in patients who carry the APOE4 allele, an earlier age of onset has also been demonstrated in patients who also have mutations in the amyloid precursor protein gene (104760) involving codon 717 (104760.0002) and codons 670 and 671 (104760.0008). On the other hand, the presence of the APOE4 allele makes no difference in familial AD patients with APP692 (104760.0005) or APP693 mutations, nor does it make a difference in chromosome 14-linked familial AD patients (AD3; 607822). Hypothesizing that receptors for APOE-containing lipoproteins act as a potential risk factor for AD, Okuizumi et al. (1995) performed an association study using a polymorphic triplet (CGG) repeat in the VLDLR gene. The frequency of the 5-repeat allele was significantly higher in all Japanese sporadic AD patients (P less than 0.02) than in Japanese controls. Moreover, the odds ratio (OR) was significantly increased in the AD patients homozygous for the 5-repeat allele; OR = 2.1, 95% confidence interval = 1.1-4.2. Multiple logistic regression analysis showed that the relative risk conferred by the presence of 2 copies of the 5-repeat allele and at least 1 copy of the APOE4 allele is 8.7; 95% CI = 2.9-25.8. Okuizumi et al. (1995) concluded that VLDLR is a susceptibility gene for AD. </p><p>In a population study of 221 subjects with dementia compared with 249 controls, Helbecque et al. (2001) found that the presence of the VLDLR 5-repeat allele was associated with an increased relative risk of dementia (OR = 1.9). The risk was more pronounced in individuals who also had cardiovascular problems (OR = 2.5) or who carried the APOE4 allele (OR = 8.4). In a clinical study of 124 patients with dementia compared with 179 neuropathologically defined controls, the OR of developing dementia when bearing at least 1 VLDLR 5-repeat allele was 8.1, and was more pronounced in subjects with mixed or vascular dementia than in patients with AD. APOE4 conferred a higher risk of AD than of vascular or mixed dementia. Helbecque et al. (2001) concluded that carrying a VLDLR 5-repeat allele is a risk factor for vascular dementia in individuals with a history of vascular disease, whereas carrying the APOE4 allele is associated with dementia in others. In general, the results suggested the influence of vascular risk factors in the occurrence of dementia. </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>Layering of neurons in the cerebral cortex and cerebellum requires reelin (RELN; 600514), an extracellular matrix protein, and mammalian disabled (DAB1; 603448), a cytosolic protein that activates tyrosine kinases. By targeted disruption experiments in mice, Trommsdorff et al. (1999) showed that 2 cell surface receptors, VLDLR and apolipoprotein E receptor-2 (APOER2; 602600), are also required. Both receptors bound Dab1 on their cytoplasmic tails and were expressed in cortical and cerebellar layers adjacent to layers expressing Reln. Dab1 expression was upregulated in knockout mice lacking both the Vldlr and Apoer2 genes. Inversion of cortical layers, absence of cerebellar foliation, and the migration of Purkinje cells in these animals precisely mimicked the phenotype of mice lacking Reln or Dab1. These findings established novel signaling functions for the LDL receptor gene family and suggested that VLDLR and APOER2 participate in transmitting the extracellular RELN signal to intracellular signaling processes initiated by DAB1. </p><p>Li et al. (2007) characterized biochemical alterations in the retinas of Vldlr knockout mice in an animal model of retinal angiomatous proliferation. Expression of the angiogenic factors vascular endothelial growth factor (VEGF; 192240) and basic fibroblast growth factor (BFGF; 134920) was significantly greater in the area of retinal neovascularization. Mueller cells around the lesion were activated, as indicated by increased expression of glial fibrillary acidic protein (GFAP; 137780). Expression of the proinflammatory cytokine IL18 (600953) and the inflammation mediator intercellular adhesion molecule-1 (ICAM1; 147840) was increased before significant intraretinal neovascularization. Furthermore, phosphorylation of Akt (164730) and mitogen-activated protein kinase (see 176948) and translocalization of nuclear factor kappa-B (see 164011) were greater in Vldlr knockout mouse retinas. Thus, Li et al. (2007) concluded that an inflammatory process was involved in the development of neovascularization in the Vldlr knockout mouse retina. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>11 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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VLDLR, DEL
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<br />
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ClinVar: RCV000012984
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Boycott et al. (2005) found that the autosomal recessive syndrome of nonprogressive ataxia and impaired intellectual development associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification occurring in the Hutterite population (CAMRQ1; 224050) is due to deletion of the VLDLR gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0002 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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VLDLR, ARG257TER
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<br />
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SNP: rs80338907,
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gnomAD: rs80338907,
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ClinVar: RCV000020557
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In affected members of a Turkish family with cerebellar hypoplasia, impaired intellectual development, and quadrupedal locomotion-1 (CAMRQ1; 224050), Ozcelik et al. (2008) identified a homozygous 769C-T transition in exon 5 of the VLDLR gene, resulting in an arg257-to-ter (R257X) substitution in the ligand-binding domain. Because the mutation is located in the extracellular region, the protein cannot be inserted into the cell membrane to function as a receptor. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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VLDLR, 1-BP DEL, 2339T
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<br />
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SNP: rs80338906,
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ClinVar: RCV000020556
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 affected members of a Turkish family with cerebellar hypoplasia, impaired intellectual development, and quadrupedal locomotion-1 (CAMRQ1; 224050), Ozcelik et al. (2008) identified a homozygous 1-bp deletion (2339delT) in exon 17 of the VLDLR gene, resulting in a frameshift and premature termination in the O-linked sugar domain of the protein. Because the mutation is located in the extracellular region, the protein could not be inserted into the cell membrane to function as a receptor. </p><p>Turkmen et al. (2008) identified homozygosity for the 2339delT deletion in 3 affected members of another Turkish family with cerebellar hypoplasia and impaired intellectual development with quadrupedal locomotion. Turkmen et al. (2008) postulated nonsense-mediated mRNA decay. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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VLDLR, ARG448TER
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<br />
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SNP: rs80338905,
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gnomAD: rs80338905,
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ClinVar: RCV000020555
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a consanguineous Iranian family with congenital cerebellar ataxia and impaired intellectual development (CAMRQ1; 224050), Moheb et al. (2008) identified a homozygous 1342C-T transition in exon 10 of the VLDLR gene, resulting in an arg448-to-ter (R448X) substitution affecting both isoforms. Affected individuals had either no speech at all or spoke only a few words, and none could walk independently. Brain imaging was not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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VLDLR, 7-BP DEL, NT1247
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<br />
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SNP: rs398122380,
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ClinVar: RCV000049269
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sibs, born of consanguineous Turkish parents, with congenital cerebellar ataxia and impaired intellectual development (CAMRQ1; 224050), Dixon-Salazar et al. (2012) identified a homozygous 7-bp deletion in the VLDLR gene (c.1247_53delGTTACAA), resulting in a frameshift and premature termination (Tyr417fsTer434). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in 200 controls. The patients had microcephaly, nystagmus, mild spasticity, arachnodactyly, and pontocerebellar hypoplasia on brain imaging. The patients were initially reported as having pontocerebellar hypoplasia (Dilber et al., 2002), but exome sequencing yielded the correct diagnosis. (Gleeson (2014) provided the correct protein change caused by this mutation, which was erroneously stated in the article by Dixon-Salazar et al. (2012) as p.G1246fsX1305.) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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VLDLR, CYS706PHE
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<br />
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SNP: rs397514750,
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ClinVar: RCV000054559, RCV004798764
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 5 patients from 2 Omani families with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; 224050), Ali et al. (2012) identified a homozygous c.2117G-T transversion in exon 15 of the VLDLR gene, resulting in a cys706-to-phe (C706F) substitution at a highly conserved residue in the extracellular EGF-like-3 domain that is predicted to be involved in a cysteine bond. Ali et al. (2012) suggested that the mutation would result in protein misfolding, possible degradation, and loss of function. The mutation was not found in over 1,000 ethnically matched control exomes or in a control database. Haplotype analysis indicated a founder effect. The patients had classic features of the disorder, including delayed psychomotor development, hypotonia, mental retardation, lack of speech development, gait and truncal ataxia, cerebellar hypoplasia, and simplified cortical gyri. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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VLDLR, ARG301TER
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<br />
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ClinVar: RCV003325251, RCV003561303
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sibs (patients 2 and 3) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; 224050), Valence et al. (2016) identified compound heterozygous mutations in the VLDLR gene: an arg301-to-ter (R301X) substitution on one allele and a c.820+1G-A (192977.0008) mutation, predicted to result in abnormal splicing of exon 54, on the other allele. The splice mutation was found in cis with an arg301-to-gln (R301Q) variant, the pathogenicity of which was unknown. Each parent was heterozygous for one of the mutations. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0008 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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VLDLR, c.820+1G-A
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<br />
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ClinVar: RCV002722922, RCV003325245
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.820+1G-A mutation in the VLDLR gene, predicted to result in abnormal splicing of exon 54, that was identified in compound heterozygous state in 2 sibs (patients 2 and 3) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; 224050) by Valence et al. (2016), see 192977.0007. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0009 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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VLDLR, TRP50TER
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<br />
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ClinVar: RCV003325252
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient (patient 4) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; 224050), Valence et al. (2016) identified compound heterozygous mutations in the VLDLR gene: a trp50-to-ter (W50X) substitution and a glu654-to-gly (E654G; 192977.0010) substitution. The mutations were identified by sequencing of the VLDLR gene; the parents were not tested for the mutations. The D654G mutation was not present in the dbSNP, ExAC, and ESP variant databases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0010 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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VLDLR, GLU654GLY
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<br />
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ClinVar: RCV003325253
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the glu654-to-gly (E654G) substitution in the VLDLR gene that was identified in compound heterozygous state in a patient (patient 4) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; 224050) by Valence et al. (2016), see 192977.0009. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0011 CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1</strong>
|
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</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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VLDLR, TRP575TER
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<br />
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ClinVar: RCV003325254
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient (patient 5) with cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ1; 224050), Valence et al. (2016) identified homozygosity for a trp575-to-ter (W575X) mutation in the VLDLR gene. The mutation, which was identified by sequencing of the VLDLR gene, was present in heterozygous state in the parents. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>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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Ali, B. R., Silhavy, J. L., Gleeson, M. J., Gleeson, J. G., Al-Gazali, L.
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<strong>A missense founder mutation in VLDLR is associated with dysequilibrium syndrome without quadrupedal locomotion.</strong>
|
|
BMC Med. Genet. 13: 80, 2012. Note: Electronic Article.
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[PubMed: 22973972]
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Boycott, K. M., Flavelle, S., Bureau, A., Glass, H. C., Fujiwara, T. M., Wirrell, E., Davey, K., Chudley, A. E., Scott, J. N., McLeod, D. R., Parboosingh, J. S.
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<strong>Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification.</strong>
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Gafvels, M. E., Paavola, L. G., Boyd, C. O., Nolan, P. M., Wittmaack, F., Chawla, A., Lazar, M. A., Bucan, M., Angelin, B., Strauss, J. F., III.
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<strong>Cloning of a complementary deoxyribonucleic acid encoding the murine homolog of the very low density lipoprotein/apolipoprotein-E receptor: expression pattern and assignment of the gene to mouse chromosome 19.</strong>
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Endocrinology 135: 387-394, 1994. Note: Erratum: Endocrinology 136: 795 only, 1995.
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Gleeson, J.
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Helbecque, N., Berr, C., Cottel, D., Fromentin-David, I., Sazdovitch, V., Ricolfi, F., Ducimetiere, P., Di Menza, C., Amouyel, P.
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Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A., Mumby, M. C., Cooper, J. A., Herz, J.
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<strong>Human very-low-density lipoprotein receptor complementary DNA and deduced amino acid sequence and localization of its gene (VLDLR) to chromosome band 9q24 by fluorescence in situ hybridization.</strong>
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Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A., Herz, J.
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<strong>Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2.</strong>
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Turkmen, S., Hoffmann, K., Demirhan, O., Aruoba, D., Humphrey, N., Mundlos, S.
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<strong>Cerebellar hypoplasia, with quadrupedal locomotion, caused by mutations in the very low-density lipoprotein receptor gene.</strong>
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Europ. J. Hum. Genet. 16: 1070-1074, 2008.
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[PubMed: 18364738]
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[Full Text: https://doi.org/10.1038/ejhg.2008.73]
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Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M. A., Mayer, M., Rodriguez, D., Burglen, L.
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<strong>RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.</strong>
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Clin. Genet. 90: 545-549, 2016.
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[PubMed: 27000652]
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[Full Text: https://doi.org/10.1111/cge.12779]
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Contributors:
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Hilary J. Vernon - updated : 08/29/2023<br>Cassandra L. Kniffin - updated : 8/28/2013<br>Cassandra L. Kniffin - updated : 7/1/2013<br>Ada Hamosh - updated : 7/8/2011<br>Patricia A. Hartz - updated : 6/4/2010<br>Cassandra L. Kniffin - updated : 2/3/2010<br>Cassandra L. Kniffin - updated : 1/8/2009<br>Cassandra L. Kniffin - updated : 6/19/2008<br>Jane Kelly - updated : 12/6/2007<br>Victor A. McKusick - updated : 9/1/2005<br>Cassandra L. Kniffin - updated : 2/3/2003<br>Dawn Watkins-Chow - updated : 11/25/2001<br>Stylianos E. Antonarakis - updated : 7/8/1999
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Victor A. McKusick : 8/26/1994
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