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Entry
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- *608749 - BROMODOMAIN-CONTAINING PROTEIN 4; BRD4
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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">*608749</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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<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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<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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<a href="#otherFeatures">Other Features</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<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/608749">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000141867;t=ENST00000679869" 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=23476" 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=608749" 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 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=ENSG00000141867;t=ENST00000679869" 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_001330384,NM_001379291,NM_001379292,NM_014299,NM_058243,XM_047438540,XM_047438541,XM_047438542,XM_047438543,XM_047438544,XR_007066712" 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_001379291" 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=608749" 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=10574&isoform_id=10574_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/BRD4" 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/3115204,3184498,7657218,14249944,16589003,19718731,20141192,33879612,45501005,60649450,71052031,116283228,116283846,116283901,119604875,119604876,119604877,119604878,119604879,589229942,1058916530,1825629150,1825629276,2217320333,2217320336,2217320338,2217320340,2217320342,2462564150,2462564152,2462564154,2462564156,2462564158" 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/O60885" 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=23476" 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=ENSG00000141867;t=ENST00000679869" 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=BRD4" 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=BRD4" 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+23476" 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/BRD4" 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:23476" 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/23476" 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=chr19&hgg_gene=ENST00000679869.1&hgg_start=15235519&hgg_end=15332539&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:13575" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608749[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=608749[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/BRD4/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/ENSG00000141867" 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=BRD4" 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=BRD4" 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=BRD4" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=BRD4&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/PA25416" 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:13575" 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/FBgn0004656.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:1888520" 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/BRD4#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:1888520" 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/23476/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=23476" 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=WBGene00022473;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-030131-267" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
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</a>
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</span>
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</span>
|
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=BRD4&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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608749
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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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BROMODOMAIN-CONTAINING PROTEIN 4; BRD4
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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MITOTIC CHROMOSOME-ASSOCIATED PROTEIN; MCAP; CAP<br />
|
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HUNK1
|
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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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<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
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</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
BRD4/NUT FUSION GENE, INCLUDED
|
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</span>
|
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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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=BRD4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">BRD4</a></em></strong>
|
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/19/394?start=-3&limit=10&highlight=394">19p13.12</a>
|
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:15235519-15332539&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'})">19:15,235,519-15,332,539</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
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</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>
|
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<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
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</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/19/394?start=-3&limit=10&highlight=394">
|
|
19p13.12
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Cornelia de Lange syndrome 6
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/620568"> 620568 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
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</td>
|
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|
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</tr>
|
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</tbody>
|
|
</table>
|
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</div>
|
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/608749" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/608749" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<p>BRD4 belongs to the BET family of nuclear proteins that carry 2 bromodomains and an additional ET domain. Bromodomains are implicated in chromatin interactions (<a href="#12" class="mim-tip-reference" title="Maruyama, T., Farina, A., Dey, A., Cheong, J., Bermudez, V. P., Tamura, T., Sciortino, S., Shuman, J., Hurwitz, J., Ozato, K. <strong>A mammalian bromodomain protein, Brd4, interacts with replication factor C and inhibits progression to S phase.</strong> Molec. Cell. Biol. 22: 6509-6520, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12192049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12192049</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12192049[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/10.1128/MCB.22.18.6509-6520.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12192049">Maruyama et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12192049" 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="#4" class="mim-tip-reference" title="Dey, A., Ellenberg, J., Farina, A., Coleman, A. E., Maruyama, T., Sciortino, S., Lippincott-Schwartz, J., Ozato, K. <strong>A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G2-to-M transition.</strong> Molec. Cell. Biol. 20: 6537-6549, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10938129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10938129</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10938129[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/10.1128/MCB.20.17.6537-6549.2000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10938129">Dey et al. (2000)</a> cloned mouse Brd4, which they called Mcap. The deduced 1,400-amino acid protein has a calculated molecular mass of 155 kD. It contains 2 N-terminal bromodomains, a central ET domain, and several kinase-like motifs in its N-terminal half. By database analysis, <a href="#4" class="mim-tip-reference" title="Dey, A., Ellenberg, J., Farina, A., Coleman, A. E., Maruyama, T., Sciortino, S., Lippincott-Schwartz, J., Ozato, K. <strong>A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G2-to-M transition.</strong> Molec. Cell. Biol. 20: 6537-6549, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10938129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10938129</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10938129[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/10.1128/MCB.20.17.6537-6549.2000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10938129">Dey et al. (2000)</a> identified a human cDNA encoding a 731-amino acid protein with the same domain organization as the N-terminal half of mouse Brd4, but lacking the C-terminal half. Northern blot analysis detected a transcript of about 6.5 kb in all adult and embryonic mouse tissues examined and in human cells. Western blot analysis of in vitro translated mouse Brd4 and HeLa cell lysates detected BRD4 at about 200 kD, suggesting posttranslational modification. Indirect immunofluorescent staining of HeLa cells and 2 mouse cell lines detected BRD4 in the nucleus. During interphase, BRD4 was uniformly distributed as fine grains in the nucleus, but it was excluded from nucleoli. In mitotic cells, BRD4 localized almost exclusively on condensed chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10938129" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="French, C. A., Miyoshi, I., Aster, J. C., Kubonishi, I., Kroll, T. G., Cin, P. D., Vargas, S. O., Perez-Atayde, A. R., Fletcher, J. A. <strong>BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19).</strong> Am. J. Path. 159: 1987-1992, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11733348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11733348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11733348[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/S0002-9440(10)63049-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11733348">French et al. (2001)</a> described 2 alternatively spliced variants of BRD4 that encode proteins identical through their N-terminal halves, which include 2 bromodomains, the ET domain, and a serine-rich region. The longer variant has a C-terminal extension that includes a proline-rich region and a glutamine-rich region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11733348" 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 EST database analysis and PCR of a human cDNA library, <a href="#19" class="mim-tip-reference" title="You, J., Croyle, J. L., Nishimura, A., Ozato, K., Howley, P. M. <strong>Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes.</strong> Cell 117: 349-360, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15109495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15109495</a>] [<a href="https://doi.org/10.1016/s0092-8674(04)00402-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15109495">You et al. (2004)</a> obtained a full-length cDNA encoding BRD4. The BRD4 protein contains 1,362 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15109495" 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, <a href="#8" class="mim-tip-reference" title="French, C. A., Miyoshi, I., Kubonishi, I., Grier, H. E., Perez-Atayde, A. R., Fletcher, J. A. <strong>BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma.</strong> Cancer Res. 63: 304-307, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12543779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12543779</a>]" pmid="12543779">French et al. (2003)</a> determined that BRD4 is ubiquitously expressed as 4.4- and 6.0-kb transcripts, which likely encode the short and long BRD4 isoforms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12543779" 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="#7" class="mim-tip-reference" title="French, C. A., Miyoshi, I., Aster, J. C., Kubonishi, I., Kroll, T. G., Cin, P. D., Vargas, S. O., Perez-Atayde, A. R., Fletcher, J. A. <strong>BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19).</strong> Am. J. Path. 159: 1987-1992, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11733348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11733348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11733348[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/S0002-9440(10)63049-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11733348">French et al. (2001)</a> reported that the coding region of the BRD4 gene contains 19 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11733348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By analysis of a translocation involving chromosome 19, <a href="#7" class="mim-tip-reference" title="French, C. A., Miyoshi, I., Aster, J. C., Kubonishi, I., Kroll, T. G., Cin, P. D., Vargas, S. O., Perez-Atayde, A. R., Fletcher, J. A. <strong>BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19).</strong> Am. J. Path. 159: 1987-1992, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11733348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11733348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11733348[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/S0002-9440(10)63049-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11733348">French et al. (2001)</a> mapped the BRD4 gene to chromosome 19p13.1. By FISH, <a href="#4" class="mim-tip-reference" title="Dey, A., Ellenberg, J., Farina, A., Coleman, A. E., Maruyama, T., Sciortino, S., Lippincott-Schwartz, J., Ozato, K. <strong>A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G2-to-M transition.</strong> Molec. Cell. Biol. 20: 6537-6549, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10938129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10938129</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10938129[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/10.1128/MCB.20.17.6537-6549.2000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10938129">Dey et al. (2000)</a> mapped the mouse Brd4 gene to the distal region of chromosome 17B, which shows homology of synteny to human chromosome 19. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11733348+10938129" 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 analyzing well-spread metaphase preparations of murine myeloid precursor cells, <a href="#4" class="mim-tip-reference" title="Dey, A., Ellenberg, J., Farina, A., Coleman, A. E., Maruyama, T., Sciortino, S., Lippincott-Schwartz, J., Ozato, K. <strong>A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G2-to-M transition.</strong> Molec. Cell. Biol. 20: 6537-6549, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10938129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10938129</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10938129[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/10.1128/MCB.20.17.6537-6549.2000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10938129">Dey et al. (2000)</a> found Brd4 staining along the entire length of chromosomes, with the exception of centromeres. Brd4 chromosome association became visible following initiation of histone H3 (see <a href="/entry/602810">602810</a>) phosphorylation and early chromosomal condensation and persisted until the end of mitosis. Differential salt extraction and FRAP analysis indicated that Brd4 was loosely associated with chromatin during interphase as well as mitosis. Supporting a role for BRD4 in G2/M transition, microinjection of anti-BRD4 antibody into HeLa cell nuclei completely inhibited entry into mitosis without abrogating ongoing DNA replication. <a href="#4" class="mim-tip-reference" title="Dey, A., Ellenberg, J., Farina, A., Coleman, A. E., Maruyama, T., Sciortino, S., Lippincott-Schwartz, J., Ozato, K. <strong>A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G2-to-M transition.</strong> Molec. Cell. Biol. 20: 6537-6549, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10938129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10938129</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10938129[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/10.1128/MCB.20.17.6537-6549.2000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10938129">Dey et al. (2000)</a> concluded that BRD4 plays a role in chromosomal dynamics during mitosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10938129" 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="#12" class="mim-tip-reference" title="Maruyama, T., Farina, A., Dey, A., Cheong, J., Bermudez, V. P., Tamura, T., Sciortino, S., Shuman, J., Hurwitz, J., Ozato, K. <strong>A mammalian bromodomain protein, Brd4, interacts with replication factor C and inhibits progression to S phase.</strong> Molec. Cell. Biol. 22: 6509-6520, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12192049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12192049</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12192049[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/10.1128/MCB.22.18.6509-6520.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12192049">Maruyama et al. (2002)</a> found that ectopic expression of mouse Brd4 in mouse fibroblasts and HeLa cells inhibited cell cycle progression from G1 to S. Endogenous and transfected Brd4 interacted with replication factor C (RFC), the conserved 5-subunit complex essential for DNA replication, with Brd4 binding directly to the largest subunit, RFC1 (<a href="/entry/102579">102579</a>). In agreement with the inhibitory activity observed in vivo, recombinant Brd4 inhibited RFC-dependent DNA elongation reactions in vitro. Analysis of Brd4 deletion mutants indicated that both the interaction with human RFC1 and the inhibition of entry into S phase were dependent on the second bromodomain of Brd4. Cotransfection with RFC1 reduced the growth-inhibitory effect of Brd4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12192049" 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="#19" class="mim-tip-reference" title="You, J., Croyle, J. L., Nishimura, A., Ozato, K., Howley, P. M. <strong>Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes.</strong> Cell 117: 349-360, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15109495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15109495</a>] [<a href="https://doi.org/10.1016/s0092-8674(04)00402-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15109495">You et al. (2004)</a> identified BRD4 as a major cellular interacting partner of the bovine papillomavirus (BPV) E2 protein. They found that BRD4 associated with mitotic chromosomes and colocalized with E2 on mitotic chromosomes. The site of E2 binding mapped to the C-terminal domain of BRD4. Expression of this C-terminal BRD4 domain functioned in a dominant-negative manner to abrogate the colocalization of E2 with BRD4 on mitotic chromosomes, to block association of the viral episomes with BRD4, and to inhibit BPV-1 DNA-mediated cellular transformation. BRD4 also associated with human papillomavirus-16 E2, indicating that BRD4 binding may be a shared property of all papillomavirus E2 proteins. <a href="#19" class="mim-tip-reference" title="You, J., Croyle, J. L., Nishimura, A., Ozato, K., Howley, P. M. <strong>Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes.</strong> Cell 117: 349-360, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15109495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15109495</a>] [<a href="https://doi.org/10.1016/s0092-8674(04)00402-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15109495">You et al. (2004)</a> concluded that the interaction of E2 with BRD4 is required to ensure the tethering of viral genomes to the host mitotic chromosomes for persistence of viral episomes in papillomavirus-infected cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15109495" 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="#9" class="mim-tip-reference" title="Jang, M. K., Mochizuki, K., Zhou, M., Jeong, H.-S., Brady, J. N., Ozato, K. <strong>The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription.</strong> Molec. Cell 19: 523-534, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16109376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16109376</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.06.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16109376">Jang et al. (2005)</a> found that epitope-tagged mouse Brd4 interacted with cyclin T1 (<a href="/entry/143055">143055</a>) and CDK9 (<a href="/entry/603251">603251</a>) in core positive transcription elongation factor b (P-TEFb) complexes contained in HeLa cell nuclear extracts. The bromodomain of Brd4 was required for the interaction. Brd4 overexpression increased P-TEFb-dependent phosphorylation of the C-terminal domain of RNA polymerase II (see POLR2A; <a href="/entry/180660">180660</a>) and stimulated transcription of a reporter plasmid driven by an HIV-1 promoter. Conversely, reduced Brd4 expression in mouse fibroblasts by small interfering RNA reduced RNA polymerase II C-terminal domain phosphorylation and transcription. Chromatin immunoprecipitation assays indicated that recruitment of P-TEFb to a promoter was dependent on Brd4, and recruitment was enhanced by increased chromatin acetylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16109376" 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>About half of cellular P-TEFb exists in an inactive complex with 7SK snRNA (<a href="/entry/606515">606515</a>) and the HEXIM1 protein (<a href="/entry/607328">607328</a>). <a href="#18" class="mim-tip-reference" title="Yang, Z., Yik, J. H. N., Chen, R., He, N., Jang, M. K., Ozato, K., Zhou, Q. <strong>Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4.</strong> Molec. Cell 19: 535-545, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16109377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16109377</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.06.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16109377">Yang et al. (2005)</a> demonstrated that the remaining half associated with BRD4. In stress-induced HeLa cells, 7SK/HEXIM1-bound P-TEFb was converted into the BRD4-associated form. The association of P-TEFb with BRD4 was necessary to form the transcriptionally active P-TEFb, to recruit P-TEFb to a promoter, and to enable P-TEFb to contact the Mediator complex (see <a href="/entry/602984">602984</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16109377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Crawford, N. P. S., Alsarraj, J., Lukes, L., Walker, R. C., Officewala, J. S., Yang, H. H., Lee, M. P., Ozato, K., Hunter, K. W. <strong>Bromodomain 4 activation predicts breast cancer survival.</strong> Proc. Nat. Acad. Sci. 105: 6380-6385, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18427120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18427120</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18427120[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.0710331105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18427120">Crawford et al. (2008)</a> showed that activation of Brd4 in mice repressed tumor growth and metastasis and that BRD4 activation in human breast carcinomas induced a gene expression profile predictive of breast cancer outcome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18427120" 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="#20" class="mim-tip-reference" title="Zuber, J., Shi, J., Wang, E., Rappaport, A. R., Herrmann, H., Sison, E. A., Magoon, D., Qi, J., Blatt, K., Wunderlich, M., Taylor, M. J., Johns, C., Chicas, A., Mulloy, J. C., Kogan, S. C., Brown, P., Valent, P., Bradner, J. E., Lowe, S. W., Vakov, C. R. <strong>RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.</strong> Nature 478: 524-528, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21814200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21814200</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21814200[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/nature10334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21814200">Zuber et al. (2011)</a> described a nonbiased approach to probe epigenetic vulnerabilities in acute myeloid leukemia (AML; <a href="/entry/601626">601626</a>), an aggressive hematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, they identified the protein BRD4 as being required for disease maintenance. Suppression of BRD4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of BRD4 suppression are, at least in part, due to its role in sustaining MYC (<a href="/entry/190080">190080</a>) expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacologic means to suppress MYC in cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21814200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Dawson, M. A., Prinjha, R. K., Dittmann, A., Giotopoulos, G., Bantscheff, M., Chan, W.-I., Robson, S. C., Chung, C., Hopf, C., Savitski, M. M., Huthmacher, C., Gudgin, E., and 15 others. <strong>Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.</strong> Nature 478: 529-533, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964340</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21964340[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/nature10509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964340">Dawson et al. (2011)</a> demonstrated that I-BET151, a novel small molecule inhibitor of the BET family, of which BRD4 is a member, has profound efficacy against human and murine MLL-fusion leukemia cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in 2 human leukemia cell lines with different MLL fusions altered the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes BCL2 (<a href="/entry/151430">151430</a>), C-MYC, and CDK6 (<a href="/entry/603368">603368</a>) through the displacement of BRD3/4, PAFc, and SEC components from chromatin. In vivo studies indicated that I-BET151 has significant therapeutic value, providing survival benefit in 2 distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964340" 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 genomewide small interfering RNA screen and secondary screens, <a href="#17" class="mim-tip-reference" title="Smith, J. A., White, E. A., Sowa, M. E., Powell, M. L. C., Ottinger, M., Harper, J. W., Howley, P. M. <strong>Genome-wide siRNA screen identifies SMCX, EP400, and Brd4 as E2-dependent regulators of human papillomavirus oncogene expression.</strong> Proc. Nat. Acad. Sci. 107: 3752-3757, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20133580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20133580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20133580[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.0914818107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20133580">Smith et al. (2010)</a> identified 96 cellular genes that contributed to viral E2 protein-mediated repression of the human papillomavirus (HPV) long control region, which controls viral oncogene expression. In addition to the E2-binding protein BRD4, other genes implicated included the demethylase SMCX (KDM5C; <a href="/entry/314690">314690</a>) and EP400 (<a href="/entry/606265">606265</a>), a component of the NUA4/TIP60 histone acetyltransferase complex (see <a href="/entry/601409">601409</a>). <a href="#17" class="mim-tip-reference" title="Smith, J. A., White, E. A., Sowa, M. E., Powell, M. L. C., Ottinger, M., Harper, J. W., Howley, P. M. <strong>Genome-wide siRNA screen identifies SMCX, EP400, and Brd4 as E2-dependent regulators of human papillomavirus oncogene expression.</strong> Proc. Nat. Acad. Sci. 107: 3752-3757, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20133580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20133580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20133580[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.0914818107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20133580">Smith et al. (2010)</a> concluded that HPV E2 uses multiple cellular proteins to inhibit expression of its oncogenes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20133580" 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="Floyd, S. R., Pacold, M. E., Huang, Q., Clarke, S. M., Lam, F. C., Cannell, I. G., Bryson, B. D., Rameseder, J., Lee, M. J., Blake, E. J., Fydrych, A., Ho, R., and 12 others. <strong>The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.</strong> Nature 498: 246-250, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23728299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23728299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23728299[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/nature12147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23728299">Floyd et al. (2013)</a> investigated the role of chromatin structure in the DNA damage response by monitoring ionizing radiation-induced signaling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. <a href="#6" class="mim-tip-reference" title="Floyd, S. R., Pacold, M. E., Huang, Q., Clarke, S. M., Lam, F. C., Cannell, I. G., Bryson, B. D., Rameseder, J., Lee, M. J., Blake, E. J., Fydrych, A., Ho, R., and 12 others. <strong>The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.</strong> Nature 498: 246-250, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23728299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23728299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23728299[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/nature12147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23728299">Floyd et al. (2013)</a> found that isoform B of BRD4, in which the C-terminal domain containing the P-TEFb-interacting region is replaced with a divergent 75-amino acid segment, functions as an endogenous inhibitor of DNA damage response signaling by recruiting the condensin II chromatin remodeling complex to acetylated histones through bromodomain interactions. Loss of this isoform resulted in relaxed chromatin structure, rapid cell cycle checkpoint recovery, and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signaling, and enhanced radiation-induced lethality. <a href="#6" class="mim-tip-reference" title="Floyd, S. R., Pacold, M. E., Huang, Q., Clarke, S. M., Lam, F. C., Cannell, I. G., Bryson, B. D., Rameseder, J., Lee, M. J., Blake, E. J., Fydrych, A., Ho, R., and 12 others. <strong>The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.</strong> Nature 498: 246-250, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23728299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23728299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23728299[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/nature12147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23728299">Floyd et al. (2013)</a> concluded that their data implicated BRD4 as an insulator of chromatin that can modulate the signaling response to DNA damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23728299" 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="#13" class="mim-tip-reference" title="Muhar, M., Ebert, A., Neumann, T., Umkehrer, C., Jude, J., Wieshofer, C., Rescheneder, P., Lipp, J. J., Herzog, V. A., Reichholf, B., Cisneros, D. A., Hoffmann, T., Schlapansky, M. F., Bhat, P., von Haeseler, A., Kocher, T., Obenauf, A. C., Popow, J., Ameres, S. L., Zuber, J. <strong>SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis.</strong> Science 360: 800-805, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29622725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29622725</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29622725[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aao2793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29622725">Muhar et al. (2018)</a> combined SLAM-seq (thiol(SH)-linked alkylation for the metabolic sequencing of RNA), a method for direct quantification of newly synthesized mRNAs, with pharmacologic and chemical-genetic perturbation in order to define regulatory functions of 2 transcriptional hubs in cancer, BRD4 and MYC (<a href="/entry/190080">190080</a>), and to interrogate direct responses to BET bromodomain inhibitors (BETis). <a href="#13" class="mim-tip-reference" title="Muhar, M., Ebert, A., Neumann, T., Umkehrer, C., Jude, J., Wieshofer, C., Rescheneder, P., Lipp, J. J., Herzog, V. A., Reichholf, B., Cisneros, D. A., Hoffmann, T., Schlapansky, M. F., Bhat, P., von Haeseler, A., Kocher, T., Obenauf, A. C., Popow, J., Ameres, S. L., Zuber, J. <strong>SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis.</strong> Science 360: 800-805, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29622725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29622725</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29622725[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aao2793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29622725">Muhar et al. (2018)</a> found that BRD4 acts as general coactivator of RNA POL2 (see <a href="/entry/180660">180660</a>)-dependent transcription, which is broadly repressed upon high-dose BETi treatment. At doses triggering selective effects in leukemia, BETis deregulate a small set of hypersensitive targets, including MYC. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator controlling metabolic processes such as ribosome biogenesis and de novo purine synthesis. <a href="#13" class="mim-tip-reference" title="Muhar, M., Ebert, A., Neumann, T., Umkehrer, C., Jude, J., Wieshofer, C., Rescheneder, P., Lipp, J. J., Herzog, V. A., Reichholf, B., Cisneros, D. A., Hoffmann, T., Schlapansky, M. F., Bhat, P., von Haeseler, A., Kocher, T., Obenauf, A. C., Popow, J., Ameres, S. L., Zuber, J. <strong>SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis.</strong> Science 360: 800-805, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29622725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29622725</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29622725[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aao2793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29622725">Muhar et al. (2018)</a> concluded that their study established a simple and scalable strategy to identify direct transcriptional targets of any gene or pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29622725" 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="#1" class="mim-tip-reference" title="Choe, J., Lin, S., Zhang, W., Liu, Q., Wang, L., Ramirez-Moya, J., Du, P., Kim, W., Tang, S., Sliz, P., Santisteban, P., George, R. E., Richards, W. G., Wong, K.-K., Locker, N., Slack, F. J., Gregory, R. I. <strong>mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis.</strong> Nature 561: 556-560, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30232453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30232453</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30232453[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/s41586-018-0538-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30232453">Choe et al. (2018)</a> demonstrated that METTL3 (<a href="/entry/612472">612472</a>) enhances translation only when tethered to reporter mRNA at sites close to the stop codon, supporting a mechanism of mRNA looping for ribosome recycling and translational control. Electron microscopy revealed the topology of individual polyribosomes with single METTL3 foci in close proximity to 5-prime cap-binding proteins. <a href="#1" class="mim-tip-reference" title="Choe, J., Lin, S., Zhang, W., Liu, Q., Wang, L., Ramirez-Moya, J., Du, P., Kim, W., Tang, S., Sliz, P., Santisteban, P., George, R. E., Richards, W. G., Wong, K.-K., Locker, N., Slack, F. J., Gregory, R. I. <strong>mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis.</strong> Nature 561: 556-560, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30232453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30232453</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30232453[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/s41586-018-0538-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30232453">Choe et al. (2018)</a> identified a direct physical and functional interaction between METTL3 and the eukaryotic translation initiation factor 3 subunit H (EIF3H; <a href="/entry/603912">603912</a>). METTL3 promotes translation of a large subset of oncogenic mRNAs, including BRD4, that is also N6-methyladenosine (m6A)-modified in human primary lung tumors. The METTL3-EIF3H interaction is required for enhanced translation, formation of densely packed polyribosomes, and oncogenic transformation. METTL3 depletion inhibits tumorigenicity and sensitizes lung cancer cells to BRD4 inhibition. <a href="#1" class="mim-tip-reference" title="Choe, J., Lin, S., Zhang, W., Liu, Q., Wang, L., Ramirez-Moya, J., Du, P., Kim, W., Tang, S., Sliz, P., Santisteban, P., George, R. E., Richards, W. G., Wong, K.-K., Locker, N., Slack, F. J., Gregory, R. I. <strong>mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis.</strong> Nature 561: 556-560, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30232453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30232453</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30232453[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/s41586-018-0538-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30232453">Choe et al. (2018)</a> concluded that these findings uncovered a mechanism of translation control that is based on mRNA looping. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30232453" 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 genetic screen, <a href="#16" class="mim-tip-reference" title="Sdelci, S., Rendeiro, A. F., Rathert, P., You, W., Lin, J.-M. G., Ringler, A., Hofstater, G., Moll, H. P., Gurtl, B., Farlik, M., Schick, S., Klepsch, F., and 25 others. <strong>MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation.</strong> Nature Genet. 51: 990-998, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31133746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31133746</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31133746[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-019-0413-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31133746">Sdelci et al. (2019)</a> identified human MTHFD1 (<a href="/entry/172460">172460</a>) as a functional partner of BRD4. BRD4 physically interacted with MTHFD1 in nucleus and recruited it to chromatin. The interaction was enhanced by binding of the BRD4 bromodomains to acetylated lysines on the surface of MTHFD1. Chromatin immunoprecipitation-sequencing analysis revealed that MTHFD1 regulated gene expression by colocalizing with BRD4 at promoter and enhancer regions, where H3K27ac was also enriched. Furthermore, BRD4 boosted the C1-tetrahydrofolate synthase activity of MTHFD1, and loss of either MTHFD1 or BRD4 resulted in similar changes in nuclear metabolite composition and gene expression, correlating BRD4-dependent epigenetic regulation and folate metabolism. Antifolates synergized with BRD4 inhibitors and impaired cancer cell proliferation without exerting general toxicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31133746" 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 ChIP-seq analysis in mouse embryonic stem cells (mESCs), <a href="#15" class="mim-tip-reference" title="Olley, G., Pradeepa, M. M., Grimes, G. R., Piquet, S., Polo, S. E., FitzPatrick, D. R., Bickmore, W. A., Boumendil, C. <strong>Cornelia de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect.</strong> Nature Commun. 12: 3127, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34035299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34035299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34035299[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/s41467-021-23500-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34035299">Olley et al. (2021)</a> showed that a Brd4 Y430C mutation reduced occupancy of Brd4 protein at cis-regulatory elements (CREs). However, the decreased occupancy of the Brd4 Y430C mutant at CREs was not sufficient to affect the transcription of associated genes in mESCs, despite the role of Brd4 in transcriptional regulation. Instead, the Brd4 Y430C mutant resulted in a delayed cell cycle, increased cell cycle checkpoint activation, increased DNA damage response (DDR) signaling, and defective double-strand break (DSB) in mESCs. The DDR defect observed in mESCs with the Brd4 Y430C mutation was also seen in lymphoblastoid cell lines with a Cornelia de Lange syndrome (CDLS; <a href="/entry/122470">122470</a>)-associated NIPBL (<a href="/entry/608667">608667</a>) mutation, suggesting that increased DDR signaling and/or impaired DNA repair pathway choice balance might contribute to the etiology of CDLS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34035299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Faivre, E. J., McDaniel, K. F., Albert, D. H., Mantena, S. R., Plotnik, J. P., Wilcox, D., Zhang, L., Bui, M. H., Sheppard, G. S., Wang, L., Sehgal, V., Lin, X., and 22 others. <strong>Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer.</strong> Nature 578: 306-310, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31969702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31969702</a>] [<a href="https://doi.org/10.1038/s41586-020-1930-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31969702">Faivre et al. (2020)</a> performed a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by dual-bromodomain BET inhibitors, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukemia (<a href="/entry/601626">601626</a>) and prostate cancer (<a href="/entry/176807">176807</a>) that expressed the full-length androgen receptor (AR; <a href="/entry/313700">313700</a>). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the dual-bromodomain BET inhibitors. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing superenhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with a dual-bromodomain BET inhibitor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31969702" 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>The balanced translocation t(15;19) has been identified in midline carcinomas adjacent to the respiratory tract in children and young adults and is associated with poor survival and a treatment-refractory course. <a href="#7" class="mim-tip-reference" title="French, C. A., Miyoshi, I., Aster, J. C., Kubonishi, I., Kroll, T. G., Cin, P. D., Vargas, S. O., Perez-Atayde, A. R., Fletcher, J. A. <strong>BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19).</strong> Am. J. Path. 159: 1987-1992, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11733348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11733348</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11733348[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/S0002-9440(10)63049-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11733348">French et al. (2001)</a> mapped the translocation breakpoints in 2 patients with t(15;19)(q13;p13.1) carcinomas. The chromosome 19 translocation breakpoints were between introns 10 and 13 in the 3-prime end of the BRD4 coding sequence in both cancers. The breakpoints split the coding sequence of the longer BRD4 transcript and left the short transcript unaltered. The breakpoints in chromosome 15q13 localized to an approximately 9-kb region containing the NOP10 gene (NOLA3; <a href="/entry/606471">606471</a>) gene. FISH screening of 13 supradiaphragmatic pediatric carcinomas revealed a sinonasal carcinoma with a chromosome 19p13.1 and 15q13 rearrangement. The other 12 carcinomas lacked chromosome 15 or 19 rearrangements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11733348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="French, C. A., Miyoshi, I., Kubonishi, I., Grier, H. E., Perez-Atayde, A. R., Fletcher, J. A. <strong>BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma.</strong> Cancer Res. 63: 304-307, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12543779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12543779</a>]" pmid="12543779">French et al. (2003)</a> determined that the BRD4 fusion partner in the t(15;19) translocation is NUT (<a href="/entry/608963">608963</a>). Sequence analysis indicated that the translocations in 2 affected tumors were identical and resulted in the in-frame fusion of exon 10 of BRD4 with exon 2 of NUT. The oncogenic fusion protein contains the N-terminal BRD4 sequence up to the serine-rich region, followed by almost the entire NUT sequence. It lacks only the first 5 NUT residues. Northern blot analysis detected a 6.4-kb fusion transcript in a t(15;19)-positive carcinoma cell line. No NUT/BRD4 transcripts were detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12543779" 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>Among 92 patients with features of Cornelia de Lange syndrome who were negative for mutations in known causative genes, <a href="#14" class="mim-tip-reference" title="Olley, G., Ansari, M., Bengani, H., Grimes, G. R., Rhodes, J., von Kriegsheim, A., Blatnik, A., Stewart, F. J., Wakeling, E., Carroll, N., Ross, A., Park, S. M., Deciphering Developmental Disorders Study, Bickmore, W. A., Pradeepa, M. M., FitzPatrick, D. R. <strong>BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome.</strong> Nature Genet. 50: 329-332, 2018. Note: Erratum: Nature Genet 50: 767, 2018; Erratum: Nature Genet. 51: 1192, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29379197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29379197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29379197[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0042-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29379197">Olley et al. (2018)</a> identified 2 unrelated patients with de novo heterozygous mutations in the BRD4 gene (see CDLS6, <a href="/entry/620568">620568</a>): a missense mutation (Y430C; <a href="#0001">608749.0001</a>) and a 1.04 Mb deletion that included BRD4 and 28 other protein-coding genes. Two additional patients who were not part of the original cohort were identified with de novo heterozygous frameshift mutations in BRD4 (see, e.g., <a href="#0002">608749.0002</a>). The authors then reviewed phenotypes of other patients with heterozygous multigenic deletions encompassing BRD4 and recognized a significant overlap with the CDLS phenotype, suggesting that BRD4 haploinsufficiency is the likely cause of CDLS6. The authors showed that the BRD4 missense variant (Y430C) resulted in more typical CDLS; this variant retained the ability to coimmunoprecipitate with NIPBL (<a href="/entry/608667">608667</a>), the causative gene in CDLS1 (<a href="/entry/122470">122470</a>), but had decreased binding to acetylated histones of promoter and superenhancer genes. Functional analyses demonstrated that BRD4 and NIPBL coregulated binding at superenhancer genes and appeared to coregulate developmental gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29379197" 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>Through an international collaboration, <a href="#10" class="mim-tip-reference" title="Jouret, G., Heide, S., Sorlin, A., Faivre, L., Chantot-Bastaraud, S., Beneteau, C., Denis-Musquer, M., Turnpenny, P. D., Coutton, C., Vieville, G., Thevenon, J., Larson, A., and 27 others. <strong>Understanding the new BRD4-related syndrome: clinical and genomic delineation with an international cohort study.</strong> Clin. Genet. 102: 117-122, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35470444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35470444</a>] [<a href="https://doi.org/10.1111/cge.14141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35470444">Jouret et al. (2022)</a> identified 2 fetuses and 12 patients aged 10 weeks to 32 years with mutations involving the BRD4 gene. The mutations included 8 point mutations and 6 large deletions. Of the 8 point mutations, 4 were premature truncating mutations (see, e.g., <a href="#0003">608749.0003</a>) and 4 were missense variants (see, e.g., <a href="#0001">608749.0001</a>, <a href="#0004">608749.0004</a>); one mutation (Y430C; <a href="/entry/608759#0001">608759.0001</a>) had previously been reported. Deletion size varied from 46 kb to 2.2 Mb; the 46-kb deletion overlapped only the BRD4 gene. Whereas some of the patients had microcephaly, arched eyebrows, synophrys, short nose, and anteverted nostrils, the authors did not think that any of the 14 patients had a classic CDLS phenotype because none had the typical features of growth failure, hypertrichosis, or radial/limb anomalies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35470444" 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="#11" class="mim-tip-reference" title="Linares-Saldana, R., Kim, W., Bolar, N. A., Zhang, H., Koch-Bojalad, B. A., Yoon, S., Shah, P. P., Karnay, A., Park, D. S., Luppino, J. M., Nguyen, S. C., Padmanabhan, A., and 10 others. <strong>BRD4 orchestrates genome folding to promote neural crest differentiation.</strong> Nature Genet. 53: 1480-1492, 2021. Note: Erratum: Nature Genet. 53: 1723, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34611363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34611363</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34611363[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-021-00934-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34611363">Linares-Saldana et al. (2021)</a> found that mice with neural crest-specific deletion of Brd4 underwent prenatal lethality. Examination of late-gestation mutant embryos revealed that loss of Brd4 in neural crest resulted in cohesinopathy-like phenotypes, including craniofacial, skeletal, and cardiac defects. These phenotypes were similar to those observed in mice with deletion of Nipbl. Immunoprecipitation analysis showed that BRD4 interacted with NIPBL in mouse and human cells. Mutation analysis revealed critical residues within a hydrophobic cleft of the extraterminal domain of human BRD4 that mediated NIPBL interaction. By interacting with NIPBL, BRD4 stabilized NIPBL binding on chromatin and regulated genome folding by maintaining normal genome folding architecture. Loss of Brd4 resulted in genomic architectural changes, but transcriptional dynamics in Brd4-depleted cells suggested that local transcriptional changes across the genome were unlikely to drive these architectural changes, indicating that the role of Brd4 in genome folding is distinct from its role in promoting transcription. Further analysis demonstrated that Brd4 regulated genome folding through Nipbl binding, and Brd4-Nipbl interaction promoted neural crest differentiation into smooth muscle. Moreover, smooth muscle differentiation defects resulting from loss of Brd4 were rescued by depletion of Wapl (<a href="/entry/610754">610754</a>), a negative regulator of cohesin complex, linking BRD4 function with regulation of cohesin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34611363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=608749[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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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003151935 OR RCV003448989" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003151935, RCV003448989" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003151935...</a>
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<p>In a 3-year-old girl (family 3049) with Cornelia de Lange syndrome (CDLS6; <a href="/entry/620568">620568</a>), <a href="#14" class="mim-tip-reference" title="Olley, G., Ansari, M., Bengani, H., Grimes, G. R., Rhodes, J., von Kriegsheim, A., Blatnik, A., Stewart, F. J., Wakeling, E., Carroll, N., Ross, A., Park, S. M., Deciphering Developmental Disorders Study, Bickmore, W. A., Pradeepa, M. M., FitzPatrick, D. R. <strong>BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome.</strong> Nature Genet. 50: 329-332, 2018. Note: Erratum: Nature Genet 50: 767, 2018; Erratum: Nature Genet. 51: 1192, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29379197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29379197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29379197[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0042-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29379197">Olley et al. (2018)</a> identified a de novo heterozygous c.1289A-G (c.1289A-G, NM_058243.2) transition in the second bromodomain of the BRD4 gene, resulting in a tyr430-to-cys (Y430C) substitution. The patient met diagnostic criteria for CDLS including typical facies. Other features included microcephaly, intellectual disability, absent speech, hip dysplasia, and a ventricular septal defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29379197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 29-year-old male (P9) with CDLS6, <a href="#10" class="mim-tip-reference" title="Jouret, G., Heide, S., Sorlin, A., Faivre, L., Chantot-Bastaraud, S., Beneteau, C., Denis-Musquer, M., Turnpenny, P. D., Coutton, C., Vieville, G., Thevenon, J., Larson, A., and 27 others. <strong>Understanding the new BRD4-related syndrome: clinical and genomic delineation with an international cohort study.</strong> Clin. Genet. 102: 117-122, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35470444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35470444</a>] [<a href="https://doi.org/10.1111/cge.14141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35470444">Jouret et al. (2022)</a> identified de novo heterozygosity for the Y430C mutation. The patient had a frontal upsweep of hair, synophrys, arched eyebrows, downslanting palpebral fissures, short nose, anteverted nares, prominent incisors, and short philtrum. His dysmorphic features evolved with age: he developed hyperphagia at age 18 years with truncal obesity, with facial features in adulthood reminiscent of Cohen syndrome (<a href="/entry/216550">216550</a>). He developed schizophrenia in adulthood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35470444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an 11-year-old girl (family CDL038) with Cornelia de Lange syndrome (CDLS6; <a href="/entry/620568">620568</a>), <a href="#14" class="mim-tip-reference" title="Olley, G., Ansari, M., Bengani, H., Grimes, G. R., Rhodes, J., von Kriegsheim, A., Blatnik, A., Stewart, F. J., Wakeling, E., Carroll, N., Ross, A., Park, S. M., Deciphering Developmental Disorders Study, Bickmore, W. A., Pradeepa, M. M., FitzPatrick, D. R. <strong>BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome.</strong> Nature Genet. 50: 329-332, 2018. Note: Erratum: Nature Genet 50: 767, 2018; Erratum: Nature Genet. 51: 1192, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29379197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29379197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29379197[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0042-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29379197">Olley et al. (2018)</a> identified a de novo heterozygous indel mutation (c.1224delinsCA, NM_058243.2), resulting in a frameshift and premature termination termination (Glu408AspfsTer4). The patient met diagnostic criteria for CDLS, including facial features (synophrys, short nose, and long philtrum). Other findings included microcephaly, developmental delay, and myopia. The authors classified the disorder in this patient as 'typical CDLS.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29379197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 10-year-old boy (P8) with Cornelia de Lange syndrome (CDLS6; <a href="/entry/620568">620568</a>), <a href="#10" class="mim-tip-reference" title="Jouret, G., Heide, S., Sorlin, A., Faivre, L., Chantot-Bastaraud, S., Beneteau, C., Denis-Musquer, M., Turnpenny, P. D., Coutton, C., Vieville, G., Thevenon, J., Larson, A., and 27 others. <strong>Understanding the new BRD4-related syndrome: clinical and genomic delineation with an international cohort study.</strong> Clin. Genet. 102: 117-122, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35470444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35470444</a>] [<a href="https://doi.org/10.1111/cge.14141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35470444">Jouret et al. (2022)</a> identified a 1-bp insertion (c.2753_2754insT) in the BRD4 gene, resulting in a frameshift and premature termination (Pro919ThrfsTer174). The phenotype consisted of intrauterine growth restriction, intellectual disability, microcephaly, and facial features of synophrys, arched and sparse eye brows, short and anteverted nose, and short philtrum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35470444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003449005 OR RCV003985032" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003449005, RCV003985032" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003449005...</a>
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<p>In a 10-year-old boy (patient P11) with Cornelia de Lange syndrome (CDLS6; <a href="/entry/620568">620568</a>), <a href="#10" class="mim-tip-reference" title="Jouret, G., Heide, S., Sorlin, A., Faivre, L., Chantot-Bastaraud, S., Beneteau, C., Denis-Musquer, M., Turnpenny, P. D., Coutton, C., Vieville, G., Thevenon, J., Larson, A., and 27 others. <strong>Understanding the new BRD4-related syndrome: clinical and genomic delineation with an international cohort study.</strong> Clin. Genet. 102: 117-122, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35470444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35470444</a>] [<a href="https://doi.org/10.1111/cge.14141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35470444">Jouret et al. (2022)</a> identified a c.883A-C transversion in the BRD4 gene, resulting in a thr295-to-pro (T295P) substitution. The patient had mild intellectual disability, a normal head size, arched and sparse eyebrows, anteverted nares, frontal upsweep of the hair, prominent incisors, and a short philtrum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35470444" 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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Choe, J., Lin, S., Zhang, W., Liu, Q., Wang, L., Ramirez-Moya, J., Du, P., Kim, W., Tang, S., Sliz, P., Santisteban, P., George, R. E., Richards, W. G., Wong, K.-K., Locker, N., Slack, F. J., Gregory, R. I.
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<strong>mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis.</strong>
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Nature 561: 556-560, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30232453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30232453</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30232453[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30232453" 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/s41586-018-0538-8" target="_blank">Full Text</a>]
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Crawford, N. P. S., Alsarraj, J., Lukes, L., Walker, R. C., Officewala, J. S., Yang, H. H., Lee, M. P., Ozato, K., Hunter, K. W.
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<strong>Bromodomain 4 activation predicts breast cancer survival.</strong>
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Proc. Nat. Acad. Sci. 105: 6380-6385, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18427120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18427120</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18427120[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18427120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0710331105" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature10509" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/MCB.20.17.6537-6549.2000" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41586-020-1930-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature12147" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0002-9440(10)63049-0" target="_blank">Full Text</a>]
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<strong>The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16109376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16109376</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16109376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2005.06.027" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35470444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35470444</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35470444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/cge.14141" target="_blank">Full Text</a>]
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Linares-Saldana, R., Kim, W., Bolar, N. A., Zhang, H., Koch-Bojalad, B. A., Yoon, S., Shah, P. P., Karnay, A., Park, D. S., Luppino, J. M., Nguyen, S. C., Padmanabhan, A., and 10 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34611363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34611363</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34611363[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34611363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41588-021-00934-8" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12192049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12192049</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12192049[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12192049" 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/10.1128/MCB.22.18.6509-6520.2002" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29622725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29622725</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29622725[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29622725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aao2793" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29379197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29379197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29379197[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29379197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41588-018-0042-y" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34035299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34035299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34035299[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34035299" 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/s41467-021-23500-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41588-019-0413-z" target="_blank">Full Text</a>]
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</p>
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<a id="17" class="mim-anchor"></a>
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<a id="Smith2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Smith, J. A., White, E. A., Sowa, M. E., Powell, M. L. C., Ottinger, M., Harper, J. W., Howley, P. M.
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<strong>Genome-wide siRNA screen identifies SMCX, EP400, and Brd4 as E2-dependent regulators of human papillomavirus oncogene expression.</strong>
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Proc. Nat. Acad. Sci. 107: 3752-3757, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20133580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20133580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20133580[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20133580" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0914818107" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Yang2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yang, Z., Yik, J. H. N., Chen, R., He, N., Jang, M. K., Ozato, K., Zhou, Q.
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<strong>Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4.</strong>
|
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Molec. Cell 19: 535-545, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16109377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16109377</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16109377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2005.06.029" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="You2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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You, J., Croyle, J. L., Nishimura, A., Ozato, K., Howley, P. M.
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<strong>Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes.</strong>
|
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Cell 117: 349-360, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15109495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15109495</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15109495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(04)00402-7" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Zuber2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zuber, J., Shi, J., Wang, E., Rappaport, A. R., Herrmann, H., Sison, E. A., Magoon, D., Qi, J., Blatt, K., Wunderlich, M., Taylor, M. J., Johns, C., Chicas, A., Mulloy, J. C., Kogan, S. C., Brown, P., Valent, P., Bradner, J. E., Lowe, S. W., Vakov, C. R.
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<strong>RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.</strong>
|
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Nature 478: 524-528, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21814200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21814200</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21814200[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21814200" 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/nature10334" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 01/18/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 12/15/2023<br>Bao Lige - updated : 11/01/2023<br>Ada Hamosh - updated : 06/29/2020<br>Bao Lige - updated : 07/08/2019<br>Ada Hamosh - updated : 03/05/2019<br>Ada Hamosh - updated : 06/27/2018<br>Ada Hamosh - updated : 07/22/2013<br>Paul J. Converse - updated : 4/4/2012<br>Ada Hamosh - updated : 1/4/2012<br>Patricia A. Hartz - updated : 6/27/2008<br>Patricia A. Hartz - updated : 9/22/2005<br>Patricia A. Hartz - updated : 10/7/2004<br>Patricia A. Hartz - updated : 8/9/2004
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Stylianos E. Antonarakis : 6/21/2004
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/27/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 04/16/2024<br>alopez : 01/25/2024<br>mgross : 01/18/2024<br>carol : 12/15/2023<br>alopez : 11/01/2023<br>alopez : 06/29/2020<br>mgross : 07/08/2019<br>alopez : 03/05/2019<br>alopez : 06/27/2018<br>alopez : 07/22/2013<br>mgross : 2/5/2013<br>mgross : 5/4/2012<br>terry : 4/4/2012<br>alopez : 1/6/2012<br>terry : 1/4/2012<br>mgross : 2/20/2009<br>mgross : 7/1/2008<br>terry : 6/27/2008<br>wwang : 9/26/2005<br>wwang : 9/22/2005<br>mgross : 10/7/2004<br>mgross : 9/9/2004<br>terry : 8/9/2004<br>mgross : 6/21/2004
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 608749
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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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BROMODOMAIN-CONTAINING PROTEIN 4; BRD4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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MITOTIC CHROMOSOME-ASSOCIATED PROTEIN; MCAP; CAP<br />
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HUNK1
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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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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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BRD4/NUT FUSION GENE, INCLUDED
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</span>
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: BRD4</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 19p13.12
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:15,235,519-15,332,539 </span>
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</em>
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</strong>
|
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
|
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<th>
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Location
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</th>
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<th>
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|
Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
|
Inheritance
|
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</th>
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<th>
|
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
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<span class="mim-font">
|
|
19p13.12
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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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Cornelia de Lange syndrome 6
|
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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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620568
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
|
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</span>
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</td>
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</tr>
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</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>BRD4 belongs to the BET family of nuclear proteins that carry 2 bromodomains and an additional ET domain. Bromodomains are implicated in chromatin interactions (Maruyama et al., 2002). </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>Dey et al. (2000) cloned mouse Brd4, which they called Mcap. The deduced 1,400-amino acid protein has a calculated molecular mass of 155 kD. It contains 2 N-terminal bromodomains, a central ET domain, and several kinase-like motifs in its N-terminal half. By database analysis, Dey et al. (2000) identified a human cDNA encoding a 731-amino acid protein with the same domain organization as the N-terminal half of mouse Brd4, but lacking the C-terminal half. Northern blot analysis detected a transcript of about 6.5 kb in all adult and embryonic mouse tissues examined and in human cells. Western blot analysis of in vitro translated mouse Brd4 and HeLa cell lysates detected BRD4 at about 200 kD, suggesting posttranslational modification. Indirect immunofluorescent staining of HeLa cells and 2 mouse cell lines detected BRD4 in the nucleus. During interphase, BRD4 was uniformly distributed as fine grains in the nucleus, but it was excluded from nucleoli. In mitotic cells, BRD4 localized almost exclusively on condensed chromosomes. </p><p>French et al. (2001) described 2 alternatively spliced variants of BRD4 that encode proteins identical through their N-terminal halves, which include 2 bromodomains, the ET domain, and a serine-rich region. The longer variant has a C-terminal extension that includes a proline-rich region and a glutamine-rich region. </p><p>By EST database analysis and PCR of a human cDNA library, You et al. (2004) obtained a full-length cDNA encoding BRD4. The BRD4 protein contains 1,362 amino acids. </p><p>By Northern blot analysis, French et al. (2003) determined that BRD4 is ubiquitously expressed as 4.4- and 6.0-kb transcripts, which likely encode the short and long BRD4 isoforms. </p>
|
|
</span>
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<div>
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<br />
|
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<span class="mim-text-font">
|
|
<p>French et al. (2001) reported that the coding region of the BRD4 gene contains 19 exons. </p>
|
|
</span>
|
|
<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>By analysis of a translocation involving chromosome 19, French et al. (2001) mapped the BRD4 gene to chromosome 19p13.1. By FISH, Dey et al. (2000) mapped the mouse Brd4 gene to the distal region of chromosome 17B, which shows homology of synteny to human chromosome 19. </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>
|
|
<span class="mim-font">
|
|
<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">
|
|
<p>By analyzing well-spread metaphase preparations of murine myeloid precursor cells, Dey et al. (2000) found Brd4 staining along the entire length of chromosomes, with the exception of centromeres. Brd4 chromosome association became visible following initiation of histone H3 (see 602810) phosphorylation and early chromosomal condensation and persisted until the end of mitosis. Differential salt extraction and FRAP analysis indicated that Brd4 was loosely associated with chromatin during interphase as well as mitosis. Supporting a role for BRD4 in G2/M transition, microinjection of anti-BRD4 antibody into HeLa cell nuclei completely inhibited entry into mitosis without abrogating ongoing DNA replication. Dey et al. (2000) concluded that BRD4 plays a role in chromosomal dynamics during mitosis. </p><p>Maruyama et al. (2002) found that ectopic expression of mouse Brd4 in mouse fibroblasts and HeLa cells inhibited cell cycle progression from G1 to S. Endogenous and transfected Brd4 interacted with replication factor C (RFC), the conserved 5-subunit complex essential for DNA replication, with Brd4 binding directly to the largest subunit, RFC1 (102579). In agreement with the inhibitory activity observed in vivo, recombinant Brd4 inhibited RFC-dependent DNA elongation reactions in vitro. Analysis of Brd4 deletion mutants indicated that both the interaction with human RFC1 and the inhibition of entry into S phase were dependent on the second bromodomain of Brd4. Cotransfection with RFC1 reduced the growth-inhibitory effect of Brd4. </p><p>You et al. (2004) identified BRD4 as a major cellular interacting partner of the bovine papillomavirus (BPV) E2 protein. They found that BRD4 associated with mitotic chromosomes and colocalized with E2 on mitotic chromosomes. The site of E2 binding mapped to the C-terminal domain of BRD4. Expression of this C-terminal BRD4 domain functioned in a dominant-negative manner to abrogate the colocalization of E2 with BRD4 on mitotic chromosomes, to block association of the viral episomes with BRD4, and to inhibit BPV-1 DNA-mediated cellular transformation. BRD4 also associated with human papillomavirus-16 E2, indicating that BRD4 binding may be a shared property of all papillomavirus E2 proteins. You et al. (2004) concluded that the interaction of E2 with BRD4 is required to ensure the tethering of viral genomes to the host mitotic chromosomes for persistence of viral episomes in papillomavirus-infected cells. </p><p>Jang et al. (2005) found that epitope-tagged mouse Brd4 interacted with cyclin T1 (143055) and CDK9 (603251) in core positive transcription elongation factor b (P-TEFb) complexes contained in HeLa cell nuclear extracts. The bromodomain of Brd4 was required for the interaction. Brd4 overexpression increased P-TEFb-dependent phosphorylation of the C-terminal domain of RNA polymerase II (see POLR2A; 180660) and stimulated transcription of a reporter plasmid driven by an HIV-1 promoter. Conversely, reduced Brd4 expression in mouse fibroblasts by small interfering RNA reduced RNA polymerase II C-terminal domain phosphorylation and transcription. Chromatin immunoprecipitation assays indicated that recruitment of P-TEFb to a promoter was dependent on Brd4, and recruitment was enhanced by increased chromatin acetylation. </p><p>About half of cellular P-TEFb exists in an inactive complex with 7SK snRNA (606515) and the HEXIM1 protein (607328). Yang et al. (2005) demonstrated that the remaining half associated with BRD4. In stress-induced HeLa cells, 7SK/HEXIM1-bound P-TEFb was converted into the BRD4-associated form. The association of P-TEFb with BRD4 was necessary to form the transcriptionally active P-TEFb, to recruit P-TEFb to a promoter, and to enable P-TEFb to contact the Mediator complex (see 602984). </p><p>Crawford et al. (2008) showed that activation of Brd4 in mice repressed tumor growth and metastasis and that BRD4 activation in human breast carcinomas induced a gene expression profile predictive of breast cancer outcome. </p><p>Zuber et al. (2011) described a nonbiased approach to probe epigenetic vulnerabilities in acute myeloid leukemia (AML; 601626), an aggressive hematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, they identified the protein BRD4 as being required for disease maintenance. Suppression of BRD4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of BRD4 suppression are, at least in part, due to its role in sustaining MYC (190080) expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacologic means to suppress MYC in cancer. </p><p>Dawson et al. (2011) demonstrated that I-BET151, a novel small molecule inhibitor of the BET family, of which BRD4 is a member, has profound efficacy against human and murine MLL-fusion leukemia cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in 2 human leukemia cell lines with different MLL fusions altered the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes BCL2 (151430), C-MYC, and CDK6 (603368) through the displacement of BRD3/4, PAFc, and SEC components from chromatin. In vivo studies indicated that I-BET151 has significant therapeutic value, providing survival benefit in 2 distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukemia. </p><p>Using a genomewide small interfering RNA screen and secondary screens, Smith et al. (2010) identified 96 cellular genes that contributed to viral E2 protein-mediated repression of the human papillomavirus (HPV) long control region, which controls viral oncogene expression. In addition to the E2-binding protein BRD4, other genes implicated included the demethylase SMCX (KDM5C; 314690) and EP400 (606265), a component of the NUA4/TIP60 histone acetyltransferase complex (see 601409). Smith et al. (2010) concluded that HPV E2 uses multiple cellular proteins to inhibit expression of its oncogenes. </p><p>Floyd et al. (2013) investigated the role of chromatin structure in the DNA damage response by monitoring ionizing radiation-induced signaling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. Floyd et al. (2013) found that isoform B of BRD4, in which the C-terminal domain containing the P-TEFb-interacting region is replaced with a divergent 75-amino acid segment, functions as an endogenous inhibitor of DNA damage response signaling by recruiting the condensin II chromatin remodeling complex to acetylated histones through bromodomain interactions. Loss of this isoform resulted in relaxed chromatin structure, rapid cell cycle checkpoint recovery, and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signaling, and enhanced radiation-induced lethality. Floyd et al. (2013) concluded that their data implicated BRD4 as an insulator of chromatin that can modulate the signaling response to DNA damage. </p><p>Muhar et al. (2018) combined SLAM-seq (thiol(SH)-linked alkylation for the metabolic sequencing of RNA), a method for direct quantification of newly synthesized mRNAs, with pharmacologic and chemical-genetic perturbation in order to define regulatory functions of 2 transcriptional hubs in cancer, BRD4 and MYC (190080), and to interrogate direct responses to BET bromodomain inhibitors (BETis). Muhar et al. (2018) found that BRD4 acts as general coactivator of RNA POL2 (see 180660)-dependent transcription, which is broadly repressed upon high-dose BETi treatment. At doses triggering selective effects in leukemia, BETis deregulate a small set of hypersensitive targets, including MYC. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator controlling metabolic processes such as ribosome biogenesis and de novo purine synthesis. Muhar et al. (2018) concluded that their study established a simple and scalable strategy to identify direct transcriptional targets of any gene or pathway. </p><p>Choe et al. (2018) demonstrated that METTL3 (612472) enhances translation only when tethered to reporter mRNA at sites close to the stop codon, supporting a mechanism of mRNA looping for ribosome recycling and translational control. Electron microscopy revealed the topology of individual polyribosomes with single METTL3 foci in close proximity to 5-prime cap-binding proteins. Choe et al. (2018) identified a direct physical and functional interaction between METTL3 and the eukaryotic translation initiation factor 3 subunit H (EIF3H; 603912). METTL3 promotes translation of a large subset of oncogenic mRNAs, including BRD4, that is also N6-methyladenosine (m6A)-modified in human primary lung tumors. The METTL3-EIF3H interaction is required for enhanced translation, formation of densely packed polyribosomes, and oncogenic transformation. METTL3 depletion inhibits tumorigenicity and sensitizes lung cancer cells to BRD4 inhibition. Choe et al. (2018) concluded that these findings uncovered a mechanism of translation control that is based on mRNA looping. </p><p>Using a genetic screen, Sdelci et al. (2019) identified human MTHFD1 (172460) as a functional partner of BRD4. BRD4 physically interacted with MTHFD1 in nucleus and recruited it to chromatin. The interaction was enhanced by binding of the BRD4 bromodomains to acetylated lysines on the surface of MTHFD1. Chromatin immunoprecipitation-sequencing analysis revealed that MTHFD1 regulated gene expression by colocalizing with BRD4 at promoter and enhancer regions, where H3K27ac was also enriched. Furthermore, BRD4 boosted the C1-tetrahydrofolate synthase activity of MTHFD1, and loss of either MTHFD1 or BRD4 resulted in similar changes in nuclear metabolite composition and gene expression, correlating BRD4-dependent epigenetic regulation and folate metabolism. Antifolates synergized with BRD4 inhibitors and impaired cancer cell proliferation without exerting general toxicity. </p><p>By ChIP-seq analysis in mouse embryonic stem cells (mESCs), Olley et al. (2021) showed that a Brd4 Y430C mutation reduced occupancy of Brd4 protein at cis-regulatory elements (CREs). However, the decreased occupancy of the Brd4 Y430C mutant at CREs was not sufficient to affect the transcription of associated genes in mESCs, despite the role of Brd4 in transcriptional regulation. Instead, the Brd4 Y430C mutant resulted in a delayed cell cycle, increased cell cycle checkpoint activation, increased DNA damage response (DDR) signaling, and defective double-strand break (DSB) in mESCs. The DDR defect observed in mESCs with the Brd4 Y430C mutation was also seen in lymphoblastoid cell lines with a Cornelia de Lange syndrome (CDLS; 122470)-associated NIPBL (608667) mutation, suggesting that increased DDR signaling and/or impaired DNA repair pathway choice balance might contribute to the etiology of CDLS. </p>
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<h4>
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<span class="mim-font">
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<strong>Other Features</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>Faivre et al. (2020) performed a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by dual-bromodomain BET inhibitors, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukemia (601626) and prostate cancer (176807) that expressed the full-length androgen receptor (AR; 313700). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the dual-bromodomain BET inhibitors. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing superenhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with a dual-bromodomain BET inhibitor. </p>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</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>The balanced translocation t(15;19) has been identified in midline carcinomas adjacent to the respiratory tract in children and young adults and is associated with poor survival and a treatment-refractory course. French et al. (2001) mapped the translocation breakpoints in 2 patients with t(15;19)(q13;p13.1) carcinomas. The chromosome 19 translocation breakpoints were between introns 10 and 13 in the 3-prime end of the BRD4 coding sequence in both cancers. The breakpoints split the coding sequence of the longer BRD4 transcript and left the short transcript unaltered. The breakpoints in chromosome 15q13 localized to an approximately 9-kb region containing the NOP10 gene (NOLA3; 606471) gene. FISH screening of 13 supradiaphragmatic pediatric carcinomas revealed a sinonasal carcinoma with a chromosome 19p13.1 and 15q13 rearrangement. The other 12 carcinomas lacked chromosome 15 or 19 rearrangements. </p><p>French et al. (2003) determined that the BRD4 fusion partner in the t(15;19) translocation is NUT (608963). Sequence analysis indicated that the translocations in 2 affected tumors were identical and resulted in the in-frame fusion of exon 10 of BRD4 with exon 2 of NUT. The oncogenic fusion protein contains the N-terminal BRD4 sequence up to the serine-rich region, followed by almost the entire NUT sequence. It lacks only the first 5 NUT residues. Northern blot analysis detected a 6.4-kb fusion transcript in a t(15;19)-positive carcinoma cell line. No NUT/BRD4 transcripts were detected. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Among 92 patients with features of Cornelia de Lange syndrome who were negative for mutations in known causative genes, Olley et al. (2018) identified 2 unrelated patients with de novo heterozygous mutations in the BRD4 gene (see CDLS6, 620568): a missense mutation (Y430C; 608749.0001) and a 1.04 Mb deletion that included BRD4 and 28 other protein-coding genes. Two additional patients who were not part of the original cohort were identified with de novo heterozygous frameshift mutations in BRD4 (see, e.g., 608749.0002). The authors then reviewed phenotypes of other patients with heterozygous multigenic deletions encompassing BRD4 and recognized a significant overlap with the CDLS phenotype, suggesting that BRD4 haploinsufficiency is the likely cause of CDLS6. The authors showed that the BRD4 missense variant (Y430C) resulted in more typical CDLS; this variant retained the ability to coimmunoprecipitate with NIPBL (608667), the causative gene in CDLS1 (122470), but had decreased binding to acetylated histones of promoter and superenhancer genes. Functional analyses demonstrated that BRD4 and NIPBL coregulated binding at superenhancer genes and appeared to coregulate developmental gene expression. </p><p>Through an international collaboration, Jouret et al. (2022) identified 2 fetuses and 12 patients aged 10 weeks to 32 years with mutations involving the BRD4 gene. The mutations included 8 point mutations and 6 large deletions. Of the 8 point mutations, 4 were premature truncating mutations (see, e.g., 608749.0003) and 4 were missense variants (see, e.g., 608749.0001, 608749.0004); one mutation (Y430C; 608759.0001) had previously been reported. Deletion size varied from 46 kb to 2.2 Mb; the 46-kb deletion overlapped only the BRD4 gene. Whereas some of the patients had microcephaly, arched eyebrows, synophrys, short nose, and anteverted nostrils, the authors did not think that any of the 14 patients had a classic CDLS phenotype because none had the typical features of growth failure, hypertrichosis, or radial/limb anomalies. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Linares-Saldana et al. (2021) found that mice with neural crest-specific deletion of Brd4 underwent prenatal lethality. Examination of late-gestation mutant embryos revealed that loss of Brd4 in neural crest resulted in cohesinopathy-like phenotypes, including craniofacial, skeletal, and cardiac defects. These phenotypes were similar to those observed in mice with deletion of Nipbl. Immunoprecipitation analysis showed that BRD4 interacted with NIPBL in mouse and human cells. Mutation analysis revealed critical residues within a hydrophobic cleft of the extraterminal domain of human BRD4 that mediated NIPBL interaction. By interacting with NIPBL, BRD4 stabilized NIPBL binding on chromatin and regulated genome folding by maintaining normal genome folding architecture. Loss of Brd4 resulted in genomic architectural changes, but transcriptional dynamics in Brd4-depleted cells suggested that local transcriptional changes across the genome were unlikely to drive these architectural changes, indicating that the role of Brd4 in genome folding is distinct from its role in promoting transcription. Further analysis demonstrated that Brd4 regulated genome folding through Nipbl binding, and Brd4-Nipbl interaction promoted neural crest differentiation into smooth muscle. Moreover, smooth muscle differentiation defects resulting from loss of Brd4 were rescued by depletion of Wapl (610754), a negative regulator of cohesin complex, linking BRD4 function with regulation of cohesin. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>4 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CORNELIA DE LANGE SYNDROME 6</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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BRD4, TYR430CYS
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<br />
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ClinVar: RCV003151935, RCV003448989
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<div>
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<span class="mim-text-font">
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<p>In a 3-year-old girl (family 3049) with Cornelia de Lange syndrome (CDLS6; 620568), Olley et al. (2018) identified a de novo heterozygous c.1289A-G (c.1289A-G, NM_058243.2) transition in the second bromodomain of the BRD4 gene, resulting in a tyr430-to-cys (Y430C) substitution. The patient met diagnostic criteria for CDLS including typical facies. Other features included microcephaly, intellectual disability, absent speech, hip dysplasia, and a ventricular septal defect. </p><p>In a 29-year-old male (P9) with CDLS6, Jouret et al. (2022) identified de novo heterozygosity for the Y430C mutation. The patient had a frontal upsweep of hair, synophrys, arched eyebrows, downslanting palpebral fissures, short nose, anteverted nares, prominent incisors, and short philtrum. His dysmorphic features evolved with age: he developed hyperphagia at age 18 years with truncal obesity, with facial features in adulthood reminiscent of Cohen syndrome (216550). He developed schizophrenia in adulthood. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CORNELIA DE LANGE SYNDROME 6</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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BRD4, c.1224delinsCA
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<br />
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ClinVar: RCV003449003
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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 an 11-year-old girl (family CDL038) with Cornelia de Lange syndrome (CDLS6; 620568), Olley et al. (2018) identified a de novo heterozygous indel mutation (c.1224delinsCA, NM_058243.2), resulting in a frameshift and premature termination termination (Glu408AspfsTer4). The patient met diagnostic criteria for CDLS, including facial features (synophrys, short nose, and long philtrum). Other findings included microcephaly, developmental delay, and myopia. The authors classified the disorder in this patient as 'typical CDLS.' </p>
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</span>
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</div>
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<div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 CORNELIA DE LANGE SYNDROME 6</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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BRD4, 1-BP INS, 2753T
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<br />
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ClinVar: RCV003449004
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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 10-year-old boy (P8) with Cornelia de Lange syndrome (CDLS6; 620568), Jouret et al. (2022) identified a 1-bp insertion (c.2753_2754insT) in the BRD4 gene, resulting in a frameshift and premature termination (Pro919ThrfsTer174). The phenotype consisted of intrauterine growth restriction, intellectual disability, microcephaly, and facial features of synophrys, arched and sparse eye brows, short and anteverted nose, and short philtrum. </p>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 CORNELIA DE LANGE SYNDROME 6</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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BRD4, THR295PRO
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<br />
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ClinVar: RCV003449005, RCV003985032
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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 10-year-old boy (patient P11) with Cornelia de Lange syndrome (CDLS6; 620568), Jouret et al. (2022) identified a c.883A-C transversion in the BRD4 gene, resulting in a thr295-to-pro (T295P) substitution. The patient had mild intellectual disability, a normal head size, arched and sparse eyebrows, anteverted nares, frontal upsweep of the hair, prominent incisors, and a short philtrum. </p>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Choe, J., Lin, S., Zhang, W., Liu, Q., Wang, L., Ramirez-Moya, J., Du, P., Kim, W., Tang, S., Sliz, P., Santisteban, P., George, R. E., Richards, W. G., Wong, K.-K., Locker, N., Slack, F. J., Gregory, R. I.
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<strong>mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis.</strong>
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Nature 561: 556-560, 2018.
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[PubMed: 30232453]
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[Full Text: https://doi.org/10.1038/s41586-018-0538-8]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Crawford, N. P. S., Alsarraj, J., Lukes, L., Walker, R. C., Officewala, J. S., Yang, H. H., Lee, M. P., Ozato, K., Hunter, K. W.
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<strong>Bromodomain 4 activation predicts breast cancer survival.</strong>
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Proc. Nat. Acad. Sci. 105: 6380-6385, 2008.
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[PubMed: 18427120]
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Linares-Saldana, R., Kim, W., Bolar, N. A., Zhang, H., Koch-Bojalad, B. A., Yoon, S., Shah, P. P., Karnay, A., Park, D. S., Luppino, J. M., Nguyen, S. C., Padmanabhan, A., and 10 others.
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<strong>BRD4 orchestrates genome folding to promote neural crest differentiation.</strong>
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Nature Genet. 53: 1480-1492, 2021. Note: Erratum: Nature Genet. 53: 1723, 2021.
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<strong>A mammalian bromodomain protein, Brd4, interacts with replication factor C and inhibits progression to S phase.</strong>
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Molec. Cell. Biol. 22: 6509-6520, 2002.
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Muhar, M., Ebert, A., Neumann, T., Umkehrer, C., Jude, J., Wieshofer, C., Rescheneder, P., Lipp, J. J., Herzog, V. A., Reichholf, B., Cisneros, D. A., Hoffmann, T., Schlapansky, M. F., Bhat, P., von Haeseler, A., Kocher, T., Obenauf, A. C., Popow, J., Ameres, S. L., Zuber, J.
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<strong>SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis.</strong>
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Science 360: 800-805, 2018.
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Olley, G., Ansari, M., Bengani, H., Grimes, G. R., Rhodes, J., von Kriegsheim, A., Blatnik, A., Stewart, F. J., Wakeling, E., Carroll, N., Ross, A., Park, S. M., Deciphering Developmental Disorders Study, Bickmore, W. A., Pradeepa, M. M., FitzPatrick, D. R.
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<strong>BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome.</strong>
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Nature Genet. 50: 329-332, 2018. Note: Erratum: Nature Genet 50: 767, 2018; Erratum: Nature Genet. 51: 1192, 2019.
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Olley, G., Pradeepa, M. M., Grimes, G. R., Piquet, S., Polo, S. E., FitzPatrick, D. R., Bickmore, W. A., Boumendil, C.
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<strong>Cornelia de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect.</strong>
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Nature Commun. 12: 3127, 2021.
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Sdelci, S., Rendeiro, A. F., Rathert, P., You, W., Lin, J.-M. G., Ringler, A., Hofstater, G., Moll, H. P., Gurtl, B., Farlik, M., Schick, S., Klepsch, F., and 25 others.
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<strong>MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation.</strong>
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Nature Genet. 51: 990-998, 2019.
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Smith, J. A., White, E. A., Sowa, M. E., Powell, M. L. C., Ottinger, M., Harper, J. W., Howley, P. M.
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<strong>Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4.</strong>
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You, J., Croyle, J. L., Nishimura, A., Ozato, K., Howley, P. M.
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<strong>Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes.</strong>
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Zuber, J., Shi, J., Wang, E., Rappaport, A. R., Herrmann, H., Sison, E. A., Magoon, D., Qi, J., Blatt, K., Wunderlich, M., Taylor, M. J., Johns, C., Chicas, A., Mulloy, J. C., Kogan, S. C., Brown, P., Valent, P., Bradner, J. E., Lowe, S. W., Vakov, C. R.
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<div class="modal-footer">
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<button type="button" id="mimDonationPopupDonate" class="btn btn-success btn-block" data-dismiss="modal"> Donate To OMIM! </button>
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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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</body>
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</html>
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