3754 lines
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Entry
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- *300128 - LYSINE DEMETHYLASE 6A; KDM6A
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- OMIM
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</form>
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<div id="mimAlertBanner">
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300128</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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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300128">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
|
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<h4 class="panel-title">
|
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
|
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
|
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</div>
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</a>
|
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</h4>
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</div>
|
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
|
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</span>
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</span>
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
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<div class="panel-body small mim-panel-body">
|
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000147050;t=ENST00000611820" 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=7403" 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=300128" 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=ENSG00000147050;t=ENST00000611820" 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_001291415,NM_001291416,NM_001291417,NM_001291418,NM_001291421,NM_001410742,NM_001419809,NM_001419810,NM_001419811,NM_001419812,NM_001419813,NM_001419814,NM_001419815,NM_021140,NR_111960,XM_011543969,XM_011543972,XM_011543974,XM_017029783,XM_024452439,XM_047442428,XM_047442429,XM_047442430,XM_047442431,XR_007068200" 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_001291415" 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=300128" 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=02131&isoform_id=02131_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/KDM6A" 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/2580570,2580572,30268222,34364753,50898235,51476861,62087170,62739574,70672792,70672794,70672796,109731235,119579772,157829327,157829345,189011544,194377488,194382620,194385276,206729942,219517767,219519945,219519947,611434998,611435000,611435003,611435005,611435010,768033504,768033518,768033526,1034675123,1370524933,2217394033,2217394037,2217394039,2217394041,2286439359,2462630776,2462630780,2462630783,2462630787,2462630789,2462630791,2462630793,2462630795,2491778563,2491778565,2491778577,2491778607,2491778630,2491778648,2492587458" 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/O15550" 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">
|
|
<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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|
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<div style="display: table-cell;">Gene Info</div>
|
|
</div>
|
|
</a>
|
|
</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">
|
|
<div class="panel-body small mim-panel-body">
|
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<div><a href="http://biogps.org/#goto=genereport&id=7403" 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=ENSG00000147050;t=ENST00000611820" 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=KDM6A" 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=KDM6A" 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+7403" 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/KDM6A" 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:7403" 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/7403" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chrX&hgg_gene=ENST00000611820.5&hgg_start=44873188&hgg_end=45112779&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:12637" 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:12637" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/kdm6a" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300128[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=300128[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/KDM6A/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/ENSG00000147050" 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=KDM6A" 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=KDM6A" 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=KDM6A" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/KDM6A" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=KDM6A&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/PA37262" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:12637" 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/FBgn0260749.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:1095419" 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/KDM6A#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:1095419" 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/7403/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=7403" 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=WBGene00017046;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-081105-56" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7403" 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=KDM6A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
300128
|
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</span>
|
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</span>
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</div>
|
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</div>
|
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
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<span class="mim-font">
|
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LYSINE DEMETHYLASE 6A; KDM6A
|
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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 />
|
|
</div>
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<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
LYSINE-SPECIFIC DEMETHYLASE 6A<br />
|
|
UBIQUITOUSLY TRANSCRIBED TETRATRICOPEPTIDE REPEAT GENE ON X CHROMOSOME; UTX
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KDM6A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KDM6A</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/X/198?start=-3&limit=10&highlight=198">Xp11.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:44873188-45112779&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">X:44,873,188-45,112,779</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">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/198?start=-3&limit=10&highlight=198">
|
|
Xp11.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Kabuki syndrome 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/300867"> 300867 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
|
|
|
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</span>
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<div class="mim-changed mim-change"><p>KDM6A, or UTX, mediates removal of repressive trimethylation of histone H3 (see <a href="/entry/602810">602810</a>) lys27 (H3K27me3) to establish transcriptionally permissive chromatin (<a href="#3" class="mim-tip-reference" title="Faralli, H., Wang, C., Nakka, K., Benyoucef, A., Sebastian, S., Zhuang, L., Chu, A., Palii, C. G., Liu, C., Camellato, B., Brand, M., Ge, K., Dilworth, F. J. <strong>UTX demethylase activity is required for satellite cell-mediated muscle regeneration.</strong> J. Clin. Invest. 126: 1555-1565, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26999603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26999603</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26999603[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/JCI83239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26999603">Faralli et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26999603" 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></div>
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<p><a href="#6" class="mim-tip-reference" title="Greenfield, A., Carrel, L., Pennisi, D., Philippe, C., Quaderi, N., Siggers, P., Steiner, K., Tam, P. P. L., Monaco, A. P., Willard, H. F., Koopman, P. <strong>The UTX gene escapes X inactivation in mice and humans.</strong> Hum. Molec. Genet. 7: 737-742, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499428</a>] [<a href="https://doi.org/10.1093/hmg/7.4.737" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499428">Greenfield et al. (1998)</a> described the isolation of an X-linked homolog of Uty (see <a href="/entry/400009">400009</a>), called Utx (ubiquitously transcribed TPR gene on the X chromosome), which is expressed from the inactive X chromosome in both mice and humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9499428" 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="#6" class="mim-tip-reference" title="Greenfield, A., Carrel, L., Pennisi, D., Philippe, C., Quaderi, N., Siggers, P., Steiner, K., Tam, P. P. L., Monaco, A. P., Willard, H. F., Koopman, P. <strong>The UTX gene escapes X inactivation in mice and humans.</strong> Hum. Molec. Genet. 7: 737-742, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499428</a>] [<a href="https://doi.org/10.1093/hmg/7.4.737" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499428">Greenfield et al. (1998)</a> determined that the mouse Utx gene maps to the proximal region of the X chromosome in an interval containing the Maoa (<a href="/entry/309850">309850</a>) and Maob (<a href="/entry/309860">309860</a>) genes, thus placing it in band A2-A3. By Southern analysis of a panel of rodent/human somatic cell hybrids carrying derivative X chromosomes, <a href="#6" class="mim-tip-reference" title="Greenfield, A., Carrel, L., Pennisi, D., Philippe, C., Quaderi, N., Siggers, P., Steiner, K., Tam, P. P. L., Monaco, A. P., Willard, H. F., Koopman, P. <strong>The UTX gene escapes X inactivation in mice and humans.</strong> Hum. Molec. Genet. 7: 737-742, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499428</a>] [<a href="https://doi.org/10.1093/hmg/7.4.737" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499428">Greenfield et al. (1998)</a> mapped the human UTX gene to Xp11.3-p11.23. By fluorescence in situ hybridization on normal human metaphase spreads, they refined the localization to Xp11.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9499428" 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="#8" class="mim-tip-reference" title="Kruidenier, L., Chung, C., Cheng, Z., Liddle, J., Che, K., Joberty, G., Bantscheff, M., Bountra, C., Bridges, A., Diallo, H., Eberhard, D., Hutchinson, S., and 19 others. <strong>A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.</strong> Nature 488: 404-408, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842901</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842901[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/nature11262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842901">Kruidenier et al. (2012)</a> presented a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 (<a href="/entry/611577">611577</a>) and UTX). The liganded structures of human and mouse JMJD3 provided novel insight into the specificity determinants for cofactor, substrate, and inhibitor recognition by the KDM6 subfamily of demethylases. <a href="#8" class="mim-tip-reference" title="Kruidenier, L., Chung, C., Cheng, Z., Liddle, J., Che, K., Joberty, G., Bantscheff, M., Bountra, C., Bridges, A., Diallo, H., Eberhard, D., Hutchinson, S., and 19 others. <strong>A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.</strong> Nature 488: 404-408, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842901</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842901[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/nature11262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842901">Kruidenier et al. (2012)</a> exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily, and demonstrated that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. <a href="#8" class="mim-tip-reference" title="Kruidenier, L., Chung, C., Cheng, Z., Liddle, J., Che, K., Joberty, G., Bantscheff, M., Bountra, C., Bridges, A., Diallo, H., Eberhard, D., Hutchinson, S., and 19 others. <strong>A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.</strong> Nature 488: 404-408, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22842901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22842901</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22842901[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/nature11262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22842901">Kruidenier et al. (2012)</a> concluded that their results resolved the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provided encouragement for designing small-molecule inhibitors to allow selective pharmacologic intervention across the JMJ family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22842901" 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="Mansour, A. A., Gafni, O., Weinberger, L., Zviran, A., Ayyash, M., Rais, Y., Krupalnik, V., Zerbib, M., Amann-Zalcenstein, D., Maza, I., Geula, S., Viukov, S., Holtzman, L., Pribluda, A., Canaani, E., Horn-Saban, S., Amit, I., Novershtern, N., Hanna, J. H. <strong>The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming.</strong> Nature 488: 409-413, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22801502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22801502</a>] [<a href="https://doi.org/10.1038/nature11272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22801502">Mansour et al. (2012)</a> demonstrated in mice and humans that the histone H3 methylated lys27 (H3K27) demethylase Utx regulates the efficient induction, rather than maintenance, of pluripotency. Murine embryonic stem cells lacking Utx can execute lineage commitment and contribute to adult chimeric animals; however, somatic cells lacking Utx fail to robustly reprogram back to the ground state of pluripotency. Utx directly partners with OSK reprogramming factors (OCT4, <a href="/entry/164177">164177</a>; SOX2, <a href="/entry/184429">184429</a>; KLF4, <a href="/entry/602253">602253</a>) and uses its histone demethylase catalytic activity to facilitate induced pluripotent stem cell formation. Genomic analysis indicates that Utx depletion results in aberrant dynamics of H3K27me3 repressive chromatin demethylation in somatic cells undergoing reprogramming. The latter directly hampers the derepression of potent pluripotency promoting gene modules (including Sall1, Sall4, and Utf1), which can cooperatively substitute for exogenous OSK supplementation in iPSC formation. Remarkably, Utx safeguards the timely execution of H3K27me3 demethylation observed in embryonic day 10.5-11 primordial germ cells (PGCs), and Utx-deficient PGCs show cell-autonomous aberrant epigenetic reprogramming dynamics during their embryonic maturation in vivo. Subsequently, this disrupts PGC development by embryonic day 12.5, and leads to diminished germline transmission in mouse chimeras generated from Utx-knockout pluripotent cells. Thus, <a href="#14" class="mim-tip-reference" title="Mansour, A. A., Gafni, O., Weinberger, L., Zviran, A., Ayyash, M., Rais, Y., Krupalnik, V., Zerbib, M., Amann-Zalcenstein, D., Maza, I., Geula, S., Viukov, S., Holtzman, L., Pribluda, A., Canaani, E., Horn-Saban, S., Amit, I., Novershtern, N., Hanna, J. H. <strong>The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming.</strong> Nature 488: 409-413, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22801502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22801502</a>] [<a href="https://doi.org/10.1038/nature11272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22801502">Mansour et al. (2012)</a> concluded that they identified Utx as a novel mediator with distinct functions during the reestablishment of pluripotency and germ cell development. They furthermore concluded that their findings highlighted the principle that molecular regulators mediating loss of repressive chromatin during in vivo germ cell reprogramming can be co-opted during in vitro reprogramming towards ground state pluripotency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22801502" 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="#9" class="mim-tip-reference" title="Lan, F., Bayliss, P. E., Rinn, J. L., Whetstine, J. R., Wang, J. K., Chen, S., Iwase, S., Alpatov, R., Issaeva, I., Canaani, E., Roberts, T. M., Chang, H. Y., Shi, Y. <strong>A histone H3 lysine 27 demethylase regulates animal posterior development.</strong> Nature 449: 689-694, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17851529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17851529</a>] [<a href="https://doi.org/10.1038/nature06192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17851529">Lan et al. (2007)</a> showed that the JmjC-domain-containing related proteins UTX and JMJD3 (<a href="/entry/611577">611577</a>) catalyze demethylation of tri/dimethylated histone H3 (see <a href="/entry/602810">602810</a>) lysine-27 (H3K27me3/2). UTX is enriched around the transcription start sites of many HOX genes in primary human fibroblasts, in which HOX genes are differentially expressed, but is selectively excluded from the HOX loci in embryonic stem cells, in which HOX genes are largely silent. Consistently, RNA interference inhibition of UTX led to increased H3K27me3 levels at some HOX gene promoters. Importantly, morpholino oligonucleotide inhibition of a zebrafish UTX homolog resulted in misregulation of HOX genes and a striking posterior developmental defect, which was partially rescued by wildtype, but not by catalytically inactive, human UTX. <a href="#9" class="mim-tip-reference" title="Lan, F., Bayliss, P. E., Rinn, J. L., Whetstine, J. R., Wang, J. K., Chen, S., Iwase, S., Alpatov, R., Issaeva, I., Canaani, E., Roberts, T. M., Chang, H. Y., Shi, Y. <strong>A histone H3 lysine 27 demethylase regulates animal posterior development.</strong> Nature 449: 689-694, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17851529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17851529</a>] [<a href="https://doi.org/10.1038/nature06192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17851529">Lan et al. (2007)</a> concluded that, taken together, their findings identified a small family of H3K27 demethylases with important evolutionarily conserved roles in H3K27 methylation regulation and in animal anterior-posterior development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17851529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Agger, K., Cloos, P. A. C., Christensen, J., Pasini, D., Rose, S., Rappsilber, J., Issaeva, I., Canaani, E., Salcini, A. E., Helin, K. <strong>UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.</strong> Nature 449: 731-734, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17713478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17713478</a>] [<a href="https://doi.org/10.1038/nature06145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17713478">Agger et al. (2007)</a> showed that human JmjC domain-containing UTX and JMJD3 demethylate trimethylated lys27 on histone H3. Furthermore, the authors demonstrated that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, <a href="#1" class="mim-tip-reference" title="Agger, K., Cloos, P. A. C., Christensen, J., Pasini, D., Rose, S., Rappsilber, J., Issaeva, I., Canaani, E., Salcini, A. E., Helin, K. <strong>UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.</strong> Nature 449: 731-734, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17713478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17713478</a>] [<a href="https://doi.org/10.1038/nature06145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17713478">Agger et al. (2007)</a> showed that UTX directly binds to the HOXB1 locus and is required for its activation. Finally, mutation of F18E9.5, a C. elegans JMJD3 ortholog, or inhibition of its expression, resulted in abnormal gonad development. <a href="#1" class="mim-tip-reference" title="Agger, K., Cloos, P. A. C., Christensen, J., Pasini, D., Rose, S., Rappsilber, J., Issaeva, I., Canaani, E., Salcini, A. E., Helin, K. <strong>UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.</strong> Nature 449: 731-734, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17713478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17713478</a>] [<a href="https://doi.org/10.1038/nature06145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17713478">Agger et al. (2007)</a> concluded that, taken together, their results suggested that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (<a href="/entry/602113">602113</a>) (<a href="#7" class="mim-tip-reference" title="Issaeva, I., Zonis, Y., Rozovskaia, T., Orlovsky, K., Croce, C. M., Nakamura, T., Mazo, A., Eisenbach, L., Canaani, E. <strong>Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth.</strong> Molec. Cell. Biol. 27: 1889-1903, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17178841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17178841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17178841[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.01506-06" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17178841">Issaeva et al., 2007</a>), supported a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17713478+17178841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Lee, M. G., Villa, R., Trojer, P., Norman, J., Yan, K.-P., Reinberg, D., Di Croce, L., Shiekhattar, R. <strong>Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination.</strong> Science 318: 447-450, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17761849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17761849</a>] [<a href="https://doi.org/10.1126/science.1149042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17761849">Lee et al. (2007)</a> showed that human UTX, a member of the Jumonji C family of proteins, is a di- and trimethyl H3K27 demethylase. UTX occupies the promoters of HOX gene clusters (see <a href="/entry/142950">142950</a>) and regulates their transcriptional output by modulating the recruitment of polycomb repressive complex 1 (PRC1) and the monoubiquitination of histone H2A (see <a href="/entry/602786">602786</a>). Moreover, UTX associates with mixed-lineage leukemia (MLL) 2/3 complexes (<a href="/entry/602113">602113</a>, <a href="/entry/606833">606833</a>, respectively), and during retinoic acid signaling events, the recruitment of the UTX complex to HOX genes results in H3K27 demethylation and a concomitant methylation of H3K4. <a href="#12" class="mim-tip-reference" title="Lee, M. G., Villa, R., Trojer, P., Norman, J., Yan, K.-P., Reinberg, D., Di Croce, L., Shiekhattar, R. <strong>Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination.</strong> Science 318: 447-450, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17761849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17761849</a>] [<a href="https://doi.org/10.1126/science.1149042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17761849">Lee et al. (2007)</a> concluded that their results suggested a concerted mechanism for transcriptional activation in which cycles of H3K4 methylation by MLL2/3 are linked with the demethylation of H3K27 through UTX. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17761849" 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="Chakraborty, A. A., Laukka, T., Myllykoski, M., Ringel, A. E., Booker, M. A., Tolstorukov, M. Y., Meng, Y. J., Meier, S. R., Jennings, R. B., Creech, A. L., Herbert, Z. T., McBrayer, S. K., Olenchock, B. A., Jaffe, J. D., Haigis, M. C., Beroukhim, R., Signoretti, S., Koivunen, P., Kaelin, W. G., Jr. <strong>Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate.</strong> Science 363: 1217-1222, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30872525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30872525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30872525[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.aaw1026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30872525">Chakraborty et al. (2019)</a> reported that hypoxia promotes histone methylation in a HIF- and 2-hydroxyglutarate-independent manner. <a href="#2" class="mim-tip-reference" title="Chakraborty, A. A., Laukka, T., Myllykoski, M., Ringel, A. E., Booker, M. A., Tolstorukov, M. Y., Meng, Y. J., Meier, S. R., Jennings, R. B., Creech, A. L., Herbert, Z. T., McBrayer, S. K., Olenchock, B. A., Jaffe, J. D., Haigis, M. C., Beroukhim, R., Signoretti, S., Koivunen, P., Kaelin, W. G., Jr. <strong>Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate.</strong> Science 363: 1217-1222, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30872525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30872525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30872525[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.aaw1026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30872525">Chakraborty et al. (2019)</a> found that the H3K27 histone demethylase KDM6A/UTX, but not its paralog KDM6B (<a href="/entry/611577">611577</a>), is oxygen sensitive. KDM6A loss, like hypoxia, prevented H3K27 demethylation and blocked cellular differentiation. Restoring H3K27 methylation homeostasis in hypoxic cells reversed these effects. <a href="#2" class="mim-tip-reference" title="Chakraborty, A. A., Laukka, T., Myllykoski, M., Ringel, A. E., Booker, M. A., Tolstorukov, M. Y., Meng, Y. J., Meier, S. R., Jennings, R. B., Creech, A. L., Herbert, Z. T., McBrayer, S. K., Olenchock, B. A., Jaffe, J. D., Haigis, M. C., Beroukhim, R., Signoretti, S., Koivunen, P., Kaelin, W. G., Jr. <strong>Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate.</strong> Science 363: 1217-1222, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30872525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30872525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30872525[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.aaw1026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30872525">Chakraborty et al. (2019)</a> concluded that oxygen directly affects chromatin regulators to control cell fate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30872525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Kabuki Syndrome 2</em></strong></p><p>
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By array CGH analysis in 2 Belgian girls with Kabuki syndrome (see KABUK2, <a href="/entry/300867">300867</a>) who were negative for mutation in the MLL2 gene (<a href="/entry/602113">602113</a>), <a href="#10" class="mim-tip-reference" title="Lederer, D., Grisart, B., Digilio, M. C., Benoit, V., Crespin, M., Ghariani, S. C., Maystadt, I., Dallapiccola, B., Verellen-Dumoulin, C. <strong>Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome.</strong> Am. J. Hum. Genet. 90: 119-124, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22197486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22197486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22197486[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.2011.11.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22197486">Lederer et al. (2012)</a> identified de novo Xp11.3 microdeletions, both of which contained part or all of the KDM6A gene. In the 13-year-old girl, the 283.5-kb deletion included KDM6A exons 21 through 29, coding for the terminal part of the catalytic domain of KDM6A, and CXORF36 (<a href="/entry/300959">300959</a>). In the 10-year-old girl, the 815.7-kb deletion completely removed KDM6A, CXORF36, DUSP21 (<a href="/entry/300678">300678</a>) and FUNDC1 (<a href="/entry/300871">300871</a>). Sequencing of the KDM6A gene as well as targeted array CGH in a cohort of 22 MLL2-negative Kabuki syndrome patients revealed a de novo 45.4-kb intragenic deletion in a 2-year-old Italian boy (<a href="#0001">300128.0001</a>). Although KDM6A escapes X inactivation, <a href="#10" class="mim-tip-reference" title="Lederer, D., Grisart, B., Digilio, M. C., Benoit, V., Crespin, M., Ghariani, S. C., Maystadt, I., Dallapiccola, B., Verellen-Dumoulin, C. <strong>Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome.</strong> Am. J. Hum. Genet. 90: 119-124, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22197486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22197486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22197486[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.2011.11.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22197486">Lederer et al. (2012)</a> found a skewed X-inactivation pattern in both girls (89:11 and 97:3, respectively), in which the deleted X chromosome was inactivated in the majority of the cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22197486" 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="#17" class="mim-tip-reference" title="Miyake, N., Mizuno, S., Okamoto, N., Ohashi, H., Shiina, M., Ogata, K., Tsurusaki, Y., Nakashima, M., Saitsu, H., Niikawa, N., Matsumoto, N. <strong>KDM6A point mutations cause Kabuki syndrome.</strong> Hum. Mutat. 34: 108-110, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23076834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23076834</a>] [<a href="https://doi.org/10.1002/humu.22229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23076834">Miyake et al. (2013)</a> analyzed the KDM6A gene in 32 patients with Kabuki syndrome who were negative for mutation in the MLL2 gene and identified nonsense mutations in 2 male patients and a 3-bp deletion in a female patient (<a href="#0002">300128.0002</a>-<a href="#0004">300128.0004</a>). The female patient had fewer dysmorphic features than the male patients, who displayed a more severe phenotype with multiple organ involvement. <a href="#17" class="mim-tip-reference" title="Miyake, N., Mizuno, S., Okamoto, N., Ohashi, H., Shiina, M., Ogata, K., Tsurusaki, Y., Nakashima, M., Saitsu, H., Niikawa, N., Matsumoto, N. <strong>KDM6A point mutations cause Kabuki syndrome.</strong> Hum. Mutat. 34: 108-110, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23076834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23076834</a>] [<a href="https://doi.org/10.1002/humu.22229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23076834">Miyake et al. (2013)</a> suggested that the mutation type as well as X-inactivation pattern in affected organs in females may determine the severity of Kabuki syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23076834" 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 direct sequencing, MLPA, and quantitative PCR, <a href="#15" class="mim-tip-reference" title="Micale, L., Augello, B., Maffeo, C., Selicorni, A., Zucchetti, F., Fusco, C., De Nittis, P., Pellico, M. T., Mandriani, B., Fischetto, R., Boccone, L., Silengo, M., and 27 others. <strong>Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients.</strong> Hum. Mutat. 35: 841-850, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24633898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24633898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24633898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24633898">Micale et al. (2014)</a> screened 303 patients with Kabuki syndrome and identified 4 KDM6A mutations, 3 of which were novel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24633898" 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 2 brothers with Kabuki syndrome who were negative for mutation in the MLL2 gene, <a href="#11" class="mim-tip-reference" title="Lederer, D., Shears, D., Benoit, V., Verellen-Dumoulin, C., Maystadt, I. <strong>A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A.</strong> Am. J. Med. Genet. 164A: 1289-1292, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24664873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24664873</a>] [<a href="https://doi.org/10.1002/ajmg.a.36442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24664873">Lederer et al. (2014)</a> identified a 4-bp deletion in the KDM6A gene (<a href="#0006">300128.0006</a>). Their mother and maternal grandmother, who also carried the mutation, exhibited attenuated phenotypes. <a href="#11" class="mim-tip-reference" title="Lederer, D., Shears, D., Benoit, V., Verellen-Dumoulin, C., Maystadt, I. <strong>A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A.</strong> Am. J. Med. Genet. 164A: 1289-1292, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24664873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24664873</a>] [<a href="https://doi.org/10.1002/ajmg.a.36442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24664873">Lederer et al. (2014)</a> reviewed the clinical features of all reported patients with KDM6A mutations and stated that the family studied by them represented the first instance of hereditary X-linked Kabuki syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24664873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Faundes, V., Goh, S., Akilapa, R., Bezuidenhout H., Bjornsson, H. T., Bradley, L., Brady, A. F., Brischoux-Boucher, E., Brunner, H., Bulk, S., Canham, N., Cody, D., and 32 others. <strong>Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.</strong> Genet. Med. 23: 1202-1210, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33674768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33674768</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33674768[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/s41436-021-01119-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33674768">Faundes et al. (2021)</a> analyzed molecular data on 36 newly reported and 49 previously reported patients with heterozygous or hemizygous mutations in the KDM6A gene. Sixty-six KDM6A mutations were identified in 78 families, including 50 premature termination variants (PTV) in 62 patients from 59 families and 16 protein-altering variants (PAVs) in 23 patients from 19 families. The PTVs were all classified as pathogenic. Fifteen PTVs were nonsense mutations, 14 affected canonical splice sites, 12 were frameshift mutations, 8 were gross deletions, and 1 resulted from a chromosome translocation disrupting the KDM6A gene. In 42 patients, including 13 males and 29 females, the KDM6A PTVs were de novo, and in 6 patients the mutations were inherited from the mother. Of the 16 PAVs, 12 were classed as pathogenic or likely pathogenic, 3 as variants of uncertain significance, and 1 as likely benign. Thirteen of the PAVs were missense, 2 were in-frame deletions, and 1 was an indel. Eight PAVs, in 2 males and 6 females, were de novo. Ten patients inherited the PAV from their mother, and 1 patient inherited the mutation from her father. Inheritance of the PAVs was not known in 4 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33674768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Somatic Mutations</em></strong></p><p>
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<a href="#18" class="mim-tip-reference" title="van Haaften, G., Dalgliesh, G. L., Davies, H., Chen, L., Bignell, G., Greenman, C., Edkins, S., Hardy, C., O'Meara, S., Teague, J., Butler, A., Hinton, J., and 50 others. <strong>Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer.</strong> Nature Genet. 41: 521-523, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19330029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19330029</a>] [<a href="https://doi.org/10.1038/ng.349" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19330029">Van Haaften et al. (2009)</a> described inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19330029" 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="#5" class="mim-tip-reference" title="Gozdecka, M., Meduri, E., Mazan, M., Tzelepis, K., Dudek, M., Knights, A. J., Pardo, M., Yu, L., Choudhary, J. S., Metzakopian, E., Iyer, V., Yun, H., and 15 others. <strong>UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.</strong> Nature Genet. 50: 883-894, 2018. Note: Erratum: Nature Genet. 54: 1062 only, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29736013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29736013</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29736013[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0114-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29736013">Gozdecka et al. (2018)</a> demonstrated that UTX suppresses myeloid leukemogenesis through noncatalytic functions, a property shared with its catalytically inactive Y-chromosome paralog, UTY (<a href="/entry/400009">400009</a>). In keeping with this, <a href="#5" class="mim-tip-reference" title="Gozdecka, M., Meduri, E., Mazan, M., Tzelepis, K., Dudek, M., Knights, A. J., Pardo, M., Yu, L., Choudhary, J. S., Metzakopian, E., Iyer, V., Yun, H., and 15 others. <strong>UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.</strong> Nature Genet. 50: 883-894, 2018. Note: Erratum: Nature Genet. 54: 1062 only, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29736013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29736013</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29736013[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0114-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29736013">Gozdecka et al. (2018)</a> demonstrated concomitant loss/mutation of KDM6A and UTY in multiple human cancers. Mechanistically, global genomic profiling showed only minor changes in H3K27 trimethylation but significant and bidirectional alterations in H3K27 acetylation and chromatin accessibility; a predominant loss of H3K4 monomethylation modifications; alterations in ETS (see ETS1, <a href="/entry/164720">164720</a>) and GATA-factor (see GATA2, <a href="/entry/137295">137295</a>) binding; and altered gene expression after UTX loss. By integrating proteomic and genomic analyses, <a href="#5" class="mim-tip-reference" title="Gozdecka, M., Meduri, E., Mazan, M., Tzelepis, K., Dudek, M., Knights, A. J., Pardo, M., Yu, L., Choudhary, J. S., Metzakopian, E., Iyer, V., Yun, H., and 15 others. <strong>UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.</strong> Nature Genet. 50: 883-894, 2018. Note: Erratum: Nature Genet. 54: 1062 only, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29736013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29736013</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29736013[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0114-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29736013">Gozdecka et al. (2018)</a> linked these changes to UTX regulation of ATP-dependent chromatin remodeling, coordination of the COMPASS complex, and enhanced pioneering activity of ETS factors during evolution to acute myeloid leukemia (AML; <a href="/entry/601626">601626</a>). <a href="#5" class="mim-tip-reference" title="Gozdecka, M., Meduri, E., Mazan, M., Tzelepis, K., Dudek, M., Knights, A. J., Pardo, M., Yu, L., Choudhary, J. S., Metzakopian, E., Iyer, V., Yun, H., and 15 others. <strong>UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.</strong> Nature Genet. 50: 883-894, 2018. Note: Erratum: Nature Genet. 54: 1062 only, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29736013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29736013</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29736013[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0114-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29736013">Gozdecka et al. (2018)</a> concluded that their findings identified a dual role for UTX in suppressing AML via repression of oncogenic ETS and upregulation of tumor-suppressive GATA programs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29736013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#16" class="mim-tip-reference" title="Miyake, N., Koshimizu, E., Okamoto, N., Mizuno, S., Ogata, T., Nagai, T., Kosho, T., Ohashi, H., Kato, M., Sasaki, G., Mabe, H., Watanabe, Y., and 31 others. <strong>MLL2 and KDM6A mutations in patients with Kabuki syndrome.</strong> Am. J. Med. Genet. 161A: 2234-2243, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23913813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23913813</a>] [<a href="https://doi.org/10.1002/ajmg.a.36072" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23913813">Miyake et al. (2013)</a> used mutation detection methods to screen 81 patients with Kabuki syndrome and identified KDM6A mutations in 5 (6.2%). Of the 5 mutations, including 2 that were novel, 4 were protein-truncating and 1 was an in-frame deletion in the Jumonji C domain. High-arched eyebrows, short fifth fingers, and infantile hypotonia were less commonly seen in patients with KDM6A mutations than in those with MLL2 mutations. All of the patients with KDM6A mutations had short stature and postnatal growth retardation, compared with only half of patients with MLL2 mutations. Among the 2 female patients with KDM6A mutations, one (KMS-65) with an in-frame deletion (<a href="#0004">300128.0004</a>) had a random X-inactivation pattern, whereas the other (KMS-81) with a frameshift truncating mutation (<a href="#0005">300128.0005</a>) showed marked skewing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23913813" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Faundes, V., Goh, S., Akilapa, R., Bezuidenhout H., Bjornsson, H. T., Bradley, L., Brady, A. F., Brischoux-Boucher, E., Brunner, H., Bulk, S., Canham, N., Cody, D., and 32 others. <strong>Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.</strong> Genet. Med. 23: 1202-1210, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33674768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33674768</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33674768[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/s41436-021-01119-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33674768">Faundes et al. (2021)</a> analyzed molecular and clinical data in 80 patients with heterozygous or hemizygous mutations in the KDM6A gene. Patients with protein-altering variants (PAVs) had shorter birth lengths compared to patients with protein termination variants (PTVs). Patients with PTVs had more impaired intellectual development (97.6% vs 80%) and a higher frequency of central nervous system anomalies (71.4% vs 28.6%) compared to patients with PAVs, although the difference did not reach statistical significance. <a href="#4" class="mim-tip-reference" title="Faundes, V., Goh, S., Akilapa, R., Bezuidenhout H., Bjornsson, H. T., Bradley, L., Brady, A. F., Brischoux-Boucher, E., Brunner, H., Bulk, S., Canham, N., Cody, D., and 32 others. <strong>Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.</strong> Genet. Med. 23: 1202-1210, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33674768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33674768</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33674768[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/s41436-021-01119-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33674768">Faundes et al. (2021)</a> concluded that individuals with PTVs overall have a more severe phenotype, and the phenotypes of patients with PAVs are more variable. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33674768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="mim-changed mim-change"><p><a href="#19" class="mim-tip-reference" title="Van Laarhoven, P. M., Neitzel, L. R., Quintana, A. M., Geiger, E. A., Zackai, E. H., Clouthier, D. E., Artinger, K. B., Ming, J. E., Shaikh, T. H. <strong>Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development.</strong> Hum. Molec. Genet. 24: 4443-4453, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25972376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25972376</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25972376[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/ddv180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25972376">Van Laarhoven et al. (2015)</a> used morpholino antisense oligonucleotides to knock down the 2 orthologs of KDM6A in zebrafish, Kdm6a and Kdm6al, and at 5 days postfertilization they observed hypoplasia of the branchial arches, the Meckel and ceratohyal cartilage, and the cleithrum and opercle in Kdm6a morphants; Kdm6al morphants did not exhibit craniofacial defects. Coinjection with in vitro synthesized KDM6A resulted in partial rescue of the craniofacial phenotype. In addition, at 48 hours postfertilization Kdm6a and Kdm6al morphants exhibited abnormal development of the atria and/or ventricle as well as prominent bulging of the myocardial wall, and Kdm6al morphants also showed progression through cardiac looping morphogenesis that was significantly lower than that observed with wildtype. When compared with wildtype embryos, cross-sectional areas of the brains of morphants were notably reduced and had a reduced cell layer thickness within the hypothalamus, optic tectum, and midbrain tegmentum. Analysis of neural precursor cell (NPC) markers demonstrated that morphant NPCs are defective in their ability to differentiate in the forebrain and midbrain; the differentiation defects were not observed in the hindbrain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25972376" 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></div>
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<p><a href="#3" class="mim-tip-reference" title="Faralli, H., Wang, C., Nakka, K., Benyoucef, A., Sebastian, S., Zhuang, L., Chu, A., Palii, C. G., Liu, C., Camellato, B., Brand, M., Ge, K., Dilworth, F. J. <strong>UTX demethylase activity is required for satellite cell-mediated muscle regeneration.</strong> J. Clin. Invest. 126: 1555-1565, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26999603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26999603</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26999603[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/JCI83239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26999603">Faralli et al. (2016)</a> noted that loss of Utx is embryonic lethal in female mice, whereas male mice lacking Utx survive due to expression of Uty, a Utx paralog that lacks H3K27 demethylase activity. They generated male and female mice with a conditional deletion (mko) of Utx in adult skeletal muscle stem cells, or satellite cells (SCs), which reside along muscle fibers. After cardiotoxin treatment, wildtype mice regenerated healthy myofibers, but female Utx mko/mko mice exhibited decreased myofiber density with increased necrosis and inflammatory cell infiltration. Male Utx mko/Y mice also showed impaired myofiber regeneration, suggesting that the H3K27 demethylase activity of Utx is required for SC-mediated adult muscle regeneration. Female mko heterozygotes showed normal muscle regeneration, whereas wildtype mice treated with an H3K27 inhibitor did not. Immunofluorescence analysis of myofiber explants demonstrated Utx expression in SCs at all stages of muscle regeneration, along with Pax7 (<a href="/entry/167410">167410</a>)-, Myod (<a href="/entry/159970">159970</a>)-, and Myog (<a href="/entry/159980">159980</a>)-expressing cell populations. However, loss of Utx or its demethylase activity impaired proliferation, Myog expression, and initiation of differentiation by progenitor cells. Functional analyses showed that Utx mediated terminal differentiation of muscle progenitor cells through removal of repressive H3K27me3 marks at key genes involved in the formation of functional myotubes, including Myog. <a href="#3" class="mim-tip-reference" title="Faralli, H., Wang, C., Nakka, K., Benyoucef, A., Sebastian, S., Zhuang, L., Chu, A., Palii, C. G., Liu, C., Camellato, B., Brand, M., Ge, K., Dilworth, F. J. <strong>UTX demethylase activity is required for satellite cell-mediated muscle regeneration.</strong> J. Clin. Invest. 126: 1555-1565, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26999603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26999603</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26999603[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/JCI83239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26999603">Faralli et al. (2016)</a> concluded that UTX H3K27 demethylase activity is essential in muscle regeneration after muscle injury. In a commentary on the work of <a href="#3" class="mim-tip-reference" title="Faralli, H., Wang, C., Nakka, K., Benyoucef, A., Sebastian, S., Zhuang, L., Chu, A., Palii, C. G., Liu, C., Camellato, B., Brand, M., Ge, K., Dilworth, F. J. <strong>UTX demethylase activity is required for satellite cell-mediated muscle regeneration.</strong> J. Clin. Invest. 126: 1555-1565, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26999603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26999603</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26999603[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/JCI83239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26999603">Faralli et al. (2016)</a>, <a href="#13" class="mim-tip-reference" title="Liu, L., Rando, T. A. <strong>UTX in muscle regeneration--the right dose and the right time.</strong> J. Clin. Invest. 126: 1233-1235, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26999609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26999609</a>] [<a href="https://doi.org/10.1172/JCI86798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26999609">Liu and Rando (2016)</a> noted the important insights the study provided into the contribution of epigenetic regulation in stem cell-mediated regeneration of adult tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26999603+26999609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>6 Selected Examples</a>):</strong>
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<a href="/allelicVariants/300128" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300128[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 KABUKI SYNDROME 2</strong>
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KDM6A, EX5-9DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022826" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022826" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022826</a>
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<p>In a 2-year-old Italian boy with a typical Kabuki syndrome phenotype (KABUK2; <a href="/entry/300867">300867</a>), <a href="#10" class="mim-tip-reference" title="Lederer, D., Grisart, B., Digilio, M. C., Benoit, V., Crespin, M., Ghariani, S. C., Maystadt, I., Dallapiccola, B., Verellen-Dumoulin, C. <strong>Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome.</strong> Am. J. Hum. Genet. 90: 119-124, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22197486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22197486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22197486[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.2011.11.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22197486">Lederer et al. (2012)</a> identified hemizygosity for a de novo 45.4-kb intragenic deletion from genomic coordinate chrX:44,866,302 to 44,912,718 (GRCh37/hg19), removing exons 5 through 9 of the KDM6A gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22197486" 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 KABUKI SYNDROME 2</strong>
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KDM6A, TRP1239TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122929 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122929;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=rs398122929" 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=rs398122929" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000033119" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033119" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033119</a>
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<p>In a 14-year-old Japanese boy with Kabuki syndrome-2 (KABUK2; <a href="/entry/300867">300867</a>), <a href="#17" class="mim-tip-reference" title="Miyake, N., Mizuno, S., Okamoto, N., Ohashi, H., Shiina, M., Ogata, K., Tsurusaki, Y., Nakashima, M., Saitsu, H., Niikawa, N., Matsumoto, N. <strong>KDM6A point mutations cause Kabuki syndrome.</strong> Hum. Mutat. 34: 108-110, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23076834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23076834</a>] [<a href="https://doi.org/10.1002/humu.22229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23076834">Miyake et al. (2013)</a> identified a 3717G-A transition in the KDM6A gene, resulting in a trp1239-to-ter (W1239X) substitution. Parental DNA was unavailable. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23076834" 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 KABUKI SYNDROME 2</strong>
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KDM6A, ARG519TER
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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> rs397514628 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514628;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/rs397514628?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=rs397514628" 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=rs397514628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000033120 OR RCV002513317 OR RCV004719670" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033120, RCV002513317, RCV004719670" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033120...</a>
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<p>In a 22-year-old Japanese man with Kabuki syndrome-2 (KABUK2; <a href="/entry/300867">300867</a>), <a href="#17" class="mim-tip-reference" title="Miyake, N., Mizuno, S., Okamoto, N., Ohashi, H., Shiina, M., Ogata, K., Tsurusaki, Y., Nakashima, M., Saitsu, H., Niikawa, N., Matsumoto, N. <strong>KDM6A point mutations cause Kabuki syndrome.</strong> Hum. Mutat. 34: 108-110, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23076834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23076834</a>] [<a href="https://doi.org/10.1002/humu.22229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23076834">Miyake et al. (2013)</a> identified a 1555C-T transition in the KDM6A gene, resulting in an arg519-to-ter (R519X) substitution. Parental DNA was unavailable. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23076834" 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 KABUKI SYNDROME 2</strong>
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KDM6A, 3-BP DEL, 3354TCT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122829 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122829;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=rs398122829" 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=rs398122829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000033121" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033121" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033121</a>
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<p>In a 21-year-old woman with Kabuki syndrome-2 (KABUK2; <a href="/entry/300867">300867</a>), <a href="#17" class="mim-tip-reference" title="Miyake, N., Mizuno, S., Okamoto, N., Ohashi, H., Shiina, M., Ogata, K., Tsurusaki, Y., Nakashima, M., Saitsu, H., Niikawa, N., Matsumoto, N. <strong>KDM6A point mutations cause Kabuki syndrome.</strong> Hum. Mutat. 34: 108-110, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23076834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23076834</a>] [<a href="https://doi.org/10.1002/humu.22229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23076834">Miyake et al. (2013)</a> identified a de novo heterozygous 3-bp deletion (c.3354_3356delTCT) in the KDM6A gene, resulting in the in-frame deletion of a highly conserved residue (leu1119del) in the catalytic Jumonji-C (JmjC) domain. The mutation was not present in either of her parents. The patient showed a random pattern of X inactivation, with a 57:43 ratio in genomic DNA from peripheral leukocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23076834" 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 id="0005" class="mim-anchor"></a>
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<strong>.0005 KABUKI SYNDROME 2</strong>
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KDM6A, 4-BP DEL, 1909TCTA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122969 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122969;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=rs398122969" 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=rs398122969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000076920" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000076920" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000076920</a>
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<p>In a female patient (KMS-81) with Kabuki syndrome-2 (KABUK2; <a href="/entry/300867">300867</a>) who showed large front teeth with wide interdentium, <a href="#16" class="mim-tip-reference" title="Miyake, N., Koshimizu, E., Okamoto, N., Mizuno, S., Ogata, T., Nagai, T., Kosho, T., Ohashi, H., Kato, M., Sasaki, G., Mabe, H., Watanabe, Y., and 31 others. <strong>MLL2 and KDM6A mutations in patients with Kabuki syndrome.</strong> Am. J. Med. Genet. 161A: 2234-2243, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23913813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23913813</a>] [<a href="https://doi.org/10.1002/ajmg.a.36072" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23913813">Miyake et al. (2013)</a> identified a 4-bp deletion in the KDM6A gene (c.1909_1912delTCTA) predicted to result in a frameshift and premature termination (Ser637ThrfsTer53). The patient showed a skewed X-inactivation pattern. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23913813" 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 id="0006" class="mim-anchor"></a>
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<strong>.0006 KABUKI SYNDROME 2</strong>
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KDM6A, 4-BP DEL, NT2515
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786205676 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205676;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=rs786205676" 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=rs786205676" 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=RCV000170468 OR RCV001818408" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000170468, RCV001818408" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000170468...</a>
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<p>In 2 brothers with Kabuki syndrome-2 (KABUK2; <a href="/entry/300867">300867</a>), <a href="#11" class="mim-tip-reference" title="Lederer, D., Shears, D., Benoit, V., Verellen-Dumoulin, C., Maystadt, I. <strong>A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A.</strong> Am. J. Med. Genet. 164A: 1289-1292, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24664873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24664873</a>] [<a href="https://doi.org/10.1002/ajmg.a.36442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24664873">Lederer et al. (2014)</a> identified a 4-bp deletion (c.2515_2518del) in exon 17 of the KDM6A gene, causing a frameshift predicted to result in a premature termination codon (Asn839ValfsTer27). Their mother and maternal grandmother, who exhibited attenuated phenotypes, also carried the mutation, which was not found in an unaffected maternal aunt or in 144 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24664873" 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/nature06145" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.aaw1026" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI83239" target="_blank">Full Text</a>]
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Faundes, V., Goh, S., Akilapa, R., Bezuidenhout H., Bjornsson, H. T., Bradley, L., Brady, A. F., Brischoux-Boucher, E., Brunner, H., Bulk, S., Canham, N., Cody, D., and 32 others.
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[<a href="https://doi.org/10.1038/s41436-021-01119-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/7.4.737" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/MCB.01506-06" target="_blank">Full Text</a>]
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Kruidenier, L., Chung, C., Cheng, Z., Liddle, J., Che, K., Joberty, G., Bantscheff, M., Bountra, C., Bridges, A., Diallo, H., Eberhard, D., Hutchinson, S., and 19 others.
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[<a href="https://doi.org/10.1038/nature11262" target="_blank">Full Text</a>]
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Lan, F., Bayliss, P. E., Rinn, J. L., Whetstine, J. R., Wang, J. K., Chen, S., Iwase, S., Alpatov, R., Issaeva, I., Canaani, E., Roberts, T. M., Chang, H. Y., Shi, Y.
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[<a href="https://doi.org/10.1038/nature06192" target="_blank">Full Text</a>]
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<a id="Lederer2012" class="mim-anchor"></a>
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Lederer, D., Grisart, B., Digilio, M. C., Benoit, V., Crespin, M., Ghariani, S. C., Maystadt, I., Dallapiccola, B., Verellen-Dumoulin, C.
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[<a href="https://doi.org/10.1016/j.ajhg.2011.11.021" target="_blank">Full Text</a>]
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<a id="Lederer2014" class="mim-anchor"></a>
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Lederer, D., Shears, D., Benoit, V., Verellen-Dumoulin, C., Maystadt, I.
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<strong>A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24664873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24664873</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24664873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.36442" target="_blank">Full Text</a>]
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<a id="Lee2007" class="mim-anchor"></a>
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Lee, M. G., Villa, R., Trojer, P., Norman, J., Yan, K.-P., Reinberg, D., Di Croce, L., Shiekhattar, R.
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[<a href="https://doi.org/10.1126/science.1149042" 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="13" class="mim-anchor"></a>
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<a id="Liu2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Liu, L., Rando, T. A.
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|
<strong>UTX in muscle regeneration--the right dose and the right time.</strong>
|
|
J. Clin. Invest. 126: 1233-1235, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26999609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26999609</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26999609" 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/JCI86798" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Mansour2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Mansour, A. A., Gafni, O., Weinberger, L., Zviran, A., Ayyash, M., Rais, Y., Krupalnik, V., Zerbib, M., Amann-Zalcenstein, D., Maza, I., Geula, S., Viukov, S., Holtzman, L., Pribluda, A., Canaani, E., Horn-Saban, S., Amit, I., Novershtern, N., Hanna, J. H.
|
|
<strong>The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming.</strong>
|
|
Nature 488: 409-413, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22801502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22801502</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22801502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature11272" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Micale2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Micale, L., Augello, B., Maffeo, C., Selicorni, A., Zucchetti, F., Fusco, C., De Nittis, P., Pellico, M. T., Mandriani, B., Fischetto, R., Boccone, L., Silengo, M., and 27 others.
|
|
<strong>Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients.</strong>
|
|
Hum. Mutat. 35: 841-850, 2014.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24633898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24633898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24633898[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=24633898" 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.22547" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Miyake2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Miyake, N., Koshimizu, E., Okamoto, N., Mizuno, S., Ogata, T., Nagai, T., Kosho, T., Ohashi, H., Kato, M., Sasaki, G., Mabe, H., Watanabe, Y., and 31 others.
|
|
<strong>MLL2 and KDM6A mutations in patients with Kabuki syndrome.</strong>
|
|
Am. J. Med. Genet. 161A: 2234-2243, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23913813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23913813</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23913813" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.36072" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Miyake2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Miyake, N., Mizuno, S., Okamoto, N., Ohashi, H., Shiina, M., Ogata, K., Tsurusaki, Y., Nakashima, M., Saitsu, H., Niikawa, N., Matsumoto, N.
|
|
<strong>KDM6A point mutations cause Kabuki syndrome.</strong>
|
|
Hum. Mutat. 34: 108-110, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23076834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23076834</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23076834" 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.22229" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="van Haaften2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van Haaften, G., Dalgliesh, G. L., Davies, H., Chen, L., Bignell, G., Greenman, C., Edkins, S., Hardy, C., O'Meara, S., Teague, J., Butler, A., Hinton, J., and 50 others.
|
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<strong>Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer.</strong>
|
|
Nature Genet. 41: 521-523, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19330029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19330029</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19330029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.349" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Van Laarhoven2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Van Laarhoven, P. M., Neitzel, L. R., Quintana, A. M., Geiger, E. A., Zackai, E. H., Clouthier, D. E., Artinger, K. B., Ming, J. E., Shaikh, T. H.
|
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<strong>Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development.</strong>
|
|
Hum. Molec. Genet. 24: 4443-4453, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25972376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25972376</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25972376[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=25972376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddv180" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 08/27/2021
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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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Ada Hamosh - updated : 08/28/2019<br>Ada Hamosh - updated : 08/27/2018<br>Paul J. Converse - updated : 01/12/2017<br>Marla J. F. O'Neill - updated : 02/04/2016<br>Marla J. F. O'Neill - updated : 4/29/2015<br>Ada Hamosh - updated : 1/22/2015<br>Sonja A. Rasmussen - updated : 12/18/2013<br>Marla J. F. O'Neill - updated : 2/14/2013<br>Ada Hamosh - updated : 9/12/2012<br>Marla J. F. O'Neill - updated : 1/26/2012<br>Ada Hamosh - updated : 8/3/2009<br>Ada Hamosh - updated : 11/26/2007<br>Ada Hamosh - updated : 10/26/2007
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 5/6/1998
|
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 01/09/2025
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/21/2023<br>carol : 08/30/2021<br>carol : 08/27/2021<br>carol : 02/09/2021<br>alopez : 08/28/2019<br>alopez : 08/27/2018<br>mgross : 01/12/2017<br>mgross : 01/12/2017<br>carol : 02/04/2016<br>mgross : 9/15/2015<br>alopez : 5/7/2015<br>mcolton : 4/29/2015<br>alopez : 1/30/2015<br>alopez : 1/22/2015<br>carol : 12/18/2013<br>carol : 12/18/2013<br>carol : 2/15/2013<br>terry : 2/14/2013<br>terry : 2/14/2013<br>mgross : 2/5/2013<br>alopez : 9/13/2012<br>terry : 9/12/2012<br>mgross : 6/25/2012<br>carol : 1/26/2012<br>terry : 1/26/2012<br>alopez : 8/4/2009<br>terry : 8/3/2009<br>alopez : 11/29/2007<br>terry : 11/26/2007<br>alopez : 11/2/2007<br>terry : 10/26/2007<br>dkim : 9/11/1998<br>carol : 8/11/1998<br>carol : 6/16/1998<br>carol : 5/6/1998
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
|
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<strong>*</strong> 300128
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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|
|
LYSINE DEMETHYLASE 6A; KDM6A
|
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</span>
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</h3>
|
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
LYSINE-SPECIFIC DEMETHYLASE 6A<br />
|
|
UBIQUITOUSLY TRANSCRIBED TETRATRICOPEPTIDE REPEAT GENE ON X CHROMOSOME; UTX
|
|
</span>
|
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: KDM6A</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: Xp11.3
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : X:44,873,188-45,112,779 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
|
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
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Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
Xp11.3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Kabuki syndrome 2
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
300867
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
X-linked dominant
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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|
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</tr>
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|
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>KDM6A, or UTX, mediates removal of repressive trimethylation of histone H3 (see 602810) lys27 (H3K27me3) to establish transcriptionally permissive chromatin (Faralli et al., 2016). </p>
|
|
</span>
|
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<div>
|
|
<br />
|
|
</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</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>Greenfield et al. (1998) described the isolation of an X-linked homolog of Uty (see 400009), called Utx (ubiquitously transcribed TPR gene on the X chromosome), which is expressed from the inactive X chromosome in both mice and humans. </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>Mapping</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>Greenfield et al. (1998) determined that the mouse Utx gene maps to the proximal region of the X chromosome in an interval containing the Maoa (309850) and Maob (309860) genes, thus placing it in band A2-A3. By Southern analysis of a panel of rodent/human somatic cell hybrids carrying derivative X chromosomes, Greenfield et al. (1998) mapped the human UTX gene to Xp11.3-p11.23. By fluorescence in situ hybridization on normal human metaphase spreads, they refined the localization to Xp11.2. </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>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Kruidenier et al. (2012) presented a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 (611577) and UTX). The liganded structures of human and mouse JMJD3 provided novel insight into the specificity determinants for cofactor, substrate, and inhibitor recognition by the KDM6 subfamily of demethylases. Kruidenier et al. (2012) exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily, and demonstrated that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. Kruidenier et al. (2012) concluded that their results resolved the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provided encouragement for designing small-molecule inhibitors to allow selective pharmacologic intervention across the JMJ family. </p><p>Mansour et al. (2012) demonstrated in mice and humans that the histone H3 methylated lys27 (H3K27) demethylase Utx regulates the efficient induction, rather than maintenance, of pluripotency. Murine embryonic stem cells lacking Utx can execute lineage commitment and contribute to adult chimeric animals; however, somatic cells lacking Utx fail to robustly reprogram back to the ground state of pluripotency. Utx directly partners with OSK reprogramming factors (OCT4, 164177; SOX2, 184429; KLF4, 602253) and uses its histone demethylase catalytic activity to facilitate induced pluripotent stem cell formation. Genomic analysis indicates that Utx depletion results in aberrant dynamics of H3K27me3 repressive chromatin demethylation in somatic cells undergoing reprogramming. The latter directly hampers the derepression of potent pluripotency promoting gene modules (including Sall1, Sall4, and Utf1), which can cooperatively substitute for exogenous OSK supplementation in iPSC formation. Remarkably, Utx safeguards the timely execution of H3K27me3 demethylation observed in embryonic day 10.5-11 primordial germ cells (PGCs), and Utx-deficient PGCs show cell-autonomous aberrant epigenetic reprogramming dynamics during their embryonic maturation in vivo. Subsequently, this disrupts PGC development by embryonic day 12.5, and leads to diminished germline transmission in mouse chimeras generated from Utx-knockout pluripotent cells. Thus, Mansour et al. (2012) concluded that they identified Utx as a novel mediator with distinct functions during the reestablishment of pluripotency and germ cell development. They furthermore concluded that their findings highlighted the principle that molecular regulators mediating loss of repressive chromatin during in vivo germ cell reprogramming can be co-opted during in vitro reprogramming towards ground state pluripotency. </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>Lan et al. (2007) showed that the JmjC-domain-containing related proteins UTX and JMJD3 (611577) catalyze demethylation of tri/dimethylated histone H3 (see 602810) lysine-27 (H3K27me3/2). UTX is enriched around the transcription start sites of many HOX genes in primary human fibroblasts, in which HOX genes are differentially expressed, but is selectively excluded from the HOX loci in embryonic stem cells, in which HOX genes are largely silent. Consistently, RNA interference inhibition of UTX led to increased H3K27me3 levels at some HOX gene promoters. Importantly, morpholino oligonucleotide inhibition of a zebrafish UTX homolog resulted in misregulation of HOX genes and a striking posterior developmental defect, which was partially rescued by wildtype, but not by catalytically inactive, human UTX. Lan et al. (2007) concluded that, taken together, their findings identified a small family of H3K27 demethylases with important evolutionarily conserved roles in H3K27 methylation regulation and in animal anterior-posterior development. </p><p>Agger et al. (2007) showed that human JmjC domain-containing UTX and JMJD3 demethylate trimethylated lys27 on histone H3. Furthermore, the authors demonstrated that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, Agger et al. (2007) showed that UTX directly binds to the HOXB1 locus and is required for its activation. Finally, mutation of F18E9.5, a C. elegans JMJD3 ortholog, or inhibition of its expression, resulted in abnormal gonad development. Agger et al. (2007) concluded that, taken together, their results suggested that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (602113) (Issaeva et al., 2007), supported a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation. </p><p>Lee et al. (2007) showed that human UTX, a member of the Jumonji C family of proteins, is a di- and trimethyl H3K27 demethylase. UTX occupies the promoters of HOX gene clusters (see 142950) and regulates their transcriptional output by modulating the recruitment of polycomb repressive complex 1 (PRC1) and the monoubiquitination of histone H2A (see 602786). Moreover, UTX associates with mixed-lineage leukemia (MLL) 2/3 complexes (602113, 606833, respectively), and during retinoic acid signaling events, the recruitment of the UTX complex to HOX genes results in H3K27 demethylation and a concomitant methylation of H3K4. Lee et al. (2007) concluded that their results suggested a concerted mechanism for transcriptional activation in which cycles of H3K4 methylation by MLL2/3 are linked with the demethylation of H3K27 through UTX. </p><p>Chakraborty et al. (2019) reported that hypoxia promotes histone methylation in a HIF- and 2-hydroxyglutarate-independent manner. Chakraborty et al. (2019) found that the H3K27 histone demethylase KDM6A/UTX, but not its paralog KDM6B (611577), is oxygen sensitive. KDM6A loss, like hypoxia, prevented H3K27 demethylation and blocked cellular differentiation. Restoring H3K27 methylation homeostasis in hypoxic cells reversed these effects. Chakraborty et al. (2019) concluded that oxygen directly affects chromatin regulators to control cell fate. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Kabuki Syndrome 2</em></strong></p><p>
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By array CGH analysis in 2 Belgian girls with Kabuki syndrome (see KABUK2, 300867) who were negative for mutation in the MLL2 gene (602113), Lederer et al. (2012) identified de novo Xp11.3 microdeletions, both of which contained part or all of the KDM6A gene. In the 13-year-old girl, the 283.5-kb deletion included KDM6A exons 21 through 29, coding for the terminal part of the catalytic domain of KDM6A, and CXORF36 (300959). In the 10-year-old girl, the 815.7-kb deletion completely removed KDM6A, CXORF36, DUSP21 (300678) and FUNDC1 (300871). Sequencing of the KDM6A gene as well as targeted array CGH in a cohort of 22 MLL2-negative Kabuki syndrome patients revealed a de novo 45.4-kb intragenic deletion in a 2-year-old Italian boy (300128.0001). Although KDM6A escapes X inactivation, Lederer et al. (2012) found a skewed X-inactivation pattern in both girls (89:11 and 97:3, respectively), in which the deleted X chromosome was inactivated in the majority of the cells. </p><p>Miyake et al. (2013) analyzed the KDM6A gene in 32 patients with Kabuki syndrome who were negative for mutation in the MLL2 gene and identified nonsense mutations in 2 male patients and a 3-bp deletion in a female patient (300128.0002-300128.0004). The female patient had fewer dysmorphic features than the male patients, who displayed a more severe phenotype with multiple organ involvement. Miyake et al. (2013) suggested that the mutation type as well as X-inactivation pattern in affected organs in females may determine the severity of Kabuki syndrome. </p><p>Using direct sequencing, MLPA, and quantitative PCR, Micale et al. (2014) screened 303 patients with Kabuki syndrome and identified 4 KDM6A mutations, 3 of which were novel. </p><p>In 2 brothers with Kabuki syndrome who were negative for mutation in the MLL2 gene, Lederer et al. (2014) identified a 4-bp deletion in the KDM6A gene (300128.0006). Their mother and maternal grandmother, who also carried the mutation, exhibited attenuated phenotypes. Lederer et al. (2014) reviewed the clinical features of all reported patients with KDM6A mutations and stated that the family studied by them represented the first instance of hereditary X-linked Kabuki syndrome. </p><p>Faundes et al. (2021) analyzed molecular data on 36 newly reported and 49 previously reported patients with heterozygous or hemizygous mutations in the KDM6A gene. Sixty-six KDM6A mutations were identified in 78 families, including 50 premature termination variants (PTV) in 62 patients from 59 families and 16 protein-altering variants (PAVs) in 23 patients from 19 families. The PTVs were all classified as pathogenic. Fifteen PTVs were nonsense mutations, 14 affected canonical splice sites, 12 were frameshift mutations, 8 were gross deletions, and 1 resulted from a chromosome translocation disrupting the KDM6A gene. In 42 patients, including 13 males and 29 females, the KDM6A PTVs were de novo, and in 6 patients the mutations were inherited from the mother. Of the 16 PAVs, 12 were classed as pathogenic or likely pathogenic, 3 as variants of uncertain significance, and 1 as likely benign. Thirteen of the PAVs were missense, 2 were in-frame deletions, and 1 was an indel. Eight PAVs, in 2 males and 6 females, were de novo. Ten patients inherited the PAV from their mother, and 1 patient inherited the mutation from her father. Inheritance of the PAVs was not known in 4 patients. </p><p><strong><em>Somatic Mutations</em></strong></p><p>
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Van Haaften et al. (2009) described inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. </p><p>Gozdecka et al. (2018) demonstrated that UTX suppresses myeloid leukemogenesis through noncatalytic functions, a property shared with its catalytically inactive Y-chromosome paralog, UTY (400009). In keeping with this, Gozdecka et al. (2018) demonstrated concomitant loss/mutation of KDM6A and UTY in multiple human cancers. Mechanistically, global genomic profiling showed only minor changes in H3K27 trimethylation but significant and bidirectional alterations in H3K27 acetylation and chromatin accessibility; a predominant loss of H3K4 monomethylation modifications; alterations in ETS (see ETS1, 164720) and GATA-factor (see GATA2, 137295) binding; and altered gene expression after UTX loss. By integrating proteomic and genomic analyses, Gozdecka et al. (2018) linked these changes to UTX regulation of ATP-dependent chromatin remodeling, coordination of the COMPASS complex, and enhanced pioneering activity of ETS factors during evolution to acute myeloid leukemia (AML; 601626). Gozdecka et al. (2018) concluded that their findings identified a dual role for UTX in suppressing AML via repression of oncogenic ETS and upregulation of tumor-suppressive GATA programs. </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>Genotype/Phenotype Correlations</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>Miyake et al. (2013) used mutation detection methods to screen 81 patients with Kabuki syndrome and identified KDM6A mutations in 5 (6.2%). Of the 5 mutations, including 2 that were novel, 4 were protein-truncating and 1 was an in-frame deletion in the Jumonji C domain. High-arched eyebrows, short fifth fingers, and infantile hypotonia were less commonly seen in patients with KDM6A mutations than in those with MLL2 mutations. All of the patients with KDM6A mutations had short stature and postnatal growth retardation, compared with only half of patients with MLL2 mutations. Among the 2 female patients with KDM6A mutations, one (KMS-65) with an in-frame deletion (300128.0004) had a random X-inactivation pattern, whereas the other (KMS-81) with a frameshift truncating mutation (300128.0005) showed marked skewing. </p><p>Faundes et al. (2021) analyzed molecular and clinical data in 80 patients with heterozygous or hemizygous mutations in the KDM6A gene. Patients with protein-altering variants (PAVs) had shorter birth lengths compared to patients with protein termination variants (PTVs). Patients with PTVs had more impaired intellectual development (97.6% vs 80%) and a higher frequency of central nervous system anomalies (71.4% vs 28.6%) compared to patients with PAVs, although the difference did not reach statistical significance. Faundes et al. (2021) concluded that individuals with PTVs overall have a more severe phenotype, and the phenotypes of patients with PAVs are more variable. </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>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Van Laarhoven et al. (2015) used morpholino antisense oligonucleotides to knock down the 2 orthologs of KDM6A in zebrafish, Kdm6a and Kdm6al, and at 5 days postfertilization they observed hypoplasia of the branchial arches, the Meckel and ceratohyal cartilage, and the cleithrum and opercle in Kdm6a morphants; Kdm6al morphants did not exhibit craniofacial defects. Coinjection with in vitro synthesized KDM6A resulted in partial rescue of the craniofacial phenotype. In addition, at 48 hours postfertilization Kdm6a and Kdm6al morphants exhibited abnormal development of the atria and/or ventricle as well as prominent bulging of the myocardial wall, and Kdm6al morphants also showed progression through cardiac looping morphogenesis that was significantly lower than that observed with wildtype. When compared with wildtype embryos, cross-sectional areas of the brains of morphants were notably reduced and had a reduced cell layer thickness within the hypothalamus, optic tectum, and midbrain tegmentum. Analysis of neural precursor cell (NPC) markers demonstrated that morphant NPCs are defective in their ability to differentiate in the forebrain and midbrain; the differentiation defects were not observed in the hindbrain. </p><p>Faralli et al. (2016) noted that loss of Utx is embryonic lethal in female mice, whereas male mice lacking Utx survive due to expression of Uty, a Utx paralog that lacks H3K27 demethylase activity. They generated male and female mice with a conditional deletion (mko) of Utx in adult skeletal muscle stem cells, or satellite cells (SCs), which reside along muscle fibers. After cardiotoxin treatment, wildtype mice regenerated healthy myofibers, but female Utx mko/mko mice exhibited decreased myofiber density with increased necrosis and inflammatory cell infiltration. Male Utx mko/Y mice also showed impaired myofiber regeneration, suggesting that the H3K27 demethylase activity of Utx is required for SC-mediated adult muscle regeneration. Female mko heterozygotes showed normal muscle regeneration, whereas wildtype mice treated with an H3K27 inhibitor did not. Immunofluorescence analysis of myofiber explants demonstrated Utx expression in SCs at all stages of muscle regeneration, along with Pax7 (167410)-, Myod (159970)-, and Myog (159980)-expressing cell populations. However, loss of Utx or its demethylase activity impaired proliferation, Myog expression, and initiation of differentiation by progenitor cells. Functional analyses showed that Utx mediated terminal differentiation of muscle progenitor cells through removal of repressive H3K27me3 marks at key genes involved in the formation of functional myotubes, including Myog. Faralli et al. (2016) concluded that UTX H3K27 demethylase activity is essential in muscle regeneration after muscle injury. In a commentary on the work of Faralli et al. (2016), Liu and Rando (2016) noted the important insights the study provided into the contribution of epigenetic regulation in stem cell-mediated regeneration of adult tissues. </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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<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>6 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 KABUKI SYNDROME 2</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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KDM6A, EX5-9DEL
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<br />
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ClinVar: RCV000022826
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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 2-year-old Italian boy with a typical Kabuki syndrome phenotype (KABUK2; 300867), Lederer et al. (2012) identified hemizygosity for a de novo 45.4-kb intragenic deletion from genomic coordinate chrX:44,866,302 to 44,912,718 (GRCh37/hg19), removing exons 5 through 9 of the KDM6A gene. </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 KABUKI SYNDROME 2</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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KDM6A, TRP1239TER
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<br />
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SNP: rs398122929,
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ClinVar: RCV000033119
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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 Japanese boy with Kabuki syndrome-2 (KABUK2; 300867), Miyake et al. (2013) identified a 3717G-A transition in the KDM6A gene, resulting in a trp1239-to-ter (W1239X) substitution. Parental DNA was unavailable. </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 KABUKI SYNDROME 2</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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KDM6A, ARG519TER
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<br />
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SNP: rs397514628,
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gnomAD: rs397514628,
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ClinVar: RCV000033120, RCV002513317, RCV004719670
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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-year-old Japanese man with Kabuki syndrome-2 (KABUK2; 300867), Miyake et al. (2013) identified a 1555C-T transition in the KDM6A gene, resulting in an arg519-to-ter (R519X) substitution. Parental DNA was unavailable. </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 KABUKI SYNDROME 2</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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KDM6A, 3-BP DEL, 3354TCT
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<br />
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SNP: rs398122829,
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ClinVar: RCV000033121
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 21-year-old woman with Kabuki syndrome-2 (KABUK2; 300867), Miyake et al. (2013) identified a de novo heterozygous 3-bp deletion (c.3354_3356delTCT) in the KDM6A gene, resulting in the in-frame deletion of a highly conserved residue (leu1119del) in the catalytic Jumonji-C (JmjC) domain. The mutation was not present in either of her parents. The patient showed a random pattern of X inactivation, with a 57:43 ratio in genomic DNA from peripheral leukocytes. </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 KABUKI SYNDROME 2</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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KDM6A, 4-BP DEL, 1909TCTA
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<br />
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SNP: rs398122969,
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ClinVar: RCV000076920
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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 female patient (KMS-81) with Kabuki syndrome-2 (KABUK2; 300867) who showed large front teeth with wide interdentium, Miyake et al. (2013) identified a 4-bp deletion in the KDM6A gene (c.1909_1912delTCTA) predicted to result in a frameshift and premature termination (Ser637ThrfsTer53). The patient showed a skewed X-inactivation pattern. </p>
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<span class="mim-font">
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<strong>.0006 KABUKI SYNDROME 2</strong>
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</h4>
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<span class="mim-text-font">
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KDM6A, 4-BP DEL, NT2515
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<br />
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SNP: rs786205676,
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ClinVar: RCV000170468, RCV001818408
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<p>In 2 brothers with Kabuki syndrome-2 (KABUK2; 300867), Lederer et al. (2014) identified a 4-bp deletion (c.2515_2518del) in exon 17 of the KDM6A gene, causing a frameshift predicted to result in a premature termination codon (Asn839ValfsTer27). Their mother and maternal grandmother, who exhibited attenuated phenotypes, also carried the mutation, which was not found in an unaffected maternal aunt or in 144 controls. </p>
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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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<p />
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<p class="mim-text-font">
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<strong>UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.</strong>
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<p class="mim-text-font">
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Chakraborty, A. A., Laukka, T., Myllykoski, M., Ringel, A. E., Booker, M. A., Tolstorukov, M. Y., Meng, Y. J., Meier, S. R., Jennings, R. B., Creech, A. L., Herbert, Z. T., McBrayer, S. K., Olenchock, B. A., Jaffe, J. D., Haigis, M. C., Beroukhim, R., Signoretti, S., Koivunen, P., Kaelin, W. G., Jr.
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<strong>Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate.</strong>
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Faralli, H., Wang, C., Nakka, K., Benyoucef, A., Sebastian, S., Zhuang, L., Chu, A., Palii, C. G., Liu, C., Camellato, B., Brand, M., Ge, K., Dilworth, F. J.
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<strong>UTX demethylase activity is required for satellite cell-mediated muscle regeneration.</strong>
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Faundes, V., Goh, S., Akilapa, R., Bezuidenhout H., Bjornsson, H. T., Bradley, L., Brady, A. F., Brischoux-Boucher, E., Brunner, H., Bulk, S., Canham, N., Cody, D., and 32 others.
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<strong>Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.</strong>
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<strong>UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs.</strong>
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Nature Genet. 50: 883-894, 2018. Note: Erratum: Nature Genet. 54: 1062 only, 2022.
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Issaeva, I., Zonis, Y., Rozovskaia, T., Orlovsky, K., Croce, C. M., Nakamura, T., Mazo, A., Eisenbach, L., Canaani, E.
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<strong>Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth.</strong>
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<p class="mim-text-font">
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Kruidenier, L., Chung, C., Cheng, Z., Liddle, J., Che, K., Joberty, G., Bantscheff, M., Bountra, C., Bridges, A., Diallo, H., Eberhard, D., Hutchinson, S., and 19 others.
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<strong>A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.</strong>
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Nature 488: 404-408, 2012.
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[PubMed: 22842901]
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<p class="mim-text-font">
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Lan, F., Bayliss, P. E., Rinn, J. L., Whetstine, J. R., Wang, J. K., Chen, S., Iwase, S., Alpatov, R., Issaeva, I., Canaani, E., Roberts, T. M., Chang, H. Y., Shi, Y.
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<strong>A histone H3 lysine 27 demethylase regulates animal posterior development.</strong>
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Nature 449: 689-694, 2007.
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[PubMed: 17851529]
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[Full Text: https://doi.org/10.1038/nature06192]
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<p class="mim-text-font">
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Lederer, D., Grisart, B., Digilio, M. C., Benoit, V., Crespin, M., Ghariani, S. C., Maystadt, I., Dallapiccola, B., Verellen-Dumoulin, C.
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<strong>Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome.</strong>
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Am. J. Hum. Genet. 90: 119-124, 2012.
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[PubMed: 22197486]
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Lederer, D., Shears, D., Benoit, V., Verellen-Dumoulin, C., Maystadt, I.
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<strong>A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A.</strong>
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Lee, M. G., Villa, R., Trojer, P., Norman, J., Yan, K.-P., Reinberg, D., Di Croce, L., Shiekhattar, R.
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<strong>Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination.</strong>
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Science 318: 447-450, 2007.
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<p class="mim-text-font">
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Liu, L., Rando, T. A.
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<strong>UTX in muscle regeneration--the right dose and the right time.</strong>
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J. Clin. Invest. 126: 1233-1235, 2016.
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[PubMed: 26999609]
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<p class="mim-text-font">
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Mansour, A. A., Gafni, O., Weinberger, L., Zviran, A., Ayyash, M., Rais, Y., Krupalnik, V., Zerbib, M., Amann-Zalcenstein, D., Maza, I., Geula, S., Viukov, S., Holtzman, L., Pribluda, A., Canaani, E., Horn-Saban, S., Amit, I., Novershtern, N., Hanna, J. H.
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<strong>The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming.</strong>
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Nature 488: 409-413, 2012.
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[PubMed: 22801502]
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Micale, L., Augello, B., Maffeo, C., Selicorni, A., Zucchetti, F., Fusco, C., De Nittis, P., Pellico, M. T., Mandriani, B., Fischetto, R., Boccone, L., Silengo, M., and 27 others.
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<strong>Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients.</strong>
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Miyake, N., Koshimizu, E., Okamoto, N., Mizuno, S., Ogata, T., Nagai, T., Kosho, T., Ohashi, H., Kato, M., Sasaki, G., Mabe, H., Watanabe, Y., and 31 others.
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<strong>MLL2 and KDM6A mutations in patients with Kabuki syndrome.</strong>
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Miyake, N., Mizuno, S., Okamoto, N., Ohashi, H., Shiina, M., Ogata, K., Tsurusaki, Y., Nakashima, M., Saitsu, H., Niikawa, N., Matsumoto, N.
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<strong>KDM6A point mutations cause Kabuki syndrome.</strong>
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van Haaften, G., Dalgliesh, G. L., Davies, H., Chen, L., Bignell, G., Greenman, C., Edkins, S., Hardy, C., O'Meara, S., Teague, J., Butler, A., Hinton, J., and 50 others.
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<strong>Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer.</strong>
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Van Laarhoven, P. M., Neitzel, L. R., Quintana, A. M., Geiger, E. A., Zackai, E. H., Clouthier, D. E., Artinger, K. B., Ming, J. E., Shaikh, T. H.
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<strong>Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development.</strong>
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[PubMed: 25972376]
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 08/27/2021<br>Ada Hamosh - updated : 08/28/2019<br>Ada Hamosh - updated : 08/27/2018<br>Paul J. Converse - updated : 01/12/2017<br>Marla J. F. O'Neill - updated : 02/04/2016<br>Marla J. F. O'Neill - updated : 4/29/2015<br>Ada Hamosh - updated : 1/22/2015<br>Sonja A. Rasmussen - updated : 12/18/2013<br>Marla J. F. O'Neill - updated : 2/14/2013<br>Ada Hamosh - updated : 9/12/2012<br>Marla J. F. O'Neill - updated : 1/26/2012<br>Ada Hamosh - updated : 8/3/2009<br>Ada Hamosh - updated : 11/26/2007<br>Ada Hamosh - updated : 10/26/2007
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<span class="mim-text-font">
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Victor A. McKusick : 5/6/1998
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alopez : 01/09/2025<br>carol : 01/21/2023<br>carol : 08/30/2021<br>carol : 08/27/2021<br>carol : 02/09/2021<br>alopez : 08/28/2019<br>alopez : 08/27/2018<br>mgross : 01/12/2017<br>mgross : 01/12/2017<br>carol : 02/04/2016<br>mgross : 9/15/2015<br>alopez : 5/7/2015<br>mcolton : 4/29/2015<br>alopez : 1/30/2015<br>alopez : 1/22/2015<br>carol : 12/18/2013<br>carol : 12/18/2013<br>carol : 2/15/2013<br>terry : 2/14/2013<br>terry : 2/14/2013<br>mgross : 2/5/2013<br>alopez : 9/13/2012<br>terry : 9/12/2012<br>mgross : 6/25/2012<br>carol : 1/26/2012<br>terry : 1/26/2012<br>alopez : 8/4/2009<br>terry : 8/3/2009<br>alopez : 11/29/2007<br>terry : 11/26/2007<br>alopez : 11/2/2007<br>terry : 10/26/2007<br>dkim : 9/11/1998<br>carol : 8/11/1998<br>carol : 6/16/1998<br>carol : 5/6/1998
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OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
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