4385 lines
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Entry
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- *600662 - MYOCYTE ENHANCER FACTOR 2C; MEF2C
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600662</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li 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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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600662">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000081189;t=ENST00000504921" 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=4208" 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=600662" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000081189;t=ENST00000504921" 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_001131005,NM_001193347,NM_001193348,NM_001193349,NM_001193350,NM_001308002,NM_001363581,NM_001364329,NM_001364330,NM_001364331,NM_001364332,NM_001364333,NM_001364334,NM_001364335,NM_001364336,NM_001364337,NM_001364338,NM_001364339,NM_001364340,NM_001364341,NM_001364342,NM_001364343,NM_001364344,NM_001364345,NM_001364346,NM_001364347,NM_001364348,NM_001364349,NM_001364350,NM_001364352,NM_001364353,NM_001364354,NM_001364355,NM_001364356,NM_001364357,NM_002397,XM_005248511,XM_011543396,XM_017009478,XM_024446055,XM_024446056,XM_024446058,XM_024446059,XM_047417181,XM_047417182,XM_047417183,XM_047417184,XM_047417185,XM_047417186,XM_047417187,XM_047417188,XM_047417189,XM_047417190,XM_047417191,XM_047417192,XM_047417193,XM_047417194,XM_047417195,XM_047417196,XM_047417197,XM_047417198,XM_047417199,XM_047417200,XM_047417201,XM_047417202,XM_047417203,XM_047417204,XM_047417205,XM_047417206,XM_047417207,XM_047417208,XM_047417209,XM_047417210,XM_047417211,XM_047417213,XM_047417214,XM_047417215,XM_047417216,XM_047417217" 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_002397" 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=600662" 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=02809&isoform_id=02809_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/MEF2C" 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/292290,298698,2500875,15524590,19923215,119616367,119616368,119616369,119616370,119616371,119616372,119616373,119616374,189065539,196114945,297210556,300681806,301069380,301069382,301069384,301069386,530379313,767935907,808175992,1034644977,1370493825,1370493836,1370493872,1370493883,1391723775,1402101513,1402101518,1402101522,1402101528,1402101531,1402101533,1402101535,1402101541,1402101543,1402101545,1402101551,1402101553,1402101556,1402101563,1402101575,1402101585,1402101587,1402101589,1402101591,1402101595,1402101599,1402101603,1402101613,1402101617,1402101622,1402101624,1402101629,1402101633,2217355835,2217355837,2217355839,2217355841,2217355843,2217355850,2217355852,2217355854,2217355858,2217355860,2217355862,2217355864,2217355866,2217355868,2217355870,2217355872,2217355874,2217355876,2217355878,2217355880,2217355882,2217355885,2217355887,2217355889,2217355891,2217355893,2217355895,2217355897,2217355899,2217355901,2217355903,2217355907,2217355909,2217355911,2217355913,2217355915,2462602536,2462602538,2462602540,2462602542,2462602544,2462602546,2462602548,2462602550,2462602552,2462602554,2462602556,2462602558,2462602560,2462602562,2462602564,2462602566,2462602568,2462602570,2462602572,2462602574,2462602576,2462602580,2462602584,2462602586,2462602588,2462602590,2462602592,2462602594,2462602596,2462602598,2462602600,2462602602,2462602604,2462602606,2462602608,2462602610,2462602612,2462602614,2462602616,2462602618,2462602620" 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/Q06413" 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=4208" 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=ENSG00000081189;t=ENST00000504921" 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=MEF2C" 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=MEF2C" 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+4208" 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/MEF2C" 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:4208" 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/4208" 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=chr5&hgg_gene=ENST00000504921.7&hgg_start=88717117&hgg_end=88904105&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">
|
|
<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">
|
|
<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:6996" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:6996" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600662[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=600662[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/MEF2C/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/ENSG00000081189" 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=MEF2C" 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=MEF2C" 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=MEF2C" 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=MEF2C&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/PA30734" 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">
|
|
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<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:6996" 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/FBgn0011656.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:99458" 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/MEF2C#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:99458" 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/4208/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=4208" 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=WBGene00003182;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-040901-7" 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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|
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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:4208" 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=MEF2C&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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|
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<div>
|
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|
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<a id="title" class="mim-anchor"></a>
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
600662
|
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</span>
|
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</span>
|
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</div>
|
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</div>
|
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<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
MYOCYTE ENHANCER FACTOR 2C; MEF2C
|
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|
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
|
<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">
|
|
MADS BOX TRANSCRIPTION ENHANCER FACTOR 2, POLYPEPTIDE C
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
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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=MEF2C" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MEF2C</a></em></strong>
|
|
</span>
|
|
</p>
|
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</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/5/318?start=-3&limit=10&highlight=318">5q14.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:88717117-88904105&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'})">5:88,717,117-88,904,105</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
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<p>MEF2C belongs to the myocyte enhancer factor-2 (MEF2) family of transcription factors. MEF2C plays a pivotal role in myogenesis, development of the anterior heart field, neural crest and craniofacial development, and neurogenesis, among others (summary by <a href="#26" class="mim-tip-reference" title="Zweier, M., Gregor, A., Zweier, C., Engels, H., Sticht, H., Wohlleber, E., Bijlsma, E. K., Holder, S. E., Zenker, M., Rossier, E., Grasshoff, U., Johnson, D. S., Robertson, L., Firth, H. V., Kraus, C., Ekici, A. B., Reis, A., Rauch, A. <strong>Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.</strong> Hum. Mutat. 31: 722-733, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513142</a>] [<a href="https://doi.org/10.1002/humu.21253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20513142">Zweier et al., 2010</a>). MEF2C is a transcription factor with changing expression patterns during brain development that correlate with roles in neuronal developmental and maturation (summary by <a href="#19" class="mim-tip-reference" title="Paciorkowski, A. R., Traylor, R. N., Rosenfeld, J. A., Hoover, J. M., Harris, C. J., Winter, S., Lacassie, Y., Bialer, M., Lamb, A. N., Schultz, R. A., Berry-Kravis, E., Porter, B. E., and 9 others. <strong>MEF2C haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways.</strong> Neurogenetics 14: 99-111, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23389741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23389741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23389741[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s10048-013-0356-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23389741">Paciorkowski et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23389741+20513142" 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>See also MEF2A (<a href="/entry/600660">600660</a>).</p>
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<p><a href="#18" class="mim-tip-reference" title="McDermott, J. C., Cardoso, M. C., Yu, Y.-T., Andres, V., Leifer, D., Krainc, D., Lipton, S. A., Nadal-Ginard, B. <strong>hMEF2C gene encodes skeletal muscle- and brain-specific transcription factors.</strong> Molec. Cell. Biol. 13: 2564-2577, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8455629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8455629</a>] [<a href="https://doi.org/10.1128/mcb.13.4.2564-2577.1993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8455629">McDermott et al. (1993)</a> cloned a member of the MEF2 family of proteins from a human skeletal muscle cDNA library using a fragment of the MEF2A cDNA as a probe. Transcripts of MEF2C were found in the skeletal muscle and brain. Alternative splice variants were found, 1 of which was unique to the brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8455629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Leifer, D., Krainc, D., Yu, Y.-T., McDermott, J., Breitbart, R. E., Heng, J., Neve, R. L., Kosofsky, B., Nadal-Ginard, B., Lipton, S. A. <strong>MEF2C, a MADS/MEF2-family transcription factor expressed in a laminar distribution in cerebral cortex.</strong> Proc. Nat. Acad. Sci. 90: 1546-1550, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7679508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7679508</a>] [<a href="https://doi.org/10.1073/pnas.90.4.1546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7679508">Leifer et al. (1993)</a> found that the brain form was expressed by neurons in particular layers of the cerebral cortex and that expression declined during postnatal development. The skeletal isoform of the cDNA encodes a 465-amino acid protein with conserved MADS and MEF2 domains. Like the other MEF2 gene products, MEF2C has both DNA binding and trans-activating activities indistinguishable from other members of the family. MEF2C, however, is induced late during myogenic differentiation and has a strict tissue-specific pattern of expression not seen in MEF2A or MEF2B. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7679508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Zweier, M., Gregor, A., Zweier, C., Engels, H., Sticht, H., Wohlleber, E., Bijlsma, E. K., Holder, S. E., Zenker, M., Rossier, E., Grasshoff, U., Johnson, D. S., Robertson, L., Firth, H. V., Kraus, C., Ekici, A. B., Reis, A., Rauch, A. <strong>Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.</strong> Hum. Mutat. 31: 722-733, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513142</a>] [<a href="https://doi.org/10.1002/humu.21253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20513142">Zweier et al. (2010)</a> found high expression of isoform 1 of the MEF2C gene in fetal and adult human brain, whereas isoform 2 was widely expressed with highest levels in skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20513142" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Paciorkowski, A. R., Traylor, R. N., Rosenfeld, J. A., Hoover, J. M., Harris, C. J., Winter, S., Lacassie, Y., Bialer, M., Lamb, A. N., Schultz, R. A., Berry-Kravis, E., Porter, B. E., and 9 others. <strong>MEF2C haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways.</strong> Neurogenetics 14: 99-111, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23389741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23389741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23389741[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s10048-013-0356-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23389741">Paciorkowski et al. (2013)</a> found expression of Mef2c in both dorsal primary neuroblasts and ventral GABAergic interneurons in the forebrain of the developing mouse. The authors noted that Mef2c has been shown to interact with other genes in the developing mouse brain, suggesting that it is involved in a complex pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23389741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Breitbart, R. E., Liang, C., Smoot, L. B., Laheru, D. A., Mahdavi, V., Nadal-Ginard, B. <strong>A fourth human MEF2 transcription factor, hMEF2D, is an early marker of the myogenic lineage.</strong> Development 118: 1095-1106, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8269842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8269842</a>] [<a href="https://doi.org/10.1242/dev.118.4.1095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8269842">Breitbart et al. (1993)</a> suggested that, while MEF2A may be involved in induction of muscle differentiation, MEF2C may be involved with maintenance of the differentiated state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8269842" 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>CREB-binding protein (CBP; <a href="/entry/600140">600140</a>)/p300 (<a href="/entry/602700">602700</a>) and p300/CBP-associated factor (PCAF; <a href="/entry/602203">602203</a>) are coactivators for MEF2C during differentiation. <a href="#6" class="mim-tip-reference" title="Chen, S. L., Dowhan, D. H., Hosking, B. M., Muscat, G. E. O. <strong>The steroid receptor coactivator, GRIP-1, is necessary for MEF-2C-dependent gene expression and skeletal muscle differentiation.</strong> Genes Dev. 14: 1209-1228, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10817756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10817756</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10817756[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10817756">Chen et al. (2000)</a> showed that NCOA2 mediates the coactivation of MEF2C-dependent transcription through interaction with the MADS box domain of MEF2C. They proposed a model of cooperative interaction between NCOA2, myogenin (MYOG; <a href="/entry/159980">159980</a>), and MEF2C in the regulation of muscle-specific gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10817756" 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>During mammalian development, electrical activity promotes the calcium-dependent survival of neurons that have made appropriate synaptic connections. <a href="#16" class="mim-tip-reference" title="Mao, Z., Bonni, A., Xia, F., Nadal-Vicans, M., Greenberg, M. E. <strong>Neuronal activity-dependent cell survival mediated by transcription factor MEF2.</strong> Science 286: 785-790, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10531066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10531066</a>] [<a href="https://doi.org/10.1126/science.286.5440.785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10531066">Mao et al. (1999)</a> showed that calcium influx into cerebellar neurons triggers the activation of the MKK6 (<a href="/entry/601254">601254</a>)-p38 MAP kinase (<a href="/entry/600289">600289</a>) cascade and that the p38 MAP kinase then phosphorylates and activates MEF2s. Once activated by this calcium-dependent p38 MAP kinase signaling pathway, MEF2 can regulate the expression of genes that are critical for survival of newly differentiated neurons. These findings demonstrated that MEF2 is a calcium-regulated transcription factor and defined a function for MEF2 during nervous system development that is distinct from previously well-characterized functions of MEF2 during muscle differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10531066" 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="Chen, S. L., Loffler, K. A., Chen, D., Stallcup, M. R., Muscat, G. E. O. <strong>The coactivator-associated arginine methyltransferase is necessary for muscle differentiation: CARM1 coactivates myocyte enhancer factor-2.</strong> J. Biol. Chem. 277: 4324-4333, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11713257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11713257</a>] [<a href="https://doi.org/10.1074/jbc.M109835200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11713257">Chen et al. (2002)</a> demonstrated that Carm1 (<a href="/entry/603934">603934</a>) and Ncoa2 cooperatively stimulated the activity of Mef2c in mouse mesenchymal stem cells and found that there was direct interaction among Mef2c, Grip1, and Carm1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11713257" 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 targeting human MEF2A or mouse Mef2c expression to mouse cardiomyocytes, <a href="#25" class="mim-tip-reference" title="Xu, J., Gong, N. L., Bodi, I., Aronow, B. J., Backx, P. H., Molkentin, J. D. <strong>Myocyte enhancer factors 2A and 2C induce dilated cardiomyopathy in transgenic mice.</strong> J. Biol. Chem. 281: 9152-9162, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16469744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16469744</a>] [<a href="https://doi.org/10.1074/jbc.M510217200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16469744">Xu et al. (2006)</a> demonstrated that overexpressing these transcription factors caused cardiomyopathy or predisposed transgenic mice to more fulminant disease following pressure overload. In cultured cardiomyocytes, MEF2A or Mef2c overexpression induced sarcomeric disorganization and focal elongation. Both MEF2A and Mef2c programmed similar profiles of gene expression in the heart that included genes involved in extracellular matrix remodeling, ion handling, and metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16469744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Potthoff, M. J., Wu, H., Arnold, M. A., Shelton, J. M., Backs, J., McAnally, J., Richardson, J. A., Bassel-Duby, R., Olson, E. N. <strong>Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers.</strong> J. Clin. Invest. 117: 2459-2467, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17786239/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17786239</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17786239[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/10.1172/JCI31960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17786239">Potthoff et al. (2007)</a> showed that class II histone deacetylases (e.g., HDAC5; <a href="/entry/605315">605315</a>) were selectively degraded by the proteasome in mouse slow, oxidative myofibers, enabling Mef2 to activate the slow myofiber gene program. Forced expression of Hdac5 in skeletal muscle or genetic deletion of Mef2c or Mef2d (<a href="/entry/600663">600663</a>) blocked activity-dependent fast to slow fiber transformation, whereas expression of hyperactive Mef2c promoted the slow fiber phenotype, enhancing endurance and enabling mice to run almost twice the distance of wildtype littermates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17786239" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a loss-of-function allele in mice, <a href="#10" class="mim-tip-reference" title="Johnnidis, J. B., Harris, M. H., Wheeler, R. T., Stehling-Sun, S., Lam, M. H., Kirak, O., Brummelkamp, T. R., Fleming, M. D., Camargo, F. D. <strong>Regulation of progenitor cell proliferation and granulocyte function by microRNA-223.</strong> Nature 451: 1125-1129, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18278031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18278031</a>] [<a href="https://doi.org/10.1038/nature06607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18278031">Johnnidis et al. (2008)</a> reported that the myeloid-specific microRNA-223 (miR223; <a href="/entry/300694">300694</a>) negatively regulates progenitor proliferation and granulocyte differentiation and activation. miR223 mutant mice had an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte progenitors. <a href="#10" class="mim-tip-reference" title="Johnnidis, J. B., Harris, M. H., Wheeler, R. T., Stehling-Sun, S., Lam, M. H., Kirak, O., Brummelkamp, T. R., Fleming, M. D., Camargo, F. D. <strong>Regulation of progenitor cell proliferation and granulocyte function by microRNA-223.</strong> Nature 451: 1125-1129, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18278031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18278031</a>] [<a href="https://doi.org/10.1038/nature06607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18278031">Johnnidis et al. (2008)</a> showed that Mef2c, a transcription factor that promotes myeloid progenitor proliferation, is a target of miR223, and that genetic ablation of Mef2c suppresses progenitor expansion and corrects the neutrophilic phenotype in miR223-null mice. In addition, granulocytes lacking miR223 were hypermature, hypersensitive to activating stimuli, and displayed increased fungicidal activity. As a consequence of this neutrophil hyperactivity, miR223 mutant mice spontaneously developed inflammatory lung pathology and exhibited exaggerated tissue destruction after endotoxin challenge. <a href="#10" class="mim-tip-reference" title="Johnnidis, J. B., Harris, M. H., Wheeler, R. T., Stehling-Sun, S., Lam, M. H., Kirak, O., Brummelkamp, T. R., Fleming, M. D., Camargo, F. D. <strong>Regulation of progenitor cell proliferation and granulocyte function by microRNA-223.</strong> Nature 451: 1125-1129, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18278031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18278031</a>] [<a href="https://doi.org/10.1038/nature06607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18278031">Johnnidis et al. (2008)</a> concluded that their data supported a model in which miR223 acts as a fine tuner of granulocyte production and the inflammatory response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18278031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Zweier, M., Gregor, A., Zweier, C., Engels, H., Sticht, H., Wohlleber, E., Bijlsma, E. K., Holder, S. E., Zenker, M., Rossier, E., Grasshoff, U., Johnson, D. S., Robertson, L., Firth, H. V., Kraus, C., Ekici, A. B., Reis, A., Rauch, A. <strong>Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.</strong> Hum. Mutat. 31: 722-733, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513142</a>] [<a href="https://doi.org/10.1002/humu.21253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20513142">Zweier et al. (2010)</a> demonstrated that MEF2C increases promoter activation of the MECP2 (<a href="/entry/300005">300005</a>) and CDKL5 (<a href="/entry/300203">300203</a>) genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20513142" 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 transcriptional profiling of human fetal brain cultures, <a href="#1" class="mim-tip-reference" title="Ataman, B., Boulting, G. L., Harmin, D. A., Yang, M. G., Baker-Salisbury, M., Yap, E.-L., Malik, A. N., Mei, K., Rubin, A. A., Spiegel, I., Durresi, E., Sharma, N., and 12 others. <strong>Evolution of Osteocrin as an activity-regulated factor in the primate brain.</strong> Nature 539: 242-247, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27830782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27830782</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27830782[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/nature20111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27830782">Ataman et al. (2016)</a> identified an activity-dependent secreted factor, osteocrin (OSTN; <a href="/entry/610280">610280</a>), that is induced by membrane depolarization of human, but not mouse, neurons. <a href="#1" class="mim-tip-reference" title="Ataman, B., Boulting, G. L., Harmin, D. A., Yang, M. G., Baker-Salisbury, M., Yap, E.-L., Malik, A. N., Mei, K., Rubin, A. A., Spiegel, I., Durresi, E., Sharma, N., and 12 others. <strong>Evolution of Osteocrin as an activity-regulated factor in the primate brain.</strong> Nature 539: 242-247, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27830782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27830782</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27830782[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/nature20111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27830782">Ataman et al. (2016)</a> found that OSTN has been repurposed in primates through the evolutionary acquisition of DNA regulatory elements that bind the activity-regulated transcription factor MEF2, specifically MEF2C. In addition, the authors demonstrated that OSTN is expressed in primate neocortex and restricts activity-dependent dendritic growth in human neurons. The authors concluded that their findings suggested that, in response to sensory input, OSTN regulates features of neuronal structure and function that are unique to primates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27830782" 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 circularized chromosome conformation capture sequencing (4C-seq), <a href="#8" class="mim-tip-reference" title="D'haene, E., Bar-Yaacov, R., Bariah, I., Vantomme, L., Van Loo, S., Cobos, F. A., Verboom, K., Eshel, R., Alatawna, R., Menten, B., Birnbaum, R. Y., Vergult, S. <strong>A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett like characteristics.</strong> Hum. Molec. Genet. 28: 818-827, 2019. Note: Erratum: Hum. Molec. Genet. 29: 879-880, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30445463/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30445463</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30445463[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddy393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30445463">D'haene et al. (2019)</a> identified a complex interaction network in which the promoter region of the MEF2C gene physically interacted with multiple distal putative enhancer elements, and that the coordinated action of these multiple enhancer elements was required for the precise spatiotemporal regulation of MEF2C. The authors tested 16 candidate regulatory sequences in vitro and found that 14 of them displayed enhancer capacity, in many cases with a higher activity being observed in SH-SY5Y than in HEK293. In vivo analyses with zebrafish further revealed that each of these enhancers had a distinct activity pattern during zebrafish development, with 8 enhancers displaying neuronal activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30445463" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#17" class="mim-tip-reference" title="Martin, J. F., Miano, J. M., Hustad, C. M., Copeland, N. G., Jenkins, N. A., Olson, E. N. <strong>A Mef2 gene that generates a muscle-specific isoform via alternative mRNA splicing.</strong> Molec. Cell. Biol. 14: 1647-1656, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8114702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8114702</a>] [<a href="https://doi.org/10.1128/mcb.14.3.1647-1656.1994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8114702">Martin et al. (1994)</a> mapped Mef2 to mouse chromosome 13. By fluorescence in situ hybridization, <a href="#11" class="mim-tip-reference" title="Krainc, D., Haas, M., Ward, D. C., Lipton, S. A., Bruns, G., Leifer, D. <strong>Assignment of human myocyte-specific enhancer binding factor 2C (hMEF2C) to human chromosome 5q14 and evidence that MEF2C is evolutionarily conserved.</strong> Genomics 29: 809-811, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575784</a>] [<a href="https://doi.org/10.1006/geno.1995.9927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8575784">Krainc et al. (1995)</a> mapped human MEF2C to chromosome 5q14, a region with homology of synteny to the mouse location. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8114702+8575784" 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 5 unrelated children with severe developmental delay, stereotypic movements, epilepsy, and/or cerebral malformations (<a href="/entry/613443">613443</a>), <a href="#12" class="mim-tip-reference" title="Le Meur, N., Holder-Espinasse, M., Jaillard, S., Goldenberg, A., Joriot, S., Amati-Bonneau, P., Guichet, A., Barth, M., Charollais, A., Journel, H., Auvin, S., Boucher, C., Kerckaert, J.-P., David, V., Manouvrier-Hanu, S., Saugier-Veber, P., Frebourg, T., Dubourg, C., Andrieux, J., Bonneau, D. <strong>MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations.</strong> J. Med. Genet. 47: 22-29, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19592390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19592390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19592390[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2009.069732" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19592390">Le Meur et al. (2010)</a> identified 5 different interstitial de novo deletions of chromosome 5q14 ranging in size from 216 kb to 8.8 Mb. The minimal common deleted region contained only the MEF2C gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19592390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a girl with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; <a href="/entry/613443">613443</a>), <a href="#12" class="mim-tip-reference" title="Le Meur, N., Holder-Espinasse, M., Jaillard, S., Goldenberg, A., Joriot, S., Amati-Bonneau, P., Guichet, A., Barth, M., Charollais, A., Journel, H., Auvin, S., Boucher, C., Kerckaert, J.-P., David, V., Manouvrier-Hanu, S., Saugier-Veber, P., Frebourg, T., Dubourg, C., Andrieux, J., Bonneau, D. <strong>MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations.</strong> J. Med. Genet. 47: 22-29, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19592390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19592390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19592390[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2009.069732" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19592390">Le Meur et al. (2010)</a> identified a de novo heterozygous nonsense mutation in the MEF2C gene (S228X; <a href="#0001">600662.0001</a>). <a href="#12" class="mim-tip-reference" title="Le Meur, N., Holder-Espinasse, M., Jaillard, S., Goldenberg, A., Joriot, S., Amati-Bonneau, P., Guichet, A., Barth, M., Charollais, A., Journel, H., Auvin, S., Boucher, C., Kerckaert, J.-P., David, V., Manouvrier-Hanu, S., Saugier-Veber, P., Frebourg, T., Dubourg, C., Andrieux, J., Bonneau, D. <strong>MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations.</strong> J. Med. Genet. 47: 22-29, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19592390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19592390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19592390[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2009.069732" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19592390">Le Meur et al. (2010)</a> noted that the role of MEF2C in synaptic plasticity is consistent with a role in learning and memory, and the authors referred to the mouse models of <a href="#14" class="mim-tip-reference" title="Li, H., Radford, J. C., Ragusa, M. J., Shea, K. L., McKercher, S. R., Zaremba, J. D., Soussou, W., Nie, Z., Kang, Y.-J., Nakanishi, N., Okamoto, S., Roberts, A. J., Schwarz, J. J., Lipton, S. A. <strong>Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo.</strong> Proc. Nat. Acad. Sci. 105: 9397-9402, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18599437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18599437</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18599437[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.0802876105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18599437">Li et al. (2008)</a> and <a href="#2" class="mim-tip-reference" title="Barbosa, A. C., Kim. M.-S., Ertunc, M., Adachi, M., Nelson, E. D., McAnally, J., Richardson, J. A., Kavalali, E. T., Monteggia, L. M., Bassel-Duby, R., Olson, E. N. <strong>MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function.</strong> Proc. Nat. Acad. Sci. 105: 9391-9396, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18599438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18599438</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18599438[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.0802679105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18599438">Barbosa et al. (2008)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19592390+18599437+18599438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Zweier, M., Gregor, A., Zweier, C., Engels, H., Sticht, H., Wohlleber, E., Bijlsma, E. K., Holder, S. E., Zenker, M., Rossier, E., Grasshoff, U., Johnson, D. S., Robertson, L., Firth, H. V., Kraus, C., Ekici, A. B., Reis, A., Rauch, A. <strong>Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.</strong> Hum. Mutat. 31: 722-733, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513142</a>] [<a href="https://doi.org/10.1002/humu.21253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20513142">Zweier et al. (2010)</a> identified 4 different de novo heterozygous mutations in the MEF2C gene (see. e.g., <a href="#0002">600662.0002</a>-<a href="#0004">600662.0004</a>) in 4 of 362 probands with impaired intellectual development who were screened for mutations in this gene. Two of the mutations were missense and 2 were truncating. Two additional patients with a similar disorder had heterozygous deletions involving the MEF2C gene. Analysis of blood-derived RNA showed significantly decreased levels of MEF2C isoform 2 mRNA in all patients with deletions in or including the MEF2C gene region, including the patients reported by <a href="#9" class="mim-tip-reference" title="Engels, H., Wohlleber, E., Zink, A., Hoyer, J., Ludwig, K. U., Brockschmidt, F. F., Wieczorek, D., Moog, U., Hellmann-Mersch, B., Weber, R. G., Willatt, L., Kreiss-Nachtsheim, M., Firth, H. V., Rauch, A. <strong>A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients.</strong> Europ. J. Hum. Genet. 17: 1592-1599, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19471318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19471318</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19471318[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.2009.90" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19471318">Engels et al. (2009)</a>, <a href="#5" class="mim-tip-reference" title="Cardoso, C., Boys, A., Parrini, E., Mignon-Ravix, C., McMahon, J. M., Khantane, S., Bertini, E., Pallesi, E., Missirian, C., Zuffardi, O., Novara, F., Villard, L., Giglio, S., Chabrol, B., Slater, H. R., Moncla, A., Scheffer, I. E., Guerrini, R. <strong>Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion.</strong> Neurology 72: 784-792, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19073947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19073947</a>] [<a href="https://doi.org/10.1212/01.wnl.0000336339.08878.2d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19073947">Cardoso et al. (2009)</a>, and <a href="#12" class="mim-tip-reference" title="Le Meur, N., Holder-Espinasse, M., Jaillard, S., Goldenberg, A., Joriot, S., Amati-Bonneau, P., Guichet, A., Barth, M., Charollais, A., Journel, H., Auvin, S., Boucher, C., Kerckaert, J.-P., David, V., Manouvrier-Hanu, S., Saugier-Veber, P., Frebourg, T., Dubourg, C., Andrieux, J., Bonneau, D. <strong>MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations.</strong> J. Med. Genet. 47: 22-29, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19592390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19592390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19592390[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2009.069732" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19592390">Le Meur et al. (2010)</a>, suggesting haploinsufficiency. Two patients with missense mutations did not show decreased MEF2C mRNA levels. All deletions and mutations caused significantly decreased MEF2C transcriptional activity, which could be rescued by wildtype MEF2C. Finally, all patients, including the 2 with missense mutations, showed decreased levels of MECP2 mRNA, and all except 2 patients had decreased levels of CDKL5 mRNA. These 2 genes are involved in Rett or Rett syndrome-like phenotypes (<a href="/entry/312750">312750</a> and <a href="/entry/300672">300672</a>, respectively), which shares some features with MRD20. <a href="#26" class="mim-tip-reference" title="Zweier, M., Gregor, A., Zweier, C., Engels, H., Sticht, H., Wohlleber, E., Bijlsma, E. K., Holder, S. E., Zenker, M., Rossier, E., Grasshoff, U., Johnson, D. S., Robertson, L., Firth, H. V., Kraus, C., Ekici, A. B., Reis, A., Rauch, A. <strong>Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.</strong> Hum. Mutat. 31: 722-733, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513142</a>] [<a href="https://doi.org/10.1002/humu.21253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20513142">Zweier et al. (2010)</a> concluded that the phenotype results from involvement of a common pathway involving these 3 genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19073947+19592390+19471318+20513142" 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 an 8-year-old girl with severe NEDHSIL, <a href="#3" class="mim-tip-reference" title="Bienvenu, T., Diebold, B., Chelly, J., Isidor, B. <strong>Refining the phenotype associated with MEF2C point mutations.</strong> Neurogenetics 14: 71-75, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23001426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23001426</a>] [<a href="https://doi.org/10.1007/s10048-012-0344-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23001426">Bienvenu et al. (2013)</a> identified a de novo heterozygous frameshift in the MEF2C gene (<a href="#0005">600662.0005</a>). Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23001426" 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 22-month-old girl with NEDHSIL, <a href="#19" class="mim-tip-reference" title="Paciorkowski, A. R., Traylor, R. N., Rosenfeld, J. A., Hoover, J. M., Harris, C. J., Winter, S., Lacassie, Y., Bialer, M., Lamb, A. N., Schultz, R. A., Berry-Kravis, E., Porter, B. E., and 9 others. <strong>MEF2C haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways.</strong> Neurogenetics 14: 99-111, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23389741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23389741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23389741[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s10048-013-0356-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23389741">Paciorkowski et al. (2013)</a> identified a heterozygous frameshift mutation in the MEF2C gene (<a href="#0006">600662.0006</a>). Functional studies of the variant, studies of patient cells, and segregation were not reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23389741" 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 10 unrelated patients with NEDHSIL, <a href="#24" class="mim-tip-reference" title="Wright, C. F., Quaife, N. M., Ramos-Hernandez, L., Danecek, P., Ferla, M. P., Samocha, K. E., Kaplanis, J., Gardner, E. J., Eberhardt, R. Y., Chao, K. R., Karczewski, K. J., Morales, J., and 22 others. <strong>Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.</strong> Am. J. Hum. Genet. 108: 1083-1094, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34022131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34022131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34022131[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.2021.04.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34022131">Wright et al. (2021)</a> identified 10 de novo heterozygous point mutations or small intragenic deletions affecting the 5-prime untranslated region (UTR) of the MEF2C gene (see, e.g., <a href="#0008">600662.0008</a>-<a href="#0010">600662.0010</a>). The mutations in the first patients were found by specific analysis of the 5-prime UTR regions in a select group of candidate genes. Additional patients with similar point mutations or small copy number variants (CNVs) affecting only the 5-prime UTR of MEF2C were subsequently identified from different patient cohorts through international collaboration. Two patients carried mutations that created upstream start codons (uAUGs) that were out-of-frame with the coding sequencing, predicted to result in premature termination. Six patients carried mutations that created uAUGs that were in-frame with the coding sequencing, predicted to result in N-terminal extensions. The CNVs identified in 2 patients were predicted to remove the promoter and part of the 5-prime UTR, which would abolish normal transcription. <a href="#24" class="mim-tip-reference" title="Wright, C. F., Quaife, N. M., Ramos-Hernandez, L., Danecek, P., Ferla, M. P., Samocha, K. E., Kaplanis, J., Gardner, E. J., Eberhardt, R. Y., Chao, K. R., Karczewski, K. J., Morales, J., and 22 others. <strong>Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.</strong> Am. J. Hum. Genet. 108: 1083-1094, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34022131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34022131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34022131[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.2021.04.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34022131">Wright et al. (2021)</a> noted that the N terminus of the protein is in direct contact with DNA, indicating that this is a functional domain. In vitro functional expression studies using a luciferase reporter showed that the point mutations decreased MEF2C translational efficiency and had reduced activation of target gene transcription to varying degrees compared to wildtype. The findings were most consistent with haploinsufficiency as the disease mechanism. <a href="#24" class="mim-tip-reference" title="Wright, C. F., Quaife, N. M., Ramos-Hernandez, L., Danecek, P., Ferla, M. P., Samocha, K. E., Kaplanis, J., Gardner, E. J., Eberhardt, R. Y., Chao, K. R., Karczewski, K. J., Morales, J., and 22 others. <strong>Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.</strong> Am. J. Hum. Genet. 108: 1083-1094, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34022131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34022131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34022131[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.2021.04.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34022131">Wright et al. (2021)</a> concluded that disease-causing 5-prime UTR variants can be detected in exome sequencing datasets that were designed to capture coding sequencing, and may be an important tool to increase diagnostic yield. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34022131" 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>Members of the MEF2 family of MADs-box transcription factors bind to an A-T-rich DNA sequence associated with muscle-specific genes. The murine Mef2c gene is expressed in heart precursor cells before formation of the linear heart tube. In mice homozygous for a known mutation of Mef2c, <a href="#15" class="mim-tip-reference" title="Lin, Q., Schwarz, J., Bucana, C., Olson, E. N. <strong>Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C.</strong> Science 276: 1404-1407, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9162005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9162005</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9162005[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.276.5317.1404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9162005">Lin et al. (1997)</a> found that the heart tube did not undergo looping morphogenesis, the future right ventricle did not form, and a subset of cardiac muscle genes was not expressed. The absence of the right ventricular region of the mutant correlated with downregulation of the dHAND gene, which encodes a basic helix-loop-helix transcription factor required for cardiac morphogenesis. The authors concluded that MEF2C is an essential regulator of cardiac morphogenesis and right ventricular development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9162005" 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="#22" class="mim-tip-reference" title="von Both, I., Silvestri, C., Erdemir, T., Lickert, H., Walls, J. R., Henkelman, R. M., Rossant, J., Harvey, R. P., Attisano, L., Wrana, J. L. <strong>Foxh1 is essential for development of the anterior heart field.</strong> Dev. Cell 7: 331-345, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15363409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15363409</a>] [<a href="https://doi.org/10.1016/j.devcel.2004.07.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15363409">Von Both et al. (2004)</a> characterized the molecular basis for defective heart formation in Foxh1 (<a href="/entry/603621">603621</a>)-null mice and determined that Mef2c is a direct target of Foxh1. They identified a composite Foxh1-Nkx2.5 (<a href="/entry/600584">600584</a>)-binding site within the Mef2c gene that was regulated by Tgf-beta (see <a href="/entry/190180">190180</a>) signaling in a Smad-dependent manner. <a href="#22" class="mim-tip-reference" title="von Both, I., Silvestri, C., Erdemir, T., Lickert, H., Walls, J. R., Henkelman, R. M., Rossant, J., Harvey, R. P., Attisano, L., Wrana, J. L. <strong>Foxh1 is essential for development of the anterior heart field.</strong> Dev. Cell 7: 331-345, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15363409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15363409</a>] [<a href="https://doi.org/10.1016/j.devcel.2004.07.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15363409">Von Both et al. (2004)</a> concluded that a TGF-beta-like SMAD signaling pathway specifies the anterior heart field through a FOXH1-NKX2.5 complex that regulates MEF2C expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15363409" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Verzi, M. P., Agarwal, P., Brown, C., McCulley, D. J., Schwarz, J. J., Black, B. L. <strong>The transcription factor MEF2C is required for craniofacial development.</strong> Dev. Cell 12: 645-652, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17420000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17420000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17420000[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.devcel.2007.03.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17420000">Verzi et al. (2007)</a> found that conditional inactivation of Mef2c in mouse neural crest resulted in neonatal lethality due to severe craniofacial defects. Mef2c was required for expression of Dlx5 (<a href="/entry/600028">600028</a>), Dlx6 (<a href="/entry/600030">600030</a>), and Hand2 (<a href="/entry/602407">602407</a>) transcription factors in the branchial arches, and <a href="#21" class="mim-tip-reference" title="Verzi, M. P., Agarwal, P., Brown, C., McCulley, D. J., Schwarz, J. J., Black, B. L. <strong>The transcription factor MEF2C is required for craniofacial development.</strong> Dev. Cell 12: 645-652, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17420000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17420000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17420000[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.devcel.2007.03.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17420000">Verzi et al. (2007)</a> identified a branchial arch-specific enhancer in the Dlx5/Dlx6 locus that was activated synergistically by Mef2c and Dlx5. Mef2c and Dlx5/Dlx6 also interacted genetically, since mice heterozygous for either Dlx5/Dlx6 or Mef2c were normal at birth and survived to weaning, whereas heterozygosity for both Dlx5/Dlx6 and Mef2c resulted in defective palate development and neonatal lethality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17420000" 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="Barbosa, A. C., Kim. M.-S., Ertunc, M., Adachi, M., Nelson, E. D., McAnally, J., Richardson, J. A., Kavalali, E. T., Monteggia, L. M., Bassel-Duby, R., Olson, E. N. <strong>MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function.</strong> Proc. Nat. Acad. Sci. 105: 9391-9396, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18599438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18599438</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18599438[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.0802679105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18599438">Barbosa et al. (2008)</a> found that mice with brain-specific deletion of the Mef2c gene were viable to adulthood, were slightly smaller than wildtype littermates, and showed impaired balance beam walking and an abnormal hind/forelimb clasping reflex at a young age. In addition, Mef2c-knockout mice showed impaired hippocampal-dependent learning and memory. These behavioral changes were accompanied by a marked increase in the number of excitatory synapses and potentiation of basal and evoked synaptic transmission resulting from altered presynaptic function. Conversely, neuronal expression of a superactivating form of Mef2c in postsynaptic cells resulted in a reduction of excitatory postsynaptic sites without affecting learning and memory performance. No changes in synapse structure were observed. The findings suggested that MEF2C activity per se does not directly determine learning, but somehow facilitates learning-related plasticity by controlling excessive synaptic input. <a href="#2" class="mim-tip-reference" title="Barbosa, A. C., Kim. M.-S., Ertunc, M., Adachi, M., Nelson, E. D., McAnally, J., Richardson, J. A., Kavalali, E. T., Monteggia, L. M., Bassel-Duby, R., Olson, E. N. <strong>MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function.</strong> Proc. Nat. Acad. Sci. 105: 9391-9396, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18599438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18599438</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18599438[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.0802679105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18599438">Barbosa et al. (2008)</a> concluded that refinement of synaptic connectivity facilitates hippocampal-dependent learning and memory. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18599438" 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="Li, H., Radford, J. C., Ragusa, M. J., Shea, K. L., McKercher, S. R., Zaremba, J. D., Soussou, W., Nie, Z., Kang, Y.-J., Nakanishi, N., Okamoto, S., Roberts, A. J., Schwarz, J. J., Lipton, S. A. <strong>Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo.</strong> Proc. Nat. Acad. Sci. 105: 9397-9402, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18599437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18599437</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18599437[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.0802876105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18599437">Li et al. (2008)</a> found that conditional knockout of Mef2c in nestin (NES; <a href="/entry/600915">600915</a>)-expressing neural stem/progenitor cells impaired neuronal differentiation in mice, resulting in aberrant aggregation and compaction of neurons migrating into the lower layers of the neocortex during development. Neural stem cell proliferation and survival were not affected. Conditional Mef2c-null mice surviving to adulthood manifested smaller, less mature neurons and smaller brain size with more immature electrophysiologic network properties. They also showed severe behavioral deficits reminiscent of Rett syndrome (RTT; <a href="/entry/312750">312750</a>), such as anxiety, decreased cognitive function, and marked paw-clasping. <a href="#14" class="mim-tip-reference" title="Li, H., Radford, J. C., Ragusa, M. J., Shea, K. L., McKercher, S. R., Zaremba, J. D., Soussou, W., Nie, Z., Kang, Y.-J., Nakanishi, N., Okamoto, S., Roberts, A. J., Schwarz, J. J., Lipton, S. A. <strong>Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo.</strong> Proc. Nat. Acad. Sci. 105: 9397-9402, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18599437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18599437</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18599437[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.0802876105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18599437">Li et al. (2008)</a> concluded that MEF2C has a crucial role in programming early neuronal differentiation and proper distribution within the layers of the neocortex during development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18599437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600662[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</strong>
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<p>In a girl (patient 7) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; <a href="/entry/613443">613443</a>), <a href="#12" class="mim-tip-reference" title="Le Meur, N., Holder-Espinasse, M., Jaillard, S., Goldenberg, A., Joriot, S., Amati-Bonneau, P., Guichet, A., Barth, M., Charollais, A., Journel, H., Auvin, S., Boucher, C., Kerckaert, J.-P., David, V., Manouvrier-Hanu, S., Saugier-Veber, P., Frebourg, T., Dubourg, C., Andrieux, J., Bonneau, D. <strong>MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations.</strong> J. Med. Genet. 47: 22-29, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19592390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19592390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19592390[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2009.069732" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19592390">Le Meur et al. (2010)</a> identified a de novo heterozygous c.683C-G transversion (c.683C-G, NM_002397.2) in exon 7 of the MEF2C gene, resulting in a ser228-to-ter (S228X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19592390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</strong>
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<p>In a 3-year-old girl (patient 5) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; <a href="/entry/613443">613443</a>), <a href="#26" class="mim-tip-reference" title="Zweier, M., Gregor, A., Zweier, C., Engels, H., Sticht, H., Wohlleber, E., Bijlsma, E. K., Holder, S. E., Zenker, M., Rossier, E., Grasshoff, U., Johnson, D. S., Robertson, L., Firth, H. V., Kraus, C., Ekici, A. B., Reis, A., Rauch, A. <strong>Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.</strong> Hum. Mutat. 31: 722-733, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513142</a>] [<a href="https://doi.org/10.1002/humu.21253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20513142">Zweier et al. (2010)</a> identified a de novo heterozygous c.113T-A transversion (c.113T-A, NM_002397.3) in exon 3 of the MEF2C gene, resulting in a leu38-to-gln (L38Q) substitution in the MADS domain. Homology modeling predicted that the mutation may alter DNA-binding affinity. The patient had severe developmental delay with absent speech, inability to walk, hypotonia, seizure onset at age 10 months, delayed myelination, and mild dysmorphic facial features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20513142" 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 HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000033230" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033230" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033230</a>
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<p>In a 14-year-old boy (patient 6) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; <a href="/entry/613443">613443</a>), <a href="#26" class="mim-tip-reference" title="Zweier, M., Gregor, A., Zweier, C., Engels, H., Sticht, H., Wohlleber, E., Bijlsma, E. K., Holder, S. E., Zenker, M., Rossier, E., Grasshoff, U., Johnson, D. S., Robertson, L., Firth, H. V., Kraus, C., Ekici, A. B., Reis, A., Rauch, A. <strong>Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.</strong> Hum. Mutat. 31: 722-733, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513142</a>] [<a href="https://doi.org/10.1002/humu.21253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20513142">Zweier et al. (2010)</a> identified a de novo heterozygous 1-bp duplication (c.99dupT, NM_002397.3) in exon 3 of the MEF2C gene, resulting in a glu34-to-ter (E34X) substitution. The patient had severe developmental delay with absent speech, hypertonia, seizure onset at age 10 months, mildly enlarged ventricles, and mild dysmorphic facial features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20513142" 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 HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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">rs397514656 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514656;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=rs397514656" 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=rs397514656" 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 10-year-old girl (patient 8) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; <a href="/entry/613443">613443</a>), <a href="#26" class="mim-tip-reference" title="Zweier, M., Gregor, A., Zweier, C., Engels, H., Sticht, H., Wohlleber, E., Bijlsma, E. K., Holder, S. E., Zenker, M., Rossier, E., Grasshoff, U., Johnson, D. S., Robertson, L., Firth, H. V., Kraus, C., Ekici, A. B., Reis, A., Rauch, A. <strong>Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.</strong> Hum. Mutat. 31: 722-733, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513142</a>] [<a href="https://doi.org/10.1002/humu.21253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20513142">Zweier et al. (2010)</a> identified a de novo heterozygous c.80G-C transversion (c.80G-C, NM_002397.3) in exon 3 of the MEF2C gene, resulting in a gly27-to-ala (G27A) substitution in the MADS domain. Homology modeling predicted that the mutation may alter DNA-binding affinity. The patient had severe developmental delay with absent speech, difficulty walking, hypotonia, seizure onset at 6 months, delayed myelination, and mild dysmorphic facial features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20513142" 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 HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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">rs730882192 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs730882192;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=rs730882192" 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=rs730882192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 8-year-old girl with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; <a href="/entry/613443">613443</a>), <a href="#3" class="mim-tip-reference" title="Bienvenu, T., Diebold, B., Chelly, J., Isidor, B. <strong>Refining the phenotype associated with MEF2C point mutations.</strong> Neurogenetics 14: 71-75, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23001426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23001426</a>] [<a href="https://doi.org/10.1007/s10048-012-0344-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23001426">Bienvenu et al. (2013)</a> identified a de novo heterozygous 1-bp deletion (c.457delA, NM_002397.3) in exon 5 of the MEF2C gene, predicted to result in premature termination (Asn153ThrfsTer33) and loss of the functional transactivation domain. In infancy, the patient had poor feeding due to marked hypotonia and poor eye contact due to strabismus. Motor milestones were delayed, and she walked at age 4 years. At age 18 months, she had a single episode of myoclonic febrile seizures that were easily controlled. At age 7 years, she had poor growth, microcephaly (-2.5 SD), lack of speech, stereotypic movements, unstable wide-based gait, and happy demeanor. There were mild dysmorphic features, including large eyebrows, open mouth with thick everted lower lip, and anteverted nares. Brain MRI was normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23001426" 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 HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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">rs587783749 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587783749;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=rs587783749" 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=rs587783749" 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=RCV000146367 OR RCV000255477 OR RCV004639143" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000146367, RCV000255477, RCV004639143" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000146367...</a>
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<p>In a 22-month-old girl (LR11-310) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; <a href="/entry/613443">613443</a>), <a href="#19" class="mim-tip-reference" title="Paciorkowski, A. R., Traylor, R. N., Rosenfeld, J. A., Hoover, J. M., Harris, C. J., Winter, S., Lacassie, Y., Bialer, M., Lamb, A. N., Schultz, R. A., Berry-Kravis, E., Porter, B. E., and 9 others. <strong>MEF2C haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways.</strong> Neurogenetics 14: 99-111, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23389741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23389741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23389741[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s10048-013-0356-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23389741">Paciorkowski et al. (2013)</a> identified a heterozygous 1-bp deletion (c.833delT) in the MEF2C gene, predicted to result in a frameshift and premature termination. The patient was part of a cohort of individuals with 5q14.3 deletions, and the phenotype was ascertained retrospectively. Functional studies of the variant, studies of patient cells, and segregation were not reported. She had developmental delay and onset of refractory myoclonic and atonic seizures at age 18 months. She also had stereotypic hand movements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23389741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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">rs2153074000 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2153074000;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=rs2153074000" 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=rs2153074000" 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 3-year-old girl (patient 5) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; <a href="/entry/613443">613443</a>), <a href="#23" class="mim-tip-reference" title="Vrecar, I., Innes, J., Jones, E. A., Kingston, H., Reardon, W., Kerr, B., Clayton-Smith, J., Douzgou, S. <strong>Further clinical delineation of the MEF2C haploinsufficiency syndrome: report on new cases and literature review of severe neurodevelopmental disorders presenting with seizures, absent speech, and involuntary movements.</strong> J. Pediat. Genet. 6: 129-141, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28794905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28794905</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28794905[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/10.1055/s-0037-1601335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28794905">Vrecar et al. (2017)</a> identified a de novo heterozygous c.220G-T transversion in exon 3 of the MEF2C gene, resulting in a glu74-to-ter (E74X) substitution. The mutation was found by next-generation sequencing on an epilepsy panel and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. The patient had onset of seizures in the first year of life; she also demonstrated developmental delay and hand wringing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28794905" 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>.0008 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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">rs2153222958 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2153222958;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=rs2153222958" 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=rs2153222958" 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=RCV001568454 OR RCV001685531 OR RCV001779254" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001568454, RCV001685531, RCV001779254" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001568454...</a>
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<p>In 3 unrelated patients (patients 3, 4, and 5) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; <a href="/entry/613443">613443</a>), <a href="#24" class="mim-tip-reference" title="Wright, C. F., Quaife, N. M., Ramos-Hernandez, L., Danecek, P., Ferla, M. P., Samocha, K. E., Kaplanis, J., Gardner, E. J., Eberhardt, R. Y., Chao, K. R., Karczewski, K. J., Morales, J., and 22 others. <strong>Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.</strong> Am. J. Hum. Genet. 108: 1083-1094, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34022131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34022131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34022131[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.2021.04.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34022131">Wright et al. (2021)</a> identified a de novo heterozygous c.-8C-T transition in the 5-prime untranslated region (UTR) of the MEF2C gene. The mutation, which was found by specific analysis of 5-prime UTR variants in selected candidate genes, was not present in the gnomAD database. The mutation created an upstream AUG codon that was in-frame with the coding sequence, creating resulting in an N-terminal extension of 3 amino acids. In vitro functional expression studies using a luciferase reporter showed that the mutation significantly decreased MEF2C translational efficiency compared to controls. These findings were consistent with haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34022131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs758320958 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs758320958;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs758320958?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs758320958" 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=rs758320958" 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=RCV001684643 OR RCV002284492 OR RCV003163791" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001684643, RCV002284492, RCV003163791" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001684643...</a>
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<p>In 3 unrelated patients (patients 6, 7, and 8) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; <a href="/entry/613443">613443</a>), <a href="#24" class="mim-tip-reference" title="Wright, C. F., Quaife, N. M., Ramos-Hernandez, L., Danecek, P., Ferla, M. P., Samocha, K. E., Kaplanis, J., Gardner, E. J., Eberhardt, R. Y., Chao, K. R., Karczewski, K. J., Morales, J., and 22 others. <strong>Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.</strong> Am. J. Hum. Genet. 108: 1083-1094, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34022131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34022131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34022131[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.2021.04.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34022131">Wright et al. (2021)</a> identified a de novo heterozygous c.-26C-T transition in the 5-prime untranslated region (UTR) of the MEF2C gene. The mutation, which was found by specific analysis of 5-prime UTR variants in selected candidate genes, was not present in the gnomAD database. The mutation created an upstream AUG codon that was in-frame with the coding sequence, creating resulting in an N-terminal extension of 9 amino acids. In vitro functional expression studies using a luciferase reporter showed that the mutation significantly decreased MEF2C translational efficiency compared to controls. These findings were consistent with haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34022131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1350600010 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1350600010;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1350600010?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1350600010" 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=rs1350600010" 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=RCV001684644" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001684644" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001684644</a>
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<p>In a patient (patient 1) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; <a href="/entry/613443">613443</a>), <a href="#24" class="mim-tip-reference" title="Wright, C. F., Quaife, N. M., Ramos-Hernandez, L., Danecek, P., Ferla, M. P., Samocha, K. E., Kaplanis, J., Gardner, E. J., Eberhardt, R. Y., Chao, K. R., Karczewski, K. J., Morales, J., and 22 others. <strong>Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.</strong> Am. J. Hum. Genet. 108: 1083-1094, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34022131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34022131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34022131[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.2021.04.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34022131">Wright et al. (2021)</a> identified a de novo heterozygous c.-66A-T transversion in the 5-prime untranslated region (UTR) of the MEF2C gene. The mutation, which was found by specific analysis of 5-prime UTR variants in selected candidate genes, was not present in the gnomAD database. The mutation created an upstream AUG codon that was out-of-frame with the coding sequence, creating an overlapping open reading frame that terminated 128 bases after the canonical start site. In vitro functional expression studies using a luciferase reporter showed that the mutation decreased MEF2C translational efficiency compared to controls. These findings were consistent with haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34022131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1038/nature20111" target="_blank">Full Text</a>]
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Barbosa, A. C., Kim. M.-S., Ertunc, M., Adachi, M., Nelson, E. D., McAnally, J., Richardson, J. A., Kavalali, E. T., Monteggia, L. M., Bassel-Duby, R., Olson, E. N.
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[<a href="https://doi.org/10.1073/pnas.0802679105" target="_blank">Full Text</a>]
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Breitbart, R. E., Liang, C., Smoot, L. B., Laheru, D. A., Mahdavi, V., Nadal-Ginard, B.
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Cardoso, C., Boys, A., Parrini, E., Mignon-Ravix, C., McMahon, J. M., Khantane, S., Bertini, E., Pallesi, E., Missirian, C., Zuffardi, O., Novara, F., Villard, L., Giglio, S., Chabrol, B., Slater, H. R., Moncla, A., Scheffer, I. E., Guerrini, R.
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Chen, S. L., Dowhan, D. H., Hosking, B. M., Muscat, G. E. O.
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<strong>The steroid receptor coactivator, GRIP-1, is necessary for MEF-2C-dependent gene expression and skeletal muscle differentiation.</strong>
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Chen, S. L., Loffler, K. A., Chen, D., Stallcup, M. R., Muscat, G. E. O.
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<strong>The coactivator-associated arginine methyltransferase is necessary for muscle differentiation: CARM1 coactivates myocyte enhancer factor-2.</strong>
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[<a href="https://doi.org/10.1074/jbc.M109835200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddy393" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ejhg.2009.90" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature06607" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1995.9927" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2009.069732" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.90.4.1546" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0802876105" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.276.5317.1404" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.286.5440.785" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/mcb.14.3.1647-1656.1994" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/mcb.13.4.2564-2577.1993" target="_blank">Full Text</a>]
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<strong>MEF2C haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways.</strong>
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[<a href="https://doi.org/10.1007/s10048-013-0356-y" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17786239/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17786239</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17786239[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=17786239" 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/10.1172/JCI31960" target="_blank">Full Text</a>]
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<strong>The transcription factor MEF2C is required for craniofacial development.</strong>
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[<a href="https://doi.org/10.1016/j.devcel.2007.03.007" target="_blank">Full Text</a>]
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<strong>Foxh1 is essential for development of the anterior heart field.</strong>
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Dev. Cell 7: 331-345, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15363409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15363409</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15363409" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.devcel.2004.07.023" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Vrecar2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vrecar, I., Innes, J., Jones, E. A., Kingston, H., Reardon, W., Kerr, B., Clayton-Smith, J., Douzgou, S.
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<strong>Further clinical delineation of the MEF2C haploinsufficiency syndrome: report on new cases and literature review of severe neurodevelopmental disorders presenting with seizures, absent speech, and involuntary movements.</strong>
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J. Pediat. Genet. 6: 129-141, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28794905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28794905</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28794905[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=28794905" 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/10.1055/s-0037-1601335" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Wright2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wright, C. F., Quaife, N. M., Ramos-Hernandez, L., Danecek, P., Ferla, M. P., Samocha, K. E., Kaplanis, J., Gardner, E. J., Eberhardt, R. Y., Chao, K. R., Karczewski, K. J., Morales, J., and 22 others.
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<strong>Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.</strong>
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Am. J. Hum. Genet. 108: 1083-1094, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34022131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34022131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34022131[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=34022131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2021.04.025" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Xu2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xu, J., Gong, N. L., Bodi, I., Aronow, B. J., Backx, P. H., Molkentin, J. D.
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<strong>Myocyte enhancer factors 2A and 2C induce dilated cardiomyopathy in transgenic mice.</strong>
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J. Biol. Chem. 281: 9152-9162, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16469744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16469744</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16469744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M510217200" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Zweier2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zweier, M., Gregor, A., Zweier, C., Engels, H., Sticht, H., Wohlleber, E., Bijlsma, E. K., Holder, S. E., Zenker, M., Rossier, E., Grasshoff, U., Johnson, D. S., Robertson, L., Firth, H. V., Kraus, C., Ekici, A. B., Reis, A., Rauch, A.
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<strong>Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.</strong>
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Hum. Mutat. 31: 722-733, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513142</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20513142" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.21253" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 12/01/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 09/15/2021<br>Ada Hamosh - updated : 09/04/2019<br>Cassandra L. Kniffin - updated : 3/5/2013<br>Cassandra L. Kniffin - updated : 6/15/2010<br>Cassandra L. Kniffin - updated : 7/29/2009<br>Ada Hamosh - updated : 3/18/2008<br>Patricia A. Hartz - updated : 11/6/2007<br>Patricia A. Hartz - updated : 5/4/2007<br>Patricia A. Hartz - updated : 8/14/2006<br>Patricia A. Hartz - updated : 8/9/2006<br>Patricia A. Hartz - updated : 10/7/2004<br>Paul J. Converse - updated : 8/11/2000<br>Ada Hamosh - updated : 10/22/1999<br>Victor A. McKusick - updated : 6/20/1997<br>Alan F. Scott - updated : 11/8/1995
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</span>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Alan F. Scott : 8/18/1995
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 05/08/2022
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/16/2022<br>carol : 12/02/2021<br>alopez : 12/01/2021<br>alopez : 09/17/2021<br>alopez : 09/17/2021<br>ckniffin : 09/15/2021<br>alopez : 09/04/2019<br>carol : 03/04/2015<br>carol : 9/16/2013<br>carol : 3/8/2013<br>ckniffin : 3/5/2013<br>wwang : 6/22/2010<br>ckniffin : 6/15/2010<br>wwang : 8/11/2009<br>ckniffin : 7/29/2009<br>ckniffin : 7/29/2009<br>wwang : 6/5/2008<br>terry : 5/30/2008<br>alopez : 3/26/2008<br>terry : 3/18/2008<br>mgross : 11/6/2007<br>terry : 11/6/2007<br>mgross : 5/23/2007<br>terry : 5/4/2007<br>wwang : 8/14/2006<br>wwang : 8/11/2006<br>terry : 8/9/2006<br>terry : 4/4/2005<br>mgross : 10/7/2004<br>mgross : 8/11/2000<br>alopez : 10/22/1999<br>alopez : 7/10/1997<br>terry : 6/23/1997<br>alopez : 6/20/1997<br>mark : 4/7/1996<br>mark : 8/18/1995
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</span>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600662
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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MYOCYTE ENHANCER FACTOR 2C; MEF2C
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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MADS BOX TRANSCRIPTION ENHANCER FACTOR 2, POLYPEPTIDE C
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</span>
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</h4>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MEF2C</em></strong>
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</span>
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</p>
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</div>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 5q14.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 5:88,717,117-88,904,105 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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5q14.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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Chromosome 5q14.3 deletion syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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613443
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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4
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</span>
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</td>
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<td>
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<span class="mim-font">
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Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language
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</span>
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</td>
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<td>
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<span class="mim-font">
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613443
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tbody>
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</table>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>MEF2C belongs to the myocyte enhancer factor-2 (MEF2) family of transcription factors. MEF2C plays a pivotal role in myogenesis, development of the anterior heart field, neural crest and craniofacial development, and neurogenesis, among others (summary by Zweier et al., 2010). MEF2C is a transcription factor with changing expression patterns during brain development that correlate with roles in neuronal developmental and maturation (summary by Paciorkowski et al., 2013). </p><p>See also MEF2A (600660).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>McDermott et al. (1993) cloned a member of the MEF2 family of proteins from a human skeletal muscle cDNA library using a fragment of the MEF2A cDNA as a probe. Transcripts of MEF2C were found in the skeletal muscle and brain. Alternative splice variants were found, 1 of which was unique to the brain. </p><p>Leifer et al. (1993) found that the brain form was expressed by neurons in particular layers of the cerebral cortex and that expression declined during postnatal development. The skeletal isoform of the cDNA encodes a 465-amino acid protein with conserved MADS and MEF2 domains. Like the other MEF2 gene products, MEF2C has both DNA binding and trans-activating activities indistinguishable from other members of the family. MEF2C, however, is induced late during myogenic differentiation and has a strict tissue-specific pattern of expression not seen in MEF2A or MEF2B. </p><p>Zweier et al. (2010) found high expression of isoform 1 of the MEF2C gene in fetal and adult human brain, whereas isoform 2 was widely expressed with highest levels in skeletal muscle. </p><p>Paciorkowski et al. (2013) found expression of Mef2c in both dorsal primary neuroblasts and ventral GABAergic interneurons in the forebrain of the developing mouse. The authors noted that Mef2c has been shown to interact with other genes in the developing mouse brain, suggesting that it is involved in a complex pathway. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Breitbart et al. (1993) suggested that, while MEF2A may be involved in induction of muscle differentiation, MEF2C may be involved with maintenance of the differentiated state. </p><p>CREB-binding protein (CBP; 600140)/p300 (602700) and p300/CBP-associated factor (PCAF; 602203) are coactivators for MEF2C during differentiation. Chen et al. (2000) showed that NCOA2 mediates the coactivation of MEF2C-dependent transcription through interaction with the MADS box domain of MEF2C. They proposed a model of cooperative interaction between NCOA2, myogenin (MYOG; 159980), and MEF2C in the regulation of muscle-specific gene expression. </p><p>During mammalian development, electrical activity promotes the calcium-dependent survival of neurons that have made appropriate synaptic connections. Mao et al. (1999) showed that calcium influx into cerebellar neurons triggers the activation of the MKK6 (601254)-p38 MAP kinase (600289) cascade and that the p38 MAP kinase then phosphorylates and activates MEF2s. Once activated by this calcium-dependent p38 MAP kinase signaling pathway, MEF2 can regulate the expression of genes that are critical for survival of newly differentiated neurons. These findings demonstrated that MEF2 is a calcium-regulated transcription factor and defined a function for MEF2 during nervous system development that is distinct from previously well-characterized functions of MEF2 during muscle differentiation. </p><p>Chen et al. (2002) demonstrated that Carm1 (603934) and Ncoa2 cooperatively stimulated the activity of Mef2c in mouse mesenchymal stem cells and found that there was direct interaction among Mef2c, Grip1, and Carm1. </p><p>By targeting human MEF2A or mouse Mef2c expression to mouse cardiomyocytes, Xu et al. (2006) demonstrated that overexpressing these transcription factors caused cardiomyopathy or predisposed transgenic mice to more fulminant disease following pressure overload. In cultured cardiomyocytes, MEF2A or Mef2c overexpression induced sarcomeric disorganization and focal elongation. Both MEF2A and Mef2c programmed similar profiles of gene expression in the heart that included genes involved in extracellular matrix remodeling, ion handling, and metabolism. </p><p>Potthoff et al. (2007) showed that class II histone deacetylases (e.g., HDAC5; 605315) were selectively degraded by the proteasome in mouse slow, oxidative myofibers, enabling Mef2 to activate the slow myofiber gene program. Forced expression of Hdac5 in skeletal muscle or genetic deletion of Mef2c or Mef2d (600663) blocked activity-dependent fast to slow fiber transformation, whereas expression of hyperactive Mef2c promoted the slow fiber phenotype, enhancing endurance and enabling mice to run almost twice the distance of wildtype littermates. </p><p>Using a loss-of-function allele in mice, Johnnidis et al. (2008) reported that the myeloid-specific microRNA-223 (miR223; 300694) negatively regulates progenitor proliferation and granulocyte differentiation and activation. miR223 mutant mice had an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte progenitors. Johnnidis et al. (2008) showed that Mef2c, a transcription factor that promotes myeloid progenitor proliferation, is a target of miR223, and that genetic ablation of Mef2c suppresses progenitor expansion and corrects the neutrophilic phenotype in miR223-null mice. In addition, granulocytes lacking miR223 were hypermature, hypersensitive to activating stimuli, and displayed increased fungicidal activity. As a consequence of this neutrophil hyperactivity, miR223 mutant mice spontaneously developed inflammatory lung pathology and exhibited exaggerated tissue destruction after endotoxin challenge. Johnnidis et al. (2008) concluded that their data supported a model in which miR223 acts as a fine tuner of granulocyte production and the inflammatory response. </p><p>Zweier et al. (2010) demonstrated that MEF2C increases promoter activation of the MECP2 (300005) and CDKL5 (300203) genes. </p><p>Using transcriptional profiling of human fetal brain cultures, Ataman et al. (2016) identified an activity-dependent secreted factor, osteocrin (OSTN; 610280), that is induced by membrane depolarization of human, but not mouse, neurons. Ataman et al. (2016) found that OSTN has been repurposed in primates through the evolutionary acquisition of DNA regulatory elements that bind the activity-regulated transcription factor MEF2, specifically MEF2C. In addition, the authors demonstrated that OSTN is expressed in primate neocortex and restricts activity-dependent dendritic growth in human neurons. The authors concluded that their findings suggested that, in response to sensory input, OSTN regulates features of neuronal structure and function that are unique to primates. </p><p>Using circularized chromosome conformation capture sequencing (4C-seq), D'haene et al. (2019) identified a complex interaction network in which the promoter region of the MEF2C gene physically interacted with multiple distal putative enhancer elements, and that the coordinated action of these multiple enhancer elements was required for the precise spatiotemporal regulation of MEF2C. The authors tested 16 candidate regulatory sequences in vitro and found that 14 of them displayed enhancer capacity, in many cases with a higher activity being observed in SH-SY5Y than in HEK293. In vivo analyses with zebrafish further revealed that each of these enhancers had a distinct activity pattern during zebrafish development, with 8 enhancers displaying neuronal activity. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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<span class="mim-text-font">
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<p>Martin et al. (1994) mapped Mef2 to mouse chromosome 13. By fluorescence in situ hybridization, Krainc et al. (1995) mapped human MEF2C to chromosome 5q14, a region with homology of synteny to the mouse location. </p>
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<strong>Cytogenetics</strong>
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<span class="mim-text-font">
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<p>In 5 unrelated children with severe developmental delay, stereotypic movements, epilepsy, and/or cerebral malformations (613443), Le Meur et al. (2010) identified 5 different interstitial de novo deletions of chromosome 5q14 ranging in size from 216 kb to 8.8 Mb. The minimal common deleted region contained only the MEF2C gene. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>In a girl with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; 613443), Le Meur et al. (2010) identified a de novo heterozygous nonsense mutation in the MEF2C gene (S228X; 600662.0001). Le Meur et al. (2010) noted that the role of MEF2C in synaptic plasticity is consistent with a role in learning and memory, and the authors referred to the mouse models of Li et al. (2008) and Barbosa et al. (2008). </p><p>Zweier et al. (2010) identified 4 different de novo heterozygous mutations in the MEF2C gene (see. e.g., 600662.0002-600662.0004) in 4 of 362 probands with impaired intellectual development who were screened for mutations in this gene. Two of the mutations were missense and 2 were truncating. Two additional patients with a similar disorder had heterozygous deletions involving the MEF2C gene. Analysis of blood-derived RNA showed significantly decreased levels of MEF2C isoform 2 mRNA in all patients with deletions in or including the MEF2C gene region, including the patients reported by Engels et al. (2009), Cardoso et al. (2009), and Le Meur et al. (2010), suggesting haploinsufficiency. Two patients with missense mutations did not show decreased MEF2C mRNA levels. All deletions and mutations caused significantly decreased MEF2C transcriptional activity, which could be rescued by wildtype MEF2C. Finally, all patients, including the 2 with missense mutations, showed decreased levels of MECP2 mRNA, and all except 2 patients had decreased levels of CDKL5 mRNA. These 2 genes are involved in Rett or Rett syndrome-like phenotypes (312750 and 300672, respectively), which shares some features with MRD20. Zweier et al. (2010) concluded that the phenotype results from involvement of a common pathway involving these 3 genes. </p><p>In an 8-year-old girl with severe NEDHSIL, Bienvenu et al. (2013) identified a de novo heterozygous frameshift in the MEF2C gene (600662.0005). Functional studies were not performed. </p><p>In a 22-month-old girl with NEDHSIL, Paciorkowski et al. (2013) identified a heterozygous frameshift mutation in the MEF2C gene (600662.0006). Functional studies of the variant, studies of patient cells, and segregation were not reported. </p><p>In 10 unrelated patients with NEDHSIL, Wright et al. (2021) identified 10 de novo heterozygous point mutations or small intragenic deletions affecting the 5-prime untranslated region (UTR) of the MEF2C gene (see, e.g., 600662.0008-600662.0010). The mutations in the first patients were found by specific analysis of the 5-prime UTR regions in a select group of candidate genes. Additional patients with similar point mutations or small copy number variants (CNVs) affecting only the 5-prime UTR of MEF2C were subsequently identified from different patient cohorts through international collaboration. Two patients carried mutations that created upstream start codons (uAUGs) that were out-of-frame with the coding sequencing, predicted to result in premature termination. Six patients carried mutations that created uAUGs that were in-frame with the coding sequencing, predicted to result in N-terminal extensions. The CNVs identified in 2 patients were predicted to remove the promoter and part of the 5-prime UTR, which would abolish normal transcription. Wright et al. (2021) noted that the N terminus of the protein is in direct contact with DNA, indicating that this is a functional domain. In vitro functional expression studies using a luciferase reporter showed that the point mutations decreased MEF2C translational efficiency and had reduced activation of target gene transcription to varying degrees compared to wildtype. The findings were most consistent with haploinsufficiency as the disease mechanism. Wright et al. (2021) concluded that disease-causing 5-prime UTR variants can be detected in exome sequencing datasets that were designed to capture coding sequencing, and may be an important tool to increase diagnostic yield. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Members of the MEF2 family of MADs-box transcription factors bind to an A-T-rich DNA sequence associated with muscle-specific genes. The murine Mef2c gene is expressed in heart precursor cells before formation of the linear heart tube. In mice homozygous for a known mutation of Mef2c, Lin et al. (1997) found that the heart tube did not undergo looping morphogenesis, the future right ventricle did not form, and a subset of cardiac muscle genes was not expressed. The absence of the right ventricular region of the mutant correlated with downregulation of the dHAND gene, which encodes a basic helix-loop-helix transcription factor required for cardiac morphogenesis. The authors concluded that MEF2C is an essential regulator of cardiac morphogenesis and right ventricular development. </p><p>Von Both et al. (2004) characterized the molecular basis for defective heart formation in Foxh1 (603621)-null mice and determined that Mef2c is a direct target of Foxh1. They identified a composite Foxh1-Nkx2.5 (600584)-binding site within the Mef2c gene that was regulated by Tgf-beta (see 190180) signaling in a Smad-dependent manner. Von Both et al. (2004) concluded that a TGF-beta-like SMAD signaling pathway specifies the anterior heart field through a FOXH1-NKX2.5 complex that regulates MEF2C expression. </p><p>Verzi et al. (2007) found that conditional inactivation of Mef2c in mouse neural crest resulted in neonatal lethality due to severe craniofacial defects. Mef2c was required for expression of Dlx5 (600028), Dlx6 (600030), and Hand2 (602407) transcription factors in the branchial arches, and Verzi et al. (2007) identified a branchial arch-specific enhancer in the Dlx5/Dlx6 locus that was activated synergistically by Mef2c and Dlx5. Mef2c and Dlx5/Dlx6 also interacted genetically, since mice heterozygous for either Dlx5/Dlx6 or Mef2c were normal at birth and survived to weaning, whereas heterozygosity for both Dlx5/Dlx6 and Mef2c resulted in defective palate development and neonatal lethality. </p><p>Barbosa et al. (2008) found that mice with brain-specific deletion of the Mef2c gene were viable to adulthood, were slightly smaller than wildtype littermates, and showed impaired balance beam walking and an abnormal hind/forelimb clasping reflex at a young age. In addition, Mef2c-knockout mice showed impaired hippocampal-dependent learning and memory. These behavioral changes were accompanied by a marked increase in the number of excitatory synapses and potentiation of basal and evoked synaptic transmission resulting from altered presynaptic function. Conversely, neuronal expression of a superactivating form of Mef2c in postsynaptic cells resulted in a reduction of excitatory postsynaptic sites without affecting learning and memory performance. No changes in synapse structure were observed. The findings suggested that MEF2C activity per se does not directly determine learning, but somehow facilitates learning-related plasticity by controlling excessive synaptic input. Barbosa et al. (2008) concluded that refinement of synaptic connectivity facilitates hippocampal-dependent learning and memory. </p><p>Li et al. (2008) found that conditional knockout of Mef2c in nestin (NES; 600915)-expressing neural stem/progenitor cells impaired neuronal differentiation in mice, resulting in aberrant aggregation and compaction of neurons migrating into the lower layers of the neocortex during development. Neural stem cell proliferation and survival were not affected. Conditional Mef2c-null mice surviving to adulthood manifested smaller, less mature neurons and smaller brain size with more immature electrophysiologic network properties. They also showed severe behavioral deficits reminiscent of Rett syndrome (RTT; 312750), such as anxiety, decreased cognitive function, and marked paw-clasping. Li et al. (2008) concluded that MEF2C has a crucial role in programming early neuronal differentiation and proper distribution within the layers of the neocortex during development. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>10 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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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MEF2C, SER228TER
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<br />
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SNP: rs267607233,
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ClinVar: RCV000009503
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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 girl (patient 7) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; 613443), Le Meur et al. (2010) identified a de novo heterozygous c.683C-G transversion (c.683C-G, NM_002397.2) in exon 7 of the MEF2C gene, resulting in a ser228-to-ter (S228X) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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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MEF2C, LEU38GLN
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<br />
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SNP: rs397514655,
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ClinVar: RCV000033229
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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 3-year-old girl (patient 5) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; 613443), Zweier et al. (2010) identified a de novo heterozygous c.113T-A transversion (c.113T-A, NM_002397.3) in exon 3 of the MEF2C gene, resulting in a leu38-to-gln (L38Q) substitution in the MADS domain. Homology modeling predicted that the mutation may alter DNA-binding affinity. The patient had severe developmental delay with absent speech, inability to walk, hypotonia, seizure onset at age 10 months, delayed myelination, and mild dysmorphic facial features. </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 HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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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MEF2C, 1-BP DUP, 99T
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<br />
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SNP: rs2153074822,
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ClinVar: RCV000033230
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 14-year-old boy (patient 6) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; 613443), Zweier et al. (2010) identified a de novo heterozygous 1-bp duplication (c.99dupT, NM_002397.3) in exon 3 of the MEF2C gene, resulting in a glu34-to-ter (E34X) substitution. The patient had severe developmental delay with absent speech, hypertonia, seizure onset at age 10 months, mildly enlarged ventricles, and mild dysmorphic facial features. </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 HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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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MEF2C, GLY27ALA
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<br />
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SNP: rs397514656,
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ClinVar: RCV000033231
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 10-year-old girl (patient 8) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; 613443), Zweier et al. (2010) identified a de novo heterozygous c.80G-C transversion (c.80G-C, NM_002397.3) in exon 3 of the MEF2C gene, resulting in a gly27-to-ala (G27A) substitution in the MADS domain. Homology modeling predicted that the mutation may alter DNA-binding affinity. The patient had severe developmental delay with absent speech, difficulty walking, hypotonia, seizure onset at 6 months, delayed myelination, and mild dysmorphic facial features. </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 HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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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MEF2C, 1-BP DEL, 457A
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<br />
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SNP: rs730882192,
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ClinVar: RCV000033232
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an 8-year-old girl with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; 613443), Bienvenu et al. (2013) identified a de novo heterozygous 1-bp deletion (c.457delA, NM_002397.3) in exon 5 of the MEF2C gene, predicted to result in premature termination (Asn153ThrfsTer33) and loss of the functional transactivation domain. In infancy, the patient had poor feeding due to marked hypotonia and poor eye contact due to strabismus. Motor milestones were delayed, and she walked at age 4 years. At age 18 months, she had a single episode of myoclonic febrile seizures that were easily controlled. At age 7 years, she had poor growth, microcephaly (-2.5 SD), lack of speech, stereotypic movements, unstable wide-based gait, and happy demeanor. There were mild dysmorphic features, including large eyebrows, open mouth with thick everted lower lip, and anteverted nares. Brain MRI was normal. </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 HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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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MEF2C, 1-BP DEL, 833T
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<br />
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SNP: rs587783749,
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ClinVar: RCV000146367, RCV000255477, RCV004639143
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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 22-month-old girl (LR11-310) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; 613443), Paciorkowski et al. (2013) identified a heterozygous 1-bp deletion (c.833delT) in the MEF2C gene, predicted to result in a frameshift and premature termination. The patient was part of a cohort of individuals with 5q14.3 deletions, and the phenotype was ascertained retrospectively. Functional studies of the variant, studies of patient cells, and segregation were not reported. She had developmental delay and onset of refractory myoclonic and atonic seizures at age 18 months. She also had stereotypic hand movements. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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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MEF2C, GLU74TER
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<br />
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SNP: rs2153074000,
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ClinVar: RCV001684642
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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 3-year-old girl (patient 5) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; 613443), Vrecar et al. (2017) identified a de novo heterozygous c.220G-T transversion in exon 3 of the MEF2C gene, resulting in a glu74-to-ter (E74X) substitution. The mutation was found by next-generation sequencing on an epilepsy panel and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. The patient had onset of seizures in the first year of life; she also demonstrated developmental delay and hand wringing. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0008 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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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MEF2C, -8C-T, 5-PRIME UTR
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<br />
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SNP: rs2153222958,
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ClinVar: RCV001568454, RCV001685531, RCV001779254
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 unrelated patients (patients 3, 4, and 5) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; 613443), Wright et al. (2021) identified a de novo heterozygous c.-8C-T transition in the 5-prime untranslated region (UTR) of the MEF2C gene. The mutation, which was found by specific analysis of 5-prime UTR variants in selected candidate genes, was not present in the gnomAD database. The mutation created an upstream AUG codon that was in-frame with the coding sequence, creating resulting in an N-terminal extension of 3 amino acids. In vitro functional expression studies using a luciferase reporter showed that the mutation significantly decreased MEF2C translational efficiency compared to controls. These findings were consistent with haploinsufficiency. </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">
|
|
<strong>.0009 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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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MEF2C, -26C-T, 5-PRIME UTR
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<br />
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SNP: rs758320958,
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gnomAD: rs758320958,
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ClinVar: RCV001684643, RCV002284492, RCV003163791
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In 3 unrelated patients (patients 6, 7, and 8) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; 613443), Wright et al. (2021) identified a de novo heterozygous c.-26C-T transition in the 5-prime untranslated region (UTR) of the MEF2C gene. The mutation, which was found by specific analysis of 5-prime UTR variants in selected candidate genes, was not present in the gnomAD database. The mutation created an upstream AUG codon that was in-frame with the coding sequence, creating resulting in an N-terminal extension of 9 amino acids. In vitro functional expression studies using a luciferase reporter showed that the mutation significantly decreased MEF2C translational efficiency compared to controls. These findings were consistent with haploinsufficiency. </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">
|
|
<strong>.0010 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE</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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MEF2C, -66A-T, 5-PRIME UTR
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<br />
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SNP: rs1350600010,
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gnomAD: rs1350600010,
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ClinVar: RCV001684644
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient (patient 1) with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL; 613443), Wright et al. (2021) identified a de novo heterozygous c.-66A-T transversion in the 5-prime untranslated region (UTR) of the MEF2C gene. The mutation, which was found by specific analysis of 5-prime UTR variants in selected candidate genes, was not present in the gnomAD database. The mutation created an upstream AUG codon that was out-of-frame with the coding sequence, creating an overlapping open reading frame that terminated 128 bases after the canonical start site. In vitro functional expression studies using a luciferase reporter showed that the mutation decreased MEF2C translational efficiency compared to controls. These findings were consistent with haploinsufficiency. </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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Ataman, B., Boulting, G. L., Harmin, D. A., Yang, M. G., Baker-Salisbury, M., Yap, E.-L., Malik, A. N., Mei, K., Rubin, A. A., Spiegel, I., Durresi, E., Sharma, N., and 12 others.
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<strong>Evolution of Osteocrin as an activity-regulated factor in the primate brain.</strong>
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Nature 539: 242-247, 2016.
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Barbosa, A. C., Kim. M.-S., Ertunc, M., Adachi, M., Nelson, E. D., McAnally, J., Richardson, J. A., Kavalali, E. T., Monteggia, L. M., Bassel-Duby, R., Olson, E. N.
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<strong>MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function.</strong>
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Breitbart, R. E., Liang, C., Smoot, L. B., Laheru, D. A., Mahdavi, V., Nadal-Ginard, B.
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<strong>A fourth human MEF2 transcription factor, hMEF2D, is an early marker of the myogenic lineage.</strong>
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Development 118: 1095-1106, 1993.
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Cardoso, C., Boys, A., Parrini, E., Mignon-Ravix, C., McMahon, J. M., Khantane, S., Bertini, E., Pallesi, E., Missirian, C., Zuffardi, O., Novara, F., Villard, L., Giglio, S., Chabrol, B., Slater, H. R., Moncla, A., Scheffer, I. E., Guerrini, R.
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<strong>Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion.</strong>
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Neurology 72: 784-792, 2009.
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[PubMed: 19073947]
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Chen, S. L., Dowhan, D. H., Hosking, B. M., Muscat, G. E. O.
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<strong>The steroid receptor coactivator, GRIP-1, is necessary for MEF-2C-dependent gene expression and skeletal muscle differentiation.</strong>
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Genes Dev. 14: 1209-1228, 2000.
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[PubMed: 10817756]
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Chen, S. L., Loffler, K. A., Chen, D., Stallcup, M. R., Muscat, G. E. O.
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<strong>The coactivator-associated arginine methyltransferase is necessary for muscle differentiation: CARM1 coactivates myocyte enhancer factor-2.</strong>
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J. Biol. Chem. 277: 4324-4333, 2002.
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[PubMed: 11713257]
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[Full Text: https://doi.org/10.1074/jbc.M109835200]
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D'haene, E., Bar-Yaacov, R., Bariah, I., Vantomme, L., Van Loo, S., Cobos, F. A., Verboom, K., Eshel, R., Alatawna, R., Menten, B., Birnbaum, R. Y., Vergult, S.
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<strong>A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett like characteristics.</strong>
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Hum. Molec. Genet. 28: 818-827, 2019. Note: Erratum: Hum. Molec. Genet. 29: 879-880, 2020.
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Engels, H., Wohlleber, E., Zink, A., Hoyer, J., Ludwig, K. U., Brockschmidt, F. F., Wieczorek, D., Moog, U., Hellmann-Mersch, B., Weber, R. G., Willatt, L., Kreiss-Nachtsheim, M., Firth, H. V., Rauch, A.
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<strong>A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients.</strong>
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Johnnidis, J. B., Harris, M. H., Wheeler, R. T., Stehling-Sun, S., Lam, M. H., Kirak, O., Brummelkamp, T. R., Fleming, M. D., Camargo, F. D.
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<strong>Regulation of progenitor cell proliferation and granulocyte function by microRNA-223.</strong>
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Krainc, D., Haas, M., Ward, D. C., Lipton, S. A., Bruns, G., Leifer, D.
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<strong>Assignment of human myocyte-specific enhancer binding factor 2C (hMEF2C) to human chromosome 5q14 and evidence that MEF2C is evolutionarily conserved.</strong>
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Genomics 29: 809-811, 1995.
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[PubMed: 8575784]
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Le Meur, N., Holder-Espinasse, M., Jaillard, S., Goldenberg, A., Joriot, S., Amati-Bonneau, P., Guichet, A., Barth, M., Charollais, A., Journel, H., Auvin, S., Boucher, C., Kerckaert, J.-P., David, V., Manouvrier-Hanu, S., Saugier-Veber, P., Frebourg, T., Dubourg, C., Andrieux, J., Bonneau, D.
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<strong>MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations.</strong>
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J. Med. Genet. 47: 22-29, 2010.
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[PubMed: 19592390]
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Leifer, D., Krainc, D., Yu, Y.-T., McDermott, J., Breitbart, R. E., Heng, J., Neve, R. L., Kosofsky, B., Nadal-Ginard, B., Lipton, S. A.
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<strong>MEF2C, a MADS/MEF2-family transcription factor expressed in a laminar distribution in cerebral cortex.</strong>
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Proc. Nat. Acad. Sci. 90: 1546-1550, 1993.
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[PubMed: 7679508]
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[Full Text: https://doi.org/10.1073/pnas.90.4.1546]
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<p class="mim-text-font">
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Li, H., Radford, J. C., Ragusa, M. J., Shea, K. L., McKercher, S. R., Zaremba, J. D., Soussou, W., Nie, Z., Kang, Y.-J., Nakanishi, N., Okamoto, S., Roberts, A. J., Schwarz, J. J., Lipton, S. A.
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<strong>Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo.</strong>
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Proc. Nat. Acad. Sci. 105: 9397-9402, 2008.
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[PubMed: 18599437]
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[Full Text: https://doi.org/10.1073/pnas.0802876105]
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Lin, Q., Schwarz, J., Bucana, C., Olson, E. N.
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<strong>Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C.</strong>
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Science 276: 1404-1407, 1997.
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[PubMed: 9162005]
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Mao, Z., Bonni, A., Xia, F., Nadal-Vicans, M., Greenberg, M. E.
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<strong>Neuronal activity-dependent cell survival mediated by transcription factor MEF2.</strong>
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Science 286: 785-790, 1999.
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[PubMed: 10531066]
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[Full Text: https://doi.org/10.1126/science.286.5440.785]
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<p class="mim-text-font">
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Martin, J. F., Miano, J. M., Hustad, C. M., Copeland, N. G., Jenkins, N. A., Olson, E. N.
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<strong>A Mef2 gene that generates a muscle-specific isoform via alternative mRNA splicing.</strong>
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Molec. Cell. Biol. 14: 1647-1656, 1994.
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[PubMed: 8114702]
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[Full Text: https://doi.org/10.1128/mcb.14.3.1647-1656.1994]
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<p class="mim-text-font">
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McDermott, J. C., Cardoso, M. C., Yu, Y.-T., Andres, V., Leifer, D., Krainc, D., Lipton, S. A., Nadal-Ginard, B.
|
|
<strong>hMEF2C gene encodes skeletal muscle- and brain-specific transcription factors.</strong>
|
|
Molec. Cell. Biol. 13: 2564-2577, 1993.
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[PubMed: 8455629]
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[Full Text: https://doi.org/10.1128/mcb.13.4.2564-2577.1993]
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</p>
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<p class="mim-text-font">
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Paciorkowski, A. R., Traylor, R. N., Rosenfeld, J. A., Hoover, J. M., Harris, C. J., Winter, S., Lacassie, Y., Bialer, M., Lamb, A. N., Schultz, R. A., Berry-Kravis, E., Porter, B. E., and 9 others.
|
|
<strong>MEF2C haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways.</strong>
|
|
Neurogenetics 14: 99-111, 2013.
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|
|
[PubMed: 23389741]
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[Full Text: https://doi.org/10.1007/s10048-013-0356-y]
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</p>
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<li>
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<p class="mim-text-font">
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Potthoff, M. J., Wu, H., Arnold, M. A., Shelton, J. M., Backs, J., McAnally, J., Richardson, J. A., Bassel-Duby, R., Olson, E. N.
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|
<strong>Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers.</strong>
|
|
J. Clin. Invest. 117: 2459-2467, 2007.
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[PubMed: 17786239]
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[Full Text: https://doi.org/10.1172/JCI31960]
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Verzi, M. P., Agarwal, P., Brown, C., McCulley, D. J., Schwarz, J. J., Black, B. L.
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<strong>The transcription factor MEF2C is required for craniofacial development.</strong>
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Dev. Cell 12: 645-652, 2007.
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[PubMed: 17420000]
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[Full Text: https://doi.org/10.1016/j.devcel.2007.03.007]
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von Both, I., Silvestri, C., Erdemir, T., Lickert, H., Walls, J. R., Henkelman, R. M., Rossant, J., Harvey, R. P., Attisano, L., Wrana, J. L.
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<strong>Foxh1 is essential for development of the anterior heart field.</strong>
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Dev. Cell 7: 331-345, 2004.
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[PubMed: 15363409]
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[Full Text: https://doi.org/10.1016/j.devcel.2004.07.023]
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Vrecar, I., Innes, J., Jones, E. A., Kingston, H., Reardon, W., Kerr, B., Clayton-Smith, J., Douzgou, S.
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<strong>Further clinical delineation of the MEF2C haploinsufficiency syndrome: report on new cases and literature review of severe neurodevelopmental disorders presenting with seizures, absent speech, and involuntary movements.</strong>
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J. Pediat. Genet. 6: 129-141, 2017.
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[PubMed: 28794905]
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[Full Text: https://doi.org/10.1055/s-0037-1601335]
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Wright, C. F., Quaife, N. M., Ramos-Hernandez, L., Danecek, P., Ferla, M. P., Samocha, K. E., Kaplanis, J., Gardner, E. J., Eberhardt, R. Y., Chao, K. R., Karczewski, K. J., Morales, J., and 22 others.
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<strong>Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.</strong>
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Am. J. Hum. Genet. 108: 1083-1094, 2021.
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[PubMed: 34022131]
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[Full Text: https://doi.org/10.1016/j.ajhg.2021.04.025]
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Xu, J., Gong, N. L., Bodi, I., Aronow, B. J., Backx, P. H., Molkentin, J. D.
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<strong>Myocyte enhancer factors 2A and 2C induce dilated cardiomyopathy in transgenic mice.</strong>
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[PubMed: 16469744]
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[Full Text: https://doi.org/10.1074/jbc.M510217200]
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Zweier, M., Gregor, A., Zweier, C., Engels, H., Sticht, H., Wohlleber, E., Bijlsma, E. K., Holder, S. E., Zenker, M., Rossier, E., Grasshoff, U., Johnson, D. S., Robertson, L., Firth, H. V., Kraus, C., Ekici, A. B., Reis, A., Rauch, A.
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<strong>Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.</strong>
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Hum. Mutat. 31: 722-733, 2010.
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[PubMed: 20513142]
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[Full Text: https://doi.org/10.1002/humu.21253]
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Bao Lige - updated : 12/01/2021<br>Cassandra L. Kniffin - updated : 09/15/2021<br>Ada Hamosh - updated : 09/04/2019<br>Cassandra L. Kniffin - updated : 3/5/2013<br>Cassandra L. Kniffin - updated : 6/15/2010<br>Cassandra L. Kniffin - updated : 7/29/2009<br>Ada Hamosh - updated : 3/18/2008<br>Patricia A. Hartz - updated : 11/6/2007<br>Patricia A. Hartz - updated : 5/4/2007<br>Patricia A. Hartz - updated : 8/14/2006<br>Patricia A. Hartz - updated : 8/9/2006<br>Patricia A. Hartz - updated : 10/7/2004<br>Paul J. Converse - updated : 8/11/2000<br>Ada Hamosh - updated : 10/22/1999<br>Victor A. McKusick - updated : 6/20/1997<br>Alan F. Scott - updated : 11/8/1995
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Alan F. Scott : 8/18/1995
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