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<title>
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Entry
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- *603324 - GAP JUNCTION PROTEIN, BETA-3; GJB3
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- OMIM
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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Advanced Search
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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</form>
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<p />
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*603324</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/603324">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
|
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
|
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</div>
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</a>
|
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000188910;t=ENST00000373366" 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=2707" 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=603324" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000188910;t=ENST00000373366" 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_001005752,NM_024009" 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_024009" 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=603324" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
|
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=04505&isoform_id=04505_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/GJB3" 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/3445287,3982600,4009520,6014758,13128960,15277749,54607056,84040221,119627847,189053581,2252622097" 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/O75712" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
|
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</div>
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</a>
|
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</span>
|
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=2707" 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=ENSG00000188910;t=ENST00000373366" 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=GJB3" 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=GJB3" 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+2707" 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/GJB3" 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:2707" 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/2707" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr1&hgg_gene=ENST00000373366.3&hgg_start=34781214&hgg_end=34786364&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:4285" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/gjb3" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603324[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=603324[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000188910" 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.gwascentral.org/search?q=GJB3" 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=GJB3" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://davinci.crg.es/deafness/" title="The Connexin-deafness homepage" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">The Connexin-deafness home…</a></div><div style="margin-left: 0.5em;"><a href="http://webh01.ua.ac.be/hhh/" title="Hereditary Hearing Loss Homepage" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Hereditary Hearing Loss Ho…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=GJB3&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/PA28696" 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:4285" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:95721" 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/GJB3#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:95721" 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/2707/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=2707" 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-050417-174" 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://reactome.org/content/query?q=GJB3&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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603324
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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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GAP JUNCTION PROTEIN, BETA-3; GJB3
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</span>
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</h3>
|
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
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GAP JUNCTION PROTEIN, 31-KD<br />
|
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CONNEXIN 31; CX31
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GJB3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GJB3</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/1/423?start=-3&limit=10&highlight=423">1p34.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:34781214-34786364&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">1:34,781,214-34,786,364</a> </span>
|
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</em>
|
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</strong>
|
|
<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>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<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>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=612644,220290,133200" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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</th>
|
|
<th>
|
|
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
|
|
</th>
|
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</tr>
|
|
</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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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>, <abbr class="mim-tip-hint" title="Digenic dominant">DD</abbr>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/radial/603324" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>Gap junctions are conduits that allow the direct cell-to-cell passage of small cytoplasmic molecules, including ions, metabolic intermediates, and second messengers, and thereby mediate intercellular metabolic and electrical communication. Gap junction channels consist of connexin protein subunits, which are encoded by a multigene family that includes GJB3 (summary by <a href="#12" class="mim-tip-reference" title="Richard, G., Smith, L. E., Bailey, R. A., Itin, P., Hohl, D., Epstein, E. H., Jr., DiGiovanna, J. J., Compton, J. G., Bale, S. J. <strong>Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.</strong> Nature Genet. 20: 366-369, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843209</a>] [<a href="https://doi.org/10.1038/3840" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843209">Richard et al., 1998</a>; <a href="#16" class="mim-tip-reference" title="Wenzel, K., Manthey, D., Willecke, K., Grzeschik, K.-H., Traub, O. <strong>Human gap junction protein connexin31: molecular cloning and expression analysis.</strong> Biochem. Biophys. Res. Commun. 248: 910-915, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9704026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9704026</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9704026">Wenzel et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9704026+9843209" 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="Richard, G., Smith, L. E., Bailey, R. A., Itin, P., Hohl, D., Epstein, E. H., Jr., DiGiovanna, J. J., Compton, J. G., Bale, S. J. <strong>Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.</strong> Nature Genet. 20: 366-369, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843209</a>] [<a href="https://doi.org/10.1038/3840" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843209">Richard et al. (1998)</a> identified 2 expressed sequence tags (ESTs) from the human EST database by their similarity to mouse Gjb3 and Gjb5. By radiation hybrid mapping, they placed them in proximity with a sequenced tag site (STS) that is linked to GJA4 (<a href="/entry/121012">121012</a>). Comparison of genomic and cDNA sequence of GJB3 showed an exon-intron organization common to that of genes encoding connexins. The complete coding sequence was contained in a single, uninterrupted open reading frame (ORF) of 813 nucleotides preceded by a putative splice junction located 25 nucleotides upstream of the ATG initiation site and followed by the 3-prime untranslated region with a polyadenylation signal at position 1,583. The protein Cx31, of predicted molecular mass 30.8 kD, consists of 270 amino acids and differs from its rodent homologs at 40 residues that are confined mainly to the cytoplasmic loop. Protein structure analysis confirmed a structural organization typical for beta-connexins, including a conserved arrangement of 3 cysteine residues in each extracellular loop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843209" 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 screening a human genomic library with a mouse Cx31 cDNA, <a href="#16" class="mim-tip-reference" title="Wenzel, K., Manthey, D., Willecke, K., Grzeschik, K.-H., Traub, O. <strong>Human gap junction protein connexin31: molecular cloning and expression analysis.</strong> Biochem. Biophys. Res. Commun. 248: 910-915, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9704026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9704026</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9704026">Wenzel et al. (1998)</a> isolated the CX31 gene. Southern blot analysis of human DNA showed that CX31 is a single-copy gene. Northern blot analysis of human keratinocyte cell lines detected approximately 2.2- and 1.8-kb CX31 transcripts. The deduced CX31 protein contains 4 putative transmembrane domains and 3 potential phosphorylation sites. Human CX31 is 83% identical to the mouse and rat Cx31 proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9704026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Xia, J., Liu, C., Tang, B., Pan, Q., Huang, L., Dai, H., Zhang, B., Xie, W., Hu, D., Zheng, D., Shi, X., Wang, D., Xia, K., Yu, K., Liao, X., Feng, Y., Yang, Y., Xiao, J., Xie, D., Huang, J. <strong>Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment.</strong> Nature Genet. 20: 370-373, 1998. Note: Erratum: Nature Genet.:21: 241 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843210</a>] [<a href="https://doi.org/10.1038/3845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843210">Xia et al. (1998)</a> cloned the gene (GJB3) encoding human gap junction protein beta-3 using homologous EST searching and nested PCR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843210" 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="Lopez-Bigas, N., Olive, M., Rabionet, R., Ben-David, O., Martinez-Matos, J. A., Bravo, O., Banchs, I., Volpini, V., Gasparini, P., Avraham, K. B., Ferrer, I., Arbones, M. L., Estivill, X. <strong>Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment.</strong> Hum. Molec. Genet. 10: 947-952, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309368</a>] [<a href="https://doi.org/10.1093/hmg/10.9.947" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309368">Lopez-Bigas et al. (2001)</a> demonstrated expression of mouse Gjb3 in the cochlea and in the auditory and sciatic nerves in a pattern similar to that of Gjb1 (<a href="/entry/304040">304040</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11309368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By analysis of somatic cell hybrids, <a href="#16" class="mim-tip-reference" title="Wenzel, K., Manthey, D., Willecke, K., Grzeschik, K.-H., Traub, O. <strong>Human gap junction protein connexin31: molecular cloning and expression analysis.</strong> Biochem. Biophys. Res. Commun. 248: 910-915, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9704026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9704026</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9704026">Wenzel et al. (1998)</a> mapped the GJB3 gene to chromosome 1p36-p34. <a href="#18" class="mim-tip-reference" title="Xia, J., Liu, C., Tang, B., Pan, Q., Huang, L., Dai, H., Zhang, B., Xie, W., Hu, D., Zheng, D., Shi, X., Wang, D., Xia, K., Yu, K., Liao, X., Feng, Y., Yang, Y., Xiao, J., Xie, D., Huang, J. <strong>Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment.</strong> Nature Genet. 20: 370-373, 1998. Note: Erratum: Nature Genet.:21: 241 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843210</a>] [<a href="https://doi.org/10.1038/3845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843210">Xia et al. (1998)</a> mapped the GJB3 gene to 1p35-p33 by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9704026+9843210" 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="Plantard, L., Huber, M., Macari, F., Meda, P., Hohl, D. <strong>Molecular interaction of connexin 30.3 and connexin 31 suggests a dominant-negative mechanism associated with erythrokeratodermia variabilis.</strong> Hum. Molec. Genet. 12: 3287-3294, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14583444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14583444</a>] [<a href="https://doi.org/10.1093/hmg/ddg364" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14583444">Plantard et al. (2003)</a> showed that expression of wildtype CX30.3 (GJB4; <a href="/entry/605425">605425</a>) in HeLa cells resulted only in minor amounts of protein addressed to the plasma membrane. Mutant CX30.3 (<a href="/entry/605425#0001">605425.0001</a>) was hardly detectable and disturbed intercellular coupling. In contrast, coexpression of both wildtype CX30.3 and CX31 proteins led to a large increase of stabilized heteromeric gap junctions. Coexpressed wildtype CX30.3 and CX31 coprecipitated, demonstrating a physical interaction. Inhibitor experiments revealed that this interaction began in the endoplasmic reticulum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14583444" 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 transfected mouse neuroblastoma and HeLa cell lines, <a href="#1" class="mim-tip-reference" title="Abrams, C. K., Freidin, M. M., Verselis, V. K., Bargiello, T. A., Kelsell, D. P., Richard, G., Bennett, M. V. L., Bukauskas, F. F. <strong>Properties of human connexin 31, which is implicated in hereditary dermatological disease and deafness.</strong> Proc. Nat. Acad. Sci. 103: 5213-5218, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16549784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16549784</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16549784[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.0511091103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16549784">Abrams et al. (2006)</a> found that CX31 channels, like other connexin channels, were gated by voltage and closed at low pH when exposed to long-chain alkanols. CX31 channels were relatively nonselective, allowing passage of both negatively and positively charged dyes. In contrast to mouse Cx31, human CX31 appeared to form functional heterotypic channels with all 4 connexins tested: CX26 (GJB2; <a href="/entry/121011">121011</a>), CX30 (GJB6; <a href="/entry/604418">604418</a>), CX32 (GJB1; <a href="/entry/304040">304040</a>), and CX45 (GJA7; <a href="/entry/608655">608655</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16549784" 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="#6" class="mim-tip-reference" title="Liu, X.-Z., Yuan, Y., Yan, D., Ding, E. H., Ouyang, X. M., Fei, Y., Tang, W., Yuan, H., Chang, Q., Du, L. L., Zhang, X., Wang, G., Ahmad, S., Kang, D. Y., Lin, X., Dai, P. <strong>Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31.</strong> Hum. Genet. 125: 53-62, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19050930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19050930</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19050930[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/s00439-008-0602-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19050930">Liu et al. (2009)</a> found that Cx31 and Cx26 were coexpressed in the mouse cochlea and coassembled into gap junctions when expressed in HEK293 cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19050930" 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>Erythrokeratodermia Variabilis et Progressiva 1</em></strong></p><p>
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Erythrokeratodermia variabilis et progressiva (EKVP1; <a href="/entry/133200">133200</a>) is a disorder of keratinization characterized by fixed erythrokeratotic plaques, associated with migratory erythematous lesions ('variabilis;' EKV) in some patients. In 4 of 12 families with EKV, <a href="#12" class="mim-tip-reference" title="Richard, G., Smith, L. E., Bailey, R. A., Itin, P., Hohl, D., Epstein, E. H., Jr., DiGiovanna, J. J., Compton, J. G., Bale, S. J. <strong>Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.</strong> Nature Genet. 20: 366-369, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843209</a>] [<a href="https://doi.org/10.1038/3840" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843209">Richard et al. (1998)</a> detected heterozygous missense mutations in the GJB3 gene leading to substitution of a conserved glycine by charged residues (G12R, <a href="#0001">603324.0001</a>; G12D, <a href="#0002">603324.0002</a>), or change of a cysteine (C86S; <a href="#0003">603324.0003</a>). These mutations were predicted to interfere with normal Cx31 structure and function, possibly due to a dominant-negative effect. Thus, the results provided evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors. <a href="#12" class="mim-tip-reference" title="Richard, G., Smith, L. E., Bailey, R. A., Itin, P., Hohl, D., Epstein, E. H., Jr., DiGiovanna, J. J., Compton, J. G., Bale, S. J. <strong>Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.</strong> Nature Genet. 20: 366-369, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843209</a>] [<a href="https://doi.org/10.1038/3840" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843209">Richard et al. (1998)</a> stated that this report was the first to link mutations in a gene encoding a connexin to a human skin disorder, and noted that further functional in vitro and in vivo studies were needed to understand how mutant Cx31 alters differentiation of the epidermis (hyperkeratosis) and affects the cutaneous microcapillary system (transient erythema). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Wilgoss, A., Leigh, I. M., Barnes, M. R., Dopping-Hepenstal, P., Eady, R. A. J., Walter, J. M., Kennedy, C. T. C., Kelsell, D. P. <strong>Identification of a novel mutation R42P in the gap junction protein beta-3 associated with autosomal dominant erythrokeratoderma variabilis.</strong> J. Invest. Derm. 113: 1119-1122, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10594760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10594760</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1999.00792.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10594760">Wilgoss et al. (1999)</a> identified heterozygosity for a missense mutation in the GJB3 gene (R42P; <a href="#0008">603324.0008</a>) in affected members of a family with EKV. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10594760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Richard, G., Brown, N., Smith, L. E., Terrinoni, A., Melino, G., MacKie, R. M., Bale, S. J., Uitto, J. <strong>The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3.</strong> Hum. Genet. 106: 321-329, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10798362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10798362</a>] [<a href="https://doi.org/10.1007/s004390051045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10798362">Richard et al. (2000)</a> analyzed the GJB3 gene in 2 families and 3 sporadic patients with EKV and in 2 families and 4 sporadic patients with the progressive, symmetric form (PSEK) of erythrokeratodermia, including a family previously described by <a href="#9" class="mim-tip-reference" title="Macfarlane, A. W., Chapman, S. J., Verbov, J. L. <strong>Is erythrokeratoderma one disorder? A clinical and ultrastructural study of two siblings.</strong> Brit. J. Derm. 124: 487-491, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1828175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1828175</a>] [<a href="https://doi.org/10.1111/j.1365-2133.1991.tb00632.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1828175">Macfarlane et al. (1991)</a> in which 1 sister had features of EKV and the other of PSEK. <a href="#11" class="mim-tip-reference" title="Richard, G., Brown, N., Smith, L. E., Terrinoni, A., Melino, G., MacKie, R. M., Bale, S. J., Uitto, J. <strong>The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3.</strong> Hum. Genet. 106: 321-329, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10798362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10798362</a>] [<a href="https://doi.org/10.1007/s004390051045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10798362">Richard et al. (2000)</a> identified 3 heterozygous mutations in GJB3 in EKV patients: in a sporadic case, they detected a mutation leading to substitution of a conserved phenylalanine (F137L) in the third transmembrane domain, which likely interferes with the proper assembly or gating properties of connexins. In another EKV family, all 3 affected individuals carried 2 distinct mutations on the same GJB3 allele; however, only the R42P mutation (<a href="#0008">603324.0008</a>) cosegregated with the disease, whereas a 12-bp deletion predicted to eliminate 4 amino acid residues in the variable carboxy-terminal domain of Cx31 was also found in clinically unaffected relatives but not in 90 unaffected controls. No mutations were detected in the 6 probands with PSEK. <a href="#11" class="mim-tip-reference" title="Richard, G., Brown, N., Smith, L. E., Terrinoni, A., Melino, G., MacKie, R. M., Bale, S. J., Uitto, J. <strong>The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3.</strong> Hum. Genet. 106: 321-329, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10798362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10798362</a>] [<a href="https://doi.org/10.1007/s004390051045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10798362">Richard et al. (2000)</a> stated that overall, they had identified GJB3 mutations in 6 of 17 families with EKV; all of the mutations presumably affect the cytoplasmic amino-terminal and transmembrane domains of Cx31. In contrast, 2 mutations linked to progressive high-tone hearing impairment (DFNA2B; <a href="/entry/612644">612644</a>) were located in the second extracellular domain, suggesting that the character and position of Cx mutations determine their phenotypic expression in different tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1828175+10798362" 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 brother and sister from an Israeli family segregating autosomal recessive EKV, <a href="#3" class="mim-tip-reference" title="Gottfried, I., Landau, M., Glaser, F., Di, W.-L., Ophir, J., Mevorah, B., Ben-Tal, N., Kelsell, D. P., Avraham, K. B. <strong>A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein.</strong> Hum. Molec. Genet. 11: 1311-1316, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019212</a>] [<a href="https://doi.org/10.1093/hmg/11.11.1311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12019212">Gottfried et al. (2002)</a> identified homozygosity for a missense mutation in the GJB3 gene (L34P; <a href="/entry/603342#0010">603342.0010</a>). The unaffected parents were heterozygous for the mutation, which was not found in 208 control chromosomes. <a href="#3" class="mim-tip-reference" title="Gottfried, I., Landau, M., Glaser, F., Di, W.-L., Ophir, J., Mevorah, B., Ben-Tal, N., Kelsell, D. P., Avraham, K. B. <strong>A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein.</strong> Hum. Molec. Genet. 11: 1311-1316, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019212</a>] [<a href="https://doi.org/10.1093/hmg/11.11.1311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12019212">Gottfried et al. (2002)</a> suggested that the missense mutation might not be able to exert a dominant-negative effect in heterozygous form, thus manifesting itself clinically only in the homozygote. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12019212" 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 4-year-old Dutch boy with the migratory form of EKVP, <a href="#15" class="mim-tip-reference" title="van Geel, M., van Steensel, M. A. M., Steijlen, P. M. <strong>Connexin 30.3 (GJB4) is not required for normal skin function in humans.</strong> Brit. J. Derm. 147: 1275-1277, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12452892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12452892</a>] [<a href="https://doi.org/10.1046/j.1365-2133.2002.05000_9.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12452892">van Geel et al. (2002)</a> identified a heterozygous R32W mutation in the GJB3 gene as well as a homozygous 4-bp deletion (154delGTCT) in the GJB4 gene. Analysis of unaffected family members revealed that both parents and the maternal grandfather were heterozygous for the GJB4 deletion, whereas the mother and maternal grandfather were heterozygous for the GJB3 variant; in addition, the patient's unaffected sister carried the identical GJB3/GJB4 genotype as the patient, thus excluding either DNA variation as causative for the disease. <a href="#15" class="mim-tip-reference" title="van Geel, M., van Steensel, M. A. M., Steijlen, P. M. <strong>Connexin 30.3 (GJB4) is not required for normal skin function in humans.</strong> Brit. J. Derm. 147: 1275-1277, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12452892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12452892</a>] [<a href="https://doi.org/10.1046/j.1365-2133.2002.05000_9.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12452892">Van Geel et al. (2002)</a> subsequently examined 84 unrelated controls and found 5 heterozygotes for the GJB4 deletion (allele frequency, 0.03) and 3 for the GJB3 variant (0.02), suggesting that both variations represent normal polymorphisms in the Dutch population. <a href="#15" class="mim-tip-reference" title="van Geel, M., van Steensel, M. A. M., Steijlen, P. M. <strong>Connexin 30.3 (GJB4) is not required for normal skin function in humans.</strong> Brit. J. Derm. 147: 1275-1277, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12452892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12452892</a>] [<a href="https://doi.org/10.1046/j.1365-2133.2002.05000_9.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12452892">Van Geel et al. (2002)</a> noted that the GJB3 variant had previously been detected in a family with palmoplantar keratoderma and hearing defects (see GJB2, <a href="/entry/121011">121011</a>) by <a href="#4" class="mim-tip-reference" title="Kelsell, D. P., Wilgoss, A. L., Richard, G., Stevens, H. P., Munro, C. S., Leigh, I. M. <strong>Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family.</strong> Europ. J. Hum. Genet. 8: 141-144, 2000. Note: Erratum: Europ. J. Hum. Genet. 8: 468 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10757647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10757647</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10757647">Kelsell et al. (2000)</a>, who suggested that it might be a polymorphism; analysis of R32W in Spanish patients and controls by <a href="#8" class="mim-tip-reference" title="Lopez-Bigas, N., Rabionet, R., Arbones, M. L., Estivill, X. <strong>R32W variant in connexin 31: mutation or polymorphism for deafness and skin disease? (Letter)</strong> Europ. J. Hum. Genet. 9: 70 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175305</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175305">Lopez-Bigas et al. (2001)</a> confirmed that the variant is a common polymorphism in the Spanish population (allele frequency, 7.5%). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10757647+11175305+12452892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Di, W.-L., Monypenny, J., Common, J. E. A., Kennedy, C. T. C., Holland, K. A., Leigh, I. M., Rugg, E. L., Zicha, D., Kelsell, D. P. <strong>Defective trafficking and cell death is characteristic of skin disease-associated connexin 31 mutations.</strong> Hum. Molec. Genet. 11: 2005-2014, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12165562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12165562</a>] [<a href="https://doi.org/10.1093/hmg/11.17.2005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12165562">Di et al. (2002)</a> observed that immunostaining of a skin biopsy taken from an EKV patient harboring the R42P mutation (<a href="#0008">603324.0008</a>) revealed sparse epidermal staining of Cx31 with aberrant perinuclear localization. Transfection and microinjection studies in keratinocytes and fibroblast cell lines demonstrated that R42P and 4 other EKV-associated mutant Cx31 proteins displayed defective trafficking to the plasma membrane. The deafness/neuropathy-only 66delD (<a href="#0009">603324.0009</a>) mutant protein had primarily a cytoplasmic localization, but some protein was visualized at the plasma membrane in a few transfected cells. Both 66delD- and R32W-Cx31/EGFP proteins had significantly impaired dye transfer rates compared to wildtype Cx31/EGFP protein. A high incidence of cell death was observed with the dominant skin disease Cx31 mutations, but not with wildtype, R32W, or 66delD Cx31 proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12165562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Tattersall, D., Scott, C. A., Gray, C., Zicha, D., Kelsell, D. P. <strong>EKV mutant connexin 31 associated cell death is mediated by ER stress.</strong> Hum. Molec. Genet. 18: 4734-4745, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19755382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19755382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19755382[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/10.1093/hmg/ddp436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19755382">Tattersall et al. (2009)</a> reported that in vitro expression of connexin-31 mutants R42P (<a href="#0008">603324.0008</a>), C86S (<a href="#0003">603324.0003</a>), and G12D (<a href="#0002">603324.0002</a>), but not wildtype or 66delD (<a href="#0009">603324.0009</a>), cause elevated levels of cell type-specific cell death. Their observations did not support the hypothesis that Cx-associated cell death is related to abnormal 'leaky' calcium hemichannels. <a href="#14" class="mim-tip-reference" title="Tattersall, D., Scott, C. A., Gray, C., Zicha, D., Kelsell, D. P. <strong>EKV mutant connexin 31 associated cell death is mediated by ER stress.</strong> Hum. Molec. Genet. 18: 4734-4745, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19755382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19755382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19755382[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/10.1093/hmg/ddp436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19755382">Tattersall et al. (2009)</a> observed upregulation of components of the unfolded protein response (UPR) in cells expressing the EKV-associated Cx31 mutants but not wildtype or 66delD. The authors concluded that the endoplasmic reticulum (ER) stress leading to the UPR may be the main mechanism of mutant Cx31-associated cell death, and that ER stress may lead to abnormal keratinocyte differentiation and hyperproliferation in EKV patient skin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19755382" 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>Deafness, Autosomal Dominant 2B</em></strong></p><p>
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In affected members of 2 Chinese families with autosomal dominant hearing loss (DFNA2B; <a href="/entry/612644">612644</a>), <a href="#18" class="mim-tip-reference" title="Xia, J., Liu, C., Tang, B., Pan, Q., Huang, L., Dai, H., Zhang, B., Xie, W., Hu, D., Zheng, D., Shi, X., Wang, D., Xia, K., Yu, K., Liao, X., Feng, Y., Yang, Y., Xiao, J., Xie, D., Huang, J. <strong>Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment.</strong> Nature Genet. 20: 370-373, 1998. Note: Erratum: Nature Genet.:21: 241 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843210</a>] [<a href="https://doi.org/10.1038/3845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843210">Xia et al. (1998)</a> identified heterozygous mutations in the GJB3 gene (<a href="#0004">603324.0004</a>; <a href="#0005">603324.0005</a>). Gjb3 expression was identified in rat inner ear tissue by RT-PCR. It is well known that age-related hearing impairment is more prevalent in males than in females. It was noteworthy that, in the 2 families studied by <a href="#18" class="mim-tip-reference" title="Xia, J., Liu, C., Tang, B., Pan, Q., Huang, L., Dai, H., Zhang, B., Xie, W., Hu, D., Zheng, D., Shi, X., Wang, D., Xia, K., Yu, K., Liao, X., Feng, Y., Yang, Y., Xiao, J., Xie, D., Huang, J. <strong>Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment.</strong> Nature Genet. 20: 370-373, 1998. Note: Erratum: Nature Genet.:21: 241 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843210</a>] [<a href="https://doi.org/10.1038/3845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843210">Xia et al. (1998)</a>, female carriers were either subclinically affected or had undetectable hearing impairment. Noise exposure for male mutation carriers was not significantly different from their female sibs (as recalled by the family members). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a 4-generation Spanish family with mild hearing impairment and peripheral neuropathy, <a href="#7" class="mim-tip-reference" title="Lopez-Bigas, N., Olive, M., Rabionet, R., Ben-David, O., Martinez-Matos, J. A., Bravo, O., Banchs, I., Volpini, V., Gasparini, P., Avraham, K. B., Ferrer, I., Arbones, M. L., Estivill, X. <strong>Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment.</strong> Hum. Molec. Genet. 10: 947-952, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309368</a>] [<a href="https://doi.org/10.1093/hmg/10.9.947" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309368">Lopez-Bigas et al. (2001)</a> identified a heterozygous 3-bp deletion in the GJB3 gene (<a href="#0009">603324.0009</a>). In situ studies in mice demonstrated expression of Gjb3 in the cochlea and auditory and sciatic nerves, similar to the expression pattern of Gjb1 (<a href="/entry/304040">304040</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11309368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Following the demonstration that mutations in the GJB3 gene can cause autosomal dominant nonsyndromic sensorineural deafness, <a href="#5" class="mim-tip-reference" title="Liu, X.-Z., Xia, X. J., Xu, L. R., Pandya, A., Liang, C. Y., Blanton, S. H., Brown, S. D. M., Steel, K. P., Nance, W. E. <strong>Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss.</strong> Hum. Molec. Genet. 9: 63-67, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10587579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10587579</a>] [<a href="https://doi.org/10.1093/hmg/9.1.63" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10587579">Liu et al. (2000)</a> screened 25 Chinese families with recessive deafness to determine whether mutations at this locus can also cause recessive nonsyndromic deafness. Among the 25 families, 2 contained individuals who were compound heterozygous for GJB3 mutations. The 3 affected individuals in the 2 families were born to nonconsanguineous parents and had an early-onset bilateral sensorineural hearing loss. In both families, differing SSCP patterns were observed in affected and unaffected individuals. Sequence analysis in both families demonstrated an in-frame 3-bp deletion (423_425delATT; <a href="#0006">603324.0006</a>) on one allele, which led to the loss of an isoleucine residue at codon 141, and a 423A-G transition on the other allele, which created an ile141-to-val missense mutation (I142V; <a href="#0007">603324.0007</a>). Neither of these mutations was detected in DNA from 100 unrelated control subjects. Both the deletion of isoleucine-141 and its substitution by valine could alter the structure of the third conserved alpha-helical transmembrane domain (M3) and impair the function of the gap junction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10587579" 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="#13" class="mim-tip-reference" title="Schnichels, M., Worsdorfer, P., Dobrowolski, R., Markopoulos, C., Kretz, M., Schwarz, G., Winterhager, E., Willecke, K. <strong>The connexin31 F137L mutant mouse as a model for the human skin disease erythrokeratodermia variabilis (EKV).</strong> Hum. Molec. Genet. 16: 1216-1224, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17446259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17446259</a>] [<a href="https://doi.org/10.1093/hmg/ddm068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17446259">Schnichels et al. (2007)</a> generated a conditional mouse model of EKV using the human F137L mutation in the Cx31 gene. Although homozygosity for the mutation was embryonic lethal, heterozygous mice were fertile and showed no obvious abnormalities. In vitro cellular functional expression studies showed that the heterozygous mutant channel had approximately 30% decreased neurobiotin transfer activity, probably due to a dominant-negative effect. Heterozygous mutant mice showed a decreased healing time of tail incision wounds by 1 day, similar to mice with decreased expression of Cx43 (<a href="/entry/121014">121014</a>) in the epidermis. These findings suggested again that the Cx31 and Cx43 proteins functionally interact. No erythema was detected in young mice before 2 weeks of age, and only about 5% of the skin area of mutant mice showed hyperproliferation of the stratum germinativum. In addition, heterozygous Cx31 mutant mice showed normal epidermal expression patterns and levels of other connexin proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17446259" 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 Swiss patient with erythrokeratodermia variabilis et progressiva (EKVP1; <a href="/entry/133200">133200</a>) who had localized hyperkeratosis, <a href="#12" class="mim-tip-reference" title="Richard, G., Smith, L. E., Bailey, R. A., Itin, P., Hohl, D., Epstein, E. H., Jr., DiGiovanna, J. J., Compton, J. G., Bale, S. J. <strong>Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.</strong> Nature Genet. 20: 366-369, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843209</a>] [<a href="https://doi.org/10.1038/3840" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843209">Richard et al. (1998)</a> detected a heterozygous 34G-C transversion in the GJB3 gene that resulted in a nonconservative change (G12R) from glycine (GGT) to a positively-charged arginine (CGT) in the site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843209" 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 parent-offspring pair with a generalized, migratory form of erythrokeratodermia variabilis et progressiva (EKVP1; <a href="/entry/133200">133200</a>), <a href="#12" class="mim-tip-reference" title="Richard, G., Smith, L. E., Bailey, R. A., Itin, P., Hohl, D., Epstein, E. H., Jr., DiGiovanna, J. J., Compton, J. G., Bale, S. J. <strong>Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.</strong> Nature Genet. 20: 366-369, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843209</a>] [<a href="https://doi.org/10.1038/3840" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843209">Richard et al. (1998)</a> identified a 35G-A transition in the GJB3 gene, changing glycine-12 to aspartic acid (G12D). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843209" 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> rs74315317 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315317;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/rs74315317?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=rs74315317" 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=rs74315317" 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=RCV000006857" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006857" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006857</a>
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<p>In a 3-generation family with erythrokeratodermia variabilis et progressiva (EKVP1; <a href="/entry/133200">133200</a>) who had localized hyperkeratosis and also in a sporadic case with generalized hyperkeratosis, <a href="#12" class="mim-tip-reference" title="Richard, G., Smith, L. E., Bailey, R. A., Itin, P., Hohl, D., Epstein, E. H., Jr., DiGiovanna, J. J., Compton, J. G., Bale, S. J. <strong>Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.</strong> Nature Genet. 20: 366-369, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843209</a>] [<a href="https://doi.org/10.1038/3840" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843209">Richard et al. (1998)</a> identified a heterozygous 256T-A transversion in the GJB3 gene, which resulted in replacement of cysteine-86 with serine (C86S). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 DEAFNESS, AUTOSOMAL DOMINANT 2B</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> rs74315318 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315318;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/rs74315318?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=rs74315318" 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=rs74315318" 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=RCV000006858 OR RCV000175942 OR RCV000377207 OR RCV000724272 OR RCV004751206" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006858, RCV000175942, RCV000377207, RCV000724272, RCV004751206" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006858...</a>
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<p>In a family (NDF006) with autosomal dominant nonsyndromic sensorineural deafness (DFNA2B; <a href="/entry/612644">612644</a>) from the Zhejiang province of China, <a href="#18" class="mim-tip-reference" title="Xia, J., Liu, C., Tang, B., Pan, Q., Huang, L., Dai, H., Zhang, B., Xie, W., Hu, D., Zheng, D., Shi, X., Wang, D., Xia, K., Yu, K., Liao, X., Feng, Y., Yang, Y., Xiao, J., Xie, D., Huang, J. <strong>Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment.</strong> Nature Genet. 20: 370-373, 1998. Note: Erratum: Nature Genet.:21: 241 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843210</a>] [<a href="https://doi.org/10.1038/3845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843210">Xia et al. (1998)</a> found a heterozygous G-to-A transition at position 547 of the GJB3 gene, resulting in a glutamic acid-to-lysine change at codon 183. (The paper by <a href="#18" class="mim-tip-reference" title="Xia, J., Liu, C., Tang, B., Pan, Q., Huang, L., Dai, H., Zhang, B., Xie, W., Hu, D., Zheng, D., Shi, X., Wang, D., Xia, K., Yu, K., Liao, X., Feng, Y., Yang, Y., Xiao, J., Xie, D., Huang, J. <strong>Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment.</strong> Nature Genet. 20: 370-373, 1998. Note: Erratum: Nature Genet.:21: 241 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843210</a>] [<a href="https://doi.org/10.1038/3845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843210">Xia et al. (1998)</a> identified the substitution as gln183 to lys, but a correction to the paper noted that the mutation was actually glu183 to lys.) The mutation was found in 4 individuals in 3 generations of the family. Two males were diagnosed with bilateral sensorineural deafness. Both had had progressive hearing difficulties and tinnitus since approximately 40 years of age. A female with the mutation, aged 27, had normal hearing with tinnitus and an audiogram showing a 20- to 25-dB decrease at frequencies of 2,000 to 8,000 Hz. Another female carrier, aged 3 years, had a normal acoustic impedance test and auditory evoked brainstem response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 DEAFNESS, AUTOSOMAL DOMINANT 2B</strong>
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GJB3, ARG180TER
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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> rs74315319 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315319;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/rs74315319?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=rs74315319" 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=rs74315319" 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=RCV000006859 OR RCV000150742 OR RCV001762035" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006859, RCV000150742, RCV001762035" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006859...</a>
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<p>In a family (NDF005) with autosomal dominant nonsyndromic sensorineural deafness (DFNA2B; <a href="/entry/612644">612644</a>) from the Hunan province of China, <a href="#18" class="mim-tip-reference" title="Xia, J., Liu, C., Tang, B., Pan, Q., Huang, L., Dai, H., Zhang, B., Xie, W., Hu, D., Zheng, D., Shi, X., Wang, D., Xia, K., Yu, K., Liao, X., Feng, Y., Yang, Y., Xiao, J., Xie, D., Huang, J. <strong>Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment.</strong> Nature Genet. 20: 370-373, 1998. Note: Erratum: Nature Genet.:21: 241 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843210</a>] [<a href="https://doi.org/10.1038/3845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843210">Xia et al. (1998)</a> found that 4 individuals carried a heterozygous C-to-T mutation at nucleotide 538 of GJB3, resulting in a stop codon at amino acid 180. Two male carriers, aged 51 and 23, had hearing difficulties with clinical symptoms and audiograms showing high frequency hearing loss beginning after 30 and 20 years of age, respectively. One female carrier, aged 46, had an audiogram similar to that of the 27-year-old carrier in family NDF0006 (see <a href="#0004">603324.0004</a>). The other female carrier, aged 43, had normal hearing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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GJB3, 3-BP DEL, 423ATT
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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> rs770247378 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs770247378;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/rs770247378?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=rs770247378" 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=rs770247378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006860" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006860" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006860</a>
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<p>This variant, formerly designated DEAFNESS, AUTOSOMAL RECESSIVE, has been reclassified because its pathogenicity has not been confirmed.</p><p>In 2 Chinese families, <a href="#5" class="mim-tip-reference" title="Liu, X.-Z., Xia, X. J., Xu, L. R., Pandya, A., Liang, C. Y., Blanton, S. H., Brown, S. D. M., Steel, K. P., Nance, W. E. <strong>Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss.</strong> Hum. Molec. Genet. 9: 63-67, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10587579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10587579</a>] [<a href="https://doi.org/10.1093/hmg/9.1.63" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10587579">Liu et al. (2000)</a> found that individuals with autosomal recessive nonsyndromic hearing loss were compound heterozygous for 2 mutations in the GJB3 gene: a 3-bp deletion (423_425delATT) leading to an in-frame deletion of codon 141 (ile141del) on one allele, and a 423A-G transition leading to an ile141-to-val substitution (I141V; <a href="#0007">603324.0007</a>) on the other allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10587579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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">rs74315320 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315320;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs74315320" 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=rs74315320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006861" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006861" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006861</a>
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<p>This variant, formerly designated DEAFNESS, AUTOSOMAL RECESSIVE, has been reclassified because its pathogenicity has not been confirmed.</p><p>For discussion of the ile141-to-val (I141V) mutation in the GJB3 gene that was found in compound heterozygous state in 2 families with autosomal recessive nonsyndromic hearing loss by <a href="#5" class="mim-tip-reference" title="Liu, X.-Z., Xia, X. J., Xu, L. R., Pandya, A., Liang, C. Y., Blanton, S. H., Brown, S. D. M., Steel, K. P., Nance, W. E. <strong>Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss.</strong> Hum. Molec. Genet. 9: 63-67, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10587579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10587579</a>] [<a href="https://doi.org/10.1093/hmg/9.1.63" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10587579">Liu et al. (2000)</a>, see <a href="#0006">603324.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10587579" 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 id="0008" class="mim-anchor"></a>
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<strong>.0008 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 1</strong>
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GJB3, ARG42PRO
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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> rs74315321 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315321;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/rs74315321?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=rs74315321" 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=rs74315321" 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 family with the migratory form of autosomal dominant erythrokeratodermia variabilis et progressiva (EKVP1; <a href="/entry/133200">133200</a>), <a href="#17" class="mim-tip-reference" title="Wilgoss, A., Leigh, I. M., Barnes, M. R., Dopping-Hepenstal, P., Eady, R. A. J., Walter, J. M., Kennedy, C. T. C., Kelsell, D. P. <strong>Identification of a novel mutation R42P in the gap junction protein beta-3 associated with autosomal dominant erythrokeratoderma variabilis.</strong> J. Invest. Derm. 113: 1119-1122, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10594760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10594760</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1999.00792.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10594760">Wilgoss et al. (1999)</a> found that affected members had an arg42-to-pro (R42P) mutation in the GJB3 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10594760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Richard, G., Brown, N., Smith, L. E., Terrinoni, A., Melino, G., MacKie, R. M., Bale, S. J., Uitto, J. <strong>The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3.</strong> Hum. Genet. 106: 321-329, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10798362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10798362</a>] [<a href="https://doi.org/10.1007/s004390051045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10798362">Richard et al. (2000)</a> found the same heterozygous mutation as the cause of EKV in another family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10798362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 DEAFNESS, AUTOSOMAL DOMINANT, WITH PERIPHERAL NEUROPATHY</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">rs786200895 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200895;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs786200895" 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=rs786200895" 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=RCV000006863 OR RCV000345579 OR RCV002243625 OR RCV002468963" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006863, RCV000345579, RCV002243625, RCV002468963" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006863...</a>
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<p>In affected members of a 4-generation Spanish family with autosomal deafness with peripheral neuropathy (DFNA2B; <a href="/entry/612644">612644</a>), <a href="#7" class="mim-tip-reference" title="Lopez-Bigas, N., Olive, M., Rabionet, R., Ben-David, O., Martinez-Matos, J. A., Bravo, O., Banchs, I., Volpini, V., Gasparini, P., Avraham, K. B., Ferrer, I., Arbones, M. L., Estivill, X. <strong>Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment.</strong> Hum. Molec. Genet. 10: 947-952, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309368</a>] [<a href="https://doi.org/10.1093/hmg/10.9.947" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309368">Lopez-Bigas et al. (2001)</a> reported a 3-bp deletion in the GJB3 gene, resulting in an asp deletion at codon 66. Nerve conduction studies revealed a markedly decreased amplitude with normal velocity, and sural nerve biopsy of 1 affected family member revealed a demyelination/remyelination appearance. In situ studies in mice demonstrated expression of Gjb3 in the cochlea and auditory nerve, and in the sciatic nerve similar to the expression pattern of Gjb1 (connexin-32; <a href="/entry/304040">304040</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11309368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28937583 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937583;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28937583" 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=rs28937583" 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=RCV000006864 OR RCV004584593" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006864, RCV004584593" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006864...</a>
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<p><a href="#3" class="mim-tip-reference" title="Gottfried, I., Landau, M., Glaser, F., Di, W.-L., Ophir, J., Mevorah, B., Ben-Tal, N., Kelsell, D. P., Avraham, K. B. <strong>A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein.</strong> Hum. Molec. Genet. 11: 1311-1316, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019212</a>] [<a href="https://doi.org/10.1093/hmg/11.11.1311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12019212">Gottfried et al. (2002)</a> identified 3 Israeli sibs with an autosomal recessive migratory form of erythrokeratodermia variabilis et progressiva (EKVP1; <a href="/entry/133200">133200</a>) who were homozygous for a 101T-C transition in GJB3. The mutation was predicted to result in a leu34-to-pro (L34P) substitution in the first transmembrane helix. In transfected keratinocytes, the mutant protein demonstrated a cytoplasmic distribution, suggesting that the mutant protein could not localize to gap junctions between adjacent cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12019212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 DEAFNESS, DIGENIC, GJB2/GJB3</strong>
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GJB3, ASN166SER
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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> rs121908851 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908851;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/rs121908851?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=rs121908851" 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=rs121908851" 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=RCV000006865" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006865" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006865</a>
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<p>In a Chinese patient with autosomal recessive profound hearing impairment (see <a href="/entry/220290">220290</a>), <a href="#6" class="mim-tip-reference" title="Liu, X.-Z., Yuan, Y., Yan, D., Ding, E. H., Ouyang, X. M., Fei, Y., Tang, W., Yuan, H., Chang, Q., Du, L. L., Zhang, X., Wang, G., Ahmad, S., Kang, D. Y., Lin, X., Dai, P. <strong>Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31.</strong> Hum. Genet. 125: 53-62, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19050930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19050930</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19050930[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/s00439-008-0602-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19050930">Liu et al. (2009)</a> found compound heterozygosity for a 497A-G transition in the GJB3 gene, resulting in an asn166-to-ser (N166S) substitution in the second extracellular loop, and a 1-bp deletion in the GJB2 gene (<a href="/entry/121011#0014">121011.0014</a>). The findings were consistent with digenic inheritance. Each unaffected parent was heterozygous for 1 of the mutant alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19050930" 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>.0012 DEAFNESS, DIGENIC, GJB2/GJB3</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> rs117385606 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs117385606;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/rs117385606?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=rs117385606" 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=rs117385606" 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=RCV000006866 OR RCV000404541 OR RCV001510379 OR RCV002504756" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006866, RCV000404541, RCV001510379, RCV002504756" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006866...</a>
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<p>In a Chinese patient with autosomal recessive profound hearing impairment (see <a href="/entry/220290">220290</a>), <a href="#6" class="mim-tip-reference" title="Liu, X.-Z., Yuan, Y., Yan, D., Ding, E. H., Ouyang, X. M., Fei, Y., Tang, W., Yuan, H., Chang, Q., Du, L. L., Zhang, X., Wang, G., Ahmad, S., Kang, D. Y., Lin, X., Dai, P. <strong>Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31.</strong> Hum. Genet. 125: 53-62, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19050930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19050930</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19050930[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/s00439-008-0602-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19050930">Liu et al. (2009)</a> found compound heterozygosity for a 580G-A transition in the GJB3 gene, resulting in an ala194-to-thr (A194T) substitution in the fourth transmembrane domain, and a 1-bp deletion in the GJB2 gene (<a href="/entry/121011#0014">121011.0014</a>). Another unrelated Chinese individual with hearing loss was compound heterozygous for A194T and another pathogenic mutation in the GJB2 gene. The findings were consistent with digenic inheritance. Each unaffected parent was heterozygous for one of the mutant alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19050930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Abrams2006" class="mim-anchor"></a>
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Abrams, C. K., Freidin, M. M., Verselis, V. K., Bargiello, T. A., Kelsell, D. P., Richard, G., Bennett, M. V. L., Bukauskas, F. F.
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[<a href="https://doi.org/10.1073/pnas.0511091103" target="_blank">Full Text</a>]
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<a id="Di2002" class="mim-anchor"></a>
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Di, W.-L., Monypenny, J., Common, J. E. A., Kennedy, C. T. C., Holland, K. A., Leigh, I. M., Rugg, E. L., Zicha, D., Kelsell, D. P.
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[<a href="https://doi.org/10.1093/hmg/11.17.2005" target="_blank">Full Text</a>]
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<a id="Gottfried2002" class="mim-anchor"></a>
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Gottfried, I., Landau, M., Glaser, F., Di, W.-L., Ophir, J., Mevorah, B., Ben-Tal, N., Kelsell, D. P., Avraham, K. B.
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<strong>A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019212</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12019212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/11.11.1311" target="_blank">Full Text</a>]
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<a id="Kelsell2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Kelsell, D. P., Wilgoss, A. L., Richard, G., Stevens, H. P., Munro, C. S., Leigh, I. M.
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<strong>Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family.</strong>
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Europ. J. Hum. Genet. 8: 141-144, 2000. Note: Erratum: Europ. J. Hum. Genet. 8: 468 only, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10757647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10757647</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10757647" 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/sj.ejhg.5200407" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
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<a id="Liu2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Liu, X.-Z., Xia, X. J., Xu, L. R., Pandya, A., Liang, C. Y., Blanton, S. H., Brown, S. D. M., Steel, K. P., Nance, W. E.
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<strong>Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss.</strong>
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Hum. Molec. Genet. 9: 63-67, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10587579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10587579</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10587579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/9.1.63" target="_blank">Full Text</a>]
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<a id="Liu2009" class="mim-anchor"></a>
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Liu, X.-Z., Yuan, Y., Yan, D., Ding, E. H., Ouyang, X. M., Fei, Y., Tang, W., Yuan, H., Chang, Q., Du, L. L., Zhang, X., Wang, G., Ahmad, S., Kang, D. Y., Lin, X., Dai, P.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19050930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19050930</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19050930[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=19050930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-008-0602-9" target="_blank">Full Text</a>]
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<a id="Lopez-Bigas2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Lopez-Bigas, N., Olive, M., Rabionet, R., Ben-David, O., Martinez-Matos, J. A., Bravo, O., Banchs, I., Volpini, V., Gasparini, P., Avraham, K. B., Ferrer, I., Arbones, M. L., Estivill, X.
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<strong>Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment.</strong>
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Hum. Molec. Genet. 10: 947-952, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309368</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11309368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/10.9.947" target="_blank">Full Text</a>]
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<a id="Lopez-Bigas2001" class="mim-anchor"></a>
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<div class="">
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Lopez-Bigas, N., Rabionet, R., Arbones, M. L., Estivill, X.
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<strong>R32W variant in connexin 31: mutation or polymorphism for deafness and skin disease? (Letter)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175305</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175305" 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/sj.ejhg.5200569" target="_blank">Full Text</a>]
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<a id="Macfarlane1991" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1828175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1828175</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1828175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2133.1991.tb00632.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg364" target="_blank">Full Text</a>]
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<a id="Richard2000" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10798362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10798362</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10798362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390051045" target="_blank">Full Text</a>]
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<a id="Richard1998" class="mim-anchor"></a>
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<div class="">
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843209</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843209" 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/10.1038/3840" target="_blank">Full Text</a>]
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<a id="Schnichels2007" class="mim-anchor"></a>
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<div class="">
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[<a href="https://doi.org/10.1093/hmg/ddm068" target="_blank">Full Text</a>]
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<a id="Tattersall2009" class="mim-anchor"></a>
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Tattersall, D., Scott, C. A., Gray, C., Zicha, D., Kelsell, D. P.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19755382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19755382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19755382[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=19755382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp436" target="_blank">Full Text</a>]
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<a id="van Geel2002" class="mim-anchor"></a>
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van Geel, M., van Steensel, M. A. M., Steijlen, P. M.
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<strong>Connexin 30.3 (GJB4) is not required for normal skin function in humans.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12452892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12452892</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12452892" 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/10.1046/j.1365-2133.2002.05000_9.x" target="_blank">Full Text</a>]
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<a id="Wenzel1998" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9704026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9704026</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9704026" 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/10.1006/bbrc.1998.9070" target="_blank">Full Text</a>]
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</p>
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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="Wilgoss1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wilgoss, A., Leigh, I. M., Barnes, M. R., Dopping-Hepenstal, P., Eady, R. A. J., Walter, J. M., Kennedy, C. T. C., Kelsell, D. P.
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<strong>Identification of a novel mutation R42P in the gap junction protein beta-3 associated with autosomal dominant erythrokeratoderma variabilis.</strong>
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J. Invest. Derm. 113: 1119-1122, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10594760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10594760</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10594760" 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/10.1046/j.1523-1747.1999.00792.x" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Xia1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xia, J., Liu, C., Tang, B., Pan, Q., Huang, L., Dai, H., Zhang, B., Xie, W., Hu, D., Zheng, D., Shi, X., Wang, D., Xia, K., Yu, K., Liao, X., Feng, Y., Yang, Y., Xiao, J., Xie, D., Huang, J.
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<strong>Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment.</strong>
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Nature Genet. 20: 370-373, 1998. Note: Erratum: Nature Genet.:21: 241 only, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843210</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843210" 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/10.1038/3845" target="_blank">Full Text</a>]
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</p>
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</ol>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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George E. Tiller - updated : 11/1/2010
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 10/7/2010<br>Cassandra L. Kniffin - updated : 2/19/2010<br>Cassandra L. Kniffin - updated : 3/3/2009<br>Patricia A. Hartz - updated : 6/9/2006<br>George E. Tiller - updated : 1/10/2006<br>George E. Tiller - updated : 7/10/2003<br>George E. Tiller - updated : 2/14/2003<br>George E. Tiller - updated : 10/2/2001<br>Victor A. McKusick - updated : 7/21/2000<br>Victor A. McKusick - updated : 3/15/2000<br>Victor A. McKusick - updated : 12/20/1999<br>Victor A. McKusick - updated : 3/2/1999<br>Victor A. McKusick - updated : 2/23/1999<br>Patti M. Sherman - updated : 12/11/1998
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</span>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 11/30/1998
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 05/24/2024
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/13/2017<br>carol : 07/16/2015<br>mcolton : 7/2/2015<br>carol : 3/9/2015<br>carol : 8/4/2014<br>terry : 12/22/2010<br>terry : 12/22/2010<br>alopez : 11/2/2010<br>terry : 11/1/2010<br>carol : 10/7/2010<br>wwang : 2/23/2010<br>ckniffin : 2/19/2010<br>carol : 3/6/2009<br>ckniffin : 3/3/2009<br>terry : 12/2/2008<br>mgross : 6/9/2006<br>wwang : 1/30/2006<br>terry : 1/10/2006<br>joanna : 3/17/2004<br>cwells : 7/10/2003<br>cwells : 2/14/2003<br>terry : 3/25/2002<br>cwells : 10/10/2001<br>cwells : 10/2/2001<br>mcapotos : 8/7/2000<br>mcapotos : 7/21/2000<br>mcapotos : 7/21/2000<br>mcapotos : 7/6/2000<br>mcapotos : 4/6/2000<br>terry : 3/15/2000<br>carol : 12/21/1999<br>terry : 12/20/1999<br>carol : 8/31/1999<br>psherman : 8/31/1999<br>carol : 3/8/1999<br>terry : 3/2/1999<br>alopez : 3/1/1999<br>terry : 2/23/1999<br>carol : 12/15/1998<br>psherman : 12/11/1998<br>dkim : 12/2/1998<br>alopez : 11/30/1998<br>alopez : 11/30/1998
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</span>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 603324
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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GAP JUNCTION PROTEIN, BETA-3; GJB3
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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GAP JUNCTION PROTEIN, 31-KD<br />
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CONNEXIN 31; CX31
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GJB3</em></strong>
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</span>
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</p>
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</div>
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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: 1p34.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:34,781,214-34,786,364 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</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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1p34.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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Deafness, autosomal dominant 2B, with or without peripheral neuropathy
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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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612644
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Deafness, digenic, GJB2/GJB3
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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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220290
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive; Digenic dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Erythrokeratodermia variabilis et progressiva 1
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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133200
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gap junctions are conduits that allow the direct cell-to-cell passage of small cytoplasmic molecules, including ions, metabolic intermediates, and second messengers, and thereby mediate intercellular metabolic and electrical communication. Gap junction channels consist of connexin protein subunits, which are encoded by a multigene family that includes GJB3 (summary by Richard et al., 1998; Wenzel et al., 1998). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Richard et al. (1998) identified 2 expressed sequence tags (ESTs) from the human EST database by their similarity to mouse Gjb3 and Gjb5. By radiation hybrid mapping, they placed them in proximity with a sequenced tag site (STS) that is linked to GJA4 (121012). Comparison of genomic and cDNA sequence of GJB3 showed an exon-intron organization common to that of genes encoding connexins. The complete coding sequence was contained in a single, uninterrupted open reading frame (ORF) of 813 nucleotides preceded by a putative splice junction located 25 nucleotides upstream of the ATG initiation site and followed by the 3-prime untranslated region with a polyadenylation signal at position 1,583. The protein Cx31, of predicted molecular mass 30.8 kD, consists of 270 amino acids and differs from its rodent homologs at 40 residues that are confined mainly to the cytoplasmic loop. Protein structure analysis confirmed a structural organization typical for beta-connexins, including a conserved arrangement of 3 cysteine residues in each extracellular loop. </p><p>By screening a human genomic library with a mouse Cx31 cDNA, Wenzel et al. (1998) isolated the CX31 gene. Southern blot analysis of human DNA showed that CX31 is a single-copy gene. Northern blot analysis of human keratinocyte cell lines detected approximately 2.2- and 1.8-kb CX31 transcripts. The deduced CX31 protein contains 4 putative transmembrane domains and 3 potential phosphorylation sites. Human CX31 is 83% identical to the mouse and rat Cx31 proteins. </p><p>Xia et al. (1998) cloned the gene (GJB3) encoding human gap junction protein beta-3 using homologous EST searching and nested PCR. </p><p>Lopez-Bigas et al. (2001) demonstrated expression of mouse Gjb3 in the cochlea and in the auditory and sciatic nerves in a pattern similar to that of Gjb1 (304040). </p>
|
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</span>
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<div>
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Mapping</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>By analysis of somatic cell hybrids, Wenzel et al. (1998) mapped the GJB3 gene to chromosome 1p36-p34. Xia et al. (1998) mapped the GJB3 gene to 1p35-p33 by fluorescence in situ hybridization. </p>
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</span>
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<div>
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Function</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p>Plantard et al. (2003) showed that expression of wildtype CX30.3 (GJB4; 605425) in HeLa cells resulted only in minor amounts of protein addressed to the plasma membrane. Mutant CX30.3 (605425.0001) was hardly detectable and disturbed intercellular coupling. In contrast, coexpression of both wildtype CX30.3 and CX31 proteins led to a large increase of stabilized heteromeric gap junctions. Coexpressed wildtype CX30.3 and CX31 coprecipitated, demonstrating a physical interaction. Inhibitor experiments revealed that this interaction began in the endoplasmic reticulum. </p><p>Using transfected mouse neuroblastoma and HeLa cell lines, Abrams et al. (2006) found that CX31 channels, like other connexin channels, were gated by voltage and closed at low pH when exposed to long-chain alkanols. CX31 channels were relatively nonselective, allowing passage of both negatively and positively charged dyes. In contrast to mouse Cx31, human CX31 appeared to form functional heterotypic channels with all 4 connexins tested: CX26 (GJB2; 121011), CX30 (GJB6; 604418), CX32 (GJB1; 304040), and CX45 (GJA7; 608655). </p><p>Liu et al. (2009) found that Cx31 and Cx26 were coexpressed in the mouse cochlea and coassembled into gap junctions when expressed in HEK293 cells. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p><strong><em>Erythrokeratodermia Variabilis et Progressiva 1</em></strong></p><p>
|
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Erythrokeratodermia variabilis et progressiva (EKVP1; 133200) is a disorder of keratinization characterized by fixed erythrokeratotic plaques, associated with migratory erythematous lesions ('variabilis;' EKV) in some patients. In 4 of 12 families with EKV, Richard et al. (1998) detected heterozygous missense mutations in the GJB3 gene leading to substitution of a conserved glycine by charged residues (G12R, 603324.0001; G12D, 603324.0002), or change of a cysteine (C86S; 603324.0003). These mutations were predicted to interfere with normal Cx31 structure and function, possibly due to a dominant-negative effect. Thus, the results provided evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors. Richard et al. (1998) stated that this report was the first to link mutations in a gene encoding a connexin to a human skin disorder, and noted that further functional in vitro and in vivo studies were needed to understand how mutant Cx31 alters differentiation of the epidermis (hyperkeratosis) and affects the cutaneous microcapillary system (transient erythema). </p><p>Wilgoss et al. (1999) identified heterozygosity for a missense mutation in the GJB3 gene (R42P; 603324.0008) in affected members of a family with EKV. </p><p>Richard et al. (2000) analyzed the GJB3 gene in 2 families and 3 sporadic patients with EKV and in 2 families and 4 sporadic patients with the progressive, symmetric form (PSEK) of erythrokeratodermia, including a family previously described by Macfarlane et al. (1991) in which 1 sister had features of EKV and the other of PSEK. Richard et al. (2000) identified 3 heterozygous mutations in GJB3 in EKV patients: in a sporadic case, they detected a mutation leading to substitution of a conserved phenylalanine (F137L) in the third transmembrane domain, which likely interferes with the proper assembly or gating properties of connexins. In another EKV family, all 3 affected individuals carried 2 distinct mutations on the same GJB3 allele; however, only the R42P mutation (603324.0008) cosegregated with the disease, whereas a 12-bp deletion predicted to eliminate 4 amino acid residues in the variable carboxy-terminal domain of Cx31 was also found in clinically unaffected relatives but not in 90 unaffected controls. No mutations were detected in the 6 probands with PSEK. Richard et al. (2000) stated that overall, they had identified GJB3 mutations in 6 of 17 families with EKV; all of the mutations presumably affect the cytoplasmic amino-terminal and transmembrane domains of Cx31. In contrast, 2 mutations linked to progressive high-tone hearing impairment (DFNA2B; 612644) were located in the second extracellular domain, suggesting that the character and position of Cx mutations determine their phenotypic expression in different tissues. </p><p>In a brother and sister from an Israeli family segregating autosomal recessive EKV, Gottfried et al. (2002) identified homozygosity for a missense mutation in the GJB3 gene (L34P; 603342.0010). The unaffected parents were heterozygous for the mutation, which was not found in 208 control chromosomes. Gottfried et al. (2002) suggested that the missense mutation might not be able to exert a dominant-negative effect in heterozygous form, thus manifesting itself clinically only in the homozygote. </p><p>In a 4-year-old Dutch boy with the migratory form of EKVP, van Geel et al. (2002) identified a heterozygous R32W mutation in the GJB3 gene as well as a homozygous 4-bp deletion (154delGTCT) in the GJB4 gene. Analysis of unaffected family members revealed that both parents and the maternal grandfather were heterozygous for the GJB4 deletion, whereas the mother and maternal grandfather were heterozygous for the GJB3 variant; in addition, the patient's unaffected sister carried the identical GJB3/GJB4 genotype as the patient, thus excluding either DNA variation as causative for the disease. Van Geel et al. (2002) subsequently examined 84 unrelated controls and found 5 heterozygotes for the GJB4 deletion (allele frequency, 0.03) and 3 for the GJB3 variant (0.02), suggesting that both variations represent normal polymorphisms in the Dutch population. Van Geel et al. (2002) noted that the GJB3 variant had previously been detected in a family with palmoplantar keratoderma and hearing defects (see GJB2, 121011) by Kelsell et al. (2000), who suggested that it might be a polymorphism; analysis of R32W in Spanish patients and controls by Lopez-Bigas et al. (2001) confirmed that the variant is a common polymorphism in the Spanish population (allele frequency, 7.5%). </p><p>Di et al. (2002) observed that immunostaining of a skin biopsy taken from an EKV patient harboring the R42P mutation (603324.0008) revealed sparse epidermal staining of Cx31 with aberrant perinuclear localization. Transfection and microinjection studies in keratinocytes and fibroblast cell lines demonstrated that R42P and 4 other EKV-associated mutant Cx31 proteins displayed defective trafficking to the plasma membrane. The deafness/neuropathy-only 66delD (603324.0009) mutant protein had primarily a cytoplasmic localization, but some protein was visualized at the plasma membrane in a few transfected cells. Both 66delD- and R32W-Cx31/EGFP proteins had significantly impaired dye transfer rates compared to wildtype Cx31/EGFP protein. A high incidence of cell death was observed with the dominant skin disease Cx31 mutations, but not with wildtype, R32W, or 66delD Cx31 proteins. </p><p>Tattersall et al. (2009) reported that in vitro expression of connexin-31 mutants R42P (603324.0008), C86S (603324.0003), and G12D (603324.0002), but not wildtype or 66delD (603324.0009), cause elevated levels of cell type-specific cell death. Their observations did not support the hypothesis that Cx-associated cell death is related to abnormal 'leaky' calcium hemichannels. Tattersall et al. (2009) observed upregulation of components of the unfolded protein response (UPR) in cells expressing the EKV-associated Cx31 mutants but not wildtype or 66delD. The authors concluded that the endoplasmic reticulum (ER) stress leading to the UPR may be the main mechanism of mutant Cx31-associated cell death, and that ER stress may lead to abnormal keratinocyte differentiation and hyperproliferation in EKV patient skin. </p><p><strong><em>Deafness, Autosomal Dominant 2B</em></strong></p><p>
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In affected members of 2 Chinese families with autosomal dominant hearing loss (DFNA2B; 612644), Xia et al. (1998) identified heterozygous mutations in the GJB3 gene (603324.0004; 603324.0005). Gjb3 expression was identified in rat inner ear tissue by RT-PCR. It is well known that age-related hearing impairment is more prevalent in males than in females. It was noteworthy that, in the 2 families studied by Xia et al. (1998), female carriers were either subclinically affected or had undetectable hearing impairment. Noise exposure for male mutation carriers was not significantly different from their female sibs (as recalled by the family members). </p><p>In affected members of a 4-generation Spanish family with mild hearing impairment and peripheral neuropathy, Lopez-Bigas et al. (2001) identified a heterozygous 3-bp deletion in the GJB3 gene (603324.0009). In situ studies in mice demonstrated expression of Gjb3 in the cochlea and auditory and sciatic nerves, similar to the expression pattern of Gjb1 (304040). </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Following the demonstration that mutations in the GJB3 gene can cause autosomal dominant nonsyndromic sensorineural deafness, Liu et al. (2000) screened 25 Chinese families with recessive deafness to determine whether mutations at this locus can also cause recessive nonsyndromic deafness. Among the 25 families, 2 contained individuals who were compound heterozygous for GJB3 mutations. The 3 affected individuals in the 2 families were born to nonconsanguineous parents and had an early-onset bilateral sensorineural hearing loss. In both families, differing SSCP patterns were observed in affected and unaffected individuals. Sequence analysis in both families demonstrated an in-frame 3-bp deletion (423_425delATT; 603324.0006) on one allele, which led to the loss of an isoleucine residue at codon 141, and a 423A-G transition on the other allele, which created an ile141-to-val missense mutation (I142V; 603324.0007). Neither of these mutations was detected in DNA from 100 unrelated control subjects. Both the deletion of isoleucine-141 and its substitution by valine could alter the structure of the third conserved alpha-helical transmembrane domain (M3) and impair the function of the gap junction. </p>
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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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</h4>
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<span class="mim-text-font">
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<p>Schnichels et al. (2007) generated a conditional mouse model of EKV using the human F137L mutation in the Cx31 gene. Although homozygosity for the mutation was embryonic lethal, heterozygous mice were fertile and showed no obvious abnormalities. In vitro cellular functional expression studies showed that the heterozygous mutant channel had approximately 30% decreased neurobiotin transfer activity, probably due to a dominant-negative effect. Heterozygous mutant mice showed a decreased healing time of tail incision wounds by 1 day, similar to mice with decreased expression of Cx43 (121014) in the epidermis. These findings suggested again that the Cx31 and Cx43 proteins functionally interact. No erythema was detected in young mice before 2 weeks of age, and only about 5% of the skin area of mutant mice showed hyperproliferation of the stratum germinativum. In addition, heterozygous Cx31 mutant mice showed normal epidermal expression patterns and levels of other connexin proteins. </p>
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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>12 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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<h4>
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<span class="mim-font">
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<strong>.0001 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GJB3, GLY12ARG
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SNP: rs74315315,
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gnomAD: rs74315315,
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ClinVar: RCV000006855
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a Swiss patient with erythrokeratodermia variabilis et progressiva (EKVP1; 133200) who had localized hyperkeratosis, Richard et al. (1998) detected a heterozygous 34G-C transversion in the GJB3 gene that resulted in a nonconservative change (G12R) from glycine (GGT) to a positively-charged arginine (CGT) in the site. </p>
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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 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GJB3, GLY12ASP
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<br />
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SNP: rs74315316,
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ClinVar: RCV000006856, RCV002512854
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a parent-offspring pair with a generalized, migratory form of erythrokeratodermia variabilis et progressiva (EKVP1; 133200), Richard et al. (1998) identified a 35G-A transition in the GJB3 gene, changing glycine-12 to aspartic acid (G12D). </p>
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</span>
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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 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GJB3, CYS86SER
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<br />
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SNP: rs74315317,
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gnomAD: rs74315317,
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ClinVar: RCV000006857
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<span class="mim-text-font">
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<p>In a 3-generation family with erythrokeratodermia variabilis et progressiva (EKVP1; 133200) who had localized hyperkeratosis and also in a sporadic case with generalized hyperkeratosis, Richard et al. (1998) identified a heterozygous 256T-A transversion in the GJB3 gene, which resulted in replacement of cysteine-86 with serine (C86S). </p>
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</span>
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<div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 DEAFNESS, AUTOSOMAL DOMINANT 2B</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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GJB3, GLU183LYS
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SNP: rs74315318,
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gnomAD: rs74315318,
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ClinVar: RCV000006858, RCV000175942, RCV000377207, RCV000724272, RCV004751206
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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 family (NDF006) with autosomal dominant nonsyndromic sensorineural deafness (DFNA2B; 612644) from the Zhejiang province of China, Xia et al. (1998) found a heterozygous G-to-A transition at position 547 of the GJB3 gene, resulting in a glutamic acid-to-lysine change at codon 183. (The paper by Xia et al. (1998) identified the substitution as gln183 to lys, but a correction to the paper noted that the mutation was actually glu183 to lys.) The mutation was found in 4 individuals in 3 generations of the family. Two males were diagnosed with bilateral sensorineural deafness. Both had had progressive hearing difficulties and tinnitus since approximately 40 years of age. A female with the mutation, aged 27, had normal hearing with tinnitus and an audiogram showing a 20- to 25-dB decrease at frequencies of 2,000 to 8,000 Hz. Another female carrier, aged 3 years, had a normal acoustic impedance test and auditory evoked brainstem response. </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>.0005 DEAFNESS, AUTOSOMAL DOMINANT 2B</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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GJB3, ARG180TER
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<br />
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SNP: rs74315319,
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gnomAD: rs74315319,
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ClinVar: RCV000006859, RCV000150742, RCV001762035
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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 family (NDF005) with autosomal dominant nonsyndromic sensorineural deafness (DFNA2B; 612644) from the Hunan province of China, Xia et al. (1998) found that 4 individuals carried a heterozygous C-to-T mutation at nucleotide 538 of GJB3, resulting in a stop codon at amino acid 180. Two male carriers, aged 51 and 23, had hearing difficulties with clinical symptoms and audiograms showing high frequency hearing loss beginning after 30 and 20 years of age, respectively. One female carrier, aged 46, had an audiogram similar to that of the 27-year-old carrier in family NDF0006 (see 603324.0004). The other female carrier, aged 43, had normal hearing. </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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<h4>
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<span class="mim-font">
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<strong>.0006 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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GJB3, 3-BP DEL, 423ATT
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<br />
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SNP: rs770247378,
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gnomAD: rs770247378,
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ClinVar: RCV000006860
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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>This variant, formerly designated DEAFNESS, AUTOSOMAL RECESSIVE, has been reclassified because its pathogenicity has not been confirmed.</p><p>In 2 Chinese families, Liu et al. (2000) found that individuals with autosomal recessive nonsyndromic hearing loss were compound heterozygous for 2 mutations in the GJB3 gene: a 3-bp deletion (423_425delATT) leading to an in-frame deletion of codon 141 (ile141del) on one allele, and a 423A-G transition leading to an ile141-to-val substitution (I141V; 603324.0007) on the other allele. </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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<h4>
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<span class="mim-font">
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<strong>.0007 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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GJB3, ILE141VAL
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<br />
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SNP: rs74315320,
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ClinVar: RCV000006861
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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>This variant, formerly designated DEAFNESS, AUTOSOMAL RECESSIVE, has been reclassified because its pathogenicity has not been confirmed.</p><p>For discussion of the ile141-to-val (I141V) mutation in the GJB3 gene that was found in compound heterozygous state in 2 families with autosomal recessive nonsyndromic hearing loss by Liu et al. (2000), see 603324.0006. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GJB3, ARG42PRO
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<br />
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SNP: rs74315321,
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gnomAD: rs74315321,
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ClinVar: RCV000006862
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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 family with the migratory form of autosomal dominant erythrokeratodermia variabilis et progressiva (EKVP1; 133200), Wilgoss et al. (1999) found that affected members had an arg42-to-pro (R42P) mutation in the GJB3 gene. </p><p>Richard et al. (2000) found the same heterozygous mutation as the cause of EKV in another family. </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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<h4>
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<span class="mim-font">
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<strong>.0009 DEAFNESS, AUTOSOMAL DOMINANT, WITH PERIPHERAL NEUROPATHY</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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GJB3, 3-BP DEL, ASP66DEL
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<br />
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SNP: rs786200895,
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ClinVar: RCV000006863, RCV000345579, RCV002243625, RCV002468963
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a 4-generation Spanish family with autosomal deafness with peripheral neuropathy (DFNA2B; 612644), Lopez-Bigas et al. (2001) reported a 3-bp deletion in the GJB3 gene, resulting in an asp deletion at codon 66. Nerve conduction studies revealed a markedly decreased amplitude with normal velocity, and sural nerve biopsy of 1 affected family member revealed a demyelination/remyelination appearance. In situ studies in mice demonstrated expression of Gjb3 in the cochlea and auditory nerve, and in the sciatic nerve similar to the expression pattern of Gjb1 (connexin-32; 304040). </p>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GJB3, LEU34PRO
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<br />
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SNP: rs28937583,
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ClinVar: RCV000006864, RCV004584593
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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>Gottfried et al. (2002) identified 3 Israeli sibs with an autosomal recessive migratory form of erythrokeratodermia variabilis et progressiva (EKVP1; 133200) who were homozygous for a 101T-C transition in GJB3. The mutation was predicted to result in a leu34-to-pro (L34P) substitution in the first transmembrane helix. In transfected keratinocytes, the mutant protein demonstrated a cytoplasmic distribution, suggesting that the mutant protein could not localize to gap junctions between adjacent cells. </p>
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</span>
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0011 DEAFNESS, DIGENIC, GJB2/GJB3</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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GJB3, ASN166SER
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<br />
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SNP: rs121908851,
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gnomAD: rs121908851,
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ClinVar: RCV000006865
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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 Chinese patient with autosomal recessive profound hearing impairment (see 220290), Liu et al. (2009) found compound heterozygosity for a 497A-G transition in the GJB3 gene, resulting in an asn166-to-ser (N166S) substitution in the second extracellular loop, and a 1-bp deletion in the GJB2 gene (121011.0014). The findings were consistent with digenic inheritance. Each unaffected parent was heterozygous for 1 of the mutant alleles. </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>.0012 DEAFNESS, DIGENIC, GJB2/GJB3</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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GJB3, ALA194THR
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<br />
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SNP: rs117385606,
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gnomAD: rs117385606,
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ClinVar: RCV000006866, RCV000404541, RCV001510379, RCV002504756
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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 Chinese patient with autosomal recessive profound hearing impairment (see 220290), Liu et al. (2009) found compound heterozygosity for a 580G-A transition in the GJB3 gene, resulting in an ala194-to-thr (A194T) substitution in the fourth transmembrane domain, and a 1-bp deletion in the GJB2 gene (121011.0014). Another unrelated Chinese individual with hearing loss was compound heterozygous for A194T and another pathogenic mutation in the GJB2 gene. The findings were consistent with digenic inheritance. Each unaffected parent was heterozygous for one of the mutant alleles. </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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Abrams, C. K., Freidin, M. M., Verselis, V. K., Bargiello, T. A., Kelsell, D. P., Richard, G., Bennett, M. V. L., Bukauskas, F. F.
|
|
<strong>Properties of human connexin 31, which is implicated in hereditary dermatological disease and deafness.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 5213-5218, 2006.
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[PubMed: 16549784]
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[Full Text: https://doi.org/10.1073/pnas.0511091103]
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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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Di, W.-L., Monypenny, J., Common, J. E. A., Kennedy, C. T. C., Holland, K. A., Leigh, I. M., Rugg, E. L., Zicha, D., Kelsell, D. P.
|
|
<strong>Defective trafficking and cell death is characteristic of skin disease-associated connexin 31 mutations.</strong>
|
|
Hum. Molec. Genet. 11: 2005-2014, 2002.
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|
[PubMed: 12165562]
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[Full Text: https://doi.org/10.1093/hmg/11.17.2005]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gottfried, I., Landau, M., Glaser, F., Di, W.-L., Ophir, J., Mevorah, B., Ben-Tal, N., Kelsell, D. P., Avraham, K. B.
|
|
<strong>A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein.</strong>
|
|
Hum. Molec. Genet. 11: 1311-1316, 2002.
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|
|
[PubMed: 12019212]
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[Full Text: https://doi.org/10.1093/hmg/11.11.1311]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Kelsell, D. P., Wilgoss, A. L., Richard, G., Stevens, H. P., Munro, C. S., Leigh, I. M.
|
|
<strong>Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family.</strong>
|
|
Europ. J. Hum. Genet. 8: 141-144, 2000. Note: Erratum: Europ. J. Hum. Genet. 8: 468 only, 2000.
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|
|
[PubMed: 10757647]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5200407]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Liu, X.-Z., Xia, X. J., Xu, L. R., Pandya, A., Liang, C. Y., Blanton, S. H., Brown, S. D. M., Steel, K. P., Nance, W. E.
|
|
<strong>Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss.</strong>
|
|
Hum. Molec. Genet. 9: 63-67, 2000.
|
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|
|
[PubMed: 10587579]
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[Full Text: https://doi.org/10.1093/hmg/9.1.63]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Liu, X.-Z., Yuan, Y., Yan, D., Ding, E. H., Ouyang, X. M., Fei, Y., Tang, W., Yuan, H., Chang, Q., Du, L. L., Zhang, X., Wang, G., Ahmad, S., Kang, D. Y., Lin, X., Dai, P.
|
|
<strong>Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31.</strong>
|
|
Hum. Genet. 125: 53-62, 2009.
|
|
|
|
|
|
[PubMed: 19050930]
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|
|
[Full Text: https://doi.org/10.1007/s00439-008-0602-9]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Lopez-Bigas, N., Olive, M., Rabionet, R., Ben-David, O., Martinez-Matos, J. A., Bravo, O., Banchs, I., Volpini, V., Gasparini, P., Avraham, K. B., Ferrer, I., Arbones, M. L., Estivill, X.
|
|
<strong>Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment.</strong>
|
|
Hum. Molec. Genet. 10: 947-952, 2001.
|
|
|
|
|
|
[PubMed: 11309368]
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|
|
[Full Text: https://doi.org/10.1093/hmg/10.9.947]
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</p>
|
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</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lopez-Bigas, N., Rabionet, R., Arbones, M. L., Estivill, X.
|
|
<strong>R32W variant in connexin 31: mutation or polymorphism for deafness and skin disease? (Letter)</strong>
|
|
Europ. J. Hum. Genet. 9: 70 only, 2001.
|
|
|
|
|
|
[PubMed: 11175305]
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|
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|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5200569]
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</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Macfarlane, A. W., Chapman, S. J., Verbov, J. L.
|
|
<strong>Is erythrokeratoderma one disorder? A clinical and ultrastructural study of two siblings.</strong>
|
|
Brit. J. Derm. 124: 487-491, 1991.
|
|
|
|
|
|
[PubMed: 1828175]
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|
|
[Full Text: https://doi.org/10.1111/j.1365-2133.1991.tb00632.x]
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|
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</p>
|
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</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Plantard, L., Huber, M., Macari, F., Meda, P., Hohl, D.
|
|
<strong>Molecular interaction of connexin 30.3 and connexin 31 suggests a dominant-negative mechanism associated with erythrokeratodermia variabilis.</strong>
|
|
Hum. Molec. Genet. 12: 3287-3294, 2003.
|
|
|
|
|
|
[PubMed: 14583444]
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddg364]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Richard, G., Brown, N., Smith, L. E., Terrinoni, A., Melino, G., MacKie, R. M., Bale, S. J., Uitto, J.
|
|
<strong>The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3.</strong>
|
|
Hum. Genet. 106: 321-329, 2000.
|
|
|
|
|
|
[PubMed: 10798362]
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|
|
[Full Text: https://doi.org/10.1007/s004390051045]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Richard, G., Smith, L. E., Bailey, R. A., Itin, P., Hohl, D., Epstein, E. H., Jr., DiGiovanna, J. J., Compton, J. G., Bale, S. J.
|
|
<strong>Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.</strong>
|
|
Nature Genet. 20: 366-369, 1998.
|
|
|
|
|
|
[PubMed: 9843209]
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|
|
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|
|
[Full Text: https://doi.org/10.1038/3840]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Schnichels, M., Worsdorfer, P., Dobrowolski, R., Markopoulos, C., Kretz, M., Schwarz, G., Winterhager, E., Willecke, K.
|
|
<strong>The connexin31 F137L mutant mouse as a model for the human skin disease erythrokeratodermia variabilis (EKV).</strong>
|
|
Hum. Molec. Genet. 16: 1216-1224, 2007.
|
|
|
|
|
|
[PubMed: 17446259]
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddm068]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Tattersall, D., Scott, C. A., Gray, C., Zicha, D., Kelsell, D. P.
|
|
<strong>EKV mutant connexin 31 associated cell death is mediated by ER stress.</strong>
|
|
Hum. Molec. Genet. 18: 4734-4745, 2009.
|
|
|
|
|
|
[PubMed: 19755382]
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddp436]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
van Geel, M., van Steensel, M. A. M., Steijlen, P. M.
|
|
<strong>Connexin 30.3 (GJB4) is not required for normal skin function in humans.</strong>
|
|
Brit. J. Derm. 147: 1275-1277, 2002.
|
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|
|
[PubMed: 12452892]
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|
|
[Full Text: https://doi.org/10.1046/j.1365-2133.2002.05000_9.x]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Wenzel, K., Manthey, D., Willecke, K., Grzeschik, K.-H., Traub, O.
|
|
<strong>Human gap junction protein connexin31: molecular cloning and expression analysis.</strong>
|
|
Biochem. Biophys. Res. Commun. 248: 910-915, 1998.
|
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|
|
[PubMed: 9704026]
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|
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[Full Text: https://doi.org/10.1006/bbrc.1998.9070]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Wilgoss, A., Leigh, I. M., Barnes, M. R., Dopping-Hepenstal, P., Eady, R. A. J., Walter, J. M., Kennedy, C. T. C., Kelsell, D. P.
|
|
<strong>Identification of a novel mutation R42P in the gap junction protein beta-3 associated with autosomal dominant erythrokeratoderma variabilis.</strong>
|
|
J. Invest. Derm. 113: 1119-1122, 1999.
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|
|
|
[PubMed: 10594760]
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[Full Text: https://doi.org/10.1046/j.1523-1747.1999.00792.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Xia, J., Liu, C., Tang, B., Pan, Q., Huang, L., Dai, H., Zhang, B., Xie, W., Hu, D., Zheng, D., Shi, X., Wang, D., Xia, K., Yu, K., Liao, X., Feng, Y., Yang, Y., Xiao, J., Xie, D., Huang, J.
|
|
<strong>Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment.</strong>
|
|
Nature Genet. 20: 370-373, 1998. Note: Erratum: Nature Genet.:21: 241 only, 1999.
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|
|
[PubMed: 9843210]
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|
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[Full Text: https://doi.org/10.1038/3845]
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</p>
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</li>
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</ol>
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<div>
|
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<br />
|
|
</div>
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|
</div>
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</div>
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<div>
|
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<div class="row">
|
|
<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
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<span class="text-nowrap mim-text-font">
|
|
Contributors:
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
George E. Tiller - updated : 11/1/2010<br>Marla J. F. O'Neill - updated : 10/7/2010<br>Cassandra L. Kniffin - updated : 2/19/2010<br>Cassandra L. Kniffin - updated : 3/3/2009<br>Patricia A. Hartz - updated : 6/9/2006<br>George E. Tiller - updated : 1/10/2006<br>George E. Tiller - updated : 7/10/2003<br>George E. Tiller - updated : 2/14/2003<br>George E. Tiller - updated : 10/2/2001<br>Victor A. McKusick - updated : 7/21/2000<br>Victor A. McKusick - updated : 3/15/2000<br>Victor A. McKusick - updated : 12/20/1999<br>Victor A. McKusick - updated : 3/2/1999<br>Victor A. McKusick - updated : 2/23/1999<br>Patti M. Sherman - updated : 12/11/1998
|
|
</span>
|
|
</div>
|
|
</div>
|
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<div class="row">
|
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
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<span class="text-nowrap mim-text-font">
|
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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">
|
|
Victor A. McKusick : 11/30/1998
|
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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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<br />
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
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<span class="text-nowrap mim-text-font">
|
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Edit History:
|
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</span>
|
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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carol : 05/24/2024<br>carol : 06/13/2017<br>carol : 07/16/2015<br>mcolton : 7/2/2015<br>carol : 3/9/2015<br>carol : 8/4/2014<br>terry : 12/22/2010<br>terry : 12/22/2010<br>alopez : 11/2/2010<br>terry : 11/1/2010<br>carol : 10/7/2010<br>wwang : 2/23/2010<br>ckniffin : 2/19/2010<br>carol : 3/6/2009<br>ckniffin : 3/3/2009<br>terry : 12/2/2008<br>mgross : 6/9/2006<br>wwang : 1/30/2006<br>terry : 1/10/2006<br>joanna : 3/17/2004<br>cwells : 7/10/2003<br>cwells : 2/14/2003<br>terry : 3/25/2002<br>cwells : 10/10/2001<br>cwells : 10/2/2001<br>mcapotos : 8/7/2000<br>mcapotos : 7/21/2000<br>mcapotos : 7/21/2000<br>mcapotos : 7/6/2000<br>mcapotos : 4/6/2000<br>terry : 3/15/2000<br>carol : 12/21/1999<br>terry : 12/20/1999<br>carol : 8/31/1999<br>psherman : 8/31/1999<br>carol : 3/8/1999<br>terry : 3/2/1999<br>alopez : 3/1/1999<br>terry : 2/23/1999<br>carol : 12/15/1998<br>psherman : 12/11/1998<br>dkim : 12/2/1998<br>alopez : 11/30/1998<br>alopez : 11/30/1998
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