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Entry
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- *605314 - HISTONE DEACETYLASE 4; HDAC4
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- OMIM
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<p>
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<span class="h4">*605314</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</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="#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/605314">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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<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 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=ENSG00000068024;t=ENST00000543185" 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=9759" 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=605314" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="small">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000068024;t=ENST00000543185" 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_001378414,NM_001378415,NM_001378416,NM_001378417,NM_006037,XM_006712877,XM_006712880,XM_011512217,XM_011512218,XM_011512219,XM_011512220,XM_011512222,XM_011512223,XM_011512224,XM_011512225,XM_011512226,XM_011512227,XM_017005394,XM_024453257,XM_047446476,XM_047446477,XM_047446478,XM_047446479,XM_047446480,XM_047446481,XM_047446482,XM_047446483,XM_047446484,XM_047446485,XM_047446486,XM_047446487,XM_047446488,XM_047446489,XM_047446490,XM_047446491,XM_047446492,XM_047446493,XM_047446494,XM_047446495,XM_047446496,XM_047446497,XM_047446498" 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_001378414" 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=605314" 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=05610&isoform_id=05610_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/HDAC4" 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/4754907,25058273,62702143,62702144,62702330,119591571,119591572,119591574,153085395,221044224,221044548,221044582,221044644,259016348,578805267,578805273,767920742,767920745,767920747,767920749,767920754,767920756,767920758,767920760,767920762,767920766,929654431,1034618060,1370479645,1808670912,1808670916,1808670922,1808670934,2217332404,2217332407,2217332409,2217332411,2217332413,2217332416,2217332419,2217332421,2217332423,2217332425,2217332429,2217332431,2217332434,2217332437,2217332439,2217332441,2217332443,2217332446,2217332448,2217332450,2217332452,2217332454,2217332456,2462578876,2462578878,2462578880,2462578882,2462578884,2462578886,2462578888,2462578890,2462578892,2462578894,2462578896,2462578898,2462578900,2462578903,2462578905,2462578907,2462578909,2462578911,2462578913,2462578915,2462578917,2462578919,2462578921,2462578923,2462578925,2462578927,2462578929,2462578931,2462578933,2462578935,2462578937,2462578939,2462578941,2462578943,2462578945,2462578947,2892108981,2892109308,2892113959,2892114071,2893883100,2893883128" 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/P56524" 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=9759" 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=ENSG00000068024;t=ENST00000543185" 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=HDAC4" 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=HDAC4" 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+9759" 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/HDAC4" 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:9759" 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/9759" 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=chr2&hgg_gene=ENST00000543185.6&hgg_start=239048168&hgg_end=239401649&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">
|
|
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:14063" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/hdac4" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605314[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=605314[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/HDAC4/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/ENSG00000068024" 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=HDAC4" 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=HDAC4" 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=HDAC4" 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=HDAC4&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/PA29229" 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:14063" 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/FBgn0041210.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:3036234" 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/HDAC4#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:3036234" 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/9759/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=9759" 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=WBGene00001837;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-061013-95" 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">
|
|
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
|
<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
|
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</a>
|
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</span>
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</span>
|
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</div>
|
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:9759" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=HDAC4&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>
|
|
<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">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
605314
|
|
</span>
|
|
</span>
|
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</div>
|
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</div>
|
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<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
HISTONE DEACETYLASE 4; HDAC4
|
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|
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
HDACA
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=HDAC4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HDAC4</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/2/1166?start=-3&limit=10&highlight=1166">2q37.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:239048168-239401649&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'})">2:239,048,168-239,401,649</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/1166?start=-3&limit=10&highlight=1166">
|
|
2q37.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Neurodevelopmental disorder with central hypotonia and dysmorphic facies
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619797"> 619797 </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>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
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<p>DNA is wrapped around histone proteins to form nucleosomes and chromatin fiber, a higher-order structure. Chromatin can become alternatively transparent or opaque to transcription factors. Acetylation (see HAT1, <a href="/entry/603053">603053</a>) of lysine residues induces conformational changes in core histones by destabilizing nucleosomes and allowing transcription factors access to recognition elements in DNA. Deacetylation (see HDAC1, <a href="/entry/601241">601241</a>) of histones, on the other hand, reseals the chromosomal package, leading to a repression of transcription. See <a href="#17" class="mim-tip-reference" title="Wolffe, A. P. <strong>Transcriptional control: sinful repression.</strong> Nature 387: 16-17, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9139815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9139815</a>] [<a href="https://doi.org/10.1038/387016a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9139815">Wolffe (1997)</a> and <a href="#5" class="mim-tip-reference" title="Pazin, M. J., Kadonaga, J. T. <strong>What's up and down with histone deacetylation and transcription?</strong> Cell 89: 325-328, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150131</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80211-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9150131">Pazin and Kadonaga (1997)</a> for reviews. There are at least 2 classes of HDACs, class I, consisting of proteins homologous to yeast Rpd3 (e.g., HDAC1, HDAC2 (<a href="/entry/605164">605164</a>), and HDAC3 (<a href="/entry/605166">605166</a>)) and class II, consisting of proteins homologous to yeast Hda1. HDAC4 is a class II HDAC. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9139815+9150131" 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 searching an EST database for sequences similar to yeast Hda1, followed by screening a cDNA library and PCR, <a href="#4" class="mim-tip-reference" title="Grozinger, C. M., Hassig, C. A., Schreiber, S. L. <strong>Three proteins define a class of human histone deacetylases related to yeast Hda1p.</strong> Proc. Nat. Acad. Sci. 96: 4868-4873, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220385</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10220385[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.96.9.4868" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220385">Grozinger et al. (1999)</a> identified cDNAs encoding the class II HDACs HDAC4, HDAC5 (<a href="/entry/605315">605315</a>), and HDAC6 (<a href="/entry/300272">300272</a>). Sequence analysis predicted that the 1,085-amino acid HDAC4 protein, which is identical to the KIAA0288 protein, contains a catalytic region beginning at residue 802. Northern blot analysis detected a 9.6-kb HDAC4 transcript apparently restricted to brain, heart, and skeletal muscle. Western blot analysis showed that HDAC4 is expressed as a 119-kD protein that coimmunoprecipitates with RbAp48 (RBBP4; <a href="/entry/602923">602923</a>) and HDAC3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10220385" 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 random sequencing of a size-selected brain cDNA library, <a href="#3" class="mim-tip-reference" title="Fischle, W., Emiliani, S., Hendzel, M. J., Nagase, T., Nomura, N., Voelter, W., Verdin, E. <strong>A new family of human histone deacetylases related to Saccharomyces cerevisiae HDA1p.</strong> J. Biol. Chem. 274: 11713-11720, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10206986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10206986</a>] [<a href="https://doi.org/10.1074/jbc.274.17.11713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10206986">Fischle et al. (1999)</a> identified a partial cDNA encoding HDAC4, which they called HDACA. Northern blot analysis detected an 8.4-kb HDAC4 transcript in all tissues tested, with a strong 3.4-kb transcript also present in testis. Immunofluorescence analysis showed a subnuclear localization excluded from nucleoli in interphase cells. SDS-PAGE analysis demonstrated that HDAC4 interacts with multiple proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10206986" 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>Functional analysis by <a href="#4" class="mim-tip-reference" title="Grozinger, C. M., Hassig, C. A., Schreiber, S. L. <strong>Three proteins define a class of human histone deacetylases related to yeast Hda1p.</strong> Proc. Nat. Acad. Sci. 96: 4868-4873, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220385</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10220385[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.96.9.4868" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220385">Grozinger et al. (1999)</a> confirmed that HDAC4 possesses deacetylation activity against all 4 core histones. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10220385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Wang, A. H., Bertos, N. R., Vezmar, M., Pelletier, N., Crosato, M., Heng, H. H., Th'ng, J., Han, J., Yang, X.-J. <strong>HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor.</strong> Molec. Cell. Biol. 19: 7816-7827, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10523670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10523670</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10523670[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.19.11.7816" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10523670">Wang et al. (1999)</a> cloned HDAC4 and demonstrated that its deacetylase activity requires histidine at residues 802 and 803. They determined that HDAC4 does not bind DNA directly, but rather through MEF2C (<a href="/entry/600662">600662</a>) and MEF2D (<a href="/entry/600663">600663</a>). Binding of the N terminus of HDAC4 to MEF2C represses MEF2C transcription activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10523670" 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="Fischle, W., Dequiedt, F., Hendzel, M. J., Guenther, M. G., Lazar, M. A., Voelter, W., Verdin, E. <strong>Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR.</strong> Molec. Cell 9: 45-57, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11804585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11804585</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00429-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11804585">Fischle et al. (2002)</a> showed that the catalytic domain of HDAC4 interacts with HDAC3 via the transcriptional corepressor NCOR2 (<a href="/entry/600848">600848</a>). All experimental conditions leading to the suppression of HDAC4 binding to NCOR2 and to HDAC3 resulted in loss of enzymatic activity associated with HDAC4. These observations indicated that class II HDACs regulate transcription by bridging the enzymatically active NCOR2-HDAC3 complex and select transcription factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11804585" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Youn, H.-D., Grozinger, C. M., Liu, J. O. <strong>Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4.</strong> J. Biol. Chem. 275: 22563-22567, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10825153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10825153</a>] [<a href="https://doi.org/10.1074/jbc.C000304200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10825153">Youn et al. (2000)</a> reported that HDAC4 and MITR (<a href="/entry/606543">606543</a>) contain calmodulin-binding domains that overlap with their MEF2 binding domains. Binding of calmodulin to HDAC4 leads to its dissociation from MEF2, relieving MEF2 from the transcriptional repression by HDAC4. Together, HDAC4, MITR, and CABIN1 (<a href="/entry/604251">604251</a>) constitute a family of calcium-sensitive transcriptional repressors of MEF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10825153" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Um, J. W., Min, D. S., Rhim, H., Kim, J., Paik, S. R., Chung, K. C. <strong>Parkin ubiquitinates and promotes the degradation of RanBP2.</strong> J. Biol. Chem. 281: 3595-3603, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16332688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16332688</a>] [<a href="https://doi.org/10.1074/jbc.M504994200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16332688">Um et al. (2006)</a> stated that HDAC4 is sumoylated by RANBP2 (<a href="/entry/601181">601181</a>). They showed that parkin (<a href="/entry/602544">602544</a>) controlled the intracellular levels of sumoylated HDAC4 by ubiquitinating RANBP2 and causing its proteasome-dependent degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16332688" 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 luciferase analysis, <a href="#6" class="mim-tip-reference" title="Portal, D., Rosendorff, A., Kieff, E. <strong>Epstein-Barr nuclear antigen leader protein coactivates transcription through interaction with histone deacetylase 4.</strong> Proc. Nat. Acad. Sci. 103: 19278-19283, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159145</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17159145[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.0609320103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159145">Portal et al. (2006)</a> showed that HDAC4 and HDAC5, but not other HDACs, repressed Epstein-Barr virus (EBV) nuclear antigen-2 (EBNA2) activation of EBV promoters, and that this repression could be reversed by EBNA leader protein (EBNALP). HDAC4 could repress EBNA2 and EBNALP coactivation of EBV promoters. Immunoprecipitation and Western blot analyses showed that HDAC4 associated with EBNA2 in the nucleus and with EBNALP in the nucleus and cytoplasm of lymphoblastoid cell lines. EBNALP reduced HDAC4 nuclear localization in B cells. Reporter gene analysis demonstrated that overexpression of HDAC4 or HDAC5 in the presence of overexpressed 14-3-3 (see <a href="/entry/605066">605066</a>) protein altered activation of different EBV promoters by EBNA2 and EBNALP. Coimmunoprecipitation and Western blot analyses revealed that 14-3-3, HDAC4, and EBNALP associated in a ternary complex. <a href="#6" class="mim-tip-reference" title="Portal, D., Rosendorff, A., Kieff, E. <strong>Epstein-Barr nuclear antigen leader protein coactivates transcription through interaction with histone deacetylase 4.</strong> Proc. Nat. Acad. Sci. 103: 19278-19283, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159145</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17159145[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.0609320103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159145">Portal et al. (2006)</a> concluded that EBNALP coactivates transcription by relocalizing HDAC4 and HDAC5 from EBNA2-activated promoters to the cytoplasm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17159145" 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="Tuddenham, L., Wheeler, G., Ntounia-Fousara, S., Waters, J., Hajihosseini, M. K., Clark, I., Dalmay, T. <strong>The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells.</strong> FEBS Lett. 580: 4214-4217, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16828749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16828749</a>] [<a href="https://doi.org/10.1016/j.febslet.2006.06.080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16828749">Tuddenham et al. (2006)</a> identified the 3-prime UTR of HDAC4 as 1 of 138 putative targets containing the miR140 (MIRN140; <a href="/entry/611894">611894</a>) seed sequence (5-prime-GTGGTTT-3-prime). A small interfering RNA that mimicked miR140 (siRNA140) downregulated expression of a reporter gene containing 800 bp of the human HDAC4 3-prime UTR, and transfection of siRNA140 into mouse fibroblasts reduced the level of endogenous Hdac4 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16828749" 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="Chen, B., Cepko, C. L. <strong>HDAC4 regulates neuronal survival in normal and diseased retinas.</strong> Science 323: 256-259, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19131628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19131628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19131628[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.1166226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19131628">Chen and Cepko (2009)</a> reported that Hdac4 regulates the survival of retinal neurons in the mouse in normal and pathologic conditions. Reduction in Hdac4 expression during normal retinal development led to apoptosis of rod photoreceptors and bipolar interneurons, whereas overexpression reduced naturally occurring cell death of the bipolar cells. Hdac4 overexpression in a mouse model of retinal degeneration prolonged photoreceptor survival. The survival effect was due to the activity of Hdac4 in the cytoplasm and relied at least partly on the activity of hypoxia-inducible factor 1-alpha (HIF1-alpha; <a href="/entry/603348">603348</a>). <a href="#1" class="mim-tip-reference" title="Chen, B., Cepko, C. L. <strong>HDAC4 regulates neuronal survival in normal and diseased retinas.</strong> Science 323: 256-259, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19131628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19131628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19131628[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.1166226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19131628">Chen and Cepko (2009)</a> concluded that their data provided evidence that HDAC4 plays an important role in promoting the survival of retinal neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19131628" 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="Robert, T., Vanoli, F., Chiolo, I., Shubassi, G., Bernstein, K. A., Rothstein, R., Botrugno, O. A., Parazzoli, D., Oldani, A., Minucci, S., Foiani, M. <strong>HDACs link the DNA damage response, processing of double-strand breaks and autophagy.</strong> Nature 471: 74-79, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21368826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21368826</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21368826[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/nature09803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21368826">Robert et al. (2011)</a> showed that HDAC inhibition/ablation specifically counteracts yeast Mec1 (ortholog of human ATR, <a href="/entry/601215">601215</a>) activation, double-strand break processing, and single-strand DNA-RFA nucleofilament formation. Moreover, the recombination protein Sae2 (human CTIP; <a href="/entry/604124">604124</a>) is acetylated and degraded after HDAC inhibition. Two HDACs, Hda1 and Rpd3 (HDAC1; <a href="/entry/601241">601241</a>) and 1 histone acetyltransferase (HAT), Gcn5 (GCN5L2; <a href="/entry/602301">602301</a>), have key roles in these processes. <a href="#7" class="mim-tip-reference" title="Robert, T., Vanoli, F., Chiolo, I., Shubassi, G., Bernstein, K. A., Rothstein, R., Botrugno, O. A., Parazzoli, D., Oldani, A., Minucci, S., Foiani, M. <strong>HDACs link the DNA damage response, processing of double-strand breaks and autophagy.</strong> Nature 471: 74-79, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21368826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21368826</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21368826[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/nature09803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21368826">Robert et al. (2011)</a> also found that HDAC inhibition triggers Sae2 degradation by promoting autophagy that affects the DNA damage sensitivity of Hda1 and Rpd3 mutants. Rapamycin, which stimulates autophagy by inhibiting Tor (MTOR; <a href="/entry/601231">601231</a>), also causes Sae2 degradation. <a href="#7" class="mim-tip-reference" title="Robert, T., Vanoli, F., Chiolo, I., Shubassi, G., Bernstein, K. A., Rothstein, R., Botrugno, O. A., Parazzoli, D., Oldani, A., Minucci, S., Foiani, M. <strong>HDACs link the DNA damage response, processing of double-strand breaks and autophagy.</strong> Nature 471: 74-79, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21368826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21368826</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21368826[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/nature09803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21368826">Robert et al. (2011)</a> proposed that Rpd3, Hda1, and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand break processing with autophagy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21368826" 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 immunofluorescence analysis and coimmunoprecipitation assays, <a href="#8" class="mim-tip-reference" title="Sasagawa, S., Takemori, H., Uebi, T., Ikegami, D., Hiramatsu, K., Ikegawa, S., Yoshikawa, H., Tsumaki, N. <strong>SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice.</strong> Development 139: 1153-1163, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22318228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22318228</a>] [<a href="https://doi.org/10.1242/dev.072652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22318228">Sasagawa et al. (2012)</a> found that salt-inducible kinase-3 (SIK3; <a href="/entry/614776">614776</a>) localized to the cytoplasm and formed a complex with Hdac4, a crucial repressor of chondrocyte hypertrophy, in mouse hypertrophic chondrocytes. The Sik3-Hdac4 interaction anchored Hdac4 in the cytoplasm. In Sik3-deficient mouse chondrocytes, Hdac4 localized to nuclei and repressed Mef2c, a crucial facilitator of chondrocyte hypertrophy, resulting in the blockage of chondrocyte hypertrophy. <a href="#8" class="mim-tip-reference" title="Sasagawa, S., Takemori, H., Uebi, T., Ikegami, D., Hiramatsu, K., Ikegawa, S., Yoshikawa, H., Tsumaki, N. <strong>SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice.</strong> Development 139: 1153-1163, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22318228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22318228</a>] [<a href="https://doi.org/10.1242/dev.072652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22318228">Sasagawa et al. (2012)</a> concluded that SIK3 plays an essential role in chondrocyte hypertrophy during skeletogenesis through its interaction with HDAC4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22318228" 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>Using FISH analysis, <a href="#14" class="mim-tip-reference" title="Wang, A. H., Bertos, N. R., Vezmar, M., Pelletier, N., Crosato, M., Heng, H. H., Th'ng, J., Han, J., Yang, X.-J. <strong>HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor.</strong> Molec. Cell. Biol. 19: 7816-7827, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10523670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10523670</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10523670[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.19.11.7816" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10523670">Wang et al. (1999)</a> mapped the HDAC4 gene to chromosome 2q37.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10523670" 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 7 unrelated patients with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; <a href="/entry/619797">619797</a>), <a href="#13" class="mim-tip-reference" title="Wakeling, E., McEntagart, M., Bruccoleri, M., Shaw-Smith, C., Stals, K. L., Wakeling, M., Barnicoat, A., Beesley, C., DDD Study, Hanson-Kahn, A. K., Kukolich, M., Stevenson, D. A., Campeau, P. M., Ellard, S., Elsea, S. H., Yang, X.-J., Caswell, R. C. <strong>Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.</strong> HGG Adv. 2: 100015, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33537682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33537682</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33537682[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.xhgg.2020.100015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33537682">Wakeling et al. (2021)</a> identified 4 different de novo heterozygous missense mutations (<a href="#0003">605314.0003</a>-<a href="#0006">605314.0006</a>) in the HDAC4 gene. The mutations, which were identified by whole-exome sequencing, were predicted to result in reduced HDAC4 affinity for 14-3-3 proteins, leading to reduced sequestration of HDAC4 in the cytoplasm by the 14-3-3 proteins and increased levels of HDAC4 in the nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33537682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of possible phenotypic consequences of deletion of the HDAC4 gene, see chromosome 2q37 deletion syndrome (<a href="/entry/600430">600430</a>).</p>
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<p><a href="#11" class="mim-tip-reference" title="Vega, R. B., Matsuda, K., Oh, J., Barbosa, A. C., Yang, X., Meadows, E., McAnally, J., Pomajzl, C., Shelton, J. M., Richardson, J. A., Karsenty, G., Olson, E. N. <strong>Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis.</strong> Cell 119: 555-566, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15537544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15537544</a>] [<a href="https://doi.org/10.1016/j.cell.2004.10.024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15537544">Vega et al. (2004)</a> reported that Hdac4, which is expressed in prehypertrophic chondrocytes, regulates chondrocyte hypertrophy and endochondral bone formation in mice by interacting with and inhibiting the activity of Runx2 (<a href="/entry/600211">600211</a>), a transcription factor necessary for chondrocyte hypertrophy. Hdac4-null mice displayed premature ossification of developing bones due to ectopic and early onset chondrocyte hypertrophy, mimicking the phenotype that results from constitutive Runx2 expression in chondrocytes. Conversely, overexpression of Hdac4 in proliferating chondrocytes in vivo inhibited chondrocyte hypertrophy and differentiation, mimicking a Runx2 loss-of-function phenotype. These results established HDAC4 as a central regulator of chondrocyte hypertrophy and skeletogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15537544" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs748900140 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs748900140;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs748900140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs748900140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>This variant, formerly titled BRACHYDACTYLY-MENTAL RETARDATION SYNDROME, has been reclassified based on the findings of <a href="#12" class="mim-tip-reference" title="Villavicencio-Lorini, P., Klopocki, E., Trimborn, M., Koll, R., Mundlos, S., Horn, D. <strong>Phenotypic variant of brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4.</strong> Europ. J. Hum. Genet. 21: 743-748, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23188045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23188045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23188045[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/ejhg.2012.240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23188045">Villavicencio-Lorini et al. (2013)</a> and <a href="#15" class="mim-tip-reference" title="Wheeler, P. G., Huang, D., Dai, Z. <strong>Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals.</strong> Am. J. Med. Genet. 164A: 1826-1829, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24715439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24715439</a>] [<a href="https://doi.org/10.1002/ajmg.a.36542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24715439">Wheeler et al. (2014)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23188045+24715439" 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 French Canadian woman with brachydactyly-mental retardation syndrome (BDMR; <a href="/entry/600430">600430</a>), <a href="#16" class="mim-tip-reference" title="Williams, S. R., Aldred, M. A., Der Kaloustian, V. M., Halal, F., Gowans, G., McLeod, D. R., Zondag, S., Toriello, H. V., Magenis, R. E., Elsea, S. H. <strong>Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.</strong> Am. J. Hum. Genet. 87: 219-228, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20691407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20691407</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20691407[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20691407">Williams et al. (2010)</a> identified a heterozygous de novo 1-bp insertion (2399insC) in exon 19 of the HDAC4 gene, resulting in a frameshift and premature termination. There was no evidence of nonsense-mediated mRNA decay, but the mutation likely resulted in haploinsufficiency. Quantitative RT-PCR analysis showed that lymphocytes from the patient did not alter HDAC4 expression, suggesting that the mutation does not result in nonsense-mediated mRNA decay and produces a nonfunctional protein. The patient had delayed psychomotor development, subvalvular aortic stenosis, dysmorphic facial features, brachydactyly type E (BDE), sleep disturbances, and behavioral problems. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20691407" 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="Villavicencio-Lorini, P., Klopocki, E., Trimborn, M., Koll, R., Mundlos, S., Horn, D. <strong>Phenotypic variant of brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4.</strong> Europ. J. Hum. Genet. 21: 743-748, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23188045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23188045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23188045[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/ejhg.2012.240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23188045">Villavicencio-Lorini et al. (2013)</a> reported a 3-generation family in which the proband, her mother, and her maternal grandmother had very mild developmental delay and dysmorphic facial features associated with an inherited heterozygous interstitial deletion of chromosome 2q37.3. None of the individuals had brachydactyly. The deletion was about 800 kb and included the HDAC4, FLJ43879, and TWIST2 (<a href="/entry/607556">607556</a>) genes. <a href="#12" class="mim-tip-reference" title="Villavicencio-Lorini, P., Klopocki, E., Trimborn, M., Koll, R., Mundlos, S., Horn, D. <strong>Phenotypic variant of brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4.</strong> Europ. J. Hum. Genet. 21: 743-748, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23188045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23188045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23188045[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/ejhg.2012.240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23188045">Villavicencio-Lorini et al. (2013)</a> concluded that the absence of BDE in this family was consistent with previous observations that BDE is a variable clinical feature associated with 2q37 deletions, and that HDAC4 haploinsufficiency is not fully penetrant for BDE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23188045" 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="#15" class="mim-tip-reference" title="Wheeler, P. G., Huang, D., Dai, Z. <strong>Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals.</strong> Am. J. Med. Genet. 164A: 1826-1829, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24715439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24715439</a>] [<a href="https://doi.org/10.1002/ajmg.a.36542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24715439">Wheeler et al. (2014)</a> provided evidence that haploinsufficiency for HDAC4 does not cause intellectual disability. They reported a mother and 2 sons with a heterozygous 887-kb deletion of chromosome 2q37.3 including the entire coding region of the HDAC4 gene, 2 noncoding RNA sequences (MGC16025 and LOC150935), and 4 microRNAs. None of the individuals had intellectual disability, but the mother and the older son had type E brachydactyly; the other son was too young for assessment of BDE. <a href="#15" class="mim-tip-reference" title="Wheeler, P. G., Huang, D., Dai, Z. <strong>Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals.</strong> Am. J. Med. Genet. 164A: 1826-1829, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24715439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24715439</a>] [<a href="https://doi.org/10.1002/ajmg.a.36542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24715439">Wheeler et al. (2014)</a> suggested that haploinsufficiency for HDAC4 may be contributing factor for BDMR, but concluded that it is not sufficient to cause intellectual disability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24715439" 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>This variant, formerly titled BRACHYDACTYLY-MENTAL RETARDATION SYNDROME, has been reclassified based on the findings of <a href="#12" class="mim-tip-reference" title="Villavicencio-Lorini, P., Klopocki, E., Trimborn, M., Koll, R., Mundlos, S., Horn, D. <strong>Phenotypic variant of brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4.</strong> Europ. J. Hum. Genet. 21: 743-748, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23188045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23188045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23188045[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/ejhg.2012.240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23188045">Villavicencio-Lorini et al. (2013)</a> and <a href="#15" class="mim-tip-reference" title="Wheeler, P. G., Huang, D., Dai, Z. <strong>Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals.</strong> Am. J. Med. Genet. 164A: 1826-1829, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24715439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24715439</a>] [<a href="https://doi.org/10.1002/ajmg.a.36542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24715439">Wheeler et al. (2014)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23188045+24715439" 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 16-year-old Caucasian girl with brachydactyly-mental retardation syndrome (BDMR; <a href="/entry/600430">600430</a>), <a href="#16" class="mim-tip-reference" title="Williams, S. R., Aldred, M. A., Der Kaloustian, V. M., Halal, F., Gowans, G., McLeod, D. R., Zondag, S., Toriello, H. V., Magenis, R. E., Elsea, S. H. <strong>Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.</strong> Am. J. Hum. Genet. 87: 219-228, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20691407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20691407</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20691407[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20691407">Williams et al. (2010)</a> identified a heterozygous de novo 65-bp deletion (490+56_121del65) in intron 5 of the HDAC4 gene, which was predicted to alter the splicing of exons 5 and 6. She had dysmorphic features, brachydactyly type E (BDE), psychomotor retardation, and severe behavioral abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20691407" 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="Villavicencio-Lorini, P., Klopocki, E., Trimborn, M., Koll, R., Mundlos, S., Horn, D. <strong>Phenotypic variant of brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4.</strong> Europ. J. Hum. Genet. 21: 743-748, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23188045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23188045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23188045[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/ejhg.2012.240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23188045">Villavicencio-Lorini et al. (2013)</a> reported a 3-generation family in which the proband, her mother, and her maternal grandmother had very mild developmental delay and dysmorphic facial features associated with an inherited heterozygous interstitial deletion of chromosome 2q37.3. None of the individuals had brachydactyly. The deletion was about 800 kb and included the HDAC4, FLJ43879, and TWIST2 (<a href="/entry/607556">607556</a>) genes. <a href="#12" class="mim-tip-reference" title="Villavicencio-Lorini, P., Klopocki, E., Trimborn, M., Koll, R., Mundlos, S., Horn, D. <strong>Phenotypic variant of brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4.</strong> Europ. J. Hum. Genet. 21: 743-748, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23188045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23188045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23188045[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/ejhg.2012.240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23188045">Villavicencio-Lorini et al. (2013)</a> concluded that the absence of BDE in this family was consistent with previous observations that BDE is a variable clinical feature associated with 2q37 deletions, and that HDAC4 haploinsufficiency is not fully penetrant for BDE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23188045" 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="#15" class="mim-tip-reference" title="Wheeler, P. G., Huang, D., Dai, Z. <strong>Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals.</strong> Am. J. Med. Genet. 164A: 1826-1829, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24715439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24715439</a>] [<a href="https://doi.org/10.1002/ajmg.a.36542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24715439">Wheeler et al. (2014)</a> provided evidence that haploinsufficiency for HDAC4 does not cause intellectual disability. They reported a mother and 2 sons with a heterozygous 887-kb deletion of chromosome 2q37.3 including the entire coding region of the HDAC4 gene, 2 noncoding RNA sequences (MGC16025 and LOC150935), and 4 microRNAs. None of the individuals had intellectual disability, but the mother and the older son had type E brachydactyly; the other son was too young for assessment of BDE. <a href="#15" class="mim-tip-reference" title="Wheeler, P. G., Huang, D., Dai, Z. <strong>Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals.</strong> Am. J. Med. Genet. 164A: 1826-1829, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24715439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24715439</a>] [<a href="https://doi.org/10.1002/ajmg.a.36542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24715439">Wheeler et al. (2014)</a> suggested that haploinsufficiency for HDAC4 may be contributing factor for BDMR, but concluded that it is not sufficient to cause intellectual disability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24715439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 NEURODEVELOPMENTAL DISORDER WITH CENTRAL HYPOTONIA AND DYSMORPHIC FACIES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1064797002 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1064797002;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1064797002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1064797002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000486144 OR RCV000622488 OR RCV001290415 OR RCV001824806 OR RCV001849182 OR RCV002286740" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000486144, RCV000622488, RCV001290415, RCV001824806, RCV001849182, RCV002286740" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000486144...</a>
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<p>In 4 unrelated patients (patients 4-7) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; <a href="/entry/619797">619797</a>), <a href="#13" class="mim-tip-reference" title="Wakeling, E., McEntagart, M., Bruccoleri, M., Shaw-Smith, C., Stals, K. L., Wakeling, M., Barnicoat, A., Beesley, C., DDD Study, Hanson-Kahn, A. K., Kukolich, M., Stevenson, D. A., Campeau, P. M., Ellard, S., Elsea, S. H., Yang, X.-J., Caswell, R. C. <strong>Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.</strong> HGG Adv. 2: 100015, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33537682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33537682</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33537682[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.xhgg.2020.100015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33537682">Wakeling et al. (2021)</a> identified a de novo heterozygous c.743C-T transition (c.743C-T, NM_006037.4) in the HDAC4 gene, resulting in a pro248-to-leu (P248L) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. he mutation is located in the HDAC4 14-3-3 binding site and is predicted to result in decreased binding of 14-3-3 proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33537682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 NEURODEVELOPMENTAL DISORDER WITH CENTRAL HYPOTONIA AND DYSMORPHIC FACIES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2152917882 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2152917882;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2152917882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs2152917882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient (patient 3) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; <a href="/entry/619797">619797</a>), <a href="#13" class="mim-tip-reference" title="Wakeling, E., McEntagart, M., Bruccoleri, M., Shaw-Smith, C., Stals, K. L., Wakeling, M., Barnicoat, A., Beesley, C., DDD Study, Hanson-Kahn, A. K., Kukolich, M., Stevenson, D. A., Campeau, P. M., Ellard, S., Elsea, S. H., Yang, X.-J., Caswell, R. C. <strong>Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.</strong> HGG Adv. 2: 100015, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33537682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33537682</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33537682[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.xhgg.2020.100015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33537682">Wakeling et al. (2021)</a> identified a de novo heterozygous c.742C-G transversion (c.742C-G, NM_006037.4) in the HDAC4 gene, resulting in a pro248-to-ala (P248A) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. The mutation is located in the HDAC4 14-3-3 binding sit and is predicted to result in decreased binding of 14-3-3 proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33537682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 NEURODEVELOPMENTAL DISORDER WITH CENTRAL HYPOTONIA AND DYSMORPHIC FACIES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2152917896 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2152917896;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2152917896" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs2152917896" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient (patient 2) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; <a href="/entry/619797">619797</a>), <a href="#13" class="mim-tip-reference" title="Wakeling, E., McEntagart, M., Bruccoleri, M., Shaw-Smith, C., Stals, K. L., Wakeling, M., Barnicoat, A., Beesley, C., DDD Study, Hanson-Kahn, A. K., Kukolich, M., Stevenson, D. A., Campeau, P. M., Ellard, S., Elsea, S. H., Yang, X.-J., Caswell, R. C. <strong>Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.</strong> HGG Adv. 2: 100015, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33537682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33537682</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33537682[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.xhgg.2020.100015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33537682">Wakeling et al. (2021)</a> identified a heterozygous c.740A-G transition (c.740A-G, NM_007037.4) in the HDAC4 gene, resulting in a glu247-to-gly (E247G) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. The mutation is located in the HDAC4 14-3-3 binding site and is predicted to result in decreased binding of 14-3-3 proteins. Coimmunoprecipitation with HDAC4 with the E247G mutation in HEK293 cells demonstrated reduced binding affinity for 14-3-3-beta (<a href="/entry/601289">601289</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33537682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 NEURODEVELOPMENTAL DISORDER WITH CENTRAL HYPOTONIA AND DYSMORPHIC FACIES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2042442594 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2042442594;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2042442594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs2042442594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001290416 OR RCV002069355 OR RCV003399032" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001290416, RCV002069355, RCV003399032" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001290416...</a>
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<p>In a patient (patient 1) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; <a href="/entry/619797">619797</a>), <a href="#13" class="mim-tip-reference" title="Wakeling, E., McEntagart, M., Bruccoleri, M., Shaw-Smith, C., Stals, K. L., Wakeling, M., Barnicoat, A., Beesley, C., DDD Study, Hanson-Kahn, A. K., Kukolich, M., Stevenson, D. A., Campeau, P. M., Ellard, S., Elsea, S. H., Yang, X.-J., Caswell, R. C. <strong>Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.</strong> HGG Adv. 2: 100015, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33537682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33537682</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33537682[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.xhgg.2020.100015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33537682">Wakeling et al. (2021)</a> identified a heterozygous 731C-A transversion in the HDAC4 gene resulting in a thr244-to-lys (T244K) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. The mutation is located in the HDAC4 14-3-3 binding site and is predicted to result in decreased binding of 14-3-3 proteins. Coimmunoprecipitation with HDAC4 with the T244K mutation in HEK293 cells demonstrated reduced binding affinity for 14-3-3-beta (<a href="/entry/601289">601289</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33537682" 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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Chen, B., Cepko, C. L.
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<strong>HDAC4 regulates neuronal survival in normal and diseased retinas.</strong>
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Science 323: 256-259, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19131628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19131628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19131628[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=19131628" 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.1166226" target="_blank">Full Text</a>]
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Fischle, W., Dequiedt, F., Hendzel, M. J., Guenther, M. G., Lazar, M. A., Voelter, W., Verdin, E.
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<strong>Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR.</strong>
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Molec. Cell 9: 45-57, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11804585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11804585</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11804585" 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/s1097-2765(01)00429-4" target="_blank">Full Text</a>]
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Fischle, W., Emiliani, S., Hendzel, M. J., Nagase, T., Nomura, N., Voelter, W., Verdin, E.
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<strong>A new family of human histone deacetylases related to Saccharomyces cerevisiae HDA1p.</strong>
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J. Biol. Chem. 274: 11713-11720, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10206986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10206986</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10206986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Grozinger, C. M., Hassig, C. A., Schreiber, S. L.
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<strong>Three proteins define a class of human histone deacetylases related to yeast Hda1p.</strong>
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Proc. Nat. Acad. Sci. 96: 4868-4873, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220385</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10220385[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=10220385" 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(00)80211-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0609320103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1242/dev.072652" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M504994200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.cell.2004.10.024" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/MCB.19.11.7816" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.36542" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2010.07.011" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/387016a0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.C000304200" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 03/17/2022
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Bao Lige - updated : 10/11/2018<br>Cassandra L. Kniffin - updated : 9/24/2015<br>Ada Hamosh - updated : 6/20/2011<br>Cassandra L. Kniffin - updated : 9/28/2010<br>Ada Hamosh - updated : 1/27/2009<br>Patricia A. Hartz - updated : 10/3/2008<br>Patricia A. Hartz - updated : 3/14/2008<br>Paul J. Converse - updated : 5/3/2007<br>Stylianos E. Antonarakis - updated : 1/4/2005<br>Ada Hamosh - updated : 5/6/2003<br>Stylianos E. Antonarakis - updated : 5/15/2002
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Paul J. Converse : 10/4/2000
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carol : 03/19/2022
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carol : 03/17/2022<br>carol : 11/30/2020<br>mgross : 10/12/2018<br>mgross : 10/11/2018<br>alopez : 09/25/2015<br>ckniffin : 9/24/2015<br>carol : 9/16/2013<br>alopez : 6/20/2011<br>wwang : 10/7/2010<br>ckniffin : 9/28/2010<br>alopez : 1/28/2009<br>terry : 1/27/2009<br>mgross : 10/7/2008<br>terry : 10/3/2008<br>mgross : 3/14/2008<br>terry : 3/14/2008<br>mgross : 5/16/2007<br>terry : 5/3/2007<br>terry : 4/5/2005<br>mgross : 1/4/2005<br>alopez : 5/7/2003<br>terry : 5/6/2003<br>mgross : 5/15/2002<br>mgross : 11/29/2000<br>mgross : 10/4/2000
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<span class="mim-font">
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<strong>*</strong> 605314
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<h3>
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<span class="mim-font">
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HISTONE DEACETYLASE 4; HDAC4
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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HDACA
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: HDAC4</em></strong>
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<strong>
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<em>
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Cytogenetic location: 2q37.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:239,048,168-239,401,649 </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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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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2q37.3
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<span class="mim-font">
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Neurodevelopmental disorder with central hypotonia and dysmorphic facies
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<span class="mim-font">
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619797
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>DNA is wrapped around histone proteins to form nucleosomes and chromatin fiber, a higher-order structure. Chromatin can become alternatively transparent or opaque to transcription factors. Acetylation (see HAT1, 603053) of lysine residues induces conformational changes in core histones by destabilizing nucleosomes and allowing transcription factors access to recognition elements in DNA. Deacetylation (see HDAC1, 601241) of histones, on the other hand, reseals the chromosomal package, leading to a repression of transcription. See Wolffe (1997) and Pazin and Kadonaga (1997) for reviews. There are at least 2 classes of HDACs, class I, consisting of proteins homologous to yeast Rpd3 (e.g., HDAC1, HDAC2 (605164), and HDAC3 (605166)) and class II, consisting of proteins homologous to yeast Hda1. HDAC4 is a class II HDAC. </p>
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<strong>Cloning and Expression</strong>
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<p>By searching an EST database for sequences similar to yeast Hda1, followed by screening a cDNA library and PCR, Grozinger et al. (1999) identified cDNAs encoding the class II HDACs HDAC4, HDAC5 (605315), and HDAC6 (300272). Sequence analysis predicted that the 1,085-amino acid HDAC4 protein, which is identical to the KIAA0288 protein, contains a catalytic region beginning at residue 802. Northern blot analysis detected a 9.6-kb HDAC4 transcript apparently restricted to brain, heart, and skeletal muscle. Western blot analysis showed that HDAC4 is expressed as a 119-kD protein that coimmunoprecipitates with RbAp48 (RBBP4; 602923) and HDAC3. </p><p>By random sequencing of a size-selected brain cDNA library, Fischle et al. (1999) identified a partial cDNA encoding HDAC4, which they called HDACA. Northern blot analysis detected an 8.4-kb HDAC4 transcript in all tissues tested, with a strong 3.4-kb transcript also present in testis. Immunofluorescence analysis showed a subnuclear localization excluded from nucleoli in interphase cells. SDS-PAGE analysis demonstrated that HDAC4 interacts with multiple proteins. </p>
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<strong>Gene Function</strong>
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<p>Functional analysis by Grozinger et al. (1999) confirmed that HDAC4 possesses deacetylation activity against all 4 core histones. </p><p>Wang et al. (1999) cloned HDAC4 and demonstrated that its deacetylase activity requires histidine at residues 802 and 803. They determined that HDAC4 does not bind DNA directly, but rather through MEF2C (600662) and MEF2D (600663). Binding of the N terminus of HDAC4 to MEF2C represses MEF2C transcription activity. </p><p>Fischle et al. (2002) showed that the catalytic domain of HDAC4 interacts with HDAC3 via the transcriptional corepressor NCOR2 (600848). All experimental conditions leading to the suppression of HDAC4 binding to NCOR2 and to HDAC3 resulted in loss of enzymatic activity associated with HDAC4. These observations indicated that class II HDACs regulate transcription by bridging the enzymatically active NCOR2-HDAC3 complex and select transcription factors. </p><p>Youn et al. (2000) reported that HDAC4 and MITR (606543) contain calmodulin-binding domains that overlap with their MEF2 binding domains. Binding of calmodulin to HDAC4 leads to its dissociation from MEF2, relieving MEF2 from the transcriptional repression by HDAC4. Together, HDAC4, MITR, and CABIN1 (604251) constitute a family of calcium-sensitive transcriptional repressors of MEF2. </p><p>Um et al. (2006) stated that HDAC4 is sumoylated by RANBP2 (601181). They showed that parkin (602544) controlled the intracellular levels of sumoylated HDAC4 by ubiquitinating RANBP2 and causing its proteasome-dependent degradation. </p><p>Using luciferase analysis, Portal et al. (2006) showed that HDAC4 and HDAC5, but not other HDACs, repressed Epstein-Barr virus (EBV) nuclear antigen-2 (EBNA2) activation of EBV promoters, and that this repression could be reversed by EBNA leader protein (EBNALP). HDAC4 could repress EBNA2 and EBNALP coactivation of EBV promoters. Immunoprecipitation and Western blot analyses showed that HDAC4 associated with EBNA2 in the nucleus and with EBNALP in the nucleus and cytoplasm of lymphoblastoid cell lines. EBNALP reduced HDAC4 nuclear localization in B cells. Reporter gene analysis demonstrated that overexpression of HDAC4 or HDAC5 in the presence of overexpressed 14-3-3 (see 605066) protein altered activation of different EBV promoters by EBNA2 and EBNALP. Coimmunoprecipitation and Western blot analyses revealed that 14-3-3, HDAC4, and EBNALP associated in a ternary complex. Portal et al. (2006) concluded that EBNALP coactivates transcription by relocalizing HDAC4 and HDAC5 from EBNA2-activated promoters to the cytoplasm. </p><p>Tuddenham et al. (2006) identified the 3-prime UTR of HDAC4 as 1 of 138 putative targets containing the miR140 (MIRN140; 611894) seed sequence (5-prime-GTGGTTT-3-prime). A small interfering RNA that mimicked miR140 (siRNA140) downregulated expression of a reporter gene containing 800 bp of the human HDAC4 3-prime UTR, and transfection of siRNA140 into mouse fibroblasts reduced the level of endogenous Hdac4 protein. </p><p>Chen and Cepko (2009) reported that Hdac4 regulates the survival of retinal neurons in the mouse in normal and pathologic conditions. Reduction in Hdac4 expression during normal retinal development led to apoptosis of rod photoreceptors and bipolar interneurons, whereas overexpression reduced naturally occurring cell death of the bipolar cells. Hdac4 overexpression in a mouse model of retinal degeneration prolonged photoreceptor survival. The survival effect was due to the activity of Hdac4 in the cytoplasm and relied at least partly on the activity of hypoxia-inducible factor 1-alpha (HIF1-alpha; 603348). Chen and Cepko (2009) concluded that their data provided evidence that HDAC4 plays an important role in promoting the survival of retinal neurons. </p><p>Robert et al. (2011) showed that HDAC inhibition/ablation specifically counteracts yeast Mec1 (ortholog of human ATR, 601215) activation, double-strand break processing, and single-strand DNA-RFA nucleofilament formation. Moreover, the recombination protein Sae2 (human CTIP; 604124) is acetylated and degraded after HDAC inhibition. Two HDACs, Hda1 and Rpd3 (HDAC1; 601241) and 1 histone acetyltransferase (HAT), Gcn5 (GCN5L2; 602301), have key roles in these processes. Robert et al. (2011) also found that HDAC inhibition triggers Sae2 degradation by promoting autophagy that affects the DNA damage sensitivity of Hda1 and Rpd3 mutants. Rapamycin, which stimulates autophagy by inhibiting Tor (MTOR; 601231), also causes Sae2 degradation. Robert et al. (2011) proposed that Rpd3, Hda1, and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand break processing with autophagy. </p><p>Using immunofluorescence analysis and coimmunoprecipitation assays, Sasagawa et al. (2012) found that salt-inducible kinase-3 (SIK3; 614776) localized to the cytoplasm and formed a complex with Hdac4, a crucial repressor of chondrocyte hypertrophy, in mouse hypertrophic chondrocytes. The Sik3-Hdac4 interaction anchored Hdac4 in the cytoplasm. In Sik3-deficient mouse chondrocytes, Hdac4 localized to nuclei and repressed Mef2c, a crucial facilitator of chondrocyte hypertrophy, resulting in the blockage of chondrocyte hypertrophy. Sasagawa et al. (2012) concluded that SIK3 plays an essential role in chondrocyte hypertrophy during skeletogenesis through its interaction with HDAC4. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using FISH analysis, Wang et al. (1999) mapped the HDAC4 gene to chromosome 2q37.2. </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 class="mim-text-font">
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<p>In 7 unrelated patients with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; 619797), Wakeling et al. (2021) identified 4 different de novo heterozygous missense mutations (605314.0003-605314.0006) in the HDAC4 gene. The mutations, which were identified by whole-exome sequencing, were predicted to result in reduced HDAC4 affinity for 14-3-3 proteins, leading to reduced sequestration of HDAC4 in the cytoplasm by the 14-3-3 proteins and increased levels of HDAC4 in the nucleus. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of possible phenotypic consequences of deletion of the HDAC4 gene, see chromosome 2q37 deletion syndrome (600430).</p>
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<h4>
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<strong>Animal Model</strong>
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<p>Vega et al. (2004) reported that Hdac4, which is expressed in prehypertrophic chondrocytes, regulates chondrocyte hypertrophy and endochondral bone formation in mice by interacting with and inhibiting the activity of Runx2 (600211), a transcription factor necessary for chondrocyte hypertrophy. Hdac4-null mice displayed premature ossification of developing bones due to ectopic and early onset chondrocyte hypertrophy, mimicking the phenotype that results from constitutive Runx2 expression in chondrocytes. Conversely, overexpression of Hdac4 in proliferating chondrocytes in vivo inhibited chondrocyte hypertrophy and differentiation, mimicking a Runx2 loss-of-function phenotype. These results established HDAC4 as a central regulator of chondrocyte hypertrophy and skeletogenesis. </p>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>6 Selected Examples):</strong>
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</h4>
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<div>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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HDAC4, 1-BP INS, 2399C
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<br />
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SNP: rs748900140,
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ClinVar: RCV000005373, RCV001753403
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<p>This variant, formerly titled BRACHYDACTYLY-MENTAL RETARDATION SYNDROME, has been reclassified based on the findings of Villavicencio-Lorini et al. (2013) and Wheeler et al. (2014). </p><p>In a French Canadian woman with brachydactyly-mental retardation syndrome (BDMR; 600430), Williams et al. (2010) identified a heterozygous de novo 1-bp insertion (2399insC) in exon 19 of the HDAC4 gene, resulting in a frameshift and premature termination. There was no evidence of nonsense-mediated mRNA decay, but the mutation likely resulted in haploinsufficiency. Quantitative RT-PCR analysis showed that lymphocytes from the patient did not alter HDAC4 expression, suggesting that the mutation does not result in nonsense-mediated mRNA decay and produces a nonfunctional protein. The patient had delayed psychomotor development, subvalvular aortic stenosis, dysmorphic facial features, brachydactyly type E (BDE), sleep disturbances, and behavioral problems. </p><p>Villavicencio-Lorini et al. (2013) reported a 3-generation family in which the proband, her mother, and her maternal grandmother had very mild developmental delay and dysmorphic facial features associated with an inherited heterozygous interstitial deletion of chromosome 2q37.3. None of the individuals had brachydactyly. The deletion was about 800 kb and included the HDAC4, FLJ43879, and TWIST2 (607556) genes. Villavicencio-Lorini et al. (2013) concluded that the absence of BDE in this family was consistent with previous observations that BDE is a variable clinical feature associated with 2q37 deletions, and that HDAC4 haploinsufficiency is not fully penetrant for BDE. </p><p>Wheeler et al. (2014) provided evidence that haploinsufficiency for HDAC4 does not cause intellectual disability. They reported a mother and 2 sons with a heterozygous 887-kb deletion of chromosome 2q37.3 including the entire coding region of the HDAC4 gene, 2 noncoding RNA sequences (MGC16025 and LOC150935), and 4 microRNAs. None of the individuals had intellectual disability, but the mother and the older son had type E brachydactyly; the other son was too young for assessment of BDE. Wheeler et al. (2014) suggested that haploinsufficiency for HDAC4 may be contributing factor for BDMR, but concluded that it is not sufficient to cause intellectual disability. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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HDAC4, 65-BP DEL, NT490+56
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ClinVar: RCV000005374
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<span class="mim-text-font">
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<p>This variant, formerly titled BRACHYDACTYLY-MENTAL RETARDATION SYNDROME, has been reclassified based on the findings of Villavicencio-Lorini et al. (2013) and Wheeler et al. (2014). </p><p>In a 16-year-old Caucasian girl with brachydactyly-mental retardation syndrome (BDMR; 600430), Williams et al. (2010) identified a heterozygous de novo 65-bp deletion (490+56_121del65) in intron 5 of the HDAC4 gene, which was predicted to alter the splicing of exons 5 and 6. She had dysmorphic features, brachydactyly type E (BDE), psychomotor retardation, and severe behavioral abnormalities. </p><p>Villavicencio-Lorini et al. (2013) reported a 3-generation family in which the proband, her mother, and her maternal grandmother had very mild developmental delay and dysmorphic facial features associated with an inherited heterozygous interstitial deletion of chromosome 2q37.3. None of the individuals had brachydactyly. The deletion was about 800 kb and included the HDAC4, FLJ43879, and TWIST2 (607556) genes. Villavicencio-Lorini et al. (2013) concluded that the absence of BDE in this family was consistent with previous observations that BDE is a variable clinical feature associated with 2q37 deletions, and that HDAC4 haploinsufficiency is not fully penetrant for BDE. </p><p>Wheeler et al. (2014) provided evidence that haploinsufficiency for HDAC4 does not cause intellectual disability. They reported a mother and 2 sons with a heterozygous 887-kb deletion of chromosome 2q37.3 including the entire coding region of the HDAC4 gene, 2 noncoding RNA sequences (MGC16025 and LOC150935), and 4 microRNAs. None of the individuals had intellectual disability, but the mother and the older son had type E brachydactyly; the other son was too young for assessment of BDE. Wheeler et al. (2014) suggested that haploinsufficiency for HDAC4 may be contributing factor for BDMR, but concluded that it is not sufficient to cause intellectual disability. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 NEURODEVELOPMENTAL DISORDER WITH CENTRAL HYPOTONIA AND DYSMORPHIC FACIES</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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HDAC4, PRO248LEU
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<br />
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SNP: rs1064797002,
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ClinVar: RCV000486144, RCV000622488, RCV001290415, RCV001824806, RCV001849182, RCV002286740
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 unrelated patients (patients 4-7) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; 619797), Wakeling et al. (2021) identified a de novo heterozygous c.743C-T transition (c.743C-T, NM_006037.4) in the HDAC4 gene, resulting in a pro248-to-leu (P248L) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. he mutation is located in the HDAC4 14-3-3 binding site and is predicted to result in decreased binding of 14-3-3 proteins. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 NEURODEVELOPMENTAL DISORDER WITH CENTRAL HYPOTONIA AND DYSMORPHIC FACIES</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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HDAC4, PRO248ALA
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<br />
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SNP: rs2152917882,
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ClinVar: RCV001849236
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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 patient (patient 3) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; 619797), Wakeling et al. (2021) identified a de novo heterozygous c.742C-G transversion (c.742C-G, NM_006037.4) in the HDAC4 gene, resulting in a pro248-to-ala (P248A) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. The mutation is located in the HDAC4 14-3-3 binding sit and is predicted to result in decreased binding of 14-3-3 proteins. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 NEURODEVELOPMENTAL DISORDER WITH CENTRAL HYPOTONIA AND DYSMORPHIC FACIES</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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HDAC4, GLU247GLY
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<br />
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SNP: rs2152917896,
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ClinVar: RCV001849237
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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 patient (patient 2) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; 619797), Wakeling et al. (2021) identified a heterozygous c.740A-G transition (c.740A-G, NM_007037.4) in the HDAC4 gene, resulting in a glu247-to-gly (E247G) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. The mutation is located in the HDAC4 14-3-3 binding site and is predicted to result in decreased binding of 14-3-3 proteins. Coimmunoprecipitation with HDAC4 with the E247G mutation in HEK293 cells demonstrated reduced binding affinity for 14-3-3-beta (601289). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 NEURODEVELOPMENTAL DISORDER WITH CENTRAL HYPOTONIA AND DYSMORPHIC FACIES</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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HDAC4, THR244LYS
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<br />
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SNP: rs2042442594,
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ClinVar: RCV001290416, RCV002069355, RCV003399032
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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 patient (patient 1) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; 619797), Wakeling et al. (2021) identified a heterozygous 731C-A transversion in the HDAC4 gene resulting in a thr244-to-lys (T244K) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. The mutation is located in the HDAC4 14-3-3 binding site and is predicted to result in decreased binding of 14-3-3 proteins. Coimmunoprecipitation with HDAC4 with the T244K mutation in HEK293 cells demonstrated reduced binding affinity for 14-3-3-beta (601289). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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|
Chen, B., Cepko, C. L.
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|
<strong>HDAC4 regulates neuronal survival in normal and diseased retinas.</strong>
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|
Science 323: 256-259, 2009.
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[PubMed: 19131628]
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[Full Text: https://doi.org/10.1126/science.1166226]
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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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|
Fischle, W., Dequiedt, F., Hendzel, M. J., Guenther, M. G., Lazar, M. A., Voelter, W., Verdin, E.
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|
<strong>Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR.</strong>
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Molec. Cell 9: 45-57, 2002.
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[Full Text: https://doi.org/10.1016/s1097-2765(01)00429-4]
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<p class="mim-text-font">
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Fischle, W., Emiliani, S., Hendzel, M. J., Nagase, T., Nomura, N., Voelter, W., Verdin, E.
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<strong>A new family of human histone deacetylases related to Saccharomyces cerevisiae HDA1p.</strong>
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J. Biol. Chem. 274: 11713-11720, 1999.
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<p class="mim-text-font">
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Grozinger, C. M., Hassig, C. A., Schreiber, S. L.
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<strong>Three proteins define a class of human histone deacetylases related to yeast Hda1p.</strong>
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Proc. Nat. Acad. Sci. 96: 4868-4873, 1999.
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[PubMed: 10220385]
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[Full Text: https://doi.org/10.1073/pnas.96.9.4868]
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<li>
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<p class="mim-text-font">
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Pazin, M. J., Kadonaga, J. T.
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<strong>What's up and down with histone deacetylation and transcription?</strong>
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Cell 89: 325-328, 1997.
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[PubMed: 9150131]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)80211-1]
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</p>
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<li>
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<p class="mim-text-font">
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|
Portal, D., Rosendorff, A., Kieff, E.
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<strong>Epstein-Barr nuclear antigen leader protein coactivates transcription through interaction with histone deacetylase 4.</strong>
|
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Proc. Nat. Acad. Sci. 103: 19278-19283, 2006.
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[PubMed: 17159145]
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[Full Text: https://doi.org/10.1073/pnas.0609320103]
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</p>
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<p class="mim-text-font">
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Robert, T., Vanoli, F., Chiolo, I., Shubassi, G., Bernstein, K. A., Rothstein, R., Botrugno, O. A., Parazzoli, D., Oldani, A., Minucci, S., Foiani, M.
|
|
<strong>HDACs link the DNA damage response, processing of double-strand breaks and autophagy.</strong>
|
|
Nature 471: 74-79, 2011.
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|
|
[PubMed: 21368826]
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[Full Text: https://doi.org/10.1038/nature09803]
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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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Sasagawa, S., Takemori, H., Uebi, T., Ikegami, D., Hiramatsu, K., Ikegawa, S., Yoshikawa, H., Tsumaki, N.
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<strong>SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice.</strong>
|
|
Development 139: 1153-1163, 2012.
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[PubMed: 22318228]
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[Full Text: https://doi.org/10.1242/dev.072652]
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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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Tuddenham, L., Wheeler, G., Ntounia-Fousara, S., Waters, J., Hajihosseini, M. K., Clark, I., Dalmay, T.
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<strong>The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells.</strong>
|
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FEBS Lett. 580: 4214-4217, 2006.
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[PubMed: 16828749]
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[Full Text: https://doi.org/10.1016/j.febslet.2006.06.080]
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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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Um, J. W., Min, D. S., Rhim, H., Kim, J., Paik, S. R., Chung, K. C.
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<strong>Parkin ubiquitinates and promotes the degradation of RanBP2.</strong>
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J. Biol. Chem. 281: 3595-3603, 2006.
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[PubMed: 16332688]
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[Full Text: https://doi.org/10.1074/jbc.M504994200]
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<li>
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<p class="mim-text-font">
|
|
Vega, R. B., Matsuda, K., Oh, J., Barbosa, A. C., Yang, X., Meadows, E., McAnally, J., Pomajzl, C., Shelton, J. M., Richardson, J. A., Karsenty, G., Olson, E. N.
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|
<strong>Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis.</strong>
|
|
Cell 119: 555-566, 2004.
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[PubMed: 15537544]
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[Full Text: https://doi.org/10.1016/j.cell.2004.10.024]
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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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Villavicencio-Lorini, P., Klopocki, E., Trimborn, M., Koll, R., Mundlos, S., Horn, D.
|
|
<strong>Phenotypic variant of brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4.</strong>
|
|
Europ. J. Hum. Genet. 21: 743-748, 2013.
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[PubMed: 23188045]
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[Full Text: https://doi.org/10.1038/ejhg.2012.240]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Wakeling, E., McEntagart, M., Bruccoleri, M., Shaw-Smith, C., Stals, K. L., Wakeling, M., Barnicoat, A., Beesley, C., DDD Study, Hanson-Kahn, A. K., Kukolich, M., Stevenson, D. A., Campeau, P. M., Ellard, S., Elsea, S. H., Yang, X.-J., Caswell, R. C.
|
|
<strong>Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.</strong>
|
|
HGG Adv. 2: 100015, 2021.
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[PubMed: 33537682]
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[Full Text: https://doi.org/10.1016/j.xhgg.2020.100015]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Wang, A. H., Bertos, N. R., Vezmar, M., Pelletier, N., Crosato, M., Heng, H. H., Th'ng, J., Han, J., Yang, X.-J.
|
|
<strong>HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor.</strong>
|
|
Molec. Cell. Biol. 19: 7816-7827, 1999.
|
|
|
|
|
|
[PubMed: 10523670]
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|
|
[Full Text: https://doi.org/10.1128/MCB.19.11.7816]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Wheeler, P. G., Huang, D., Dai, Z.
|
|
<strong>Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals.</strong>
|
|
Am. J. Med. Genet. 164A: 1826-1829, 2014.
|
|
|
|
|
|
[PubMed: 24715439]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.36542]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Williams, S. R., Aldred, M. A., Der Kaloustian, V. M., Halal, F., Gowans, G., McLeod, D. R., Zondag, S., Toriello, H. V., Magenis, R. E., Elsea, S. H.
|
|
<strong>Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.</strong>
|
|
Am. J. Hum. Genet. 87: 219-228, 2010.
|
|
|
|
|
|
[PubMed: 20691407]
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|
|
[Full Text: https://doi.org/10.1016/j.ajhg.2010.07.011]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Wolffe, A. P.
|
|
<strong>Transcriptional control: sinful repression.</strong>
|
|
Nature 387: 16-17, 1997.
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|
|
[PubMed: 9139815]
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[Full Text: https://doi.org/10.1038/387016a0]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Youn, H.-D., Grozinger, C. M., Liu, J. O.
|
|
<strong>Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4.</strong>
|
|
J. Biol. Chem. 275: 22563-22567, 2000.
|
|
|
|
|
|
[PubMed: 10825153]
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|
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[Full Text: https://doi.org/10.1074/jbc.C000304200]
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</p>
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</li>
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</ol>
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<div>
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<br />
|
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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="row">
|
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
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<span class="text-nowrap mim-text-font">
|
|
Contributors:
|
|
</span>
|
|
</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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Hilary J. Vernon - updated : 03/17/2022<br>Bao Lige - updated : 10/11/2018<br>Cassandra L. Kniffin - updated : 9/24/2015<br>Ada Hamosh - updated : 6/20/2011<br>Cassandra L. Kniffin - updated : 9/28/2010<br>Ada Hamosh - updated : 1/27/2009<br>Patricia A. Hartz - updated : 10/3/2008<br>Patricia A. Hartz - updated : 3/14/2008<br>Paul J. Converse - updated : 5/3/2007<br>Stylianos E. Antonarakis - updated : 1/4/2005<br>Ada Hamosh - updated : 5/6/2003<br>Stylianos E. Antonarakis - updated : 5/15/2002
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Paul J. Converse : 10/4/2000
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