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Entry
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- *300188 - MEDIATOR COMPLEX SUBUNIT 12; MED12
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300188</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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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300188">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 role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<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=ENSG00000184634;t=ENST00000374080" 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=9968" 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=300188" 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=ENSG00000184634;t=ENST00000374080" 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_005120,XM_047442699,XM_047442700,XM_047442701,XM_047442702,XM_047442703,XM_047442704" 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_005120" 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=300188" 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=02176&isoform_id=02176_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/MED12" 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/1663694,2565059,3426320,5524203,17529625,33353873,33353875,33353877,33353879,33353881,33353883,33353885,33353887,33353889,33353891,33353893,33353895,33353897,33353899,33353901,33353903,33353905,33353907,33353909,33353911,33353933,33353935,33353937,33353939,33353941,33353943,33353945,33353947,33353949,33353951,33353953,33353955,33353957,33353959,33353961,33353963,33353965,33353967,33353969,33353971,33353993,33353995,33353997,33353999,33354001,33354003,33354005,33354007,33354009,33354011,33354013,33354015,33354017,33354019,33354021,33354023,33354025,33354027,33354029,33354031,33354107,110347429,119625719,119625720,119625721,119625722,119625723,194380096,209572775,340343125,2194521894,2217397235,2217397237,2217397239,2217397241,2217397243,2217397245,2462631853,2462631855,2462631857,2462631859,2462631861,2462631863" 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/Q93074" 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=9968" 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=ENSG00000184634;t=ENST00000374080" 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=MED12" 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=MED12" 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+9968" 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/MED12" 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:9968" 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/9968" 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=chrX&hgg_gene=ENST00000374080.8&hgg_start=71118596&hgg_end=71142450&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:11957" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11957" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/med12" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300188[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=300188[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/MED12/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000184634" 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=MED12" 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=MED12" 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=MED12" 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="http://www.LOVD.nl/MED12" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MED12&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/PA36645" 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:11957" 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/FBgn0001324.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:1926212" 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/MED12#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:1926212" 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/9968/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=9968" 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=WBGene00001081;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-060125-1" 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">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:9968" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=MED12&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> 422437002, 49984004, 699297004, 720636001<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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300188
|
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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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MEDIATOR COMPLEX SUBUNIT 12; MED12
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
MEDIATOR OF RNA POLYMERASE II TRANSCRIPTION, SUBUNIT 12, S. CEREVISIAE, HOMOLOG OF<br />
|
|
TRINUCLEOTIDE REPEAT-CONTAINING GENE 11; TNRC11<br />
|
|
THYROID HORMONE RECEPTOR-ASSOCIATED PROTEIN, 230-KD SUBUNIT; TRAP230<br />
|
|
HUMAN OPPOSITE PAIRED GENE; HOPA<br />
|
|
KIAA0192
|
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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=MED12" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MED12</a></em></strong>
|
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/X/404?start=-3&limit=10&highlight=404">Xq13.1</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:71118596-71142450&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'})">X:71,118,596-71,142,450</a> </span>
|
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</em>
|
|
</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>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=301068,309520,300895,305450" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/404?start=-3&limit=10&highlight=404">
|
|
Xq13.1
|
|
</a>
|
|
</span>
|
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</td>
|
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|
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<td>
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PheneGene Graphics <span class="caret"></span>
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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>Mediator is a multiprotein complex that can function in transcriptional activation or repression depending on the factors with which it interacts. The Mediator subunit MED12 has roles in both transcriptional activation and repression (<a href="#4" class="mim-tip-reference" title="Ding, N., Zhou, H., Esteve, P.-O., Chin, H. G., Kim, S., Xu, X., Joseph, S. M., Friez, M. J., Schwartz, C. E., Pradhan, S., Boyer, T. G. <strong>Mediator links epigenetic silencing of neuronal gene expression with X-linked mental retardation.</strong> Molec. Cell 31: 347-359, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18691967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18691967</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18691967[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.molcel.2008.05.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18691967">Ding et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18691967" 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="#16" class="mim-tip-reference" title="Nagase, T., Seki, N., Ishikawa, K., Tanaka, A., Nomura, N. <strong>Prediction of the coding sequences of unidentified human genes. V. The coding sequences of 40 new genes (KIAA0161-KIAA0200) deduced by analysis of cDNA clones from human cell line KG-1.</strong> DNA Res. 3: 17-24, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8724849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8724849</a>] [<a href="https://doi.org/10.1093/dnares/3.1.17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8724849">Nagase et al. (1996)</a> cloned a cDNA, which they referred to as KIAA0192, from the human cell line KG-1. They found that the cDNA contains stretches of CAG (gln) repeats and encodes a 2,124-amino acid protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8724849" 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 a HeLa cell line, <a href="#9" class="mim-tip-reference" title="Ito, M., Yuan, C.-X., Malik, S., Gu, W., Fondell, J. D., Yamamura, S., Fu, Z.-Y., Zhang, X., Qin, J., Roeder, R. G. <strong>Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators.</strong> Molec. Cell 3: 361-370, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10198638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10198638</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80463-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10198638">Ito et al. (1999)</a> cloned the same gene, TRAP230, which encodes the 230-kD subunit of the thyroid hormone receptor-associated protein (TRAP) complex (see <a href="/entry/300182">300182</a>). The sequence of the TRAP230 protein was found in 2 other reports of partial sequences: CAG H45 (<a href="#15" class="mim-tip-reference" title="Margolis, R. L., Abraham, M. R., Gatchell, S. B., Li, S. H., Kidwai, A. S., Breschel, T. S., Stine, O. C., Callahan, C., McInnis, M. G., Ross, C. A. <strong>cDNAs with long CAG trinucleotide repeats from human brain.</strong> Hum. Genet. 100: 114-122, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9225980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9225980</a>] [<a href="https://doi.org/10.1007/s004390050476" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9225980">Margolis et al., 1997</a>), and an opposite paired (OPA)-containing protein called HOPA by <a href="#17" class="mim-tip-reference" title="Philibert, R. A., King, B. H., Winfield, S., Cook, E. H., Lee, Y.-H., Stubblefield, B., Damschroder-Williams, P., Dea, C., Palotie, A., Tengstrom, C., Martin, B. M., Ginns, E. I. <strong>Association of an X-chromosome dodecamer insertional variant allele with mental retardation.</strong> Molec. Psychiat. 3: 303-309, 1998. Note: Erratum: Molec. Psychiat. 4: 197 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9702738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9702738</a>] [<a href="https://doi.org/10.1038/sj.mp.4000442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9702738">Philibert et al. (1998)</a> located on chromosome Xq13. TRAP230 also contains 2 overlapping ligand-dependent nuclear hormone receptor signature recognition motifs (LxxLL motifs) near the N terminus and a highly glutamine-rich C-terminal region that results from the CAG trinucleotide repeats. Sequence comparisons revealed that TRAP230 also has significant homology with a hypothetical C. elegans protein (CEF47A4). This protein has a regional identity of 23% and similarity of 40% with TRAP230 and also possesses a characteristic glutamine-rich sequence near the C terminus. Northern blot analysis of multiple human tissues showed that the TRAP230 gene is ubiquitously expressed as an approximately 7.6-kb transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9702738+9225980+10198638" 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 Northern blot analysis of the HOPA gene transcript and its murine ortholog, Mopa1, <a href="#18" class="mim-tip-reference" title="Philibert, R. A., Winfield, S. L., Damschroder-Williams, P., Tengstrom, C., Martin, B. M., Ginns, E. I. <strong>The genomic structure and developmental expression patterns of the human OPA-containing gene (HOPA).</strong> Hum. Genet. 105: 174-178, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10480376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10480376</a>] [<a href="https://doi.org/10.1007/s004399900084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10480376">Philibert et al. (1999)</a> demonstrated that only 1 transcript is expressed throughout the central nervous system and other tissues, and that the transcript is highly expressed during early fetal development. The presence of an OPA (opposite paired) element strongly suggested that HOPA is under tissue- or developmental-specific control (<a href="#7" class="mim-tip-reference" title="Grabowski, D. T., Carney, J. P., Kelley, M. R. <strong>An adult male specific gene in Drosophila containing the repetitive element opa.</strong> Biochim. Biophys. Acta 1090: 115-118, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1883837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1883837</a>] [<a href="https://doi.org/10.1016/0167-4781(91)90045-n" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1883837">Grabowski et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10480376+1883837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#18" class="mim-tip-reference" title="Philibert, R. A., Winfield, S. L., Damschroder-Williams, P., Tengstrom, C., Martin, B. M., Ginns, E. I. <strong>The genomic structure and developmental expression patterns of the human OPA-containing gene (HOPA).</strong> Hum. Genet. 105: 174-178, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10480376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10480376</a>] [<a href="https://doi.org/10.1007/s004399900084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10480376">Philibert et al. (1999)</a> sequenced the HOPA gene and found that spans 25 kb and contains 44 exons. A promoter scan analysis demonstrated 2 possible transcription initiation sites without TATA boxes upstream from the putative translation initiation start site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10480376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Risheg, H., Graham, J. M., Jr., Clark, R. D., Rogers, R. C., Opitz, J. M., Moeschler, J. B., Peiffer, A. P., May, M., Joseph, S. M., Jones, J. R., Stevenson, R. E., Schwartz, C. E., Friez, M. J. <strong>A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome.</strong> Nature Genet. 39: 451-453, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17334363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17334363</a>] [<a href="https://doi.org/10.1038/ng1992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17334363">Risheg et al. (2007)</a> stated that the MED12 gene contains 45 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17334363" 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 use of human/rodent hybrid cell lines, <a href="#16" class="mim-tip-reference" title="Nagase, T., Seki, N., Ishikawa, K., Tanaka, A., Nomura, N. <strong>Prediction of the coding sequences of unidentified human genes. V. The coding sequences of 40 new genes (KIAA0161-KIAA0200) deduced by analysis of cDNA clones from human cell line KG-1.</strong> DNA Res. 3: 17-24, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8724849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8724849</a>] [<a href="https://doi.org/10.1093/dnares/3.1.17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8724849">Nagase et al. (1996)</a> mapped the MED12 gene to the X chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8724849" 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 yeast 2-hybrid analysis of a human embryo cDNA expression library, <a href="#28" class="mim-tip-reference" title="Zhou, R., Bonneaud, N., Yuan, C.-X., de Santa Barbara, P., Boizet, B., Schomber, T., Scherer, G., Roeder, R. G., Poulat, F., Berta, P. <strong>SOX9 interacts with a component of the human thyroid hormone receptor-associated protein complex.</strong> Nucleic Acids Res. 30: 3245-3252, 2002. Note: Erratum: Nucleic Acids Res. 30: 3917 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12136106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12136106</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12136106[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/nar/gkf443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12136106">Zhou et al. (2002)</a> found that the transcription activation domain of SOX9 (<a href="/entry/608160">608160</a>) interacted with the proline-, glutamine-, and leucine-rich (PQL) domain of TRAP230. In vitro and in vivo assays confirmed that the proteins interact endogenously and associate with several other TRAP complex proteins in HeLa cell nuclear lysates. SOX9 and TRAP230 colocalized in nuclei of cultured human embryo chondrocytes. The isolated PQL domain of TRAP230 acted as a dominant-negative inhibitor of SOX9 activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12136106" 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>p21 (CDKN1A; <a href="/entry/116899">116899</a>) is a key mediator of p53 (TP53; <a href="/entry/191170">191170</a>)-dependent cell cycle arrest. <a href="#5" class="mim-tip-reference" title="Donner, A. J., Szostek, S., Hoover, J. M., Espinosa, J. M. <strong>CDK8 is a stimulus-specific positive coregulator of p53 target genes.</strong> Molec. Cell 27: 121-133, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17612495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17612495</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17612495[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.molcel.2007.05.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17612495">Donner et al. (2007)</a> found that transcriptional activity of the p21 promoter in human cell lines varied in response to distinct p53-activating stimuli. Core Mediator subunits MED1 (PPARBP; <a href="/entry/604311">604311</a>) and MED17 (<a href="/entry/603810">603810</a>) were recruited to the p21 gene regardless of the p53-activating stimuli used. In contrast, 3 subunits of the CDK module of Mediator, CDK8 (<a href="/entry/603184">603184</a>), MED12, and cyclin C (CCNC; <a href="/entry/123838">123838</a>), were recruited following treatment with nutlin-3, a nongenotoxic drug that activates p53, but not in response to DNA damage induced by ultraviolet light C. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17612495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Ding, N., Zhou, H., Esteve, P.-O., Chin, H. G., Kim, S., Xu, X., Joseph, S. M., Friez, M. J., Schwartz, C. E., Pradhan, S., Boyer, T. G. <strong>Mediator links epigenetic silencing of neuronal gene expression with X-linked mental retardation.</strong> Molec. Cell 31: 347-359, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18691967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18691967</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18691967[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.molcel.2008.05.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18691967">Ding et al. (2008)</a> showed that MED12 was required for transcriptional repression of a subset of neuron-specific genes in human nonneuronal cell lines, and that this repression was independent of CDK8 and CYCC. Yeast 2-hybrid analysis showed that the C-terminal domain of MED12 interacted directly with the H3K9 histone methyltransferase G9A (EHMT2; <a href="/entry/604599">604599</a>). Mutation analysis revealed that the pro-glu-leu (PQL) domain of MED12 interacted with an ankyrin-repeat domain on G9A and, more weakly, with a cys-rich domain on G9A. Purified HeLa cell Mediator complexes that included MED12 interacted directly with G9A and REST (<a href="/entry/600571">600571</a>), a gene repressor that functions through repressor element-1 (RE1). Endogenous REST in HEK293 cells suppressed expression of a reporter gene bearing RE1 sites, and knockdown of either MED12 or G9A abrogated the suppression. Depletion of MED12 significantly reduced the association of G9A with RE1 elements and decreased the level of H3K9 dimethylation by G9A without influencing RE1 site occupancy by REST. Both the MED12 arg961-to-trp (R961W; <a href="#0001">300188.0001</a>) mutation associated with Opitz-Kaveggia syndrome (<a href="/entry/305450">305450</a>) and the MED12 asn1007-to-ser (N1007S; <a href="#0002">300188.0002</a>) mutation associated with Lujan-Fryns syndrome (<a href="/entry/309520">309520</a>) compromised recruitment of Mediator to RE1 elements and selectively interfered with repression of REST target genes. <a href="#4" class="mim-tip-reference" title="Ding, N., Zhou, H., Esteve, P.-O., Chin, H. G., Kim, S., Xu, X., Joseph, S. M., Friez, M. J., Schwartz, C. E., Pradhan, S., Boyer, T. G. <strong>Mediator links epigenetic silencing of neuronal gene expression with X-linked mental retardation.</strong> Molec. Cell 31: 347-359, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18691967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18691967</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18691967[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.molcel.2008.05.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18691967">Ding et al. (2008)</a> concluded that MED12 within the Mediator complex links REST with G9A in epigenetic silencing of neuronal genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18691967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>A class of long noncoding RNAs (lncRNAs) termed noncoding RNA-activating (ncRNA-a) functions to activate their neighboring genes using a cis-mediated mechanism. <a href="#10" class="mim-tip-reference" title="Lai, F., Orom, U. A., Cesaroni, M., Beringer, M., Taatjes, D. J., Blobel, G. A., Shiekhattar, R. <strong>Activating RNAs associate with Mediator to enhance chromatin architecture and transcription.</strong> Nature 494: 497-501, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23417068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23417068</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23417068[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/nature11884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23417068">Lai et al. (2013)</a> reported that the depletion of the components of the coactivator complex, Mediator, specifically and potently diminished the noncoding RNA-induced activation of transcription in a heterologous reporter assay using human HEK293 cells. In vivo, Mediator is recruited to ncRNA-a target genes and regulates their expression. <a href="#10" class="mim-tip-reference" title="Lai, F., Orom, U. A., Cesaroni, M., Beringer, M., Taatjes, D. J., Blobel, G. A., Shiekhattar, R. <strong>Activating RNAs associate with Mediator to enhance chromatin architecture and transcription.</strong> Nature 494: 497-501, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23417068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23417068</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23417068[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/nature11884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23417068">Lai et al. (2013)</a> showed that ncRNA-a interact with Mediator to regulate its chromatin localization and kinase activity towards histone H3 serine-10. The Mediator complex harboring disease-causing MED12 mutations displayed diminished ability to associate with activating ncRNAs. Chromosome conformation capture confirmed the presence of DNA looping between the ncRNA-a loci and its targets. Importantly, depletion of Mediator subunits or ncRNA-a reduced the chromatin looping between the 2 loci. <a href="#10" class="mim-tip-reference" title="Lai, F., Orom, U. A., Cesaroni, M., Beringer, M., Taatjes, D. J., Blobel, G. A., Shiekhattar, R. <strong>Activating RNAs associate with Mediator to enhance chromatin architecture and transcription.</strong> Nature 494: 497-501, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23417068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23417068</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23417068[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/nature11884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23417068">Lai et al. (2013)</a> concluded that their results identified the human Mediator complex as the transducer of activating ncRNAs and highlighted the importance of Mediator and activating ncRNA association in human disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23417068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Opitz-Kaveggia Syndrome</em></strong></p><p>
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Opitz-Kaveggia syndrome (<a href="/entry/305450">305450</a>), also known as FG syndrome, is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia, and constipation. <a href="#21" class="mim-tip-reference" title="Risheg, H., Graham, J. M., Jr., Clark, R. D., Rogers, R. C., Opitz, J. M., Moeschler, J. B., Peiffer, A. P., May, M., Joseph, S. M., Jones, J. R., Stevenson, R. E., Schwartz, C. E., Friez, M. J. <strong>A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome.</strong> Nature Genet. 39: 451-453, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17334363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17334363</a>] [<a href="https://doi.org/10.1038/ng1992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17334363">Risheg et al. (2007)</a> reported that the original family from which the designation FG was derived and 5 other families had a recurrent mutation in the MED12 gene, 2881C-T (R961W; <a href="#0001">300188.0001</a>). MED12 was considered a candidate gene because of its mapping to Xq13 and because it encodes a thyroid hormone receptor-associated protein (TRAP). <a href="#21" class="mim-tip-reference" title="Risheg, H., Graham, J. M., Jr., Clark, R. D., Rogers, R. C., Opitz, J. M., Moeschler, J. B., Peiffer, A. P., May, M., Joseph, S. M., Jones, J. R., Stevenson, R. E., Schwartz, C. E., Friez, M. J. <strong>A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome.</strong> Nature Genet. 39: 451-453, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17334363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17334363</a>] [<a href="https://doi.org/10.1038/ng1992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17334363">Risheg et al. (2007)</a> sequenced the 45 exons of MED12 in 24 index cases from XLMR families with linkage to Xq13. Two of the 24 index cases had the identical R961W missense mutation. In both of these individuals, the diagnosis of Opitz-Kaveggia syndrome had been made a priori. In all affected males who survived long enough for mental or cognitive assessment, mental retardation was present. Partial or complete absence of the corpus callosum was noted in all 6 cases in which brain imaging was available. High, prominent forehead and small, low-set, simple ears were the most consistent craniofacial manifestations. Imperforate anus, wide flat thumbs, and wide great toes were present in 7 of 10 cases. Cryptorchidism, inguinal hernia, cardiac defects, and short stature were noted in fewer than half of affected males. <a href="#21" class="mim-tip-reference" title="Risheg, H., Graham, J. M., Jr., Clark, R. D., Rogers, R. C., Opitz, J. M., Moeschler, J. B., Peiffer, A. P., May, M., Joseph, S. M., Jones, J. R., Stevenson, R. E., Schwartz, C. E., Friez, M. J. <strong>A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome.</strong> Nature Genet. 39: 451-453, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17334363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17334363</a>] [<a href="https://doi.org/10.1038/ng1992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17334363">Risheg et al. (2007)</a> proposed that the Opitz-Kaveggia syndrome designation be reserved for those individuals with MED12 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17334363" 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>Intellectual Developmental Disorder, X-linked, Syndromic, Lujan-Fryns Type</em></strong></p><p>
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In 4 affected members of a family with Lujan-Fryns syndrome (MRXSLF; <a href="/entry/309520">309520</a>) originally reported by <a href="#12" class="mim-tip-reference" title="Lujan, J. E., Carlin, M. E., Lubs, H. A. <strong>A form of X-linked mental retardation with marfanoid habitus.</strong> Am. J. Med. Genet. 17: 311-322, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6711603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6711603</a>] [<a href="https://doi.org/10.1002/ajmg.1320170124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6711603">Lujan et al. (1984)</a>, <a href="#24" class="mim-tip-reference" title="Schwartz, C. E., Tarpey, P. S., Lubs, H. A., Verloes, A., May, M. M., Risheg, H., Friez, M. J., Futreal, P. A., Edkins, S., Teague, J., Briault, S., Skinner, C., Bauer-Carlin, A., Simensen, R. J., Joseph, S. M., Jones, J. R., Gecz, J., Stratton, M. R., Raymond, F. L., Stevenson, R. E. <strong>The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. (Letter)</strong> J. Med. Genet. 44: 472-477, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17369503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17369503</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17369503[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/10.1136/jmg.2006.048637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17369503">Schwartz et al. (2007)</a> identified a mutation in the MED12 gene (<a href="#0002">300188.0002</a>). The same mutation was found in affected members of an unrelated family. The findings indicated that Lujan-Fryns syndrome and Opitz-Kaveggia syndrome are allelic disorders. Clinically, Lujan-Fryns syndrome could be distinguished by tall stature, hypernasal voice, hyperextensible digits, and high nasal root. <a href="#24" class="mim-tip-reference" title="Schwartz, C. E., Tarpey, P. S., Lubs, H. A., Verloes, A., May, M. M., Risheg, H., Friez, M. J., Futreal, P. A., Edkins, S., Teague, J., Briault, S., Skinner, C., Bauer-Carlin, A., Simensen, R. J., Joseph, S. M., Jones, J. R., Gecz, J., Stratton, M. R., Raymond, F. L., Stevenson, R. E. <strong>The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. (Letter)</strong> J. Med. Genet. 44: 472-477, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17369503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17369503</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17369503[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/10.1136/jmg.2006.048637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17369503">Schwartz et al. (2007)</a> suggested that the Lujan-Fryns syndrome designation be used only for those cases with a compatible clinical phenotype and mutations in the MED12 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17369503+6711603" 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>Ohdo Syndrome, X-Linked</em></strong></p><p>
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<a href="#26" class="mim-tip-reference" title="Vulto-van Silfhout, A. T., de Vries, B. B. A., van Bon, B. W. M., Hoischen, A., Ruiterkamp-Versteeg, M., Gilissen, C., Gao, F., van Zwam, M., Harteveld, C. L., van Essen, A. J., Hamel, B. C. J., Kleefstra, T., Willemsen, M. A. A. P., Yntema, H. G., van Bokhoven, H., Brunner, H. G., Boyer, T. G., de Brouwer, A. P. M. <strong>Mutations in MED12 cause X-linked Ohdo syndrome.</strong> Am. J. Hum. Genet. 92: 401-406, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23395478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23395478</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23395478[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.2013.01.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23395478">Vulto-van Silfhout et al. (2013)</a> performed exome sequencing in 2 families segregating X-linked Ohdo syndrome (OHDOX; <a href="/entry/300895">300895</a>), including the family originally studied by <a href="#13" class="mim-tip-reference" title="Maat-Kievit, A., Brunner, H. G., Maaswinkel-Mooij, P. <strong>Two additional cases of the Ohdo blepharophimosis syndrome.</strong> Am. J. Med. Genet. 47: 901-906, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8279489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8279489</a>] [<a href="https://doi.org/10.1002/ajmg.1320470618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8279489">Maat-Kievit et al. (1993)</a> and another family with 2 affected males, and identified hemizygous missense mutations in the MED12 gene (R1148H, <a href="#0003">300188.0003</a> and S1165P, <a href="#0004">300188.0004</a>) that segregated with the disorder in each family. By analysis of an additional cohort of 9 simplex male patients with Ohdo syndrome, they identified another MED12 missense mutation (H1729N; <a href="#0005">300188.0005</a>) in 1 patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23395478+8279489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Vulto-van Silfhout, A. T., de Vries, B. B. A., van Bon, B. W. M., Hoischen, A., Ruiterkamp-Versteeg, M., Gilissen, C., Gao, F., van Zwam, M., Harteveld, C. L., van Essen, A. J., Hamel, B. C. J., Kleefstra, T., Willemsen, M. A. A. P., Yntema, H. G., van Bokhoven, H., Brunner, H. G., Boyer, T. G., de Brouwer, A. P. M. <strong>Mutations in MED12 cause X-linked Ohdo syndrome.</strong> Am. J. Hum. Genet. 92: 401-406, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23395478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23395478</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23395478[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.2013.01.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23395478">Vulto-van Silfhout et al. (2013)</a> comparatively examined siRNA-resistant wildtype FLAG-tagged MED12 (FLAG-MED12) and its corresponding R1148H and S1165P mutant derivatives for their respective abilities to suppress enhanced REST target gene expression triggered by RNAi-mediated depletion of endogenous MED12 in HEK293 cells. MED12 knockdown triggered derepression of REST target genes, including CHRM4 (<a href="/entry/118495">118495</a>), SNAP25 (<a href="/entry/600322">600322</a>), and SYN1 (<a href="/entry/313440">313440</a>). Introduction of wildtype FLAG-MED12 in these cells reversed this effect; in contrast, the R1148H and S1165P mutants were significantly compromised in this ability. <a href="#26" class="mim-tip-reference" title="Vulto-van Silfhout, A. T., de Vries, B. B. A., van Bon, B. W. M., Hoischen, A., Ruiterkamp-Versteeg, M., Gilissen, C., Gao, F., van Zwam, M., Harteveld, C. L., van Essen, A. J., Hamel, B. C. J., Kleefstra, T., Willemsen, M. A. A. P., Yntema, H. G., van Bokhoven, H., Brunner, H. G., Boyer, T. G., de Brouwer, A. P. M. <strong>Mutations in MED12 cause X-linked Ohdo syndrome.</strong> Am. J. Hum. Genet. 92: 401-406, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23395478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23395478</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23395478[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.2013.01.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23395478">Vulto-van Silfhout et al. (2013)</a> also showed that neither amino acid change deleteriously affected the incorporation of MED12 into Mediator or its direct interaction with G9A, indicating that the MED12 mutations in Ohdo syndrome do not disrupt the function of MED12 as a stable G9A interface in Mediator. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23395478" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 brothers of Moldavian descent with Ohdo syndrome, <a href="#22" class="mim-tip-reference" title="Rubin, Z., Grange, D. K., Cooper, M. A. <strong>Siblings with a novel MED12 variant and Odho (sic) syndrome with immune defects. (Letter)</strong> Clin. Genet. 98: 308-310, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32715471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32715471</a>] [<a href="https://doi.org/10.1111/cge.13806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32715471">Rubin et al. (2020)</a> identified a hemizygous mutation in the MED12 gene (Q2159P; <a href="#0006">300188.0006</a>). The mutation was identified by whole-exome sequencing. The unaffected mother was heterozygous for the mutation. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32715471" 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>Hardikar Syndrome</em></strong></p><p>
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In 7 unrelated females with Hardikar syndrome (HDKR; <a href="/entry/301068">301068</a>), <a href="#11" class="mim-tip-reference" title="Li, D., Strong, A., Shen, K. M., Cassiman, D., Van Dyck, M., Linhares, N. D., Valadares, E. R., Wang, T., Pena, S. D. J., Jaeken, J., Vergano, S., Zackai, E., Hing, A., Chow, P., Ganguly, A., Scholz, T., Bierhals, T., Philipp, D., Hakonarson, H., Bhoj, E. <strong>De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.</strong> Genet. Med. 23: 637-644, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33244166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33244166</a>] [<a href="https://doi.org/10.1038/s41436-020-01031-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33244166">Li et al. (2021)</a> identified heterozygous nonsense or frameshift mutations in the MED12 gene (see, e.g., <a href="#0007">300188.0007</a>-<a href="#0009">300188.0009</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, occurred throughout the gene. All were predicted to lead to nonsense-mediated mRNA decay, resulting in haploinsufficiency. All of the mutations either occurred de novo or were presumed de novo. Functional studies of the variants were not performed. Patient cells showed skewed X inactivation. <a href="#11" class="mim-tip-reference" title="Li, D., Strong, A., Shen, K. M., Cassiman, D., Van Dyck, M., Linhares, N. D., Valadares, E. R., Wang, T., Pena, S. D. J., Jaeken, J., Vergano, S., Zackai, E., Hing, A., Chow, P., Ganguly, A., Scholz, T., Bierhals, T., Philipp, D., Hakonarson, H., Bhoj, E. <strong>De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.</strong> Genet. Med. 23: 637-644, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33244166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33244166</a>] [<a href="https://doi.org/10.1038/s41436-020-01031-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33244166">Li et al. (2021)</a> postulated that complete loss of MED12 may be lethal in males. The authors noted that the HDKR phenotype is unique in that neurodevelopment is preserved and that the manifestations include distinct structural abnormalities affecting several organ systems. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33244166" 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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Susceptibility to Impaired Intellectual Development</p><p><a href="#17" class="mim-tip-reference" title="Philibert, R. A., King, B. H., Winfield, S., Cook, E. H., Lee, Y.-H., Stubblefield, B., Damschroder-Williams, P., Dea, C., Palotie, A., Tengstrom, C., Martin, B. M., Ginns, E. I. <strong>Association of an X-chromosome dodecamer insertional variant allele with mental retardation.</strong> Molec. Psychiat. 3: 303-309, 1998. Note: Erratum: Molec. Psychiat. 4: 197 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9702738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9702738</a>] [<a href="https://doi.org/10.1038/sj.mp.4000442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9702738">Philibert et al. (1998)</a> reported a strong association of a variant polymorphism, a 12-bp duplication (CAGCAACACCAG), in the HOPA gene with an X-linked mental retardation/hypothyroidism syndrome in several independent cohorts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9702738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Friez, M. J., Essop, F. B., Krause, A., Castiglia, L., Ragusa, A., Sossey-Alaoui, K., Nelson, R. L., May, M. M., Michaelis, R. C., Srivastava, A. K., Schwartz, C. E., Stevenson, R. E., Goldman, A., Villard, L., Longshore, J. W. <strong>Evidence that a dodecamer duplication in the gene HOPA in Xq13 is not associated with mental retardation.</strong> Hum. Genet. 106: 36-39, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10982179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10982179</a>] [<a href="https://doi.org/10.1007/s004390051006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10982179">Friez et al. (2000)</a> concluded that the 12-bp duplication in the HOPA gene is not associated with mental retardation. They determined the incidence of the dodecamer duplication in cohorts of non-fragile X males with mental retardation from 3 countries, cohorts of fragile X males from 2 countries, 43 probands from families with X-linked mental retardation, and control cohorts from 3 countries. The duplication was found in 3.6 to 4.0% of male patients from 2 non-fragile X groups, in 1.2% from another non-fragile X group, but in no male patients from families with X-linked mental retardation. The dodecamer duplication was also found in several white males with fragile X syndrome from France (5%) and South Africa (22.2%). Additionally, the duplication was found in 1.5% of South Carolinian newborn males, 2.5% of South Carolinian male college students, 5% of Italian male controls, and 4.5% of white South African controls. The duplication appeared to be rare in the black South African population. The incidence of the duplication was not significantly different between any of the groups in the study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10982179" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>A study by <a href="#2" class="mim-tip-reference" title="Beyer, K. S., Klauck, S. M., Benner, A., Poustka, F., Poustka, A. <strong>Association studies of the HOPA dodecamer duplication variant in different subtypes of autism.</strong> Am. J. Med. Genet. 114: 110-115, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11840515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11840515</a>] [<a href="https://doi.org/10.1002/ajmg.1613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11840515">Beyer et al. (2002)</a> also failed to sustain the hypothesis that the HOPA gene is a significant susceptibility factor for infantile autism and mental retardation. The 12-bp duplication in the HOPA gene appeared to function as a benign polymorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11840515" 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>Uterine Leiomyoma</p><p><a href="#14" class="mim-tip-reference" title="Makinen, N., Mehine, M., Tolvanen, J., Kaasinen, E., Li, Y., Lehtonen, H. J., Gentile, M., Yan, J., Enge, M., Taipale, M., Aavikko, M., Katainen, R., Virolainen, E., Bohling, T., Koski, T. A., Launonen, V., Sjoberg, J., Taipale, J., Vahteristo, P., Aaltonen, L. A. <strong>MED12, the Mediator Complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas.</strong> Science 334: 252-255, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21868628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21868628</a>] [<a href="https://doi.org/10.1126/science.1208930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21868628">Makinen et al. (2011)</a> performed whole-exome sequencing on 18 uterine leiomyomas derived from 17 different patients and identified tumor-specific mutations in the MED12 gene in 10. Analysis of 207 additional tumors identified MED12 mutations in 70% (159/225) of tumors from a total of 80 patients. The Mediator complex is a 26-subunit transcriptional regulator that bridges DNA regulatory sequences to the RNA polymerase II initiation complex. All mutations identified by <a href="#14" class="mim-tip-reference" title="Makinen, N., Mehine, M., Tolvanen, J., Kaasinen, E., Li, Y., Lehtonen, H. J., Gentile, M., Yan, J., Enge, M., Taipale, M., Aavikko, M., Katainen, R., Virolainen, E., Bohling, T., Koski, T. A., Launonen, V., Sjoberg, J., Taipale, J., Vahteristo, P., Aaltonen, L. A. <strong>MED12, the Mediator Complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas.</strong> Science 334: 252-255, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21868628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21868628</a>] [<a href="https://doi.org/10.1126/science.1208930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21868628">Makinen et al. (2011)</a> resided in exon 2, suggesting that aberrant function of this region of MED12 contributes to tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21868628" 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>Prostate Cancer</p><p><a href="#1" class="mim-tip-reference" title="Barbieri, C. E., Baca, S. C., Lawrence, M. S., Demichelis, F., Blattner, M., Theurillat, J.-P., White, T. A., Stojanov, P., Van Allen, E., Stransky, N., Nickerson, E., Chae, S.-S., and 34 others. <strong>Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer.</strong> Nature Genet. 44: 685-689, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22610119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22610119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22610119[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/ng.2279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22610119">Barbieri et al. (2012)</a> sequenced the exomes of 112 prostate tumor (see <a href="/entry/176807">176807</a>) and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1 (<a href="/entry/602294">602294</a>). SPOP (<a href="/entry/602650">602650</a>) was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6 to 15% of tumors across multiple independent cohorts. Prostate tumors with mutant SPOP lacked ETS family (see <a href="/entry/164720">164720</a>) gene rearrangements and showed a distinct pattern of genomic alterations. <a href="#1" class="mim-tip-reference" title="Barbieri, C. E., Baca, S. C., Lawrence, M. S., Demichelis, F., Blattner, M., Theurillat, J.-P., White, T. A., Stojanov, P., Van Allen, E., Stransky, N., Nickerson, E., Chae, S.-S., and 34 others. <strong>Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer.</strong> Nature Genet. 44: 685-689, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22610119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22610119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22610119[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/ng.2279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22610119">Barbieri et al. (2012)</a> concluded that SPOP mutations may define a novel molecular subtype of prostate cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22610119" 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="#8" class="mim-tip-reference" title="Hong, S.-K., Haldin, C. E., Lawson, N. D., Weinstein, B. M., Dawid, I. B., Hukriede, N. A. <strong>The zebrafish kohtalo/trap230 gene is required for the development of the brain, neural crest, and pronephric kidney.</strong> Proc. Nat. Acad. Sci. 102: 18473-18478, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16344459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16344459</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16344459[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0509457102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16344459">Hong et al. (2005)</a> showed that med12-deficient zebrafish embryos showed defects in brain, neural crest, and kidney development and do not survive beyond 1 week after fertilization. <a href="#20" class="mim-tip-reference" title="Rau, M. J., Fischer, S., Neumann, C. J. <strong>Zebrafish Trap230/Med12 is required as a coactivator for Sox9-dependent neural crest, cartilage and ear development.</strong> Dev. Biol. 296: 83-93, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16712834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16712834</a>] [<a href="https://doi.org/10.1016/j.ydbio.2006.04.437" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16712834">Rau et al. (2006)</a> showed, also in zebrafish, that med12 is required as a coactivator of Sox9 (<a href="/entry/608160">608160</a>)-dependent neural crest, cartilage, and ear development. Mutations in med12 are responsible for the zebrafish mutant 'motionless' (mot), and med12 transcripts are enriched in brain, where the gene is responsible for regulating the expression of other neuronal determination genes (<a href="#27" class="mim-tip-reference" title="Wang, X., Yang, N., Uno, E., Roeder, R. G., Guo, S. <strong>A subunit of the mediator complex regulates vertebrate neuronal development.</strong> Proc. Nat. Acad. Sci. 103: 17284-17289, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17088561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17088561</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17088561[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0605414103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17088561">Wang et al., 2006</a>). These and other studies suggested that a variety of signaling pathways interact with MED12. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16712834+16344459+17088561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>9 Selected Examples</a>):</strong>
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<a href="/allelicVariants/300188" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300188[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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<strong>.0001 OPITZ-KAVEGGIA SYNDROME</strong>
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MED12, ARG961TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338758 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338758;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=rs80338758" 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=rs80338758" 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=RCV000012276 OR RCV000415294 OR RCV000763632 OR RCV001261368 OR RCV001330015 OR RCV001528259 OR RCV003764560 OR RCV004018614" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012276, RCV000415294, RCV000763632, RCV001261368, RCV001330015, RCV001528259, RCV003764560, RCV004018614" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012276...</a>
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<p>In the original family with what was designated the FG syndrome (<a href="/entry/305450">305450</a>) after the family initials, <a href="#21" class="mim-tip-reference" title="Risheg, H., Graham, J. M., Jr., Clark, R. D., Rogers, R. C., Opitz, J. M., Moeschler, J. B., Peiffer, A. P., May, M., Joseph, S. M., Jones, J. R., Stevenson, R. E., Schwartz, C. E., Friez, M. J. <strong>A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome.</strong> Nature Genet. 39: 451-453, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17334363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17334363</a>] [<a href="https://doi.org/10.1038/ng1992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17334363">Risheg et al. (2007)</a> found a 2881C-T transition in exon 21 of the MED12 gene that caused an arg961-to-trp amino acid substitution (R961W). They also found the same mutation in 5 other families. Failure to find the change in 451 normal men and in 343 consecutive newborn males suggested that it is not a rare polymorphic variant. The finding of the mutation in patients of various ethnic backgrounds suggested that families did not share a common ancestor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17334363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Ding, N., Zhou, H., Esteve, P.-O., Chin, H. G., Kim, S., Xu, X., Joseph, S. M., Friez, M. J., Schwartz, C. E., Pradhan, S., Boyer, T. G. <strong>Mediator links epigenetic silencing of neuronal gene expression with X-linked mental retardation.</strong> Molec. Cell 31: 347-359, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18691967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18691967</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18691967[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.molcel.2008.05.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18691967">Ding et al. (2008)</a> showed that both the R961W mutation associated with Opitz-Kaveggia syndrome and the MED12 asn1007-to-ser (N1007S; <a href="#0002">300188.0002</a>) mutation associated with Lujan-Fryns syndrome (<a href="/entry/309520">309520</a>) compromised recruitment of Mediator to RE1 elements and selectively interfered with repression of REST (<a href="/entry/600571">600571</a>) target genes. The authors noted that these mutations do not alter the ability of MED12 to support beta-catenin (see CTNNB1; <a href="/entry/116806">116806</a>) transactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18691967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, LUJAN-FRYNS TYPE</strong>
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MED12, ASN1007SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338759 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338759;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=rs80338759" 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=rs80338759" 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=RCV000012277 OR RCV001529623 OR RCV001580265 OR RCV005089235" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012277, RCV001529623, RCV001580265, RCV005089235" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012277...</a>
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<p>In 4 affected members of a family with Lujan-Fryns syndrome (MRXSLF; <a href="/entry/309520">309520</a>) originally reported by <a href="#12" class="mim-tip-reference" title="Lujan, J. E., Carlin, M. E., Lubs, H. A. <strong>A form of X-linked mental retardation with marfanoid habitus.</strong> Am. J. Med. Genet. 17: 311-322, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6711603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6711603</a>] [<a href="https://doi.org/10.1002/ajmg.1320170124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6711603">Lujan et al. (1984)</a>, <a href="#24" class="mim-tip-reference" title="Schwartz, C. E., Tarpey, P. S., Lubs, H. A., Verloes, A., May, M. M., Risheg, H., Friez, M. J., Futreal, P. A., Edkins, S., Teague, J., Briault, S., Skinner, C., Bauer-Carlin, A., Simensen, R. J., Joseph, S. M., Jones, J. R., Gecz, J., Stratton, M. R., Raymond, F. L., Stevenson, R. E. <strong>The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. (Letter)</strong> J. Med. Genet. 44: 472-477, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17369503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17369503</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17369503[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/10.1136/jmg.2006.048637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17369503">Schwartz et al. (2007)</a> identified a 3020A-G transition in exon 22 of the MED12 gene, resulting in an asn1007-to-ser (N1007S) substitution. Affected members of an unrelated family carried the same mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17369503+6711603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Ding, N., Zhou, H., Esteve, P.-O., Chin, H. G., Kim, S., Xu, X., Joseph, S. M., Friez, M. J., Schwartz, C. E., Pradhan, S., Boyer, T. G. <strong>Mediator links epigenetic silencing of neuronal gene expression with X-linked mental retardation.</strong> Molec. Cell 31: 347-359, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18691967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18691967</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18691967[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.molcel.2008.05.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18691967">Ding et al. (2008)</a> showed that both the N1007S mutation associated with Lujan-Fryns syndrome and the MED12 arg961-to-trp (R961W; <a href="#0001">300188.0001</a>) mutation associated with Opitz-Kaveggia syndrome (<a href="/entry/305450">305450</a>) compromised recruitment of Mediator to RE1 elements and selectively interfered with repression of REST (<a href="/entry/600571">600571</a>) target genes. The authors noted that these mutations do not alter the ability of MED12 to support beta-catenin (see CTNNB1; <a href="/entry/116806">116806</a>) transactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18691967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 OHDO SYNDROME, X-LINKED</strong>
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MED12, ARG1148HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387907360 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907360;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=rs387907360" 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=rs387907360" 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=RCV000043499 OR RCV001268310 OR RCV001580266 OR RCV005089401" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043499, RCV001268310, RCV001580266, RCV005089401" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043499...</a>
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<p>By exome sequencing in a family in which 2 males had Ohdo syndrome (OHDOX; <a href="/entry/300895">300895</a>), originally described by <a href="#13" class="mim-tip-reference" title="Maat-Kievit, A., Brunner, H. G., Maaswinkel-Mooij, P. <strong>Two additional cases of the Ohdo blepharophimosis syndrome.</strong> Am. J. Med. Genet. 47: 901-906, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8279489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8279489</a>] [<a href="https://doi.org/10.1002/ajmg.1320470618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8279489">Maat-Kievit et al. (1993)</a> and <a href="#25" class="mim-tip-reference" title="Verloes, A., Bremond-Gignac, D., Isidor, B., David, A., Baumann, C., Leroy, M.-A., Stevens, R., Gillerot, Y., Heron, D., Heron, B., Benzacken, B., Lacombe, D., Brunner, H., Bitoun, P. <strong>Blepharophimosis-mental retardation (BMR) syndromes: a proposed clinical classification of the so-called Ohdo syndrome, and delineation of two new BMR syndromes, one X-linked and one autosomal recessive.</strong> Am. J. Med. Genet. 140A: 1285-1296, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16700052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16700052</a>] [<a href="https://doi.org/10.1002/ajmg.a.31270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16700052">Verloes et al. (2006)</a>, <a href="#26" class="mim-tip-reference" title="Vulto-van Silfhout, A. T., de Vries, B. B. A., van Bon, B. W. M., Hoischen, A., Ruiterkamp-Versteeg, M., Gilissen, C., Gao, F., van Zwam, M., Harteveld, C. L., van Essen, A. J., Hamel, B. C. J., Kleefstra, T., Willemsen, M. A. A. P., Yntema, H. G., van Bokhoven, H., Brunner, H. G., Boyer, T. G., de Brouwer, A. P. M. <strong>Mutations in MED12 cause X-linked Ohdo syndrome.</strong> Am. J. Hum. Genet. 92: 401-406, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23395478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23395478</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23395478[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.2013.01.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23395478">Vulto-van Silfhout et al. (2013)</a> identified a hemizygous c.3443G-A transition in the MED12 gene, resulting in an arg1148-to-his (R1148H) substitution, that segregated with the phenotype. Arg1148 is a highly conserved residue, and the mutation was predicted to be damaging to protein function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16700052+23395478+8279489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 OHDO SYNDROME, X-LINKED</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">rs387907361 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907361;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=rs387907361" 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=rs387907361" 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=RCV000043500 OR RCV001580267" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043500, RCV001580267" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043500...</a>
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<p>By exome sequencing in a family in which 2 males had Ohdo syndrome (OHDOX; <a href="/entry/300895">300895</a>), <a href="#26" class="mim-tip-reference" title="Vulto-van Silfhout, A. T., de Vries, B. B. A., van Bon, B. W. M., Hoischen, A., Ruiterkamp-Versteeg, M., Gilissen, C., Gao, F., van Zwam, M., Harteveld, C. L., van Essen, A. J., Hamel, B. C. J., Kleefstra, T., Willemsen, M. A. A. P., Yntema, H. G., van Bokhoven, H., Brunner, H. G., Boyer, T. G., de Brouwer, A. P. M. <strong>Mutations in MED12 cause X-linked Ohdo syndrome.</strong> Am. J. Hum. Genet. 92: 401-406, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23395478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23395478</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23395478[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.2013.01.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23395478">Vulto-van Silfhout et al. (2013)</a> identified a hemizygous c.3493T-C transition in the MED12 gene, resulting in a ser1165-to-pro (S1165P) substitution, that segregated with the phenotype. Ser1165 is a highly conserved residue, and the mutation was predicted to be damaging to protein function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23395478" 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">rs387907362 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907362;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=rs387907362" 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=rs387907362" 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=RCV000043501 OR RCV001580268" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043501, RCV001580268" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043501...</a>
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<p><a href="#26" class="mim-tip-reference" title="Vulto-van Silfhout, A. T., de Vries, B. B. A., van Bon, B. W. M., Hoischen, A., Ruiterkamp-Versteeg, M., Gilissen, C., Gao, F., van Zwam, M., Harteveld, C. L., van Essen, A. J., Hamel, B. C. J., Kleefstra, T., Willemsen, M. A. A. P., Yntema, H. G., van Bokhoven, H., Brunner, H. G., Boyer, T. G., de Brouwer, A. P. M. <strong>Mutations in MED12 cause X-linked Ohdo syndrome.</strong> Am. J. Hum. Genet. 92: 401-406, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23395478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23395478</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23395478[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.2013.01.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23395478">Vulto-van Silfhout et al. (2013)</a> sequenced the MED12 in a cohort of 9 simplex male individuals with Ohdo syndrome (OHDOX; <a href="/entry/300895">300895</a>) and identified a hemizygous de novo c.5185C-A transversion, resulting in a his1729-to-asn (H1729N) substitution in the PQL domain. His1729 is a highly conserved residue, and the mutation was predicted to be damaging to protein function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23395478" 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">rs1085307941 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1085307941;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=rs1085307941" 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=rs1085307941" 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=RCV000488923 OR RCV001290305 OR RCV001580333" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000488923, RCV001290305, RCV001580333" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000488923...</a>
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<p>In 3 Moldavian brothers with Ohdo syndrome (OHDOX; <a href="/entry/300895">300895</a>), <a href="#22" class="mim-tip-reference" title="Rubin, Z., Grange, D. K., Cooper, M. A. <strong>Siblings with a novel MED12 variant and Odho (sic) syndrome with immune defects. (Letter)</strong> Clin. Genet. 98: 308-310, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32715471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32715471</a>] [<a href="https://doi.org/10.1111/cge.13806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32715471">Rubin et al. (2020)</a> identified a hemizygous c.6476A-C transversion in exon 44 of the MED12 gene, resulting in a gln2159-to-pro (Q2159P) substitution at a highly conserved location within the OPA (glutamine-rich) domain. The mutation was identified by whole-exome sequencing. The unaffected mother was heterozygous for the mutation. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32715471" 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">rs2147823333 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147823333;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=rs2147823333" 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=rs2147823333" 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=RCV001580323 OR RCV001796996" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001580323, RCV001796996" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001580323...</a>
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<p>In a 14-year-old girl (patient 4) with Hardikar syndrome (HDKR; <a href="/entry/301068">301068</a>), <a href="#11" class="mim-tip-reference" title="Li, D., Strong, A., Shen, K. M., Cassiman, D., Van Dyck, M., Linhares, N. D., Valadares, E. R., Wang, T., Pena, S. D. J., Jaeken, J., Vergano, S., Zackai, E., Hing, A., Chow, P., Ganguly, A., Scholz, T., Bierhals, T., Philipp, D., Hakonarson, H., Bhoj, E. <strong>De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.</strong> Genet. Med. 23: 637-644, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33244166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33244166</a>] [<a href="https://doi.org/10.1038/s41436-020-01031-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33244166">Li et al. (2021)</a> identified a presumed de novo heterozygous del/ins (c.4903_4906delinsCCAGCA) in the MED12 gene, predicted to result in a frameshift and premature termination (Val1635ProfsTer61). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was predicted to lead to nonsense-mediated mRNA decay, resulting in haploinsufficiency. Functional studies of the variant were not performed. Patient cells showed skewed X inactivation (97:3). The patient had previously been reported by <a href="#19" class="mim-tip-reference" title="Poley, J. R., Proud, V. K. <strong>Hardikar syndrome: new features.</strong> Am. J. Med. Genet. 146A: 2473-2479, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18792981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18792981</a>] [<a href="https://doi.org/10.1002/ajmg.a.32266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18792981">Poley and Proud (2008)</a> and <a href="#23" class="mim-tip-reference" title="Ryan, K. M., Ellis, A. R., Raafat, R., Bhoj, E. J., Hakonarson, H., Li, D., Schrier Vergano, S. <strong>Aortic coarctation and carotid artery aneurysm in a patient with Hardikar syndrome: cardiovascular implications for affected individuals.</strong> Am. J. Med. Genet. 170A: 482-486, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26471230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26471230</a>] [<a href="https://doi.org/10.1002/ajmg.a.37438" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26471230">Ryan et al. (2016)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=33244166+26471230+18792981" 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">rs2147826070 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147826070;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=rs2147826070" 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=rs2147826070" 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=RCV001580324 OR RCV001796997" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001580324, RCV001796997" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001580324...</a>
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<p>In a 21-year-old woman (patient 5) with Hardikar syndrome (HDKR; <a href="/entry/301068">301068</a>), <a href="#11" class="mim-tip-reference" title="Li, D., Strong, A., Shen, K. M., Cassiman, D., Van Dyck, M., Linhares, N. D., Valadares, E. R., Wang, T., Pena, S. D. J., Jaeken, J., Vergano, S., Zackai, E., Hing, A., Chow, P., Ganguly, A., Scholz, T., Bierhals, T., Philipp, D., Hakonarson, H., Bhoj, E. <strong>De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.</strong> Genet. Med. 23: 637-644, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33244166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33244166</a>] [<a href="https://doi.org/10.1038/s41436-020-01031-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33244166">Li et al. (2021)</a> identified a presumed de novo heterozygous c.5111G-A transition in the MED12 gene, predicted to result in a trp1704-to-ter (W1704X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was predicted to lead to nonsense-mediated mRNA decay, resulting in haploinsufficiency. Functional studies of the variant were not performed. Patient cells showed skewed X inactivation (99:1). The patient died at age 21 years from an intracranial hemorrhage. The patient had previously been reported by <a href="#3" class="mim-tip-reference" title="Cools, F., Jaeken, J. <strong>Hardikar syndrome: a new syndrome with cleft lip/palate, pigmentary retinopathy and cholestasis.</strong> Am. J. Med. Genet. 71: 472-474, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9286458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9286458</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19970905)71:4<472::aid-ajmg19>3.0.co;2-d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9286458">Cools and Jaeken (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=33244166+9286458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 HARDIKAR SYNDROME</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">rs2147829167 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147829167;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=rs2147829167" 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=rs2147829167" 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=RCV001580325 OR RCV001797847" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001580325, RCV001797847" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001580325...</a>
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<p>In a 4-year-old girl (patient 6) with Hardikar syndrome (HDKR; <a href="/entry/301068">301068</a>), <a href="#11" class="mim-tip-reference" title="Li, D., Strong, A., Shen, K. M., Cassiman, D., Van Dyck, M., Linhares, N. D., Valadares, E. R., Wang, T., Pena, S. D. J., Jaeken, J., Vergano, S., Zackai, E., Hing, A., Chow, P., Ganguly, A., Scholz, T., Bierhals, T., Philipp, D., Hakonarson, H., Bhoj, E. <strong>De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.</strong> Genet. Med. 23: 637-644, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33244166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33244166</a>] [<a href="https://doi.org/10.1038/s41436-020-01031-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33244166">Li et al. (2021)</a> identified a de novo heterozygous c.5622C-A transversion in the MED12 gene, resulting in a tyr1874-to-ter (Y1874X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was predicted to lead to nonsense-mediated mRNA decay, resulting in haploinsufficiency. Functional studies of the variant were not performed. Patient cells showed skewed X inactivation (97:3). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33244166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19970905)71:4<472::aid-ajmg19>3.0.co;2-d" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2008.05.023" target="_blank">Full Text</a>]
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Li, D., Strong, A., Shen, K. M., Cassiman, D., Van Dyck, M., Linhares, N. D., Valadares, E. R., Wang, T., Pena, S. D. J., Jaeken, J., Vergano, S., Zackai, E., Hing, A., Chow, P., Ganguly, A., Scholz, T., Bierhals, T., Philipp, D., Hakonarson, H., Bhoj, E.
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<strong>De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33244166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33244166</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33244166" 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/s41436-020-01031-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320470618" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1208930" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.mp.4000442" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004399900084" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32266" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ydbio.2006.04.437" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1992" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/cge.13806" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.37438" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2006.048637" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31270" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.01.007" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0605414103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/nar/gkf443" target="_blank">Full Text</a>]
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/14/2021
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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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Hilary J. Vernon - updated : 02/01/2021<br>Ada Hamosh - updated : 7/2/2014<br>Nara Sobreira - updated : 5/7/2013<br>Ada Hamosh - updated : 3/7/2013<br>Ada Hamosh - updated : 9/7/2011<br>Patricia A. Hartz - updated : 8/20/2009<br>Cassandra L. Kniffin - updated : 8/27/2007<br>Patricia A. Hartz - updated : 8/6/2007<br>Victor A. McKusick - updated : 4/26/2007<br>Patricia A. Hartz - updated : 12/6/2005<br>Victor A. McKusick - updated : 2/4/2002<br>Victor A. McKusick - updated : 2/17/2000<br>Victor A. McKusick - updated : 9/9/1999
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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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<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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Stylianos E. Antonarakis : 5/14/1999
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</span>
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</div>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 07/01/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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carol : 04/15/2022<br>alopez : 12/16/2021<br>alopez : 12/16/2021<br>ckniffin : 12/14/2021<br>carol : 02/01/2021<br>carol : 03/13/2020<br>carol : 03/02/2017<br>carol : 02/28/2017<br>carol : 02/19/2016<br>alopez : 7/2/2014<br>carol : 5/30/2013<br>carol : 5/8/2013<br>carol : 5/7/2013<br>terry : 3/28/2013<br>terry : 3/28/2013<br>alopez : 3/8/2013<br>terry : 3/7/2013<br>carol : 6/4/2012<br>alopez : 10/21/2011<br>alopez : 9/9/2011<br>terry : 9/7/2011<br>alopez : 10/8/2010<br>alopez : 10/8/2010<br>terry : 10/7/2010<br>mgross : 8/24/2009<br>mgross : 8/24/2009<br>terry : 8/20/2009<br>terry : 9/20/2007<br>carol : 9/6/2007<br>ckniffin : 8/27/2007<br>mgross : 8/10/2007<br>terry : 8/6/2007<br>alopez : 4/27/2007<br>terry : 4/26/2007<br>mgross : 12/6/2005<br>mgross : 12/6/2005<br>mgross : 12/6/2005<br>carol : 6/7/2002<br>carol : 2/11/2002<br>terry : 2/4/2002<br>alopez : 2/28/2000<br>terry : 2/17/2000<br>mgross : 1/27/2000<br>jlewis : 9/13/1999<br>carol : 9/9/1999<br>carol : 9/9/1999<br>terry : 6/9/1999<br>mgross : 5/18/1999
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<h3>
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<span class="mim-font">
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<strong>*</strong> 300188
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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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MEDIATOR COMPLEX SUBUNIT 12; MED12
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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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<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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<h4>
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<span class="mim-font">
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MEDIATOR OF RNA POLYMERASE II TRANSCRIPTION, SUBUNIT 12, S. CEREVISIAE, HOMOLOG OF<br />
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TRINUCLEOTIDE REPEAT-CONTAINING GENE 11; TNRC11<br />
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THYROID HORMONE RECEPTOR-ASSOCIATED PROTEIN, 230-KD SUBUNIT; TRAP230<br />
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HUMAN OPPOSITE PAIRED GENE; HOPA<br />
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KIAA0192
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</span>
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</h4>
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</div>
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</div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MED12</em></strong>
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</span>
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</p>
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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> 422437002, 49984004, 699297004, 720636001;
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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: Xq13.1
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Genomic coordinates <span class="small">(GRCh38)</span> : X:71,118,596-71,142,450 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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<tbody>
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<td rowspan="4">
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<span class="mim-font">
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Xq13.1
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</span>
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</td>
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<td>
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<span class="mim-font">
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Hardikar syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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301068
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</span>
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</td>
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<td>
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<span class="mim-font">
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X-linked dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Lujan-Fryns syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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309520
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</span>
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</td>
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<td>
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<span class="mim-font">
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X-linked recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Ohdo syndrome, X-linked
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</span>
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</td>
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<td>
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<span class="mim-font">
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300895
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</span>
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</td>
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<td>
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<span class="mim-font">
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X-linked recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Opitz-Kaveggia syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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305450
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</span>
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</td>
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<td>
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<span class="mim-font">
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X-linked recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Mediator is a multiprotein complex that can function in transcriptional activation or repression depending on the factors with which it interacts. The Mediator subunit MED12 has roles in both transcriptional activation and repression (Ding et al., 2008). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Nagase et al. (1996) cloned a cDNA, which they referred to as KIAA0192, from the human cell line KG-1. They found that the cDNA contains stretches of CAG (gln) repeats and encodes a 2,124-amino acid protein. </p><p>Using a HeLa cell line, Ito et al. (1999) cloned the same gene, TRAP230, which encodes the 230-kD subunit of the thyroid hormone receptor-associated protein (TRAP) complex (see 300182). The sequence of the TRAP230 protein was found in 2 other reports of partial sequences: CAG H45 (Margolis et al., 1997), and an opposite paired (OPA)-containing protein called HOPA by Philibert et al. (1998) located on chromosome Xq13. TRAP230 also contains 2 overlapping ligand-dependent nuclear hormone receptor signature recognition motifs (LxxLL motifs) near the N terminus and a highly glutamine-rich C-terminal region that results from the CAG trinucleotide repeats. Sequence comparisons revealed that TRAP230 also has significant homology with a hypothetical C. elegans protein (CEF47A4). This protein has a regional identity of 23% and similarity of 40% with TRAP230 and also possesses a characteristic glutamine-rich sequence near the C terminus. Northern blot analysis of multiple human tissues showed that the TRAP230 gene is ubiquitously expressed as an approximately 7.6-kb transcript. </p><p>By Northern blot analysis of the HOPA gene transcript and its murine ortholog, Mopa1, Philibert et al. (1999) demonstrated that only 1 transcript is expressed throughout the central nervous system and other tissues, and that the transcript is highly expressed during early fetal development. The presence of an OPA (opposite paired) element strongly suggested that HOPA is under tissue- or developmental-specific control (Grabowski et al., 1991). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Philibert et al. (1999) sequenced the HOPA gene and found that spans 25 kb and contains 44 exons. A promoter scan analysis demonstrated 2 possible transcription initiation sites without TATA boxes upstream from the putative translation initiation start site. </p><p>Risheg et al. (2007) stated that the MED12 gene contains 45 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
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</h4>
|
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</div>
|
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<span class="mim-text-font">
|
|
<p>By use of human/rodent hybrid cell lines, Nagase et al. (1996) mapped the MED12 gene to the X chromosome. </p>
|
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</span>
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<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Function</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
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<p>By yeast 2-hybrid analysis of a human embryo cDNA expression library, Zhou et al. (2002) found that the transcription activation domain of SOX9 (608160) interacted with the proline-, glutamine-, and leucine-rich (PQL) domain of TRAP230. In vitro and in vivo assays confirmed that the proteins interact endogenously and associate with several other TRAP complex proteins in HeLa cell nuclear lysates. SOX9 and TRAP230 colocalized in nuclei of cultured human embryo chondrocytes. The isolated PQL domain of TRAP230 acted as a dominant-negative inhibitor of SOX9 activity. </p><p>p21 (CDKN1A; 116899) is a key mediator of p53 (TP53; 191170)-dependent cell cycle arrest. Donner et al. (2007) found that transcriptional activity of the p21 promoter in human cell lines varied in response to distinct p53-activating stimuli. Core Mediator subunits MED1 (PPARBP; 604311) and MED17 (603810) were recruited to the p21 gene regardless of the p53-activating stimuli used. In contrast, 3 subunits of the CDK module of Mediator, CDK8 (603184), MED12, and cyclin C (CCNC; 123838), were recruited following treatment with nutlin-3, a nongenotoxic drug that activates p53, but not in response to DNA damage induced by ultraviolet light C. </p><p>Ding et al. (2008) showed that MED12 was required for transcriptional repression of a subset of neuron-specific genes in human nonneuronal cell lines, and that this repression was independent of CDK8 and CYCC. Yeast 2-hybrid analysis showed that the C-terminal domain of MED12 interacted directly with the H3K9 histone methyltransferase G9A (EHMT2; 604599). Mutation analysis revealed that the pro-glu-leu (PQL) domain of MED12 interacted with an ankyrin-repeat domain on G9A and, more weakly, with a cys-rich domain on G9A. Purified HeLa cell Mediator complexes that included MED12 interacted directly with G9A and REST (600571), a gene repressor that functions through repressor element-1 (RE1). Endogenous REST in HEK293 cells suppressed expression of a reporter gene bearing RE1 sites, and knockdown of either MED12 or G9A abrogated the suppression. Depletion of MED12 significantly reduced the association of G9A with RE1 elements and decreased the level of H3K9 dimethylation by G9A without influencing RE1 site occupancy by REST. Both the MED12 arg961-to-trp (R961W; 300188.0001) mutation associated with Opitz-Kaveggia syndrome (305450) and the MED12 asn1007-to-ser (N1007S; 300188.0002) mutation associated with Lujan-Fryns syndrome (309520) compromised recruitment of Mediator to RE1 elements and selectively interfered with repression of REST target genes. Ding et al. (2008) concluded that MED12 within the Mediator complex links REST with G9A in epigenetic silencing of neuronal genes. </p><p>A class of long noncoding RNAs (lncRNAs) termed noncoding RNA-activating (ncRNA-a) functions to activate their neighboring genes using a cis-mediated mechanism. Lai et al. (2013) reported that the depletion of the components of the coactivator complex, Mediator, specifically and potently diminished the noncoding RNA-induced activation of transcription in a heterologous reporter assay using human HEK293 cells. In vivo, Mediator is recruited to ncRNA-a target genes and regulates their expression. Lai et al. (2013) showed that ncRNA-a interact with Mediator to regulate its chromatin localization and kinase activity towards histone H3 serine-10. The Mediator complex harboring disease-causing MED12 mutations displayed diminished ability to associate with activating ncRNAs. Chromosome conformation capture confirmed the presence of DNA looping between the ncRNA-a loci and its targets. Importantly, depletion of Mediator subunits or ncRNA-a reduced the chromatin looping between the 2 loci. Lai et al. (2013) concluded that their results identified the human Mediator complex as the transducer of activating ncRNAs and highlighted the importance of Mediator and activating ncRNA association in human disease. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Opitz-Kaveggia Syndrome</em></strong></p><p>
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Opitz-Kaveggia syndrome (305450), also known as FG syndrome, is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia, and constipation. Risheg et al. (2007) reported that the original family from which the designation FG was derived and 5 other families had a recurrent mutation in the MED12 gene, 2881C-T (R961W; 300188.0001). MED12 was considered a candidate gene because of its mapping to Xq13 and because it encodes a thyroid hormone receptor-associated protein (TRAP). Risheg et al. (2007) sequenced the 45 exons of MED12 in 24 index cases from XLMR families with linkage to Xq13. Two of the 24 index cases had the identical R961W missense mutation. In both of these individuals, the diagnosis of Opitz-Kaveggia syndrome had been made a priori. In all affected males who survived long enough for mental or cognitive assessment, mental retardation was present. Partial or complete absence of the corpus callosum was noted in all 6 cases in which brain imaging was available. High, prominent forehead and small, low-set, simple ears were the most consistent craniofacial manifestations. Imperforate anus, wide flat thumbs, and wide great toes were present in 7 of 10 cases. Cryptorchidism, inguinal hernia, cardiac defects, and short stature were noted in fewer than half of affected males. Risheg et al. (2007) proposed that the Opitz-Kaveggia syndrome designation be reserved for those individuals with MED12 mutations. </p><p><strong><em>Intellectual Developmental Disorder, X-linked, Syndromic, Lujan-Fryns Type</em></strong></p><p>
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In 4 affected members of a family with Lujan-Fryns syndrome (MRXSLF; 309520) originally reported by Lujan et al. (1984), Schwartz et al. (2007) identified a mutation in the MED12 gene (300188.0002). The same mutation was found in affected members of an unrelated family. The findings indicated that Lujan-Fryns syndrome and Opitz-Kaveggia syndrome are allelic disorders. Clinically, Lujan-Fryns syndrome could be distinguished by tall stature, hypernasal voice, hyperextensible digits, and high nasal root. Schwartz et al. (2007) suggested that the Lujan-Fryns syndrome designation be used only for those cases with a compatible clinical phenotype and mutations in the MED12 gene. </p><p><strong><em>Ohdo Syndrome, X-Linked</em></strong></p><p>
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Vulto-van Silfhout et al. (2013) performed exome sequencing in 2 families segregating X-linked Ohdo syndrome (OHDOX; 300895), including the family originally studied by Maat-Kievit et al. (1993) and another family with 2 affected males, and identified hemizygous missense mutations in the MED12 gene (R1148H, 300188.0003 and S1165P, 300188.0004) that segregated with the disorder in each family. By analysis of an additional cohort of 9 simplex male patients with Ohdo syndrome, they identified another MED12 missense mutation (H1729N; 300188.0005) in 1 patient. </p><p>Vulto-van Silfhout et al. (2013) comparatively examined siRNA-resistant wildtype FLAG-tagged MED12 (FLAG-MED12) and its corresponding R1148H and S1165P mutant derivatives for their respective abilities to suppress enhanced REST target gene expression triggered by RNAi-mediated depletion of endogenous MED12 in HEK293 cells. MED12 knockdown triggered derepression of REST target genes, including CHRM4 (118495), SNAP25 (600322), and SYN1 (313440). Introduction of wildtype FLAG-MED12 in these cells reversed this effect; in contrast, the R1148H and S1165P mutants were significantly compromised in this ability. Vulto-van Silfhout et al. (2013) also showed that neither amino acid change deleteriously affected the incorporation of MED12 into Mediator or its direct interaction with G9A, indicating that the MED12 mutations in Ohdo syndrome do not disrupt the function of MED12 as a stable G9A interface in Mediator. </p><p>In 3 brothers of Moldavian descent with Ohdo syndrome, Rubin et al. (2020) identified a hemizygous mutation in the MED12 gene (Q2159P; 300188.0006). The mutation was identified by whole-exome sequencing. The unaffected mother was heterozygous for the mutation. Functional studies were not performed. </p><p><strong><em>Hardikar Syndrome</em></strong></p><p>
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In 7 unrelated females with Hardikar syndrome (HDKR; 301068), Li et al. (2021) identified heterozygous nonsense or frameshift mutations in the MED12 gene (see, e.g., 300188.0007-300188.0009). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, occurred throughout the gene. All were predicted to lead to nonsense-mediated mRNA decay, resulting in haploinsufficiency. All of the mutations either occurred de novo or were presumed de novo. Functional studies of the variants were not performed. Patient cells showed skewed X inactivation. Li et al. (2021) postulated that complete loss of MED12 may be lethal in males. The authors noted that the HDKR phenotype is unique in that neurodevelopment is preserved and that the manifestations include distinct structural abnormalities affecting several organ systems. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Susceptibility to Impaired Intellectual Development</p><p>Philibert et al. (1998) reported a strong association of a variant polymorphism, a 12-bp duplication (CAGCAACACCAG), in the HOPA gene with an X-linked mental retardation/hypothyroidism syndrome in several independent cohorts. </p><p>Friez et al. (2000) concluded that the 12-bp duplication in the HOPA gene is not associated with mental retardation. They determined the incidence of the dodecamer duplication in cohorts of non-fragile X males with mental retardation from 3 countries, cohorts of fragile X males from 2 countries, 43 probands from families with X-linked mental retardation, and control cohorts from 3 countries. The duplication was found in 3.6 to 4.0% of male patients from 2 non-fragile X groups, in 1.2% from another non-fragile X group, but in no male patients from families with X-linked mental retardation. The dodecamer duplication was also found in several white males with fragile X syndrome from France (5%) and South Africa (22.2%). Additionally, the duplication was found in 1.5% of South Carolinian newborn males, 2.5% of South Carolinian male college students, 5% of Italian male controls, and 4.5% of white South African controls. The duplication appeared to be rare in the black South African population. The incidence of the duplication was not significantly different between any of the groups in the study. </p><p>A study by Beyer et al. (2002) also failed to sustain the hypothesis that the HOPA gene is a significant susceptibility factor for infantile autism and mental retardation. The 12-bp duplication in the HOPA gene appeared to function as a benign polymorphism. </p><p>Uterine Leiomyoma</p><p>Makinen et al. (2011) performed whole-exome sequencing on 18 uterine leiomyomas derived from 17 different patients and identified tumor-specific mutations in the MED12 gene in 10. Analysis of 207 additional tumors identified MED12 mutations in 70% (159/225) of tumors from a total of 80 patients. The Mediator complex is a 26-subunit transcriptional regulator that bridges DNA regulatory sequences to the RNA polymerase II initiation complex. All mutations identified by Makinen et al. (2011) resided in exon 2, suggesting that aberrant function of this region of MED12 contributes to tumorigenesis. </p><p>Prostate Cancer</p><p>Barbieri et al. (2012) sequenced the exomes of 112 prostate tumor (see 176807) and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1 (602294). SPOP (602650) was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6 to 15% of tumors across multiple independent cohorts. Prostate tumors with mutant SPOP lacked ETS family (see 164720) gene rearrangements and showed a distinct pattern of genomic alterations. Barbieri et al. (2012) concluded that SPOP mutations may define a novel molecular subtype of prostate cancer. </p>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Hong et al. (2005) showed that med12-deficient zebrafish embryos showed defects in brain, neural crest, and kidney development and do not survive beyond 1 week after fertilization. Rau et al. (2006) showed, also in zebrafish, that med12 is required as a coactivator of Sox9 (608160)-dependent neural crest, cartilage, and ear development. Mutations in med12 are responsible for the zebrafish mutant 'motionless' (mot), and med12 transcripts are enriched in brain, where the gene is responsible for regulating the expression of other neuronal determination genes (Wang et al., 2006). These and other studies suggested that a variety of signaling pathways interact with MED12. </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>9 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<h4>
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<span class="mim-font">
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<strong>.0001 OPITZ-KAVEGGIA SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MED12, ARG961TRP
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<br />
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SNP: rs80338758,
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ClinVar: RCV000012276, RCV000415294, RCV000763632, RCV001261368, RCV001330015, RCV001528259, RCV003764560, RCV004018614
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In the original family with what was designated the FG syndrome (305450) after the family initials, Risheg et al. (2007) found a 2881C-T transition in exon 21 of the MED12 gene that caused an arg961-to-trp amino acid substitution (R961W). They also found the same mutation in 5 other families. Failure to find the change in 451 normal men and in 343 consecutive newborn males suggested that it is not a rare polymorphic variant. The finding of the mutation in patients of various ethnic backgrounds suggested that families did not share a common ancestor. </p><p>Ding et al. (2008) showed that both the R961W mutation associated with Opitz-Kaveggia syndrome and the MED12 asn1007-to-ser (N1007S; 300188.0002) mutation associated with Lujan-Fryns syndrome (309520) compromised recruitment of Mediator to RE1 elements and selectively interfered with repression of REST (600571) target genes. The authors noted that these mutations do not alter the ability of MED12 to support beta-catenin (see CTNNB1; 116806) transactivation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, LUJAN-FRYNS TYPE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MED12, ASN1007SER
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<br />
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SNP: rs80338759,
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ClinVar: RCV000012277, RCV001529623, RCV001580265, RCV005089235
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 affected members of a family with Lujan-Fryns syndrome (MRXSLF; 309520) originally reported by Lujan et al. (1984), Schwartz et al. (2007) identified a 3020A-G transition in exon 22 of the MED12 gene, resulting in an asn1007-to-ser (N1007S) substitution. Affected members of an unrelated family carried the same mutation. </p><p>Ding et al. (2008) showed that both the N1007S mutation associated with Lujan-Fryns syndrome and the MED12 arg961-to-trp (R961W; 300188.0001) mutation associated with Opitz-Kaveggia syndrome (305450) compromised recruitment of Mediator to RE1 elements and selectively interfered with repression of REST (600571) target genes. The authors noted that these mutations do not alter the ability of MED12 to support beta-catenin (see CTNNB1; 116806) transactivation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 OHDO SYNDROME, X-LINKED</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MED12, ARG1148HIS
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<br />
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SNP: rs387907360,
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ClinVar: RCV000043499, RCV001268310, RCV001580266, RCV005089401
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>By exome sequencing in a family in which 2 males had Ohdo syndrome (OHDOX; 300895), originally described by Maat-Kievit et al. (1993) and Verloes et al. (2006), Vulto-van Silfhout et al. (2013) identified a hemizygous c.3443G-A transition in the MED12 gene, resulting in an arg1148-to-his (R1148H) substitution, that segregated with the phenotype. Arg1148 is a highly conserved residue, and the mutation was predicted to be damaging to protein function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 OHDO SYNDROME, X-LINKED</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MED12, SER1165PRO
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<br />
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SNP: rs387907361,
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ClinVar: RCV000043500, RCV001580267
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>By exome sequencing in a family in which 2 males had Ohdo syndrome (OHDOX; 300895), Vulto-van Silfhout et al. (2013) identified a hemizygous c.3493T-C transition in the MED12 gene, resulting in a ser1165-to-pro (S1165P) substitution, that segregated with the phenotype. Ser1165 is a highly conserved residue, and the mutation was predicted to be damaging to protein function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 OHDO SYNDROME, X-LINKED</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MED12, HIS1729ASN
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<br />
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SNP: rs387907362,
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ClinVar: RCV000043501, RCV001580268
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Vulto-van Silfhout et al. (2013) sequenced the MED12 in a cohort of 9 simplex male individuals with Ohdo syndrome (OHDOX; 300895) and identified a hemizygous de novo c.5185C-A transversion, resulting in a his1729-to-asn (H1729N) substitution in the PQL domain. His1729 is a highly conserved residue, and the mutation was predicted to be damaging to protein function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 OHDO SYNDROME, X-LINKED</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MED12, GLN2159PRO
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<br />
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SNP: rs1085307941,
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ClinVar: RCV000488923, RCV001290305, RCV001580333
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 Moldavian brothers with Ohdo syndrome (OHDOX; 300895), Rubin et al. (2020) identified a hemizygous c.6476A-C transversion in exon 44 of the MED12 gene, resulting in a gln2159-to-pro (Q2159P) substitution at a highly conserved location within the OPA (glutamine-rich) domain. The mutation was identified by whole-exome sequencing. The unaffected mother was heterozygous for the mutation. Functional studies were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 HARDIKAR SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MED12, DEL/INS, NT4903
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<br />
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SNP: rs2147823333,
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ClinVar: RCV001580323, RCV001796996
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 14-year-old girl (patient 4) with Hardikar syndrome (HDKR; 301068), Li et al. (2021) identified a presumed de novo heterozygous del/ins (c.4903_4906delinsCCAGCA) in the MED12 gene, predicted to result in a frameshift and premature termination (Val1635ProfsTer61). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was predicted to lead to nonsense-mediated mRNA decay, resulting in haploinsufficiency. Functional studies of the variant were not performed. Patient cells showed skewed X inactivation (97:3). The patient had previously been reported by Poley and Proud (2008) and Ryan et al. (2016). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 HARDIKAR SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MED12, TRP1704TER
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<br />
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SNP: rs2147826070,
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ClinVar: RCV001580324, RCV001796997
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 21-year-old woman (patient 5) with Hardikar syndrome (HDKR; 301068), Li et al. (2021) identified a presumed de novo heterozygous c.5111G-A transition in the MED12 gene, predicted to result in a trp1704-to-ter (W1704X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was predicted to lead to nonsense-mediated mRNA decay, resulting in haploinsufficiency. Functional studies of the variant were not performed. Patient cells showed skewed X inactivation (99:1). The patient died at age 21 years from an intracranial hemorrhage. The patient had previously been reported by Cools and Jaeken (1997). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 HARDIKAR SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MED12, TYR1874TER
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<br />
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SNP: rs2147829167,
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ClinVar: RCV001580325, RCV001797847
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 4-year-old girl (patient 6) with Hardikar syndrome (HDKR; 301068), Li et al. (2021) identified a de novo heterozygous c.5622C-A transversion in the MED12 gene, resulting in a tyr1874-to-ter (Y1874X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was predicted to lead to nonsense-mediated mRNA decay, resulting in haploinsufficiency. Functional studies of the variant were not performed. Patient cells showed skewed X inactivation (97:3). </p>
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</span>
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</div>
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<div>
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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Cassandra L. Kniffin - updated : 12/14/2021<br>Hilary J. Vernon - updated : 02/01/2021<br>Ada Hamosh - updated : 7/2/2014<br>Nara Sobreira - updated : 5/7/2013<br>Ada Hamosh - updated : 3/7/2013<br>Ada Hamosh - updated : 9/7/2011<br>Patricia A. Hartz - updated : 8/20/2009<br>Cassandra L. Kniffin - updated : 8/27/2007<br>Patricia A. Hartz - updated : 8/6/2007<br>Victor A. McKusick - updated : 4/26/2007<br>Patricia A. Hartz - updated : 12/6/2005<br>Victor A. McKusick - updated : 2/4/2002<br>Victor A. McKusick - updated : 2/17/2000<br>Victor A. McKusick - updated : 9/9/1999
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Stylianos E. Antonarakis : 5/14/1999
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