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Entry
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- *605837 - HECT DOMAIN AND RCC1-LIKE DOMAIN 2; HERC2
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- OMIM
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<p>
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<span class="h4">*605837</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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/605837">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 role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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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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<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 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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<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=ENSG00000128731;t=ENST00000261609" 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=8924" 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=605837" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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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=ENSG00000128731;t=ENST00000261609" 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_004667,XM_005268276,XM_006720726,XM_006720727,XM_017022695,XM_017022696,XM_017022697,XM_017022698,XM_047433206,XM_047433207,XM_047433208,XM_047433209" 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_004667" 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=605837" 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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<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=06905&isoform_id=06905_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/HERC2" 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/4079809,21739679,27923071,27923072,27923075,27923090,27923093,126032348,158253947,308153453,444738409,444738411,530405220,578827505,578827509,1034592223,1034592226,1034592233,1034592235,2217303070,2217303075,2217303077,2217303079,2462498434,2462498436,2462498438,2462498440,2462498442,2462498444,2462498446,2462498448,2462498450,2462498452,2462498454,2462546379,2462546381,2462546383,2462546385,2462546387,2462546389,2462546391,2462546393,2462546395,2462546397,2462546399" 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/O95714" 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 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=8924" 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=ENSG00000128731;t=ENST00000261609" 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=HERC2" 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=HERC2" 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+8924" 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/HERC2" 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:8924" 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/8924" 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=chr15&hgg_gene=ENST00000261609.13&hgg_start=28111040&hgg_end=28322179&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 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605837[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=605837[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/HERC2/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/ENSG00000128731" 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=HERC2" 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=HERC2" 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=HERC2" 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=HERC2&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/PA29243" 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:4868" 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/FBgn0031107.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:103234" 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/HERC2#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:103234" 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/8924/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=8924" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-070718-6" 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:8924" 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=HERC2&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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605837
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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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HECT DOMAIN AND RCC1-LIKE DOMAIN 2; HERC2
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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=HERC2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HERC2</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/15/45?start=-3&limit=10&highlight=45">15q13.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:28111040-28322179&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'})">15:28,111,040-28,322,179</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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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=227220,227220,615516" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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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="3">
|
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<span class="mim-font">
|
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<a href="/geneMap/15/45?start=-3&limit=10&highlight=45">
|
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15q13.1
|
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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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[Skin/hair/eye pigmentation 1, blond/brown hair]
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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/227220"> 227220 </a>
|
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|
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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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<tr>
|
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<td>
|
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<span class="mim-font">
|
|
[Skin/hair/eye pigmentation 1, blue/nonblue eyes]
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/227220"> 227220 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<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">
|
|
|
|
<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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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Intellectual developmental disorder, autosomal recessive 38
|
|
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/615516"> 615516 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<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>
|
|
<span class="mim-font">
|
|
|
|
<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">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/605837" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<p>HERC2 shuttles between the nucleus and cytoplasm and functions as an E3 ubiquitin ligase for the ubiquitination and degradation of target proteins (<a href="#17" class="mim-tip-reference" title="Wu, W., Sato, K., Koike, A., Nishikawa, H., Koizumi, H., Venkitaraman, A. R., Ohta, T. <strong>HERC2 is an E3 ligase that targets BRCA1 for degradation.</strong> Cancer Res. 70: 6384-6392, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20631078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20631078</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-10-1304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20631078">Wu et al., 2010</a>), as an activator of other E3 ubiquitin ligases (<a href="#9" class="mim-tip-reference" title="Kuhnle, S., Kogel, U., Glockzin, S., Marquardt, A., Ciechanover, A., Matentzoglu, K., Scheffner, M. <strong>Physical and functional interaction of the HECT ubiquitin-protein ligases E6AP and HERC2.</strong> J. Biol. Chem. 286: 19410-19416, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21493713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21493713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21493713[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/10.1074/jbc.M110.205211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21493713">Kuhnle et al., 2011</a>), and as an adaptor for assembly of DNA damage response proteins (<a href="#1" class="mim-tip-reference" title="Bekker-Jensen, S., Rendtlew Danielsen, J., Fugger, K., Gromova, I., Nerstedt, A., Lukas, C., Bartek, J., Lukas, J., Mailand, N. <strong>HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes.</strong> Nature Cell Biol. 12: 80-86, 2010. Note: Erratum: Nature Cell Biol. 12: 412 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20023648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20023648</a>] [<a href="https://doi.org/10.1038/ncb2008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20023648">Bekker-Jensen et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20023648+20631078+21493713" 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>For background information on the HERC gene family, see HERC1 (<a href="/entry/605109">605109</a>).</p>
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<p>Prader-Willi syndrome (PWS; <a href="/entry/176270">176270</a>) and Angelman syndrome (AS; <a href="/entry/105830">105830</a>) result from deletions and loss of function of oppositely imprinted genes located within the proximal 2 Mb of the 15q11-q13 region. Low-copy repeat elements have been identified in the vicinity of the 3 deletion breakpoint hotspots using molecular and cytologic methods. Using positional cloning from low-copy repeats flanking 15q11-q13, genomic sequence analysis, EST database searching, PCR, and long-range RT-PCR, <a href="#7" class="mim-tip-reference" title="Ji, Y., Walkowicz, M. J., Buiting, K., Johnson, D. K., Tarvin, R. E., Rinchik, E. M., Horsthemke, B., Stubbs, L., Nicholls, R. D. <strong>The ancestral gene for transcribed, low-copy repeats in the Prader-Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities.</strong> Hum. Molec. Genet. 8: 533-542, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949213</a>] [<a href="https://doi.org/10.1093/hmg/8.3.533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9949213">Ji et al. (1999)</a> obtained a cDNA encoding HERC2, which is identical to a partial cDNA, KIAA0393, identified by <a href="#12" class="mim-tip-reference" title="Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong> DNA Res. 4: 141-150, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9205841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9205841</a>] [<a href="https://doi.org/10.1093/dnares/4.2.141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9205841">Nagase et al. (1997)</a>. Sequence analysis predicted that the 4,834-amino acid protein, which is 95% identical and 99% similar to the mouse protein, contains 3 RCC1-like domains (RLDs); a putative ZZ-type zinc finger motif with 6 conserved cysteines and 2 outlying histidine residues; a C-terminal HECT or E3 ubiquitin ligase (see UBE3A; <a href="/entry/601623">601623</a>) domain; and several potential phosphorylation sites. The overall structure is similar to that of HERC1, although HERC1 has only 2 RLDs and no zinc finger motif. The C-terminal region of HERC2 resembles that of HERC3 (<a href="/entry/605200">605200</a>). Northern blot analysis revealed ubiquitous expression of a 15.5-kb HERC2 transcript, with high levels in fetal tissues and adult skeletal muscle, heart, ovary, testis, and brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9205841+9949213" 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="Lehman, A. L., Nakatsu, Y., Ching, A., Bronson, R. T., Oakey, R. J., Keiper-Hrynko, N., Finger, J. N., Durham-Pierre, D., Horton, D. B., Newton, J. M., Lyon, M. F., Brilliant, M. H. <strong>A very large protein with diverse functional motifs is deficient in rjs (runty, jerky, sterile) mice.</strong> Proc. Nat. Acad. Sci. 95: 9436-9441, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9689098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9689098</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9689098[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.95.16.9436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9689098">Lehman et al. (1998)</a> identified and cloned the murine Herc2 gene, which encodes a 4,836-residue protein containing 3 RCC1 repeats and a HECT domain in common with E6AP (UBE3A). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9689098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using SDS-PAGE, <a href="#1" class="mim-tip-reference" title="Bekker-Jensen, S., Rendtlew Danielsen, J., Fugger, K., Gromova, I., Nerstedt, A., Lukas, C., Bartek, J., Lukas, J., Mailand, N. <strong>HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes.</strong> Nature Cell Biol. 12: 80-86, 2010. Note: Erratum: Nature Cell Biol. 12: 412 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20023648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20023648</a>] [<a href="https://doi.org/10.1038/ncb2008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20023648">Bekker-Jensen et al. (2010)</a> found that endogenous human HERC2 had an apparent molecular mass of 500 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20023648" 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="#12" class="mim-tip-reference" title="Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong> DNA Res. 4: 141-150, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9205841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9205841</a>] [<a href="https://doi.org/10.1093/dnares/4.2.141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9205841">Nagase et al. (1997)</a> mapped the HERC2 gene, which they called KIAA0393, to chromosome 15 using radiation hybrid analysis. By Southern blot analysis of YACs and radiation hybrid analysis, <a href="#7" class="mim-tip-reference" title="Ji, Y., Walkowicz, M. J., Buiting, K., Johnson, D. K., Tarvin, R. E., Rinchik, E. M., Horsthemke, B., Stubbs, L., Nicholls, R. D. <strong>The ancestral gene for transcribed, low-copy repeats in the Prader-Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities.</strong> Hum. Molec. Genet. 8: 533-542, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949213</a>] [<a href="https://doi.org/10.1093/hmg/8.3.533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9949213">Ji et al. (1999)</a> mapped the HERC2 gene to 15q11-q13, very close to the P gene (OCA2; <a href="/entry/611409">611409</a>). Southern blot analysis of PWS and AS patients resulted in HERC2 signals of 50% intensity compared with controls. The mouse Herc2 gene maps to chromosome 7C, within the juvenile development and fertility-2 (jdf2) interval (<a href="#7" class="mim-tip-reference" title="Ji, Y., Walkowicz, M. J., Buiting, K., Johnson, D. K., Tarvin, R. E., Rinchik, E. M., Horsthemke, B., Stubbs, L., Nicholls, R. D. <strong>The ancestral gene for transcribed, low-copy repeats in the Prader-Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities.</strong> Hum. Molec. Genet. 8: 533-542, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949213</a>] [<a href="https://doi.org/10.1093/hmg/8.3.533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9949213">Ji et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9205841+9949213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Kayser, M., Liu, F., Janssens, A. C. J. W., Rivadeneira, F., Lao, O., van Duijn, K., Vermeulen, M., Arp, P., Jhamai, M. M., van IJcken, W. F. J., den Dunnen, J. T., Heath, S., and 10 others. <strong>Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene.</strong> Am. J. Hum. Genet. 82: 411-423, 2008. Note: Erratum: Am. J. Hum. Genet. 82: 801 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252221</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252221[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.2007.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252221">Kayser et al. (2008)</a> identified the HERC2 gene within a region on chromosome 15q13.1 linked to determination of human iris color. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18252221" 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>RNF8 (<a href="/entry/611685">611685</a>) is an E3 ubiquitin ligase that interacts with the E2 ubiquitin-conjugating enzyme UBC13 (UBE2N; <a href="/entry/603679">603679</a>) and catalyzes formation of lys63-linked ubiquitin chains on histone H2A (see <a href="/entry/613499">613499</a>) flanking sites of DNA damage. Using mass spectrometric analysis, <a href="#1" class="mim-tip-reference" title="Bekker-Jensen, S., Rendtlew Danielsen, J., Fugger, K., Gromova, I., Nerstedt, A., Lukas, C., Bartek, J., Lukas, J., Mailand, N. <strong>HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes.</strong> Nature Cell Biol. 12: 80-86, 2010. Note: Erratum: Nature Cell Biol. 12: 412 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20023648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20023648</a>] [<a href="https://doi.org/10.1038/ncb2008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20023648">Bekker-Jensen et al. (2010)</a> found that endogenous HERC2 affinity purified with RNF8 from HEK293T cells. RNF8 interacted with the C-terminal HECT domain of HERC2, and phosphorylation of thr4827 within the HECT domain was required for the interaction. Association of HERC2 with RNF8 increased following exposure to DNA damage-inducing ionizing radiation. The DNA damage response kinases ATM (<a href="/entry/607585">607585</a>), ATR (<a href="/entry/601215">601215</a>), and DNAPK (see <a href="/entry/600899">600899</a>) also interacted with the C terminus of HERC2, and inhibition of these kinases interfered with the RNF8-HERC2 association in an additive manner. HERC2 also interacted in a ternary complex with MDC1 (<a href="/entry/607593">607593</a>) and RNF8, and all 3 proteins accumulated at sites of DNA double-strand breaks. Depletion of HERC2 in HEK293T cells did not impair accumulation of RNF8 and MDC1 at sites of DNA damage, but it caused failure to recruit UBC13 to RNF8, leading to failure of histone H2A polyubiquitination and accumulation of downstream DNA damage repair and signaling factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20023648" 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>BRCA1 (<a href="/entry/113705">113705</a>) maintains genomic stability by functioning in DNA damage repair, cell cycle checkpoint, and apoptosis. BRCA1 forms a heterodimeric E3 ubiquitin ligase with BARD1 (<a href="/entry/601593">601593</a>), and loss of this interaction results in BRCA1 degradation. <a href="#17" class="mim-tip-reference" title="Wu, W., Sato, K., Koike, A., Nishikawa, H., Koizumi, H., Venkitaraman, A. R., Ohta, T. <strong>HERC2 is an E3 ligase that targets BRCA1 for degradation.</strong> Cancer Res. 70: 6384-6392, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20631078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20631078</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-10-1304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20631078">Wu et al. (2010)</a> found that HERC2 countered the stabilizing effect of BARD1 on BRCA1 and caused BRCA1 degradation. The HECT domain of HERC2 interacted with and caused ubiquitination of an N-terminal degradation domain of BRCA1, targeting BRCA1 for degradation. The reaction depended on cys4762 within the catalytic ubiquitin-binding site of HERC2. The HERC2-BRCA1 interaction and BRCA1 degradation were maximal during S phase in synchronized HeLa cells and rapidly diminished as cells entered G2-M. <a href="#17" class="mim-tip-reference" title="Wu, W., Sato, K., Koike, A., Nishikawa, H., Koizumi, H., Venkitaraman, A. R., Ohta, T. <strong>HERC2 is an E3 ligase that targets BRCA1 for degradation.</strong> Cancer Res. 70: 6384-6392, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20631078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20631078</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-10-1304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20631078">Wu et al. (2010)</a> concluded that HERC2 is an E3 ligase that targets BRCA1 for degradation during S phase of the cell cycle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20631078" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid analysis and coprecipitation analysis of cotransfected and endogenous proteins, <a href="#9" class="mim-tip-reference" title="Kuhnle, S., Kogel, U., Glockzin, S., Marquardt, A., Ciechanover, A., Matentzoglu, K., Scheffner, M. <strong>Physical and functional interaction of the HECT ubiquitin-protein ligases E6AP and HERC2.</strong> J. Biol. Chem. 286: 19410-19416, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21493713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21493713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21493713[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/10.1074/jbc.M110.205211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21493713">Kuhnle et al. (2011)</a> found that HERC2 interacted with the 852-amino acid isoform of the E3 ubiquitin ligase E6AP (UBE3A; <a href="/entry/601623">601623</a>). Domain analysis revealed that the central RLD2 domain of HERC2 and a domain near the N terminus of E6AP were required for the interaction. Full-length HERC2 or the isolated RLD2 domain of HERC2 stimulated the E3 activity of E6AP in autoubiquitination and in ubiquitination of an E6AP substrate. Stimulation of E6AP did not require catalytically active HERC2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21493713" 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>Skin, Hair, Eye Pigmentation</em></strong></p><p>
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In a large genomewide scan to identify variants associated with hair and eye pigmentation, skin sensitivity to sun, and freckling, <a href="#15" class="mim-tip-reference" title="Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Magnusson, K. P., Manolescu, A., Karason, A., Palsson, A., Thorleifsson, G., Jakobsdottir, M., Steinberg, S., and 13 others. <strong>Genetic determinants of hair, eye and skin pigmentation in Europeans.</strong> Nature Genet. 39: 1443-1452, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17952075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17952075</a>] [<a href="https://doi.org/10.1038/ng.2007.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17952075">Sulem et al. (2007)</a> identified a single-nucleotide polymorphism (SNP), <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1667394;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1667394</a>, in intron 4 of the HERC2 gene (<a href="#0001">605837.0001</a>) that was associated with blue eye color and blond hair. Of several SNPs within a 1-Mb region of linkage overlapping the OCA2 gene (<a href="/entry/611409">611409</a>), <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1667394;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1667394</a> had the strongest association with pigmentation. Given the established relationship between OCA2 and pigmentation, <a href="#15" class="mim-tip-reference" title="Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Magnusson, K. P., Manolescu, A., Karason, A., Palsson, A., Thorleifsson, G., Jakobsdottir, M., Steinberg, S., and 13 others. <strong>Genetic determinants of hair, eye and skin pigmentation in Europeans.</strong> Nature Genet. 39: 1443-1452, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17952075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17952075</a>] [<a href="https://doi.org/10.1038/ng.2007.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17952075">Sulem et al. (2007)</a> considered it unlikely that the association signal provided by this SNP was due to a functional effect on HERC2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17952075" 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 3 independent genomewide association studies and a genomewide linkage study involving over 2,600 persons from the Netherlands, <a href="#8" class="mim-tip-reference" title="Kayser, M., Liu, F., Janssens, A. C. J. W., Rivadeneira, F., Lao, O., van Duijn, K., Vermeulen, M., Arp, P., Jhamai, M. M., van IJcken, W. F. J., den Dunnen, J. T., Heath, S., and 10 others. <strong>Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene.</strong> Am. J. Hum. Genet. 82: 411-423, 2008. Note: Erratum: Am. J. Hum. Genet. 82: 801 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252221</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252221[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.2007.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252221">Kayser et al. (2008)</a> found that the chromosome 15q13.1 region is the predominant region involved in human iris color. There were no other regions showing consistent genomewide evidence for association and linkage to iris color. SNPs in the HERC2 gene and, to a lesser extent, in the neighboring OCA2 gene (<a href="/entry/611409">611409</a>) were independently associated with iris color variation. <a href="#8" class="mim-tip-reference" title="Kayser, M., Liu, F., Janssens, A. C. J. W., Rivadeneira, F., Lao, O., van Duijn, K., Vermeulen, M., Arp, P., Jhamai, M. M., van IJcken, W. F. J., den Dunnen, J. T., Heath, S., and 10 others. <strong>Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene.</strong> Am. J. Hum. Genet. 82: 411-423, 2008. Note: Erratum: Am. J. Hum. Genet. 82: 801 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252221</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252221[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.2007.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252221">Kayser et al. (2008)</a> found that HERC2 <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs916977;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs916977</a> (<a href="#0002">605837.0002</a>) showed a clinal allele distribution across 23 European populations that was significantly correlated to iris color variation. They suggested that genetic variants regulating expression of the OCA2 gene exist in the HERC2 gene or, alternatively, with the 11.7 kb of sequence between OCA2 and HERC2, and that most iris color variation in Europeans is explained by those 2 genes. They further suggested that testing markers in the HERC2-OCA2 region may be useful in forensic applications to predict eye color phenotypes of unknown persons of European genetic origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18252221" 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="#4" class="mim-tip-reference" title="Duffy, D. L., Montgomery, G. W., Chen, W., Zhao, Z. Z., Le, L., James, M. R., Hayward, N. K., Martin, N. G., Sturm, R. A. <strong>A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation.</strong> Am. J. Hum. Genet. 80: 241-252, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17236130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17236130</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17236130[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/10.1086/510885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17236130">Duffy et al. (2007)</a> demonstrated that haplotypes of 3 SNPs within the first intron of the OCA2 gene are strongly associated with variation in human eye color. Following up on this study, <a href="#14" class="mim-tip-reference" title="Sturm, R. A., Duffy, D. L., Zhao, Z. Z., Leite, F. P. N., Stark, M. S., Hayward, N. K., Martin, N. G., Montgomery, G. W. <strong>A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color.</strong> Am. J. Hum. Genet. 82: 424-431, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252222[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.2007.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252222">Sturm et al. (2008)</a> described additional fine association mapping of eye color SNPs in the intergenic region upstream of OCA2 and within the neighboring HERC2 gene. They screened an additional 92 SNPs in 300 to 3,000 European individuals and found that a single SNP in intron 86 of HERC2, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a> (<a href="#0003">605837.0003</a>), predicted eye color significantly better than their previous best OCA2 haplotype. Comparison of sequence alignments of multiple species showed that this SNP lies in the center of a short highly conserved sequence and that the blue eye-associated allele (frequency 78%) breaks up this conserved sequence, part of which forms a consensus binding site for the helicase-like transcription factor (HLTF; <a href="/entry/603257">603257</a>). <a href="#14" class="mim-tip-reference" title="Sturm, R. A., Duffy, D. L., Zhao, Z. Z., Leite, F. P. N., Stark, M. S., Hayward, N. K., Martin, N. G., Montgomery, G. W. <strong>A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color.</strong> Am. J. Hum. Genet. 82: 424-431, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252222[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.2007.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252222">Sturm et al. (2008)</a> also demonstrated that the OCA2 coding SNP R419Q (<a href="/entry/611409#0012">611409.0012</a>) acts as a penetrance modifier of this new HERC2 SNP for eye color and, somewhat independently, of melanoma risk. <a href="#14" class="mim-tip-reference" title="Sturm, R. A., Duffy, D. L., Zhao, Z. Z., Leite, F. P. N., Stark, M. S., Hayward, N. K., Martin, N. G., Montgomery, G. W. <strong>A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color.</strong> Am. J. Hum. Genet. 82: 424-431, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252222[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.2007.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252222">Sturm et al. (2008)</a> concluded that the conserved region around <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a> (the SNP in intron 86 of HERC2) represents a regulatory region controlling constitutive expression of OCA2 and that the C allele at this SNP leads to decreased expression of OCA2, particularly within iris melanocytes, which they postulated to be the ultimate cause of blue eye color. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18252222+17236130" 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 3-generation Danish family segregating blue and brown eye color, <a href="#5" class="mim-tip-reference" title="Eiberg, H., Troelsen, J., Nielsen, M., Mikkelsen, A., Mengel-From, J., Kjaer, K. W., Hansen, L. <strong>Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression.</strong> Hum. Genet. 123: 177-187, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18172690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18172690</a>] [<a href="https://doi.org/10.1007/s00439-007-0460-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18172690">Eiberg et al. (2008)</a> used fine mapping to identify a 166-kb candidate region within the HERC2 gene. Further studies of SNPs within this region among 144 blue-eyed and 45 brown-eyed individuals identified 2 SNPs, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1129038;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1129038</a> and the strongly conserved <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a>, that showed significant associations with the blue-eyed phenotype (p = 6.2 x 10(-46)). A common founder haplotype containing these SNPs was identified among blue-eyed persons from Denmark, Turkey, and Jordan. In vitro functional expression studies in human colon carcinoma cells showed that what the authors referred to as the 'G' allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a>, present in blue-eyed individuals, had an inhibitory effect on OCA2 promoter activity. In the 3-generation Danish family, blond hair color was associated with lighter brown/blue eyes and brown hair color was associated with brown eyes. Hair color also associated with several SNPs in the HERC2 gene. However, linkage analysis also implicated a region associated with hair color on chromosome 14 (lod score of 4.21 at D14S72), close to the RABGGTA gene (<a href="/entry/601905">601905</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18172690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Donnelly, M. P., Paschou, P., Grigorenko, E., Gurwitz, D., Barta, C., Lu, R.-B., Zhukova, O. V., Kim, J.-J., Siniscalco, M., New, M., Li, H., Kajuna, S. L. B., Manolopoulos, V. G., Speed, W. C., Pakstis, A. J., Kidd, J. R., Kidd, K. K. <strong>A global view of the OCA2-HERC2 region and pigmentation.</strong> Hum. Genet. 131: 683-696, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22065085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22065085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22065085[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/10.1007/s00439-011-1110-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22065085">Donnelly et al. (2012)</a> genotyped 3,432 individuals from 72 populations for 21 SNPs in the OCA2-HERC2 region, and found that blue-eye-associated alleles in all 3 haplotypes that previously had been associated with eye pigmentation in Europeans occurred at high frequencies in Europe; however, 1 was restricted to Europe and surrounding regions, whereas the other 2 were found at moderate to high frequencies throughout the world. Their data suggested that the TG allele of the haplotype restricted to Europe, consisting of the SNPs <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1129038;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1129038</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a> and which they designated 'BEH2,' was the best marker for blue eyes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22065085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By examining 1,570 ethnically diverse African genomes from individuals with quantified pigmentation levels, <a href="#2" class="mim-tip-reference" title="Crawford, N. G., Kelly, D. E., Hansen, M. E. B., Beltrame, M. H., Fan, S., Bowman, S. L., Jewett, E., Ranciaro, A., Thompson, S., Lo, Y., Pfeifer, S. P., Jensen, J. D., and 36 others. <strong>Loci associated with skin pigmentation identified in African populations.</strong> Science 358: eaan8433, 2017. Note: Electronic Article. Erratum: Science 367: eaba7178, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29025994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29025994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29025994[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aan8433" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29025994">Crawford et al. (2017)</a> identified 10 SNPs in the OCA2/HERC2 region that were highly associated with pigmentation. The HERC2 SNP with the highest probability of being causal was <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4932620;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4932620</a> (p = 3.2 x 10(-9)), located within intron 11. The derived <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4932620;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4932620</a>T allele, associated with dark skin pigmentation, is most common in Ethiopian populations with high levels of Nilo-Saharan ancestry and is at moderate frequency in other Ethiopian, Hadza, and Tanzania Nilo-Saharan populations. The <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4932620;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4932620</a>T variant is identical by descent in South Asian and Australo-Melanesian populations. <a href="#2" class="mim-tip-reference" title="Crawford, N. G., Kelly, D. E., Hansen, M. E. B., Beltrame, M. H., Fan, S., Bowman, S. L., Jewett, E., Ranciaro, A., Thompson, S., Lo, Y., Pfeifer, S. P., Jensen, J. D., and 36 others. <strong>Loci associated with skin pigmentation identified in African populations.</strong> Science 358: eaan8433, 2017. Note: Electronic Article. Erratum: Science 367: eaba7178, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29025994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29025994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29025994[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aan8433" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29025994">Crawford et al. (2017)</a> noted the extensive linkage disequilibrium among SNPs in the OCA2/HERC2 region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29025994" 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>Impaired Intellectual Development 38, Autosomal Recessive</em></strong></p><p>
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In 7 patients of Amish or mixed Amish/Mennonite descent with autosomal recessive impaired intellectual development-38 (MRT38; <a href="/entry/615516">615516</a>), <a href="#13" class="mim-tip-reference" title="Puffenberger, E. G., Jinks, R. N., Wang, H., Xin, B., Fiorentini, C., Sherman, E. A., Degrazio, D., Shaw, C., Sougnez, C., Cibulskis, K., Gabriel, S., Kelley, R. I., Morton, D. H., Strauss, K. A. <strong>A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder.</strong> Hum. Mutat. 33: 1639-1646, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23065719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23065719</a>] [<a href="https://doi.org/10.1002/humu.22237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23065719">Puffenberger et al. (2012)</a> identified a homozygous missense mutation in the HERC2 gene (P594L; <a href="#0004">605837.0004</a>). The mutation was found by a combination of homozygosity mapping and exome sequencing. Cellular transfection studies showed that the mutant protein was less stable than wildtype and had a diffuse cytosolic localization with the formation of abnormal aggregates. Decreased abundance and/or activity of HERC2 could produce a toxic loss of E3 ubiquitin ligase activity, leading to decreased degradation of ARC (<a href="/entry/612461">612461</a>) and decreased postsynaptic glutamatergic AMPA receptor density. <a href="#13" class="mim-tip-reference" title="Puffenberger, E. G., Jinks, R. N., Wang, H., Xin, B., Fiorentini, C., Sherman, E. A., Degrazio, D., Shaw, C., Sougnez, C., Cibulskis, K., Gabriel, S., Kelley, R. I., Morton, D. H., Strauss, K. A. <strong>A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder.</strong> Hum. Mutat. 33: 1639-1646, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23065719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23065719</a>] [<a href="https://doi.org/10.1002/humu.22237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23065719">Puffenberger et al. (2012)</a> noted that this pathophysiologic mechanism is similar to that thought to underlie Angelman syndrome (<a href="/entry/105830">105830</a>), which results from loss of function of the UBE3A gene (<a href="/entry/601623">601623</a>) on chromosome 15q11. The individuals with MRT38 had some features similar to those of AS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23065719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By genomewide linkage analysis and candidate gene analysis, <a href="#6" class="mim-tip-reference" title="Harlalka, G. V., Baple, E. L., Cross, H., Kuhnle, S., Cubillos-Rojas, M., Matentzoglu, K., Patton, M. A., Wagner, K., Coblentz, R., Ford, D. L., Mackay, D. J. G., Chioza, B. A., Scheffner, M., Rosa, J. L., Crosby, A. H. <strong>Mutation of HERC2 causes developmental delay with Angelman-like features.</strong> J. Med. Genet. 50: 65-73, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23243086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23243086</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-101367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23243086">Harlalka et al. (2013)</a> identified homozygosity for the P594L mutation in the HERC2 gene in 15 Old Order Amish patients with a severe neurodevelopmental disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23243086" 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="#10" class="mim-tip-reference" title="Lehman, A. L., Nakatsu, Y., Ching, A., Bronson, R. T., Oakey, R. J., Keiper-Hrynko, N., Finger, J. N., Durham-Pierre, D., Horton, D. B., Newton, J. M., Lyon, M. F., Brilliant, M. H. <strong>A very large protein with diverse functional motifs is deficient in rjs (runty, jerky, sterile) mice.</strong> Proc. Nat. Acad. Sci. 95: 9436-9441, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9689098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9689098</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9689098[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.95.16.9436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9689098">Lehman et al. (1998)</a> identified the murine Herc2 gene as responsible for the 'rjs' (runty, jerky, sterile) radiation-induced mouse phenotype, which has additional features associated with mutations in the neighboring Oca2 gene (<a href="/entry/611409">611409</a>) (<a href="#11" class="mim-tip-reference" title="Lyon, M. F., King, T. R., Gondo, Y., Gardner, J. M., Nakatsu, Y., Eicher, E. M., Brilliant, M. H. <strong>Genetic and molecular analysis of recessive alleles at the pink-eyed dilution (p) locus of the mouse.</strong> Proc. Nat. Acad. Sci. 89: 6968-6972, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1495987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1495987</a>] [<a href="https://doi.org/10.1073/pnas.89.15.6968" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1495987">Lyon et al., 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1495987+9689098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Ji, Y., Walkowicz, M. J., Buiting, K., Johnson, D. K., Tarvin, R. E., Rinchik, E. M., Horsthemke, B., Stubbs, L., Nicholls, R. D. <strong>The ancestral gene for transcribed, low-copy repeats in the Prader-Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities.</strong> Hum. Molec. Genet. 8: 533-542, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949213</a>] [<a href="https://doi.org/10.1093/hmg/8.3.533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9949213">Ji et al. (1999)</a> identified splice junction mutations in the Herc2 gene in chemically-induced mouse jdf2 mutant alleles. The mutations led to exon skipping and premature termination, resulting in neuromuscular secretory vesicle defects, sperm acrosome defects, and juvenile lethality in jdf2 mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9949213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a discovery sample of 2,986 Icelanders and replication samples of 2,718 Icelanders and 1,214 Dutch, <a href="#15" class="mim-tip-reference" title="Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Magnusson, K. P., Manolescu, A., Karason, A., Palsson, A., Thorleifsson, G., Jakobsdottir, M., Steinberg, S., and 13 others. <strong>Genetic determinants of hair, eye and skin pigmentation in Europeans.</strong> Nature Genet. 39: 1443-1452, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17952075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17952075</a>] [<a href="https://doi.org/10.1038/ng.2007.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17952075">Sulem et al. (2007)</a> found association of the A allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1667394;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1667394</a> with blue versus brown eyes (OR = 35.42, P = 1.4 x 10(-124)), with blue versus green eyes (OR = 7.02, P = 5.1 x 10(-25)), and with blond versus brown hair (OR = 5.62, P = 4.4 x 10(-16)). Although the <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1667394;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1667394</a> variant resides in the HERC2 gene, <a href="#15" class="mim-tip-reference" title="Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Magnusson, K. P., Manolescu, A., Karason, A., Palsson, A., Thorleifsson, G., Jakobsdottir, M., Steinberg, S., and 13 others. <strong>Genetic determinants of hair, eye and skin pigmentation in Europeans.</strong> Nature Genet. 39: 1443-1452, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17952075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17952075</a>] [<a href="https://doi.org/10.1038/ng.2007.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17952075">Sulem et al. (2007)</a> considered it unlikely that the association signal provided by this SNP was due to a functional effect on HERC2. Because of the established relationship between the OCA2 gene (<a href="/entry/611409">611409</a>) and blue eye color and lighter hair and skin tones (<a href="/entry/227220">227220</a>), the authors suggested that perhaps sequence variation in the introns of HERC2 affects the expression of OCA2, or that functional variants exist within OCA2 that correlate with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1667394;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1667394</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17952075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs916977 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs916977;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/rs916977?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=rs916977" 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=rs916977" 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=RCV000005010" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005010" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005010</a>
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<p>In 3 independent genomewide association studies of a total of 1,406 persons and a genomewide linkage study of 1,292 relatives, all from the Netherlands, <a href="#8" class="mim-tip-reference" title="Kayser, M., Liu, F., Janssens, A. C. J. W., Rivadeneira, F., Lao, O., van Duijn, K., Vermeulen, M., Arp, P., Jhamai, M. M., van IJcken, W. F. J., den Dunnen, J. T., Heath, S., and 10 others. <strong>Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene.</strong> Am. J. Hum. Genet. 82: 411-423, 2008. Note: Erratum: Am. J. Hum. Genet. 82: 801 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252221</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252221[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.2007.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252221">Kayser et al. (2008)</a> found that the HERC2 variant <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs916977;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs916977</a> showed a gradient-wise (clinal) allele distribution across 23 European populations that was significantly correlated to iris color variation (<a href="/entry/227220">227220</a>), with the C allele, associated with blue eyes, being more common in northern Europe and the T allele, associated with brown eyes, more common in southern Europe. Analysis of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs916977;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs916977</a> together with the 3 SNPs in intron 1 of the OCA2 gene identified by <a href="#4" class="mim-tip-reference" title="Duffy, D. L., Montgomery, G. W., Chen, W., Zhao, Z. Z., Le, L., James, M. R., Hayward, N. K., Martin, N. G., Sturm, R. A. <strong>A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation.</strong> Am. J. Hum. Genet. 80: 241-252, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17236130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17236130</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17236130[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/10.1086/510885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17236130">Duffy et al. (2007)</a> (<a href="/entry/611409#0013">611409.0013</a>) revealed significant genomewide association for only the HERC2 SNP (P = 3.53 x 10(-18)). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18252221+17236130" 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 SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES</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> rs12913832 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;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/rs12913832?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=rs12913832" 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=rs12913832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a study of the association with eye color (<a href="/entry/227220">227220</a>) with haplotype-tagging SNPs proximal to intron 1 of the OCA2 gene (<a href="/entry/611409">611409</a>) that span the intergenic region and encompass the 3-prime end of the upstream gene HERC2, <a href="#14" class="mim-tip-reference" title="Sturm, R. A., Duffy, D. L., Zhao, Z. Z., Leite, F. P. N., Stark, M. S., Hayward, N. K., Martin, N. G., Montgomery, G. W. <strong>A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color.</strong> Am. J. Hum. Genet. 82: 424-431, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252222[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.2007.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252222">Sturm et al. (2008)</a> identified a SNP in intron 86 of HERC2, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a>, that was strongly associated with eye color in 3011 European individuals (P = 2 x 10(-78)). Individuals carrying the CC genotype had only a 1% probability of having brown eyes, while those with the TT genotype had an 80% probability. Haplotype analysis combining the 3 SNPs in OCA2 identified by <a href="#4" class="mim-tip-reference" title="Duffy, D. L., Montgomery, G. W., Chen, W., Zhao, Z. Z., Le, L., James, M. R., Hayward, N. K., Martin, N. G., Sturm, R. A. <strong>A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation.</strong> Am. J. Hum. Genet. 80: 241-252, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17236130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17236130</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17236130[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/10.1086/510885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17236130">Duffy et al. (2007)</a> (<a href="/entry/611409#0013">611409.0013</a>) with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a> followed by multiple ordinal logistic regression showed that the HERC2 SNP alone was the best predictor of eye color. <a href="#14" class="mim-tip-reference" title="Sturm, R. A., Duffy, D. L., Zhao, Z. Z., Leite, F. P. N., Stark, M. S., Hayward, N. K., Martin, N. G., Montgomery, G. W. <strong>A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color.</strong> Am. J. Hum. Genet. 82: 424-431, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252222[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.2007.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252222">Sturm et al. (2008)</a> concluded that the conserved region around <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a> represents a regulatory region controlling constitutive expression of OCA2, and that the C allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a> leads to decreased expression of OCA2, particularly within iris melanocytes, by abrogation of the binding site for HLTF (<a href="/entry/603257">603257</a>) that regulates transcription of OCA2. <a href="#14" class="mim-tip-reference" title="Sturm, R. A., Duffy, D. L., Zhao, Z. Z., Leite, F. P. N., Stark, M. S., Hayward, N. K., Martin, N. G., Montgomery, G. W. <strong>A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color.</strong> Am. J. Hum. Genet. 82: 424-431, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252222[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.2007.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252222">Sturm et al. (2008)</a> also demonstrated that the OCA2 coding SNP R419Q (<a href="/entry/611409#0012">611409.0012</a>) acts as a penetrance modifier of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18252222+17236130" 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 3-generation Danish family segregating blue and brown eye color, <a href="#5" class="mim-tip-reference" title="Eiberg, H., Troelsen, J., Nielsen, M., Mikkelsen, A., Mengel-From, J., Kjaer, K. W., Hansen, L. <strong>Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression.</strong> Hum. Genet. 123: 177-187, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18172690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18172690</a>] [<a href="https://doi.org/10.1007/s00439-007-0460-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18172690">Eiberg et al. (2008)</a> used fine mapping to identify a 166-kb candidate region within the HERC2 gene. Further studies of SNPs within this region among 144 blue-eyed and 45 brown-eyed individuals identified 2 SNPs, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1129038;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1129038</a> and the strongly conserved <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a>, that showed significant associations with the blue-eyed phenotype (p = 6.2 x 10(-46)). A common founder haplotype containing these SNPs was identified among blue-eyed persons from Denmark, Turkey, and Jordan. In vitro functional expression studies in human colon carcinoma cells showed that what the authors referred to as the 'G' allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a>, present in blue-eyed individuals, had an inhibitory effect on OCA2 promoter activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18172690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Visser, M., Kayser, M., Palstra, R.-J. <strong>HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter.</strong> Genome Res. 22: 446-455, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22234890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22234890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22234890[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/10.1101/gr.128652.111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22234890">Visser et al. (2012)</a> found that HLTF, LEF1 (<a href="/entry/153245">153245</a>), and MITF (<a href="/entry/156845">156845</a>) bound to the enhancer region surrounding <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a> in darkly pigmented human melanocytes carrying the T allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a>. Binding was associated with long-range chromatin looping between the enhancer and the OCA2 promoter, leading to elevated OCA2 expression. In contrast, lightly pigmented melanocytes carrying the C allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12913832;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12913832</a> showed reduced enhancer binding, chromatin looping, and OCA2 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22234890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397518474 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397518474;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/rs397518474?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=rs397518474" 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=rs397518474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 7 patients of Amish or mixed Amish/Mennonite descent with autosomal recessive intellectual developmental disorder-38 (MRT38; <a href="/entry/615516">615516</a>), <a href="#13" class="mim-tip-reference" title="Puffenberger, E. G., Jinks, R. N., Wang, H., Xin, B., Fiorentini, C., Sherman, E. A., Degrazio, D., Shaw, C., Sougnez, C., Cibulskis, K., Gabriel, S., Kelley, R. I., Morton, D. H., Strauss, K. A. <strong>A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder.</strong> Hum. Mutat. 33: 1639-1646, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23065719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23065719</a>] [<a href="https://doi.org/10.1002/humu.22237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23065719">Puffenberger et al. (2012)</a> identified a homozygous c.1781C-T transition in the HERC2 gene, resulting in a pro594-to-leu (P594L) substitution at a highly conserved residue in the first RLD1 domain. The mutation was found by a combination of homozygosity mapping and exome sequencing. The mutation was not present in the dbSNP database or in 760 alleles from Amish and Mennonite controls. Cellular transfection studies demonstrated that the mutant protein was less stable than wildtype and showed diffuse cytosolic localization with the formation of abnormal aggregates. Decreased abundance and/or activity of HERC2 could produce a toxic loss of E3 ubiquitin ligase activity, leading to decreased degradation of ARC (<a href="/entry/612461">612461</a>) and decreased postsynaptic glutamatergic AMPA receptor density. <a href="#13" class="mim-tip-reference" title="Puffenberger, E. G., Jinks, R. N., Wang, H., Xin, B., Fiorentini, C., Sherman, E. A., Degrazio, D., Shaw, C., Sougnez, C., Cibulskis, K., Gabriel, S., Kelley, R. I., Morton, D. H., Strauss, K. A. <strong>A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder.</strong> Hum. Mutat. 33: 1639-1646, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23065719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23065719</a>] [<a href="https://doi.org/10.1002/humu.22237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23065719">Puffenberger et al. (2012)</a> noted that this pathophysiologic mechanism is similar to that thought to underlie Angelman syndrome (<a href="/entry/105830">105830</a>), which results from loss of function of the UBE3A gene (<a href="/entry/601623">601623</a>) on chromosome 15q11. The affected individuals with the HERC2 mutation had global developmental delay and autistic features similar to Angelman syndrome; they also had blue irides. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23065719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By genomewide linkage analysis and candidate gene analysis, <a href="#6" class="mim-tip-reference" title="Harlalka, G. V., Baple, E. L., Cross, H., Kuhnle, S., Cubillos-Rojas, M., Matentzoglu, K., Patton, M. A., Wagner, K., Coblentz, R., Ford, D. L., Mackay, D. J. G., Chioza, B. A., Scheffner, M., Rosa, J. L., Crosby, A. H. <strong>Mutation of HERC2 causes developmental delay with Angelman-like features.</strong> J. Med. Genet. 50: 65-73, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23243086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23243086</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-101367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23243086">Harlalka et al. (2013)</a> identified a homozygous P594L mutation in the HERC2 gene in 15 Old Order Amish patients with a severe neurodevelopmental disorder. The mutation, which was not present in the Exome Variant Server or 1000 Genomes Project databases, segregated with the disorder in the families. Two of 158 control chromosomes from the same Amish community carried the mutation, consistent with a founder effect. Patient fibroblasts showed a dramatic reduction in HERC2 protein levels due to mutant protein instability. In vitro functional expression studies showed that the mutation caused a modest disruption of HERC2 activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23243086" 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://doi.org/10.1126/science.aan8433" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-011-1110-x" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17236130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17236130</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17236130[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=17236130" 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/10.1086/510885" target="_blank">Full Text</a>]
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Harlalka, G. V., Baple, E. L., Cross, H., Kuhnle, S., Cubillos-Rojas, M., Matentzoglu, K., Patton, M. A., Wagner, K., Coblentz, R., Ford, D. L., Mackay, D. J. G., Chioza, B. A., Scheffner, M., Rosa, J. L., Crosby, A. H.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23243086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23243086</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23243086" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2012-101367" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/8.3.533" target="_blank">Full Text</a>]
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Kayser, M., Liu, F., Janssens, A. C. J. W., Rivadeneira, F., Lao, O., van Duijn, K., Vermeulen, M., Arp, P., Jhamai, M. M., van IJcken, W. F. J., den Dunnen, J. T., Heath, S., and 10 others.
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<strong>Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252221</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252221[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=18252221" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2007.10.003" target="_blank">Full Text</a>]
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Kuhnle, S., Kogel, U., Glockzin, S., Marquardt, A., Ciechanover, A., Matentzoglu, K., Scheffner, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21493713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21493713</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21493713[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=21493713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M110.205211" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.95.16.9436" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1495987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1495987</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1495987" 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.89.15.6968" target="_blank">Full Text</a>]
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Nagase1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O.
|
|
<strong>Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong>
|
|
DNA Res. 4: 141-150, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9205841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9205841</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9205841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/dnares/4.2.141" 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="13" class="mim-anchor"></a>
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<a id="Puffenberger2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Puffenberger, E. G., Jinks, R. N., Wang, H., Xin, B., Fiorentini, C., Sherman, E. A., Degrazio, D., Shaw, C., Sougnez, C., Cibulskis, K., Gabriel, S., Kelley, R. I., Morton, D. H., Strauss, K. A.
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|
<strong>A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder.</strong>
|
|
Hum. Mutat. 33: 1639-1646, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23065719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23065719</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23065719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.22237" 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="14" class="mim-anchor"></a>
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<a id="Sturm2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sturm, R. A., Duffy, D. L., Zhao, Z. Z., Leite, F. P. N., Stark, M. S., Hayward, N. K., Martin, N. G., Montgomery, G. W.
|
|
<strong>A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color.</strong>
|
|
Am. J. Hum. Genet. 82: 424-431, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252222[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=18252222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2007.11.005" 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="15" class="mim-anchor"></a>
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<a id="Sulem2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Magnusson, K. P., Manolescu, A., Karason, A., Palsson, A., Thorleifsson, G., Jakobsdottir, M., Steinberg, S., and 13 others.
|
|
<strong>Genetic determinants of hair, eye and skin pigmentation in Europeans.</strong>
|
|
Nature Genet. 39: 1443-1452, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17952075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17952075</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17952075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.2007.13" 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="16" class="mim-anchor"></a>
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<a id="Visser2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
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Visser, M., Kayser, M., Palstra, R.-J.
|
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<strong>HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter.</strong>
|
|
Genome Res. 22: 446-455, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22234890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22234890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22234890[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=22234890" 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/10.1101/gr.128652.111" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Wu2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, W., Sato, K., Koike, A., Nishikawa, H., Koizumi, H., Venkitaraman, A. R., Ohta, T.
|
|
<strong>HERC2 is an E3 ligase that targets BRCA1 for degradation.</strong>
|
|
Cancer Res. 70: 6384-6392, 2010.
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20631078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20631078</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20631078" 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/10.1158/0008-5472.CAN-10-1304" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<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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Ada Hamosh - updated : 02/13/2018
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
|
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Cassandra L. Kniffin - updated : 6/19/2014<br>Patricia A. Hartz - updated : 1/14/2014<br>Cassandra L. Kniffin - updated : 11/6/2013<br>Marla J. F. O'Neill - updated : 9/18/2012<br>Cassandra L. Kniffin - updated : 4/11/2008<br>Victor A. McKusick - updated : 3/31/2008<br>Anne M. Stumpf - updated : 1/16/2008
|
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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">
|
|
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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Paul J. Converse : 4/11/2001
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="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">
|
|
carol : 12/14/2021
|
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</span>
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</div>
|
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</div>
|
|
<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">
|
|
alopez : 02/17/2021<br>alopez : 02/13/2018<br>carol : 07/21/2015<br>mcolton : 6/19/2014<br>ckniffin : 6/19/2014<br>mgross : 1/14/2014<br>carol : 11/7/2013<br>ckniffin : 11/6/2013<br>terry : 11/13/2012<br>alopez : 9/18/2012<br>carol : 2/11/2011<br>wwang : 4/18/2008<br>ckniffin : 4/11/2008<br>alopez : 4/11/2008<br>alopez : 4/3/2008<br>terry : 3/31/2008<br>alopez : 1/17/2008<br>alopez : 1/16/2008<br>carol : 9/12/2007<br>mgross : 4/11/2001
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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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>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 605837
|
|
</span>
|
|
</h3>
|
|
</div>
|
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|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
HECT DOMAIN AND RCC1-LIKE DOMAIN 2; HERC2
|
|
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: HERC2</em></strong>
|
|
</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">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 15q13.1
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 15:28,111,040-28,322,179 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</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">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
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<th>
|
|
Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
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|
</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
|
<th>
|
|
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="3">
|
|
<span class="mim-font">
|
|
15q13.1
|
|
</span>
|
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</td>
|
|
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<td>
|
|
<span class="mim-font">
|
|
[Skin/hair/eye pigmentation 1, blond/brown hair]
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
227220
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
[Skin/hair/eye pigmentation 1, blue/nonblue eyes]
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
227220
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Intellectual developmental disorder, autosomal recessive 38
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
615516
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<span class="mim-text-font">
|
|
<p>HERC2 shuttles between the nucleus and cytoplasm and functions as an E3 ubiquitin ligase for the ubiquitination and degradation of target proteins (Wu et al., 2010), as an activator of other E3 ubiquitin ligases (Kuhnle et al., 2011), and as an adaptor for assembly of DNA damage response proteins (Bekker-Jensen et al., 2010). </p><p>For background information on the HERC gene family, see HERC1 (605109).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<span class="mim-text-font">
|
|
<p>Prader-Willi syndrome (PWS; 176270) and Angelman syndrome (AS; 105830) result from deletions and loss of function of oppositely imprinted genes located within the proximal 2 Mb of the 15q11-q13 region. Low-copy repeat elements have been identified in the vicinity of the 3 deletion breakpoint hotspots using molecular and cytologic methods. Using positional cloning from low-copy repeats flanking 15q11-q13, genomic sequence analysis, EST database searching, PCR, and long-range RT-PCR, Ji et al. (1999) obtained a cDNA encoding HERC2, which is identical to a partial cDNA, KIAA0393, identified by Nagase et al. (1997). Sequence analysis predicted that the 4,834-amino acid protein, which is 95% identical and 99% similar to the mouse protein, contains 3 RCC1-like domains (RLDs); a putative ZZ-type zinc finger motif with 6 conserved cysteines and 2 outlying histidine residues; a C-terminal HECT or E3 ubiquitin ligase (see UBE3A; 601623) domain; and several potential phosphorylation sites. The overall structure is similar to that of HERC1, although HERC1 has only 2 RLDs and no zinc finger motif. The C-terminal region of HERC2 resembles that of HERC3 (605200). Northern blot analysis revealed ubiquitous expression of a 15.5-kb HERC2 transcript, with high levels in fetal tissues and adult skeletal muscle, heart, ovary, testis, and brain. </p><p>Lehman et al. (1998) identified and cloned the murine Herc2 gene, which encodes a 4,836-residue protein containing 3 RCC1 repeats and a HECT domain in common with E6AP (UBE3A). </p><p>Using SDS-PAGE, Bekker-Jensen et al. (2010) found that endogenous human HERC2 had an apparent molecular mass of 500 kD. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Nagase et al. (1997) mapped the HERC2 gene, which they called KIAA0393, to chromosome 15 using radiation hybrid analysis. By Southern blot analysis of YACs and radiation hybrid analysis, Ji et al. (1999) mapped the HERC2 gene to 15q11-q13, very close to the P gene (OCA2; 611409). Southern blot analysis of PWS and AS patients resulted in HERC2 signals of 50% intensity compared with controls. The mouse Herc2 gene maps to chromosome 7C, within the juvenile development and fertility-2 (jdf2) interval (Ji et al., 1999). </p><p>Kayser et al. (2008) identified the HERC2 gene within a region on chromosome 15q13.1 linked to determination of human iris color. </p>
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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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<span class="mim-text-font">
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<p>RNF8 (611685) is an E3 ubiquitin ligase that interacts with the E2 ubiquitin-conjugating enzyme UBC13 (UBE2N; 603679) and catalyzes formation of lys63-linked ubiquitin chains on histone H2A (see 613499) flanking sites of DNA damage. Using mass spectrometric analysis, Bekker-Jensen et al. (2010) found that endogenous HERC2 affinity purified with RNF8 from HEK293T cells. RNF8 interacted with the C-terminal HECT domain of HERC2, and phosphorylation of thr4827 within the HECT domain was required for the interaction. Association of HERC2 with RNF8 increased following exposure to DNA damage-inducing ionizing radiation. The DNA damage response kinases ATM (607585), ATR (601215), and DNAPK (see 600899) also interacted with the C terminus of HERC2, and inhibition of these kinases interfered with the RNF8-HERC2 association in an additive manner. HERC2 also interacted in a ternary complex with MDC1 (607593) and RNF8, and all 3 proteins accumulated at sites of DNA double-strand breaks. Depletion of HERC2 in HEK293T cells did not impair accumulation of RNF8 and MDC1 at sites of DNA damage, but it caused failure to recruit UBC13 to RNF8, leading to failure of histone H2A polyubiquitination and accumulation of downstream DNA damage repair and signaling factors. </p><p>BRCA1 (113705) maintains genomic stability by functioning in DNA damage repair, cell cycle checkpoint, and apoptosis. BRCA1 forms a heterodimeric E3 ubiquitin ligase with BARD1 (601593), and loss of this interaction results in BRCA1 degradation. Wu et al. (2010) found that HERC2 countered the stabilizing effect of BARD1 on BRCA1 and caused BRCA1 degradation. The HECT domain of HERC2 interacted with and caused ubiquitination of an N-terminal degradation domain of BRCA1, targeting BRCA1 for degradation. The reaction depended on cys4762 within the catalytic ubiquitin-binding site of HERC2. The HERC2-BRCA1 interaction and BRCA1 degradation were maximal during S phase in synchronized HeLa cells and rapidly diminished as cells entered G2-M. Wu et al. (2010) concluded that HERC2 is an E3 ligase that targets BRCA1 for degradation during S phase of the cell cycle. </p><p>Using yeast 2-hybrid analysis and coprecipitation analysis of cotransfected and endogenous proteins, Kuhnle et al. (2011) found that HERC2 interacted with the 852-amino acid isoform of the E3 ubiquitin ligase E6AP (UBE3A; 601623). Domain analysis revealed that the central RLD2 domain of HERC2 and a domain near the N terminus of E6AP were required for the interaction. Full-length HERC2 or the isolated RLD2 domain of HERC2 stimulated the E3 activity of E6AP in autoubiquitination and in ubiquitination of an E6AP substrate. Stimulation of E6AP did not require catalytically active HERC2. </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>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Skin, Hair, Eye Pigmentation</em></strong></p><p>
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In a large genomewide scan to identify variants associated with hair and eye pigmentation, skin sensitivity to sun, and freckling, Sulem et al. (2007) identified a single-nucleotide polymorphism (SNP), rs1667394, in intron 4 of the HERC2 gene (605837.0001) that was associated with blue eye color and blond hair. Of several SNPs within a 1-Mb region of linkage overlapping the OCA2 gene (611409), rs1667394 had the strongest association with pigmentation. Given the established relationship between OCA2 and pigmentation, Sulem et al. (2007) considered it unlikely that the association signal provided by this SNP was due to a functional effect on HERC2. </p><p>In 3 independent genomewide association studies and a genomewide linkage study involving over 2,600 persons from the Netherlands, Kayser et al. (2008) found that the chromosome 15q13.1 region is the predominant region involved in human iris color. There were no other regions showing consistent genomewide evidence for association and linkage to iris color. SNPs in the HERC2 gene and, to a lesser extent, in the neighboring OCA2 gene (611409) were independently associated with iris color variation. Kayser et al. (2008) found that HERC2 rs916977 (605837.0002) showed a clinal allele distribution across 23 European populations that was significantly correlated to iris color variation. They suggested that genetic variants regulating expression of the OCA2 gene exist in the HERC2 gene or, alternatively, with the 11.7 kb of sequence between OCA2 and HERC2, and that most iris color variation in Europeans is explained by those 2 genes. They further suggested that testing markers in the HERC2-OCA2 region may be useful in forensic applications to predict eye color phenotypes of unknown persons of European genetic origin. </p><p>Duffy et al. (2007) demonstrated that haplotypes of 3 SNPs within the first intron of the OCA2 gene are strongly associated with variation in human eye color. Following up on this study, Sturm et al. (2008) described additional fine association mapping of eye color SNPs in the intergenic region upstream of OCA2 and within the neighboring HERC2 gene. They screened an additional 92 SNPs in 300 to 3,000 European individuals and found that a single SNP in intron 86 of HERC2, rs12913832 (605837.0003), predicted eye color significantly better than their previous best OCA2 haplotype. Comparison of sequence alignments of multiple species showed that this SNP lies in the center of a short highly conserved sequence and that the blue eye-associated allele (frequency 78%) breaks up this conserved sequence, part of which forms a consensus binding site for the helicase-like transcription factor (HLTF; 603257). Sturm et al. (2008) also demonstrated that the OCA2 coding SNP R419Q (611409.0012) acts as a penetrance modifier of this new HERC2 SNP for eye color and, somewhat independently, of melanoma risk. Sturm et al. (2008) concluded that the conserved region around rs12913832 (the SNP in intron 86 of HERC2) represents a regulatory region controlling constitutive expression of OCA2 and that the C allele at this SNP leads to decreased expression of OCA2, particularly within iris melanocytes, which they postulated to be the ultimate cause of blue eye color. </p><p>In a 3-generation Danish family segregating blue and brown eye color, Eiberg et al. (2008) used fine mapping to identify a 166-kb candidate region within the HERC2 gene. Further studies of SNPs within this region among 144 blue-eyed and 45 brown-eyed individuals identified 2 SNPs, rs1129038 and the strongly conserved rs12913832, that showed significant associations with the blue-eyed phenotype (p = 6.2 x 10(-46)). A common founder haplotype containing these SNPs was identified among blue-eyed persons from Denmark, Turkey, and Jordan. In vitro functional expression studies in human colon carcinoma cells showed that what the authors referred to as the 'G' allele of rs12913832, present in blue-eyed individuals, had an inhibitory effect on OCA2 promoter activity. In the 3-generation Danish family, blond hair color was associated with lighter brown/blue eyes and brown hair color was associated with brown eyes. Hair color also associated with several SNPs in the HERC2 gene. However, linkage analysis also implicated a region associated with hair color on chromosome 14 (lod score of 4.21 at D14S72), close to the RABGGTA gene (601905). </p><p>Donnelly et al. (2012) genotyped 3,432 individuals from 72 populations for 21 SNPs in the OCA2-HERC2 region, and found that blue-eye-associated alleles in all 3 haplotypes that previously had been associated with eye pigmentation in Europeans occurred at high frequencies in Europe; however, 1 was restricted to Europe and surrounding regions, whereas the other 2 were found at moderate to high frequencies throughout the world. Their data suggested that the TG allele of the haplotype restricted to Europe, consisting of the SNPs rs1129038 and rs12913832 and which they designated 'BEH2,' was the best marker for blue eyes. </p><p>By examining 1,570 ethnically diverse African genomes from individuals with quantified pigmentation levels, Crawford et al. (2017) identified 10 SNPs in the OCA2/HERC2 region that were highly associated with pigmentation. The HERC2 SNP with the highest probability of being causal was rs4932620 (p = 3.2 x 10(-9)), located within intron 11. The derived rs4932620T allele, associated with dark skin pigmentation, is most common in Ethiopian populations with high levels of Nilo-Saharan ancestry and is at moderate frequency in other Ethiopian, Hadza, and Tanzania Nilo-Saharan populations. The rs4932620T variant is identical by descent in South Asian and Australo-Melanesian populations. Crawford et al. (2017) noted the extensive linkage disequilibrium among SNPs in the OCA2/HERC2 region. </p><p><strong><em>Impaired Intellectual Development 38, Autosomal Recessive</em></strong></p><p>
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In 7 patients of Amish or mixed Amish/Mennonite descent with autosomal recessive impaired intellectual development-38 (MRT38; 615516), Puffenberger et al. (2012) identified a homozygous missense mutation in the HERC2 gene (P594L; 605837.0004). The mutation was found by a combination of homozygosity mapping and exome sequencing. Cellular transfection studies showed that the mutant protein was less stable than wildtype and had a diffuse cytosolic localization with the formation of abnormal aggregates. Decreased abundance and/or activity of HERC2 could produce a toxic loss of E3 ubiquitin ligase activity, leading to decreased degradation of ARC (612461) and decreased postsynaptic glutamatergic AMPA receptor density. Puffenberger et al. (2012) noted that this pathophysiologic mechanism is similar to that thought to underlie Angelman syndrome (105830), which results from loss of function of the UBE3A gene (601623) on chromosome 15q11. The individuals with MRT38 had some features similar to those of AS. </p><p>By genomewide linkage analysis and candidate gene analysis, Harlalka et al. (2013) identified homozygosity for the P594L mutation in the HERC2 gene in 15 Old Order Amish patients with a severe neurodevelopmental disorder. </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>Lehman et al. (1998) identified the murine Herc2 gene as responsible for the 'rjs' (runty, jerky, sterile) radiation-induced mouse phenotype, which has additional features associated with mutations in the neighboring Oca2 gene (611409) (Lyon et al., 1992). </p><p>Ji et al. (1999) identified splice junction mutations in the Herc2 gene in chemically-induced mouse jdf2 mutant alleles. The mutations led to exon skipping and premature termination, resulting in neuromuscular secretory vesicle defects, sperm acrosome defects, and juvenile lethality in jdf2 mice. </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>4 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 SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES</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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SKIN/HAIR/EYE PIGMENTATION 1, BLOND/BROWN HAIR, INCLUDED
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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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HERC2, IVS4, A/G
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<br />
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SNP: rs1667394,
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gnomAD: rs1667394,
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ClinVar: RCV000005009
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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 discovery sample of 2,986 Icelanders and replication samples of 2,718 Icelanders and 1,214 Dutch, Sulem et al. (2007) found association of the A allele of rs1667394 with blue versus brown eyes (OR = 35.42, P = 1.4 x 10(-124)), with blue versus green eyes (OR = 7.02, P = 5.1 x 10(-25)), and with blond versus brown hair (OR = 5.62, P = 4.4 x 10(-16)). Although the rs1667394 variant resides in the HERC2 gene, Sulem et al. (2007) considered it unlikely that the association signal provided by this SNP was due to a functional effect on HERC2. Because of the established relationship between the OCA2 gene (611409) and blue eye color and lighter hair and skin tones (227220), the authors suggested that perhaps sequence variation in the introns of HERC2 affects the expression of OCA2, or that functional variants exist within OCA2 that correlate with rs1667394. </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 SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES</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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HERC2, IVS12, C/T
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<br />
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SNP: rs916977,
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gnomAD: rs916977,
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ClinVar: RCV000005010
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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 independent genomewide association studies of a total of 1,406 persons and a genomewide linkage study of 1,292 relatives, all from the Netherlands, Kayser et al. (2008) found that the HERC2 variant rs916977 showed a gradient-wise (clinal) allele distribution across 23 European populations that was significantly correlated to iris color variation (227220), with the C allele, associated with blue eyes, being more common in northern Europe and the T allele, associated with brown eyes, more common in southern Europe. Analysis of rs916977 together with the 3 SNPs in intron 1 of the OCA2 gene identified by Duffy et al. (2007) (611409.0013) revealed significant genomewide association for only the HERC2 SNP (P = 3.53 x 10(-18)). </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 SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES</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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HERC2, IVS86, C/T
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<br />
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SNP: rs12913832,
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gnomAD: rs12913832,
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ClinVar: RCV000005011
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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 study of the association with eye color (227220) with haplotype-tagging SNPs proximal to intron 1 of the OCA2 gene (611409) that span the intergenic region and encompass the 3-prime end of the upstream gene HERC2, Sturm et al. (2008) identified a SNP in intron 86 of HERC2, rs12913832, that was strongly associated with eye color in 3011 European individuals (P = 2 x 10(-78)). Individuals carrying the CC genotype had only a 1% probability of having brown eyes, while those with the TT genotype had an 80% probability. Haplotype analysis combining the 3 SNPs in OCA2 identified by Duffy et al. (2007) (611409.0013) with rs12913832 followed by multiple ordinal logistic regression showed that the HERC2 SNP alone was the best predictor of eye color. Sturm et al. (2008) concluded that the conserved region around rs12913832 represents a regulatory region controlling constitutive expression of OCA2, and that the C allele of rs12913832 leads to decreased expression of OCA2, particularly within iris melanocytes, by abrogation of the binding site for HLTF (603257) that regulates transcription of OCA2. Sturm et al. (2008) also demonstrated that the OCA2 coding SNP R419Q (611409.0012) acts as a penetrance modifier of rs12913832. </p><p>In a 3-generation Danish family segregating blue and brown eye color, Eiberg et al. (2008) used fine mapping to identify a 166-kb candidate region within the HERC2 gene. Further studies of SNPs within this region among 144 blue-eyed and 45 brown-eyed individuals identified 2 SNPs, rs1129038 and the strongly conserved rs12913832, that showed significant associations with the blue-eyed phenotype (p = 6.2 x 10(-46)). A common founder haplotype containing these SNPs was identified among blue-eyed persons from Denmark, Turkey, and Jordan. In vitro functional expression studies in human colon carcinoma cells showed that what the authors referred to as the 'G' allele of rs12913832, present in blue-eyed individuals, had an inhibitory effect on OCA2 promoter activity. </p><p>Visser et al. (2012) found that HLTF, LEF1 (153245), and MITF (156845) bound to the enhancer region surrounding rs12913832 in darkly pigmented human melanocytes carrying the T allele of rs12913832. Binding was associated with long-range chromatin looping between the enhancer and the OCA2 promoter, leading to elevated OCA2 expression. In contrast, lightly pigmented melanocytes carrying the C allele of rs12913832 showed reduced enhancer binding, chromatin looping, and OCA2 expression. </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 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 38</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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HERC2, PRO594LEU
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<br />
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SNP: rs397518474,
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gnomAD: rs397518474,
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ClinVar: RCV000074397
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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 7 patients of Amish or mixed Amish/Mennonite descent with autosomal recessive intellectual developmental disorder-38 (MRT38; 615516), Puffenberger et al. (2012) identified a homozygous c.1781C-T transition in the HERC2 gene, resulting in a pro594-to-leu (P594L) substitution at a highly conserved residue in the first RLD1 domain. The mutation was found by a combination of homozygosity mapping and exome sequencing. The mutation was not present in the dbSNP database or in 760 alleles from Amish and Mennonite controls. Cellular transfection studies demonstrated that the mutant protein was less stable than wildtype and showed diffuse cytosolic localization with the formation of abnormal aggregates. Decreased abundance and/or activity of HERC2 could produce a toxic loss of E3 ubiquitin ligase activity, leading to decreased degradation of ARC (612461) and decreased postsynaptic glutamatergic AMPA receptor density. Puffenberger et al. (2012) noted that this pathophysiologic mechanism is similar to that thought to underlie Angelman syndrome (105830), which results from loss of function of the UBE3A gene (601623) on chromosome 15q11. The affected individuals with the HERC2 mutation had global developmental delay and autistic features similar to Angelman syndrome; they also had blue irides. </p><p>By genomewide linkage analysis and candidate gene analysis, Harlalka et al. (2013) identified a homozygous P594L mutation in the HERC2 gene in 15 Old Order Amish patients with a severe neurodevelopmental disorder. The mutation, which was not present in the Exome Variant Server or 1000 Genomes Project databases, segregated with the disorder in the families. Two of 158 control chromosomes from the same Amish community carried the mutation, consistent with a founder effect. Patient fibroblasts showed a dramatic reduction in HERC2 protein levels due to mutant protein instability. In vitro functional expression studies showed that the mutation caused a modest disruption of HERC2 activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Bekker-Jensen, S., Rendtlew Danielsen, J., Fugger, K., Gromova, I., Nerstedt, A., Lukas, C., Bartek, J., Lukas, J., Mailand, N.
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<strong>HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes.</strong>
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Nature Cell Biol. 12: 80-86, 2010. Note: Erratum: Nature Cell Biol. 12: 412 only, 2010.
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[PubMed: 20023648]
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[Full Text: https://doi.org/10.1038/ncb2008]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Crawford, N. G., Kelly, D. E., Hansen, M. E. B., Beltrame, M. H., Fan, S., Bowman, S. L., Jewett, E., Ranciaro, A., Thompson, S., Lo, Y., Pfeifer, S. P., Jensen, J. D., and 36 others.
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<strong>Loci associated with skin pigmentation identified in African populations.</strong>
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Science 358: eaan8433, 2017. Note: Electronic Article. Erratum: Science 367: eaba7178, 2020.
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[PubMed: 29025994]
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[Full Text: https://doi.org/10.1126/science.aan8433]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Donnelly, M. P., Paschou, P., Grigorenko, E., Gurwitz, D., Barta, C., Lu, R.-B., Zhukova, O. V., Kim, J.-J., Siniscalco, M., New, M., Li, H., Kajuna, S. L. B., Manolopoulos, V. G., Speed, W. C., Pakstis, A. J., Kidd, J. R., Kidd, K. K.
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<strong>A global view of the OCA2-HERC2 region and pigmentation.</strong>
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<strong>The ancestral gene for transcribed, low-copy repeats in the Prader-Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities.</strong>
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<strong>Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene.</strong>
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Lehman, A. L., Nakatsu, Y., Ching, A., Bronson, R. T., Oakey, R. J., Keiper-Hrynko, N., Finger, J. N., Durham-Pierre, D., Horton, D. B., Newton, J. M., Lyon, M. F., Brilliant, M. H.
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<strong>A very large protein with diverse functional motifs is deficient in rjs (runty, jerky, sterile) mice.</strong>
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Lyon, M. F., King, T. R., Gondo, Y., Gardner, J. M., Nakatsu, Y., Eicher, E. M., Brilliant, M. H.
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<strong>Genetic and molecular analysis of recessive alleles at the pink-eyed dilution (p) locus of the mouse.</strong>
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Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O.
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<strong>Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong>
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Puffenberger, E. G., Jinks, R. N., Wang, H., Xin, B., Fiorentini, C., Sherman, E. A., Degrazio, D., Shaw, C., Sougnez, C., Cibulskis, K., Gabriel, S., Kelley, R. I., Morton, D. H., Strauss, K. A.
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<strong>A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder.</strong>
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Sturm, R. A., Duffy, D. L., Zhao, Z. Z., Leite, F. P. N., Stark, M. S., Hayward, N. K., Martin, N. G., Montgomery, G. W.
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<strong>A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color.</strong>
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Sulem, P., Gudbjartsson, D. F., Stacey, S. N., Helgason, A., Rafnar, T., Magnusson, K. P., Manolescu, A., Karason, A., Palsson, A., Thorleifsson, G., Jakobsdottir, M., Steinberg, S., and 13 others.
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<strong>Genetic determinants of hair, eye and skin pigmentation in Europeans.</strong>
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Visser, M., Kayser, M., Palstra, R.-J.
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<strong>HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter.</strong>
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Wu, W., Sato, K., Koike, A., Nishikawa, H., Koizumi, H., Venkitaraman, A. R., Ohta, T.
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<strong>HERC2 is an E3 ligase that targets BRCA1 for degradation.</strong>
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[PubMed: 20631078]
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