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<title>
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Entry
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- *608576 - GRAINYHEAD-LIKE 2; GRHL2
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- OMIM
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</ul>
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</div>
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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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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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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="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="row">
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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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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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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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>
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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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<li role="separator" class="divider"></li>
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<li>
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<a href="/history"> Search History </a>
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</ul>
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</div>
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<div class="autocomplete" id="mimEntrySearchAutocomplete"></div>
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</form>
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<div class="row">
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<p />
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</div>
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<div id="mimAlertBanner">
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*608576</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>
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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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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</li>
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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>
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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>
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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/608576">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=ENSG00000083307;t=ENST00000646743" 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=79977" 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=608576" 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=ENSG00000083307;t=ENST00000646743" 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_001330593,NM_024915,XM_011517306,XM_011517307" 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_024915" 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=608576" 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=10545&isoform_id=10545_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/GRHL2" 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/10435904,46854865,47480845,47480852,74736618,119612239,119612240,120537868,120538535,158259167,170784817,194384460,283893440,767953634,767953636,1060099339,2462621172,2462621174" 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/Q6ISB3" 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=79977" 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=ENSG00000083307;t=ENST00000646743" 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=GRHL2" 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=GRHL2" 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+79977" 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/GRHL2" 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:79977" 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/79977" 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=chr8&hgg_gene=ENST00000646743.1&hgg_start=101492439&hgg_end=101681200&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:2799" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608576[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=608576[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/ENSG00000083307" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=GRHL2" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=GRHL2" 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=GRHL2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=GRHL2&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/PA27270" 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:2799" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0259211.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:2182543" 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/GRHL2#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:2182543" 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/79977/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=79977" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00001707;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050913-123" 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=GRHL2&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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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 764995008<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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608576
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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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GRAINYHEAD-LIKE 2; GRHL2
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
GRAINYHEAD, DROSOPHILA, HOMOLOG OF, 2<br />
|
|
BROTHER OF GRAINYHEAD; BOM<br />
|
|
TRANSCRIPTION FACTOR CP2-LIKE 3; TFCP2L3
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GRHL2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GRHL2</a></em></strong>
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/8/450?start=-3&limit=10&highlight=450">8q22.3</a>
|
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr8:101492439-101681200&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'})">8:101,492,439-101,681,200</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>
|
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<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<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=618031,608641,616029" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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</th>
|
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<th>
|
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Phenotype <br /> MIM number
|
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</th>
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<th>
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<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>Members of the grainyhead-like transcription factor family, such as GRHL2, have essential roles in epithelial morphogenesis and epidermal development (<a href="#2" class="mim-tip-reference" title="Han, Y., Mu, Y., Li, X., Xu, P., Tong, J., Liu, Z., Ma, T., Zeng, G., Yang, S., Du, J., Meng, A. <strong>Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28.</strong> Hum. Molec. Genet. 20: 3213-3226, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21610158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21610158</a>] [<a href="https://doi.org/10.1093/hmg/ddr234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21610158">Han et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21610158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By PCR analysis of a human fetal cochlea cDNA library, <a href="#5" class="mim-tip-reference" title="Peters, L. M., Anderson, D. W., Griffith, A. J., Grundfast, K. M., San Agustin, T. B., Madeo, A. C., Friedman, T. B., Morell, R. J. <strong>Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28.</strong> Hum. Molec. Genet. 11: 2877-2885, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12393799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12393799</a>] [<a href="https://doi.org/10.1093/hmg/11.23.2877" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12393799">Peters et al. (2002)</a> cloned GRHL2, which they called TFCP2L3. The gene contains a 4,793-bp open reading frame encoding a protein of 625 amino acids that shares 34% identity in the DNA-binding region and 27% overall identity with TFCP2 (<a href="/entry/189889">189889</a>). Northern blot analysis of human tissues detected a major 6.5-kb transcript and a minor 8.4-kb transcript in prostate. Analysis of a human multiple tissue Northern blot confirmed that TFCP2L3 was highly expressed in the prostate, as well as the placenta, and also showed lower level expression in a variety of epithelial tissues such as thymus, kidney, lung, salivary gland, mammary gland, and digestive tract. Northern blot analyses and in situ hybridization studies showed that mouse Tfcp2l3 was expressed in many epithelial tissues, including cells lining the cochlear duct. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12393799" 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 RT-PCR, <a href="#4" class="mim-tip-reference" title="Liskova, P., Dudakova, L., Evans, C. J., Rojas Lopez, K. E., Pontikos, N., Athanasiou, D., Jama, H., Sach, J., Skalicka, P., Stranecky, V., Kmoch, S., Thaung, C., Filipec, M., Cheetham, M. E., Davidson, A. E., Tuft, S. J., Hardcastle, A. J. <strong>Ectopic GRHL2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4.</strong> Am. J. Hum. Genet. 102: 447-459, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29499165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29499165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29499165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.02.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29499165">Liskova et al. (2018)</a> detected GRHL2 expression in 2 different human corneal epithelial cell lines, but not in a corneal endothelial cell line or endothelial tissue, or in stromal fibroblasts. In a full-thickness corneal sample from a control individual, immunohistochemistry detected GRHL2 in the nuclei of epithelial cells, but not in the endothelium or stroma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29499165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Peters, L. M., Anderson, D. W., Griffith, A. J., Grundfast, K. M., San Agustin, T. B., Madeo, A. C., Friedman, T. B., Morell, R. J. <strong>Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28.</strong> Hum. Molec. Genet. 11: 2877-2885, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12393799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12393799</a>] [<a href="https://doi.org/10.1093/hmg/11.23.2877" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12393799">Peters et al. (2002)</a> determined that the GRHL2 gene contains 16 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12393799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Peters, L. M., Anderson, D. W., Griffith, A. J., Grundfast, K. M., San Agustin, T. B., Madeo, A. C., Friedman, T. B., Morell, R. J. <strong>Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28.</strong> Hum. Molec. Genet. 11: 2877-2885, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12393799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12393799</a>] [<a href="https://doi.org/10.1093/hmg/11.23.2877" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12393799">Peters et al. (2002)</a> identified the GRHL2 gene within the DFNA28 locus (<a href="/entry/608641">608641</a>) on chromosome 8q22. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12393799" 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>Cellular life span is associated with maintenance of telomere length by telomerase, a ribonucleoprotein complex minimally composed of the protein subunit TERT (<a href="/entry/187270">187270</a>) and an RNA template (TERC; <a href="/entry/602322">602322</a>). <a href="#1" class="mim-tip-reference" title="Chen, W., Dong, Q., Shin, K.-H., Kim, R. H., Oh, J.-E., Park, N.-H., Kang, M. K. <strong>Grainyhead-like 2 enhances the human telomerase reverse transcriptase gene expression by inhibiting DNA methylation at the 5-prime-CpG island in normal human keratinocytes.</strong> J. Biol. Chem. 285: 40852-40863, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20938050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20938050</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20938050[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M110.103812" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20938050">Chen et al. (2010)</a> found that GRHL2 was expressed in nuclear fractions of growing normal human keratinocytes (NHKs) in culture, but that its nuclear expression was dramatically reduced during cell senescence. Ectopic overexpression of GRHL2 in NHKs increased telomerase activity and led to a significant extension of replicative life span, but it did not promote immortalization. GRHL2 increased expression of TERT and markers of cell growth, including PCNA (<a href="/entry/176740">176740</a>) and inactivating hyperphosphorylated RB (<a href="/entry/614041">614041</a>). GRHL2 overexpression also led to downregulation of GRHL1 (<a href="/entry/609786">609786</a>), GRHL3 (<a href="/entry/608317">608317</a>), and numerous genes involved in keratinocyte differentiation. In contrast, knockdown of GRHL2 repressed TERT and PCNA expression, telomerase activity, and cell proliferation. In a human tongue carcinoma cell line, knockdown of GRHL2 caused epithelial atrophy, reduced epithelial thickness, and loss of invasive phenotype. Knockdown of TERT in GRHL2-expressing cells abrogated the positive effect of GRHL2 on cell proliferation. GRHL2 directly bound the TERT promoter region near an SP1 (<a href="/entry/189906">189906</a>)-binding site and inhibited methylation of the CpG island. Knockdown of GRHL2 was associated with TERT promoter hypermethylation. <a href="#1" class="mim-tip-reference" title="Chen, W., Dong, Q., Shin, K.-H., Kim, R. H., Oh, J.-E., Park, N.-H., Kang, M. K. <strong>Grainyhead-like 2 enhances the human telomerase reverse transcriptase gene expression by inhibiting DNA methylation at the 5-prime-CpG island in normal human keratinocytes.</strong> J. Biol. Chem. 285: 40852-40863, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20938050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20938050</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20938050[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M110.103812" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20938050">Chen et al. (2010)</a> concluded that GRHL2 enhances TERT expression in keratinocytes by an epigenetic mechanism, resulting in keratinocyte proliferation and increased cellular life span. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20938050" 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 ATAC-seq analysis, <a href="#3" class="mim-tip-reference" title="Jacobs, J., Atkins, M., Davie, K., Imrichova, H., Romanelli, L., Christiaens, V., Hulselmans, G., Potier, D., Wouters, J., Taskiran, I. I., Paciello, G., Gonzalez-Blas, C. B., Koldere, D., Aibar, S., Halder, G., Aerts, S. <strong>The transcription factor grainy head primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes.</strong> Nature Genet. 50: 1011-1020, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29867222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29867222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29867222[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/10.1038/s41588-018-0140-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29867222">Jacobs et al. (2018)</a> profiled open chromatin across a cohort of inbred Drosophila strains, and found that a Grh-binding site can causally determine the in vivo accessibility of an enhancer-sized region, predicting the presence of potential chromatin regulators for chromatin accessibility. In Drosophila eye-antennal discs, evaluation of the occupancy of Grh-binding sites showed that whenever a region with a Grh motif was accessible, Grh was stably bound there, suggesting that Grh plays a key role in the accessible chromatin landscape of epithelial cells. Further analysis showed that Grh-binding sites are necessary for enhancer accessibility, and Grh binding opens its target enhancers but does not directly activate them. Evolutionary conservation analysis identified some candidate co-transcription factors such as Atonal (Ato; see <a href="/entry/601461">601461</a>), indicating that the activity of enhancers primed through Grh binding requires the recruitment of additional factors. Loss-of-function and gain-of-function experiments showed that deletion of Grh causes the loss of DNA accessibility but ectopic expression recovers it, demonstrating that Grh is a 'pioneer factor' that is sufficient to directly and specifically open its target regions in different tissues. Investigation of the local sequence context around the Grh motifs revealed that, like other pioneer factors, Grh preferentially binds to DNA sites in regions that have a high intrinsic affinity for nucleosomes. <a href="#3" class="mim-tip-reference" title="Jacobs, J., Atkins, M., Davie, K., Imrichova, H., Romanelli, L., Christiaens, V., Hulselmans, G., Potier, D., Wouters, J., Taskiran, I. I., Paciello, G., Gonzalez-Blas, C. B., Koldere, D., Aibar, S., Halder, G., Aerts, S. <strong>The transcription factor grainy head primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes.</strong> Nature Genet. 50: 1011-1020, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29867222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29867222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29867222[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/10.1038/s41588-018-0140-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29867222">Jacobs et al. (2018)</a> showed that the 3 Grh-like transcription factors GRHL1, GRHL2, and GRHL3 have similar functions in human cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29867222" 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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In a large American family with an autosomal dominant form of progressive nonsyndromic sensorineural hearing loss (DFNA28; <a href="/entry/608641">608641</a>), <a href="#5" class="mim-tip-reference" title="Peters, L. M., Anderson, D. W., Griffith, A. J., Grundfast, K. M., San Agustin, T. B., Madeo, A. C., Friedman, T. B., Morell, R. J. <strong>Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28.</strong> Hum. Molec. Genet. 11: 2877-2885, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12393799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12393799</a>] [<a href="https://doi.org/10.1093/hmg/11.23.2877" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12393799">Peters et al. (2002)</a> identified a mutation in the GRHL2 gene (<a href="#0001">608576.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12393799" 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 large 5-generation family segregating autosomal dominant postlingual hearing loss with a highly variable age of onset and progression, <a href="#7" class="mim-tip-reference" title="Vona, B., Nanda, I., Neuner, C., Muller, T., Haaf, T. <strong>Confirmation of GRHL2 as the gene for the DFNA28 locus.</strong> Am. J. Med. Genet. 161A: 2060-2065, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23813623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23813623</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23813623[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/10.1002/ajmg.a.36017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23813623">Vona et al. (2013)</a> identified heterozygosity for a splice site mutation in the GRHL2 gene (<a href="#0002">608576.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23813623" 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>Ectodermal Dysplasia/Short Stature Syndrome</em></strong></p><p>
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In affected individuals from 2 unrelated consanguineous Kuwaiti families with short stature and ectodermal defects (ECTDS; <a href="/entry/616029">616029</a>), <a href="#6" class="mim-tip-reference" title="Petrof, G., Nanda, A., Howden, J., Takeichi, T., McMillan, J. R., Aristodemou, S., Ozoemena, L., Liu, L., South, A. P., Pourreyron, C., Dafou, D., Proudfoot, L. E., Al-Ajmi, H., Akiyama, M., McLean, W. H. I., Simpson, M. A., Parsons, M., McGrath, J. A. <strong>Mutations in GRHL2 result in an autosomal-recessive ectodermal dysplasia syndrome.</strong> Am. J. Hum. Genet. 95: 308-314, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25152456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25152456</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25152456[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.08.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25152456">Petrof et al. (2014)</a> identified homozygosity for 2 different missense mutations in the GRHL2 gene, Y398H (<a href="#0003">608576.0003</a>) and I482K (<a href="#0004">608576.0004</a>). The mutations, which segregated with disease in each family, were not found in controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25152456" 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>Posterior Polymorphous Corneal Dystrophy 4</em></strong></p><p>
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In 4 Czech families and 2 British families with posterior polymorphous corneal dystrophy (PPCD4; <a href="/entry/618031">618031</a>), <a href="#4" class="mim-tip-reference" title="Liskova, P., Dudakova, L., Evans, C. J., Rojas Lopez, K. E., Pontikos, N., Athanasiou, D., Jama, H., Sach, J., Skalicka, P., Stranecky, V., Kmoch, S., Thaung, C., Filipec, M., Cheetham, M. E., Davidson, A. E., Tuft, S. J., Hardcastle, A. J. <strong>Ectopic GRHL2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4.</strong> Am. J. Hum. Genet. 102: 447-459, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29499165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29499165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29499165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.02.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29499165">Liskova et al. (2018)</a> identified heterozygosity for mutations in intron 1 of the GRHL2 gene (see, e.g., <a href="#0005">608576.0005</a> and <a href="#0006">608576.0006</a>) that segregated with disease and were not found in public variant databases. Functional analysis indicated that the mutants significantly increased promoter activity of the intron 1 regulatory region compared to wildtype GRLH2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29499165" 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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See <a href="/entry/612448">612448</a> for discussion of a possible association between variation in the GRHL2 gene and age-related hearing impairment.</p>
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<p>Using a gene trap strategy, <a href="#2" class="mim-tip-reference" title="Han, Y., Mu, Y., Li, X., Xu, P., Tong, J., Liu, Z., Ma, T., Zeng, G., Yang, S., Du, J., Meng, A. <strong>Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28.</strong> Hum. Molec. Genet. 20: 3213-3226, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21610158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21610158</a>] [<a href="https://doi.org/10.1093/hmg/ddr234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21610158">Han et al. (2011)</a> developed a line of zebrafish with a disruption of the Grhl2b gene. Homozygous Grhl2b mutant embryos appeared grossly normal, including apparently normal patterning and specification of otic vesicles and differentiation of hair cells. However, Grhl2b mutant embryos had enlarged otocysts, thinner otic epithelia, and smaller or eliminated otoliths. Later, Grhl2b mutant fish showed abnormal swimming behavior and reduced survival compared with wildtype. Morpholino-mediated knockdown of Grhl2b in zebrafish resulted in similar defects in otic development. <a href="#2" class="mim-tip-reference" title="Han, Y., Mu, Y., Li, X., Xu, P., Tong, J., Liu, Z., Ma, T., Zeng, G., Yang, S., Du, J., Meng, A. <strong>Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28.</strong> Hum. Molec. Genet. 20: 3213-3226, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21610158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21610158</a>] [<a href="https://doi.org/10.1093/hmg/ddr234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21610158">Han et al. (2011)</a> found that zebrafish Grhl2b was required for normal otic expression of the apical junction protein claudin-b (see CLDN4; <a href="/entry/602909">602909</a>) and the basolateral junction protein Epcam (<a href="/entry/185535">185535</a>). Overexpression of wildtype mouse or human GRHL2, but not human GRHL2 with the 1609insC mutation (<a href="#0001">608576.0001</a>), rescued claudin-b and Epcam expression and otic development in Grhl2b mutant embryos. <a href="#2" class="mim-tip-reference" title="Han, Y., Mu, Y., Li, X., Xu, P., Tong, J., Liu, Z., Ma, T., Zeng, G., Yang, S., Du, J., Meng, A. <strong>Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28.</strong> Hum. Molec. Genet. 20: 3213-3226, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21610158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21610158</a>] [<a href="https://doi.org/10.1093/hmg/ddr234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21610158">Han et al. (2011)</a> concluded that, while Grhl2b is widely expressed in the developing zebrafish, it is uniquely critical for inner ear development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21610158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a large American family with an autosomal dominant form of progressive nonsyndromic sensorineural hearing loss (DFNA28; <a href="/entry/608641">608641</a>), <a href="#5" class="mim-tip-reference" title="Peters, L. M., Anderson, D. W., Griffith, A. J., Grundfast, K. M., San Agustin, T. B., Madeo, A. C., Friedman, T. B., Morell, R. J. <strong>Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28.</strong> Hum. Molec. Genet. 11: 2877-2885, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12393799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12393799</a>] [<a href="https://doi.org/10.1093/hmg/11.23.2877" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12393799">Peters et al. (2002)</a> identified a 1-bp insertion in exon 14 of the GRHL2 gene, 1609insC, resulting in a frameshift with a premature stop codon following 10 novel codons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12393799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000077792" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000077792" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000077792</a>
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<p>In affected members of a large 5-generation family segregating autosomal dominant postlingual hearing loss with a highly variable age of onset and progression (DFNA28; <a href="/entry/608641">608641</a>), <a href="#7" class="mim-tip-reference" title="Vona, B., Nanda, I., Neuner, C., Muller, T., Haaf, T. <strong>Confirmation of GRHL2 as the gene for the DFNA28 locus.</strong> Am. J. Med. Genet. 161A: 2060-2065, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23813623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23813623</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23813623[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/10.1002/ajmg.a.36017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23813623">Vona et al. (2013)</a> identified heterozygosity for a c.1258-1G-A transition in intron 9 of the GRHL2 gene, creating a new 3-prime AG splice site that is shifted by only 1 nucleotide in the 3-prime direction, which causes heterozygous deletion of the first guanine in exon 10 and predicts a premature termination codon in exon 13 (Gly420GlufsTer111). The mutation was present in heterozygosity in the proband's affected mother but was not found in his unaffected father, and it was detected in 4 other family members with hearing loss as well as 2 family members under the age of 44 who had not yet developed hearing loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23813623" 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">rs587777737 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777737;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=rs587777737" 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=rs587777737" 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=RCV000144237 OR RCV001281606" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144237, RCV001281606" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144237...</a>
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<p>In a brother and sister from a consanguineous Kuwaiti family with ectodermal dysplasia/short stature syndrome (ECTDS; <a href="/entry/616029">616029</a>), <a href="#6" class="mim-tip-reference" title="Petrof, G., Nanda, A., Howden, J., Takeichi, T., McMillan, J. R., Aristodemou, S., Ozoemena, L., Liu, L., South, A. P., Pourreyron, C., Dafou, D., Proudfoot, L. E., Al-Ajmi, H., Akiyama, M., McLean, W. H. I., Simpson, M. A., Parsons, M., McGrath, J. A. <strong>Mutations in GRHL2 result in an autosomal-recessive ectodermal dysplasia syndrome.</strong> Am. J. Hum. Genet. 95: 308-314, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25152456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25152456</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25152456[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.08.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25152456">Petrof et al. (2014)</a> identified homozygosity for a c.1192T-C transition in exon 9 of the GRHL2 gene, resulting in a tyr398-to-his (Y398H) substitution within the DNA-binding domain. The mutation was not found in unaffected family members, in 260 ethnically matched controls, in approximately 1,200 control in-house exomes, or in the 1000 Genomes Project database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25152456" 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> rs587777738 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777738;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/rs587777738?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=rs587777738" 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=rs587777738" 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=RCV000144238" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144238" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144238</a>
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<p>In 2 sisters and a sister and brother from 2 sibships in a consanguineous Kuwaiti family with ectodermal dysplasia/short stature syndrome (ECTDS; <a href="/entry/616029">616029</a>), <a href="#6" class="mim-tip-reference" title="Petrof, G., Nanda, A., Howden, J., Takeichi, T., McMillan, J. R., Aristodemou, S., Ozoemena, L., Liu, L., South, A. P., Pourreyron, C., Dafou, D., Proudfoot, L. E., Al-Ajmi, H., Akiyama, M., McLean, W. H. I., Simpson, M. A., Parsons, M., McGrath, J. A. <strong>Mutations in GRHL2 result in an autosomal-recessive ectodermal dysplasia syndrome.</strong> Am. J. Hum. Genet. 95: 308-314, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25152456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25152456</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25152456[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2014.08.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25152456">Petrof et al. (2014)</a> identified homozygosity for a c.1445T-A transversion in exon 11 of the GRHL2 gene, resulting in an ile482-to-lys (I482K) substitution within the DNA-binding domain. The mutation was not found in unaffected family members, in 260 ethnically matched controls, in approximately 1,200 control in-house exomes, or in the 1000 Genomes Project database. Quantitative PCR in cultured patient keratinocytes showed reduced expression, and immunoblotting of whole-cell lysates revealed markedly reduced or undetectable amounts of GRHL2. Confocal microscopy of immortalized patient keratinocytes showed that the I482K mutant cells had a less cuboidal, elongated phenotype and failed to form intact cell junctions compared to wildtype cells. There was a reduction in cell-membrane labeling for E-cadherin (CDH1; <a href="/entry/192090">192090</a>) at the adherens junctions and for zona occludens-2 (TJP2; <a href="/entry/607709">607709</a>) at the tight junctions compared to controls. Mutant GRHL2 staining showed fragmented punctate nuclear localization rather than localization to the cell-cell contact areas and within the nucleus, as with wildtype GRHL2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25152456" 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 CORNEAL DYSTROPHY, POSTERIOR POLYMORPHOUS, 4</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">rs1554579878 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554579878;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=rs1554579878" 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=rs1554579878" 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=RCV000656692 OR RCV000656697" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000656692, RCV000656697" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000656692...</a>
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<p>In 4 Czech families (C15, C23, C26, and C33) with posterior polymorphous corneal dystrophy (PPCD4; <a href="/entry/618031">618031</a>), <a href="#4" class="mim-tip-reference" title="Liskova, P., Dudakova, L., Evans, C. J., Rojas Lopez, K. E., Pontikos, N., Athanasiou, D., Jama, H., Sach, J., Skalicka, P., Stranecky, V., Kmoch, S., Thaung, C., Filipec, M., Cheetham, M. E., Davidson, A. E., Tuft, S. J., Hardcastle, A. J. <strong>Ectopic GRHL2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4.</strong> Am. J. Hum. Genet. 102: 447-459, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29499165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29499165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29499165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.02.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29499165">Liskova et al. (2018)</a> identified heterozygosity for a c.20+544G-T transversion (c.20+544G-T, NM_024915) (chr8:101,493,333G-T, GRCh38) within a conserved promoter region in intron 1 of the GRHL2 gene, involving a specific base known to be a bivalent histone modification site as well as a location marking a DNase I hypersensitive site and CTCF binding site. In 3 of the families, the mutation segregated with disease and haplotype analysis suggested that the mutation arose from a common ancestor; in the fourth family (C33), the mutation was shown to have arisen de novo in the proband. The mutation was not found in the gnomAD, 1000 Genomes Project, UK 10K, GoNL, or Kaviar databases. Functional analysis in transfected HEK293 cells showed that the mutant significantly increased promoter activity of the intron 1 regulatory region compared to wildtype GRHL2. Immunohistochemical analysis of a full-thickness corneal sample from an affected individual in family C23 revealed ectopic expression of GRHL2 in endothelial cell nuclei. In addition, differences in levels of epithelial, mesenchymal, and endothelial markers that were observed between patient and control corneal tissue indicated that PPCD4 endothelial cells were in transition to an epithelial-like cell type or had already diverged. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29499165" 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">rs1554579819 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554579819;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=rs1554579819" 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=rs1554579819" 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=RCV000656694 OR RCV000656696" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000656694, RCV000656696" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000656694...</a>
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<p>In a sister and brother from a British family (B5) with posterior polymorphous corneal dystrophy (PPCD4; <a href="/entry/618031">618031</a>), <a href="#4" class="mim-tip-reference" title="Liskova, P., Dudakova, L., Evans, C. J., Rojas Lopez, K. E., Pontikos, N., Athanasiou, D., Jama, H., Sach, J., Skalicka, P., Stranecky, V., Kmoch, S., Thaung, C., Filipec, M., Cheetham, M. E., Davidson, A. E., Tuft, S. J., Hardcastle, A. J. <strong>Ectopic GRHL2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4.</strong> Am. J. Hum. Genet. 102: 447-459, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29499165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29499165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29499165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.02.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29499165">Liskova et al. (2018)</a> identified heterozygosity for a 1-bp deletion (c.20+133delA, NM_024915) (chr8:101,492,922delA, GRCh38) within a conserved regulatory region in intron 1 of the GRHL2 gene. The mutation was not found in their unaffected mother or sister, or in 210 Czech controls; DNA from their unaffected deceased father was unavailable. Functional analysis in transfected HEK293 cells showed that the mutant significantly increased promoter activity of the intron 1 regulatory region compared to wildtype GRHL2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29499165" 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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</span>
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</h4>
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<div>
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<p />
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<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
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<ol>
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<a id="1" class="mim-anchor"></a>
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<a id="Chen2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Chen, W., Dong, Q., Shin, K.-H., Kim, R. H., Oh, J.-E., Park, N.-H., Kang, M. K.
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<strong>Grainyhead-like 2 enhances the human telomerase reverse transcriptase gene expression by inhibiting DNA methylation at the 5-prime-CpG island in normal human keratinocytes.</strong>
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J. Biol. Chem. 285: 40852-40863, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20938050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20938050</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20938050[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=20938050" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M110.103812" target="_blank">Full Text</a>]
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</p>
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<a id="2" class="mim-anchor"></a>
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<a id="Han2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Han, Y., Mu, Y., Li, X., Xu, P., Tong, J., Liu, Z., Ma, T., Zeng, G., Yang, S., Du, J., Meng, A.
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<strong>Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28.</strong>
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Hum. Molec. Genet. 20: 3213-3226, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21610158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21610158</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21610158" 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/ddr234" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="3" class="mim-anchor"></a>
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<a id="Jacobs2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Jacobs, J., Atkins, M., Davie, K., Imrichova, H., Romanelli, L., Christiaens, V., Hulselmans, G., Potier, D., Wouters, J., Taskiran, I. I., Paciello, G., Gonzalez-Blas, C. B., Koldere, D., Aibar, S., Halder, G., Aerts, S.
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<strong>The transcription factor grainy head primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes.</strong>
|
|
Nature Genet. 50: 1011-1020, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29867222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29867222</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29867222[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=29867222" 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/s41588-018-0140-x" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="4" class="mim-anchor"></a>
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<a id="Liskova2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Liskova, P., Dudakova, L., Evans, C. J., Rojas Lopez, K. E., Pontikos, N., Athanasiou, D., Jama, H., Sach, J., Skalicka, P., Stranecky, V., Kmoch, S., Thaung, C., Filipec, M., Cheetham, M. E., Davidson, A. E., Tuft, S. J., Hardcastle, A. J.
|
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<strong>Ectopic GRHL2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4.</strong>
|
|
Am. J. Hum. Genet. 102: 447-459, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29499165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29499165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29499165[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=29499165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2018.02.002" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="5" class="mim-anchor"></a>
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<a id="Peters2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Peters, L. M., Anderson, D. W., Griffith, A. J., Grundfast, K. M., San Agustin, T. B., Madeo, A. C., Friedman, T. B., Morell, R. J.
|
|
<strong>Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28.</strong>
|
|
Hum. Molec. Genet. 11: 2877-2885, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12393799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12393799</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12393799" 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/11.23.2877" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Petrof2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Petrof, G., Nanda, A., Howden, J., Takeichi, T., McMillan, J. R., Aristodemou, S., Ozoemena, L., Liu, L., South, A. P., Pourreyron, C., Dafou, D., Proudfoot, L. E., Al-Ajmi, H., Akiyama, M., McLean, W. H. I., Simpson, M. A., Parsons, M., McGrath, J. A.
|
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<strong>Mutations in GRHL2 result in an autosomal-recessive ectodermal dysplasia syndrome.</strong>
|
|
Am. J. Hum. Genet. 95: 308-314, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25152456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25152456</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25152456[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=25152456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2014.08.001" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Vona2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vona, B., Nanda, I., Neuner, C., Muller, T., Haaf, T.
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<strong>Confirmation of GRHL2 as the gene for the DFNA28 locus.</strong>
|
|
Am. J. Med. Genet. 161A: 2060-2065, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23813623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23813623</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23813623[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=23813623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.36017" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 08/22/2018
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 06/26/2018<br>Marla J. F. O'Neill - updated : 9/24/2014<br>Marla J. F. O'Neill - updated : 1/7/2014<br>Patricia A. Hartz - updated : 6/15/2012<br>Patricia A. Hartz - updated : 11/16/2011
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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="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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George E. Tiller : 4/8/2004
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 01/12/2022
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 08/22/2018<br>alopez : 06/26/2018<br>carol : 09/26/2014<br>carol : 9/25/2014<br>mcolton : 9/24/2014<br>carol : 1/7/2014<br>mgross : 6/20/2012<br>mgross : 6/20/2012<br>terry : 6/15/2012<br>mgross : 2/7/2012<br>terry : 11/16/2011<br>wwang : 5/19/2009<br>ckniffin : 4/29/2009<br>terry : 12/2/2008<br>mgross : 12/13/2005<br>mgross : 12/13/2005<br>alopez : 5/9/2005<br>tkritzer : 5/10/2004<br>tkritzer : 4/16/2004
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 608576
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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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GRAINYHEAD-LIKE 2; GRHL2
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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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<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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GRAINYHEAD, DROSOPHILA, HOMOLOG OF, 2<br />
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BROTHER OF GRAINYHEAD; BOM<br />
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TRANSCRIPTION FACTOR CP2-LIKE 3; TFCP2L3
|
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GRHL2</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 764995008;
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</span>
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</p>
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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-text-font">
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<strong>
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<em>
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Cytogenetic location: 8q22.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 8:101,492,439-101,681,200 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
|
</thead>
|
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<tbody>
|
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<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
8q22.3
|
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</span>
|
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</td>
|
|
|
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<td>
|
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<span class="mim-font">
|
|
Corneal dystrophy, posterior polymorphous, 4
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
618031
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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">
|
|
Deafness, autosomal dominant 28
|
|
</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
608641
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
|
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<span class="mim-font">
|
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Ectodermal dysplasia/short stature syndrome
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<span class="mim-font">
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616029
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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</tr>
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</tbody>
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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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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</h4>
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<span class="mim-text-font">
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<p>Members of the grainyhead-like transcription factor family, such as GRHL2, have essential roles in epithelial morphogenesis and epidermal development (Han et al., 2011). </p>
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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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<p>By PCR analysis of a human fetal cochlea cDNA library, Peters et al. (2002) cloned GRHL2, which they called TFCP2L3. The gene contains a 4,793-bp open reading frame encoding a protein of 625 amino acids that shares 34% identity in the DNA-binding region and 27% overall identity with TFCP2 (189889). Northern blot analysis of human tissues detected a major 6.5-kb transcript and a minor 8.4-kb transcript in prostate. Analysis of a human multiple tissue Northern blot confirmed that TFCP2L3 was highly expressed in the prostate, as well as the placenta, and also showed lower level expression in a variety of epithelial tissues such as thymus, kidney, lung, salivary gland, mammary gland, and digestive tract. Northern blot analyses and in situ hybridization studies showed that mouse Tfcp2l3 was expressed in many epithelial tissues, including cells lining the cochlear duct. </p><p>By RT-PCR, Liskova et al. (2018) detected GRHL2 expression in 2 different human corneal epithelial cell lines, but not in a corneal endothelial cell line or endothelial tissue, or in stromal fibroblasts. In a full-thickness corneal sample from a control individual, immunohistochemistry detected GRHL2 in the nuclei of epithelial cells, but not in the endothelium or stroma. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</h4>
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<span class="mim-text-font">
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<p>Peters et al. (2002) determined that the GRHL2 gene contains 16 exons. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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<span class="mim-text-font">
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<p>Peters et al. (2002) identified the GRHL2 gene within the DFNA28 locus (608641) on chromosome 8q22. </p>
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<h4>
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<strong>Gene Function</strong>
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</h4>
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<p>Cellular life span is associated with maintenance of telomere length by telomerase, a ribonucleoprotein complex minimally composed of the protein subunit TERT (187270) and an RNA template (TERC; 602322). Chen et al. (2010) found that GRHL2 was expressed in nuclear fractions of growing normal human keratinocytes (NHKs) in culture, but that its nuclear expression was dramatically reduced during cell senescence. Ectopic overexpression of GRHL2 in NHKs increased telomerase activity and led to a significant extension of replicative life span, but it did not promote immortalization. GRHL2 increased expression of TERT and markers of cell growth, including PCNA (176740) and inactivating hyperphosphorylated RB (614041). GRHL2 overexpression also led to downregulation of GRHL1 (609786), GRHL3 (608317), and numerous genes involved in keratinocyte differentiation. In contrast, knockdown of GRHL2 repressed TERT and PCNA expression, telomerase activity, and cell proliferation. In a human tongue carcinoma cell line, knockdown of GRHL2 caused epithelial atrophy, reduced epithelial thickness, and loss of invasive phenotype. Knockdown of TERT in GRHL2-expressing cells abrogated the positive effect of GRHL2 on cell proliferation. GRHL2 directly bound the TERT promoter region near an SP1 (189906)-binding site and inhibited methylation of the CpG island. Knockdown of GRHL2 was associated with TERT promoter hypermethylation. Chen et al. (2010) concluded that GRHL2 enhances TERT expression in keratinocytes by an epigenetic mechanism, resulting in keratinocyte proliferation and increased cellular life span. </p><p>Using ATAC-seq analysis, Jacobs et al. (2018) profiled open chromatin across a cohort of inbred Drosophila strains, and found that a Grh-binding site can causally determine the in vivo accessibility of an enhancer-sized region, predicting the presence of potential chromatin regulators for chromatin accessibility. In Drosophila eye-antennal discs, evaluation of the occupancy of Grh-binding sites showed that whenever a region with a Grh motif was accessible, Grh was stably bound there, suggesting that Grh plays a key role in the accessible chromatin landscape of epithelial cells. Further analysis showed that Grh-binding sites are necessary for enhancer accessibility, and Grh binding opens its target enhancers but does not directly activate them. Evolutionary conservation analysis identified some candidate co-transcription factors such as Atonal (Ato; see 601461), indicating that the activity of enhancers primed through Grh binding requires the recruitment of additional factors. Loss-of-function and gain-of-function experiments showed that deletion of Grh causes the loss of DNA accessibility but ectopic expression recovers it, demonstrating that Grh is a 'pioneer factor' that is sufficient to directly and specifically open its target regions in different tissues. Investigation of the local sequence context around the Grh motifs revealed that, like other pioneer factors, Grh preferentially binds to DNA sites in regions that have a high intrinsic affinity for nucleosomes. Jacobs et al. (2018) showed that the 3 Grh-like transcription factors GRHL1, GRHL2, and GRHL3 have similar functions in human cells. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Autosomal Dominant Nonsyndromic Deafness 28</em></strong></p><p>
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In a large American family with an autosomal dominant form of progressive nonsyndromic sensorineural hearing loss (DFNA28; 608641), Peters et al. (2002) identified a mutation in the GRHL2 gene (608576.0001). </p><p>In affected members of a large 5-generation family segregating autosomal dominant postlingual hearing loss with a highly variable age of onset and progression, Vona et al. (2013) identified heterozygosity for a splice site mutation in the GRHL2 gene (608576.0002). </p><p><strong><em>Ectodermal Dysplasia/Short Stature Syndrome</em></strong></p><p>
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In affected individuals from 2 unrelated consanguineous Kuwaiti families with short stature and ectodermal defects (ECTDS; 616029), Petrof et al. (2014) identified homozygosity for 2 different missense mutations in the GRHL2 gene, Y398H (608576.0003) and I482K (608576.0004). The mutations, which segregated with disease in each family, were not found in controls. </p><p><strong><em>Posterior Polymorphous Corneal Dystrophy 4</em></strong></p><p>
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In 4 Czech families and 2 British families with posterior polymorphous corneal dystrophy (PPCD4; 618031), Liskova et al. (2018) identified heterozygosity for mutations in intron 1 of the GRHL2 gene (see, e.g., 608576.0005 and 608576.0006) that segregated with disease and were not found in public variant databases. Functional analysis indicated that the mutants significantly increased promoter activity of the intron 1 regulatory region compared to wildtype GRLH2. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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See 612448 for discussion of a possible association between variation in the GRHL2 gene and age-related hearing impairment.</p>
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<h4>
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<strong>Animal Model</strong>
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</h4>
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<p>Using a gene trap strategy, Han et al. (2011) developed a line of zebrafish with a disruption of the Grhl2b gene. Homozygous Grhl2b mutant embryos appeared grossly normal, including apparently normal patterning and specification of otic vesicles and differentiation of hair cells. However, Grhl2b mutant embryos had enlarged otocysts, thinner otic epithelia, and smaller or eliminated otoliths. Later, Grhl2b mutant fish showed abnormal swimming behavior and reduced survival compared with wildtype. Morpholino-mediated knockdown of Grhl2b in zebrafish resulted in similar defects in otic development. Han et al. (2011) found that zebrafish Grhl2b was required for normal otic expression of the apical junction protein claudin-b (see CLDN4; 602909) and the basolateral junction protein Epcam (185535). Overexpression of wildtype mouse or human GRHL2, but not human GRHL2 with the 1609insC mutation (608576.0001), rescued claudin-b and Epcam expression and otic development in Grhl2b mutant embryos. Han et al. (2011) concluded that, while Grhl2b is widely expressed in the developing zebrafish, it is uniquely critical for inner ear development. </p>
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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>6 Selected Examples):</strong>
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</h4>
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<h4>
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<span class="mim-font">
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<strong>.0001 DEAFNESS, AUTOSOMAL DOMINANT 28</strong>
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</span>
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</h4>
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GRHL2, 1-BP INS, 1609C
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SNP: rs398122997,
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ClinVar: RCV000002279
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<p>In affected members of a large American family with an autosomal dominant form of progressive nonsyndromic sensorineural hearing loss (DFNA28; 608641), Peters et al. (2002) identified a 1-bp insertion in exon 14 of the GRHL2 gene, 1609insC, resulting in a frameshift with a premature stop codon following 10 novel codons. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 DEAFNESS, AUTOSOMAL DOMINANT 28</strong>
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</span>
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</h4>
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GRHL2, IVS9AS, G-A, -1
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SNP: rs398123006,
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ClinVar: RCV000077792
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<span class="mim-text-font">
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<p>In affected members of a large 5-generation family segregating autosomal dominant postlingual hearing loss with a highly variable age of onset and progression (DFNA28; 608641), Vona et al. (2013) identified heterozygosity for a c.1258-1G-A transition in intron 9 of the GRHL2 gene, creating a new 3-prime AG splice site that is shifted by only 1 nucleotide in the 3-prime direction, which causes heterozygous deletion of the first guanine in exon 10 and predicts a premature termination codon in exon 13 (Gly420GlufsTer111). The mutation was present in heterozygosity in the proband's affected mother but was not found in his unaffected father, and it was detected in 4 other family members with hearing loss as well as 2 family members under the age of 44 who had not yet developed hearing loss. </p>
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<h4>
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<span class="mim-font">
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<strong>.0003 ECTODERMAL DYSPLASIA/SHORT STATURE SYNDROME</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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GRHL2, TYR398HIS
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SNP: rs587777737,
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ClinVar: RCV000144237, RCV001281606
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<span class="mim-text-font">
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<p>In a brother and sister from a consanguineous Kuwaiti family with ectodermal dysplasia/short stature syndrome (ECTDS; 616029), Petrof et al. (2014) identified homozygosity for a c.1192T-C transition in exon 9 of the GRHL2 gene, resulting in a tyr398-to-his (Y398H) substitution within the DNA-binding domain. The mutation was not found in unaffected family members, in 260 ethnically matched controls, in approximately 1,200 control in-house exomes, or in the 1000 Genomes Project database. </p>
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<h4>
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<span class="mim-font">
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<strong>.0004 ECTODERMAL DYSPLASIA/SHORT STATURE SYNDROME</strong>
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</span>
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GRHL2, ILE482LYS
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SNP: rs587777738,
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gnomAD: rs587777738,
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ClinVar: RCV000144238
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<span class="mim-text-font">
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<p>In 2 sisters and a sister and brother from 2 sibships in a consanguineous Kuwaiti family with ectodermal dysplasia/short stature syndrome (ECTDS; 616029), Petrof et al. (2014) identified homozygosity for a c.1445T-A transversion in exon 11 of the GRHL2 gene, resulting in an ile482-to-lys (I482K) substitution within the DNA-binding domain. The mutation was not found in unaffected family members, in 260 ethnically matched controls, in approximately 1,200 control in-house exomes, or in the 1000 Genomes Project database. Quantitative PCR in cultured patient keratinocytes showed reduced expression, and immunoblotting of whole-cell lysates revealed markedly reduced or undetectable amounts of GRHL2. Confocal microscopy of immortalized patient keratinocytes showed that the I482K mutant cells had a less cuboidal, elongated phenotype and failed to form intact cell junctions compared to wildtype cells. There was a reduction in cell-membrane labeling for E-cadherin (CDH1; 192090) at the adherens junctions and for zona occludens-2 (TJP2; 607709) at the tight junctions compared to controls. Mutant GRHL2 staining showed fragmented punctate nuclear localization rather than localization to the cell-cell contact areas and within the nucleus, as with wildtype GRHL2. </p>
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<h4>
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<span class="mim-font">
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<strong>.0005 CORNEAL DYSTROPHY, POSTERIOR POLYMORPHOUS, 4</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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GRHL2, IVS1, G-T, +544
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<br />
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SNP: rs1554579878,
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ClinVar: RCV000656692, RCV000656697
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<span class="mim-text-font">
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<p>In 4 Czech families (C15, C23, C26, and C33) with posterior polymorphous corneal dystrophy (PPCD4; 618031), Liskova et al. (2018) identified heterozygosity for a c.20+544G-T transversion (c.20+544G-T, NM_024915) (chr8:101,493,333G-T, GRCh38) within a conserved promoter region in intron 1 of the GRHL2 gene, involving a specific base known to be a bivalent histone modification site as well as a location marking a DNase I hypersensitive site and CTCF binding site. In 3 of the families, the mutation segregated with disease and haplotype analysis suggested that the mutation arose from a common ancestor; in the fourth family (C33), the mutation was shown to have arisen de novo in the proband. The mutation was not found in the gnomAD, 1000 Genomes Project, UK 10K, GoNL, or Kaviar databases. Functional analysis in transfected HEK293 cells showed that the mutant significantly increased promoter activity of the intron 1 regulatory region compared to wildtype GRHL2. Immunohistochemical analysis of a full-thickness corneal sample from an affected individual in family C23 revealed ectopic expression of GRHL2 in endothelial cell nuclei. In addition, differences in levels of epithelial, mesenchymal, and endothelial markers that were observed between patient and control corneal tissue indicated that PPCD4 endothelial cells were in transition to an epithelial-like cell type or had already diverged. </p>
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<h4>
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<span class="mim-font">
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<strong>.0006 CORNEAL DYSTROPHY, POSTERIOR POLYMORPHOUS, 4</strong>
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<span class="mim-text-font">
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GRHL2, IVS1, 1-BP DEL, +133A
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<br />
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SNP: rs1554579819,
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ClinVar: RCV000656694, RCV000656696
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<span class="mim-text-font">
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<p>In a sister and brother from a British family (B5) with posterior polymorphous corneal dystrophy (PPCD4; 618031), Liskova et al. (2018) identified heterozygosity for a 1-bp deletion (c.20+133delA, NM_024915) (chr8:101,492,922delA, GRCh38) within a conserved regulatory region in intron 1 of the GRHL2 gene. The mutation was not found in their unaffected mother or sister, or in 210 Czech controls; DNA from their unaffected deceased father was unavailable. Functional analysis in transfected HEK293 cells showed that the mutant significantly increased promoter activity of the intron 1 regulatory region compared to wildtype GRHL2. </p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<ol>
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<strong>Grainyhead-like 2 enhances the human telomerase reverse transcriptase gene expression by inhibiting DNA methylation at the 5-prime-CpG island in normal human keratinocytes.</strong>
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Han, Y., Mu, Y., Li, X., Xu, P., Tong, J., Liu, Z., Ma, T., Zeng, G., Yang, S., Du, J., Meng, A.
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<strong>Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28.</strong>
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Jacobs, J., Atkins, M., Davie, K., Imrichova, H., Romanelli, L., Christiaens, V., Hulselmans, G., Potier, D., Wouters, J., Taskiran, I. I., Paciello, G., Gonzalez-Blas, C. B., Koldere, D., Aibar, S., Halder, G., Aerts, S.
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Liskova, P., Dudakova, L., Evans, C. J., Rojas Lopez, K. E., Pontikos, N., Athanasiou, D., Jama, H., Sach, J., Skalicka, P., Stranecky, V., Kmoch, S., Thaung, C., Filipec, M., Cheetham, M. E., Davidson, A. E., Tuft, S. J., Hardcastle, A. J.
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<strong>Ectopic GRHL2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4.</strong>
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<strong>Mutations in GRHL2 result in an autosomal-recessive ectodermal dysplasia syndrome.</strong>
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<strong>Confirmation of GRHL2 as the gene for the DFNA28 locus.</strong>
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