4167 lines
338 KiB
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Entry
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- *606834 - LYSINE-SPECIFIC METHYLTRANSFERASE 2B; KMT2B
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*606834</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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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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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/606834">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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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=ENSG00000272333;t=ENST00000420124" 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=9757" 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=606834" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="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=ENSG00000272333;t=ENST00000420124" 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_014727,XM_011527561,XM_011527562,XM_047439787,XR_935878" 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_014727" 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=606834" 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=06017&isoform_id=06017_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/KMT2B" 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/4336749,4588363,4588365,5123787,5923931,7662046,12643900,40225368,71891784,211828317,768012351,2217324158,2217324160,2462569035,2462569037,2462569039" 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/Q9UMN6" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=9757" 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=ENSG00000272333;t=ENST00000420124" 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=KMT2B" 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=KMT2B" 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+9757" 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/KMT2B" 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:9757" 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/9757" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr19&hgg_gene=ENST00000420124.4&hgg_start=35718003&hgg_end=35738878&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:15840" 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:15840" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=606834[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=606834[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/KMT2B/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/ENSG00000272333" 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=KMT2B" 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=KMT2B" 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=KMT2B" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=KMT2B&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/PA166123699" 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:15840" 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/FBgn0003862.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:109565" 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/KMT2B#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:109565" 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/9757/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=9757" 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://zfin.org/ZDB-GENE-060503-376" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:9757" 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=KMT2B&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1281844004<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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606834
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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LYSINE-SPECIFIC METHYLTRANSFERASE 2B; KMT2B
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
MYELOID/LYMPHOID OR MIXED-LINEAGE LEUKEMIA 4; MLL4<br />
|
|
MYELOID/LYMPHOID OR MIXED-LINEAGE LEUKEMIA 2; MLL2<br />
|
|
TRITHORAX, DROSOPHILA, HOMOLOG OF, 2; TRX2<br />
|
|
KIAA0304
|
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</span>
|
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KMT2B" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KMT2B</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/19/595?start=-3&limit=10&highlight=595">19q13.12</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:35718003-35738878&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">19:35,718,003-35,738,878</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=617284,619934" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
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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="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/19/595?start=-3&limit=10&highlight=595">
|
|
19q13.12
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
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|
|
<td>
|
|
<span class="mim-font">
|
|
Dystonia 28, childhood-onset
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/617284"> 617284 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Intellectual developmental disorder, autosomal dominant 68
|
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619934"> 619934 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
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<p>Methylation of histone H3 (see <a href="/entry/602810">602810</a>) lys4 (H3K4) is an important epigenetic modification involved in gene activation. H3K4 di- and trimethylation (H3K4me2 and H3K4me3, respectively) residues mark the transcription start sites of actively transcribed genes, whereas a high level of H3K4 monomethylation (H3K4me1) is associated with enhancer sequences. Members of the SET/MLL protein family, including KMT2B, are responsible for the generation of H3K4me1, H3K4me2, and H3K4me3 marks to induce gene activation and are essential for normal development (summary by <a href="#12" class="mim-tip-reference" title="Shao, G.-B., Chen, J.-C., Zhang, L.-P., Huang, P., Lu, H.-Y., Jin, J., Gong, A.-H., Sang, J.-R. <strong>Dynamic patterns of histone H3 lysine 4 methyltransferases and demethylases during mouse preimplantation development.</strong> In Vitro Cell. Dev. Biol. Anim. 50: 603-613, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24619213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24619213</a>] [<a href="https://doi.org/10.1007/s11626-014-9741-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24619213">Shao et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24619213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By searching for cDNA sequences encoding large proteins expressed in brain, <a href="#10" class="mim-tip-reference" title="Nagase, T., Ishikawa, I., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., O'Hara, O. <strong>Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong> DNA Res. 4: 141-150, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9205841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9205841</a>] [<a href="https://doi.org/10.1093/dnares/4.2.141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9205841">Nagase et al. (1997)</a> identified a partial cDNA encoding MLL4, which they called KIAA0304. The deduced 1,529-amino acid protein was predicted to be 36% homologous to the mouse Hrx zinc finger protein (MLL; <a href="/entry/159555">159555</a>). RT-PCR analysis detected wide expression that was strongest in kidney, thymus, liver, small intestine, testis, ovary, and prostate. Expression was weak or undetectable in heart, skeletal muscle, and pancreas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9205841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By PCR on placenta and bone marrow cDNA libraries using primers for putative exons in a chromosome 19 clone with similarity to MLL, <a href="#4" class="mim-tip-reference" title="FitzGerald, K. T., Diaz, M. O. <strong>MLL2: a new mammalian member of the trx/MLL family of genes.</strong> Genomics 59: 187-192, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10409430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10409430</a>] [<a href="https://doi.org/10.1006/geno.1999.5860" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10409430">FitzGerald and Diaz (1999)</a> isolated partial cDNAs encoding different domains of MLL4, which they termed MLL2. MLL4 has higher similarity to MLL than do Drosophila Trx or human ALR (KMT2D; <a href="/entry/602113">602113</a>). Northern blot analysis revealed expression of a 9.0-kb transcript in all tissues tested, including pancreas, heart, and muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10409430" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By EST database searching with MLL as the probe, followed by screening of a testis cDNA library and RT-PCR, <a href="#6" class="mim-tip-reference" title="Huntsman, D. G., Chin, S.-F., Muleris, M., Batley, S. J., Collins, V. P., Wiedemann, L. M., Aparicio, S., Caldas, C. <strong>MLL2, the second human homolog of the Drosophila trithorax gene, maps to 19q31.1 and is amplified in solid tumor cell lines.</strong> Oncogene 18: 7975-7984, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10637508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10637508</a>] [<a href="https://doi.org/10.1038/sj.onc.1203291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10637508">Huntsman et al. (1999)</a> assembled a cDNA encoding MLL4, which they also designated MLL2. Depending on the exact initiation codon used, <a href="#6" class="mim-tip-reference" title="Huntsman, D. G., Chin, S.-F., Muleris, M., Batley, S. J., Collins, V. P., Wiedemann, L. M., Aparicio, S., Caldas, C. <strong>MLL2, the second human homolog of the Drosophila trithorax gene, maps to 19q31.1 and is amplified in solid tumor cell lines.</strong> Oncogene 18: 7975-7984, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10637508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10637508</a>] [<a href="https://doi.org/10.1038/sj.onc.1203291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10637508">Huntsman et al. (1999)</a> predicted that the MLL4 protein contains 2,605 or 2,716 amino acids with all the domains identified in MLL. Northern blot analysis detected ubiquitous expression that was most prominent in testis. FISH and slot-blot analysis detected amplified expression in some pancreatic carcinoma and glioblastoma cell lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10637508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By PCR analysis, <a href="#9" class="mim-tip-reference" title="Meyer, E., Carss, K. J., Rankin, J., Nichols, J. M. E., Grozeva, D., Joseph, A. P., Mencacci, N. E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., and 61 others. <strong>Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.</strong> Nature Genet. 49: 223-237, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27992417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27992417</a>] [<a href="https://doi.org/10.1038/ng.3740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27992417">Meyer et al. (2017)</a> found expression of KMT2B in a variety of fetal and adult human tissues. It was ubiquitously expressed in brain, with highest expression in the cerebellum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27992417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="FitzGerald, K. T., Diaz, M. O. <strong>MLL2: a new mammalian member of the trx/MLL family of genes.</strong> Genomics 59: 187-192, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10409430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10409430</a>] [<a href="https://doi.org/10.1006/geno.1999.5860" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10409430">FitzGerald and Diaz (1999)</a> noted that MLL4 did not compensate for loss of Mll1 in mice, suggesting that their functions do not totally overlap. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10409430" 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="Demers, C., Chaturvedi, C.-P., Ranish, J. A., Juban, G., Lai, P., Morle, F., Aebersold, R., Dilworth, F. J., Groudine, M., Brand, M. <strong>Activator-mediated recruitment of the MLL2 methyltransferase complex to the beta-globin locus.</strong> Molec. Cell 27: 573-584, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17707229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17707229</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17707229[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.06.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17707229">Demers et al. (2007)</a> showed that a complex containing Mll4, which they called Mll2, associated with the hematopoietic activator Nfe2 (<a href="/entry/601490">601490</a>) in mouse erythroid cells. Mll4 was recruited to the beta-globin (HBB; <a href="/entry/141900">141900</a>) locus in a Nfe2-dependent manner and was important for H3K4 trimethylation and maximal transcription at the beta-globin locus. Although recruitment of the Mll4 complex was limited to the beta-globin locus control region located 38 kb upstream of the active major beta-globin gene, the Mll4 protein spread across the beta-globin locus, and spreading increased during erythroid differentiation. Mll4 was fully activated only when it reached the coding region of the active major beta-globin gene, because H3K4 trimethylation was restricted to this part of the locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17707229" 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="Shao, G.-B., Chen, J.-C., Zhang, L.-P., Huang, P., Lu, H.-Y., Jin, J., Gong, A.-H., Sang, J.-R. <strong>Dynamic patterns of histone H3 lysine 4 methyltransferases and demethylases during mouse preimplantation development.</strong> In Vitro Cell. Dev. Biol. Anim. 50: 603-613, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24619213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24619213</a>] [<a href="https://doi.org/10.1007/s11626-014-9741-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24619213">Shao et al. (2014)</a> examined the changes of H3K4me and its key regulators in mouse oocytes and preimplantation embryos. They observed increased levels of H3K4me2 and H3K4me3 at the 1- to 2-cell stages, corresponding to the period of embryonic genome activation. The H3K4me2 level dramatically decreased at the 4-cell stage and remained low until the blastocyst stage. In contrast, the H3K4me3 level transiently decreased in 4-cell embryos but steadily increased to peak in blastocysts. Quantitative real-time PCR and immunofluorescence analyses showed that the high level of H3K4me2 during embryonic genome activation coincided with peak expression of its methyltransferase, Ash2l (<a href="/entry/604782">604782</a>), and a concomitant decrease in its demethylases, Kdm5b (<a href="/entry/605393">605393</a>) and Kdm1a (<a href="/entry/609132">609132</a>). H3K4me3 correlated with expression of its methyltransferase, Kmt2b, and demethylase, Kdm5a (<a href="/entry/180202">180202</a>). <a href="#12" class="mim-tip-reference" title="Shao, G.-B., Chen, J.-C., Zhang, L.-P., Huang, P., Lu, H.-Y., Jin, J., Gong, A.-H., Sang, J.-R. <strong>Dynamic patterns of histone H3 lysine 4 methyltransferases and demethylases during mouse preimplantation development.</strong> In Vitro Cell. Dev. Biol. Anim. 50: 603-613, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24619213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24619213</a>] [<a href="https://doi.org/10.1007/s11626-014-9741-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24619213">Shao et al. (2014)</a> proposed that these enzymes function in embryonic genome activation and first lineage segregation in preimplantation mouse embryos. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24619213" 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="#11" class="mim-tip-reference" title="Santos, M. A., Faryabi, R. B., Ergen, A. V., Day, A. M., Malhowski, A., Canela, A., Onozawa, M., Lee, J.-E., Callen, E., Gutierrez-Martinez, P., Chen, H.-T., Wong, N., and 9 others. <strong>DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier.</strong> Nature 514: 107-111, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25079327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25079327</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25079327[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/nature13483" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25079327">Santos et al. (2014)</a> showed that the histone methyltransferase MLL4, a suppressor of B-cell lymphoma, is required for stem cell activity and an aggressive form of acute myeloid leukemia (AML; <a href="/entry/601626">601626</a>) harboring the MLL-AF9 oncogene. Deletion of MLL4 enhances myelopoiesis and myeloid differentiation of leukemic blasts, which protects mice from death related to AML. MLL4 exerts its function by regulating transcriptional programs associated with the antioxidant response. Addition of reactive oxygen species scavengers or ectopic expression of FOXO3 (<a href="/entry/602681">602681</a>) protects MLL4-null MLL-AF9 cells from DNA damage and inhibits myeloid maturation. Similar to MLL4 deficiency, loss of ATM (<a href="/entry/607585">607585</a>) or BRCA1 (<a href="/entry/113705">113705</a>) sensitizes transformed cells to differentiation, suggesting that myeloid differentiation is promoted by loss of genome integrity. <a href="#11" class="mim-tip-reference" title="Santos, M. A., Faryabi, R. B., Ergen, A. V., Day, A. M., Malhowski, A., Canela, A., Onozawa, M., Lee, J.-E., Callen, E., Gutierrez-Martinez, P., Chen, H.-T., Wong, N., and 9 others. <strong>DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier.</strong> Nature 514: 107-111, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25079327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25079327</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25079327[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/nature13483" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25079327">Santos et al. (2014)</a> showed that restriction enzyme-induced double-strand breaks are sufficient to induce differentiation of MLL-AF9 blasts, which requires cyclin-dependent kinase inhibitor p21 (CDKN1A; <a href="/entry/116899">116899</a>) activity. The authors concluded that they had uncovered an unexpected tumor-promoting role of genome guardians in enforcing the oncogene-induced differentiation blockade in AML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25079327" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Li, Y., Han, J., Zhang, Y., Cao, F., Liu, Z., Li, S., Wu, J., Hu, C., Wang, Y., Shuai, J., Chen, J., Cao, L., Li, D., Shi, P., Tian, C., Zhang, J., Dou, Y., Li, G., Chen, Y., Lei, M. <strong>Structural basis for activity regulation of MLL family methyltransferases.</strong> Nature 530: 447-452, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26886794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26886794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26886794[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/nature16952" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26886794">Li et al. (2016)</a> demonstrated that a minimized human RBBP5 (<a href="/entry/600697">600697</a>)-ASH2L heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases (MLL1, <a href="/entry/159555">159555</a>; MLL2, <a href="/entry/602113">602113</a>; MLL3; MLL4; SET1A, <a href="/entry/611052">611052</a>; SET1B, <a href="/entry/611055">611055</a>). Their structural, biochemical, and computational analyses revealed a 2-step activation mechanism of MLL family proteins. <a href="#8" class="mim-tip-reference" title="Li, Y., Han, J., Zhang, Y., Cao, F., Liu, Z., Li, S., Wu, J., Hu, C., Wang, Y., Shuai, J., Chen, J., Cao, L., Li, D., Shi, P., Tian, C., Zhang, J., Dou, Y., Li, G., Chen, Y., Lei, M. <strong>Structural basis for activity regulation of MLL family methyltransferases.</strong> Nature 530: 447-452, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26886794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26886794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26886794[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/nature16952" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26886794">Li et al. (2016)</a> concluded that their findings provided unprecedented insights into the common theme and functional plasticity in complex assembly and activity regulation of MLL family methyltransferases, and also suggested a universal regulation mechanism for most histone methyltransferases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26886794" 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 conditional knockout of Mll2 in mouse embryonic stem (ES) cells, <a href="#5" class="mim-tip-reference" title="Glaser, S., Lubitz, S., Loveland, K. L., Ohbo, K., Robb, L., Schwenk, F., Seibler, J., Roellig, D., Kranz, A., Anastassiadis, K., Stewart, A. F. <strong>The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis.</strong> Epigenetics Chromatin 2: 5, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19348672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19348672</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19348672[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/10.1186/1756-8935-2-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19348672">Glaser et al. (2009)</a> demonstrated that Mll2 regulates the expression of MagohB (<a href="/entry/619552">619552</a>), which they termed Magoh2. Mll2 repressed the Magoh2 promoter as its direct target, and the repression of the Magoh2 promoter was further accompanied by DNA methylation. Loss of Mll2 caused loss of H3K4me3 at the Magoh2 promoter and concomitant gain of opposing histone methylation at H3K27me3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19348672" 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 RT-qPCR analysis, <a href="#7" class="mim-tip-reference" title="Ladopoulos, V., Hofemeister, H., Hoogenkamp, M., Riggs, A. D., Stewart, A. F., Bonifer, C. <strong>The histone methyltransferase KMT2B is required for RNA polymerase II association and protection from DNA methylation at the MagohB CpG island promoter.</strong> Molec. Cell. Biol. 33: 1383-1393, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23358417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23358417</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23358417[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.01721-12" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23358417">Ladopoulos et al. (2013)</a> showed that MagohB expression was abolished in Mll2 -/- mouse ES cells, suggesting that MagohB expression absolutely requires Mll2 expression. Conditional knockout of Mll2 in mouse ES cells indicated that MagohB was transcriptionally silenced 4 days after Mll2 deletion. Examination of the entire MagohB gene revealed that the main element driving the expression of MagohB was its CpG island promoter. Mll2 was required for maintenance of the activating histone mark H3K4me3 and a stable RNA polymerase II association on the MagohB promoter. Consequently, chromatin structure of the MagohB promoter was perturbed after Mll2 depletion in ES cells, altering the nuclease accessibility on the MagohB promoter and surrounding region. After Mll2 depletion and soon after subsequent transcriptional silencing of MagohB, rapid DNA methylation of the MagohB CpG island promoter was seen. However, at that time, the H3K4me3 and H3K9ac histone marks along with RNA polymerase II were already removed and transcription was ceased, suggesting that DNA methylation was not responsible for initiating MagohB silencing. RNA polymerase II recruitment on the MagohB promoter and transcription were not required for maintenance of the H3K4me3 mark and for protection from DNA methylation, indicating that the presence of Mll2 and/or the H3K4me3 mark was sufficient to protect the MagohB promoter from the action of DNA methyltransferases. DNA methylation did not permanently lock the MagohB promoter in the inactive state, as reactivation of endogenous Mll2 alleles was sufficient to reestablish the normal H3K4me3 pattern and revert MagohB to its active state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23358417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using radiation hybrid analysis, <a href="#10" class="mim-tip-reference" title="Nagase, T., Ishikawa, I., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., O'Hara, O. <strong>Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong> DNA Res. 4: 141-150, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9205841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9205841</a>] [<a href="https://doi.org/10.1093/dnares/4.2.141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9205841">Nagase et al. (1997)</a> mapped the KIAA0304 gene to chromosome 19. By genomic sequence analysis and FISH, respectively, <a href="#4" class="mim-tip-reference" title="FitzGerald, K. T., Diaz, M. O. <strong>MLL2: a new mammalian member of the trx/MLL family of genes.</strong> Genomics 59: 187-192, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10409430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10409430</a>] [<a href="https://doi.org/10.1006/geno.1999.5860" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10409430">FitzGerald and Diaz (1999)</a> and <a href="#6" class="mim-tip-reference" title="Huntsman, D. G., Chin, S.-F., Muleris, M., Batley, S. J., Collins, V. P., Wiedemann, L. M., Aparicio, S., Caldas, C. <strong>MLL2, the second human homolog of the Drosophila trithorax gene, maps to 19q31.1 and is amplified in solid tumor cell lines.</strong> Oncogene 18: 7975-7984, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10637508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10637508</a>] [<a href="https://doi.org/10.1038/sj.onc.1203291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10637508">Huntsman et al. (1999)</a> localized the MLL4 gene to chromosome 19q13.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9205841+10637508+10409430" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The KMT2B and KMT2D (<a href="/entry/602113">602113</a>) genes have both been referred to as MLL2 and MLL4 in the literature.</p>
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<p><strong><em>Dystonia 28, Childhood-Onset</em></strong></p><p>
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In 4 unrelated probands with childhood-onset dystonia-28 (DYT28; <a href="/entry/617284">617284</a>), <a href="#13" class="mim-tip-reference" title="Zech, M., Boesch, S., Maier, E. M., Borggraefe, I., Vill, K., Laccone, F., Pilshofer, V., Ceballos-Baumann, A., Alhaddad, B., Berutti, R., Poewe, W., Haack, T. B., Haslinger, B., Strom, T. M., Winkelmann, J. <strong>Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia.</strong> Am. J. Hum. Genet. 99: 1377-1387, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27839873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27839873</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27839873[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.2016.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27839873">Zech et al. (2016)</a> identified 4 different heterozygous loss-of-function mutations in the KMT2B gene (<a href="#0001">606834.0001</a>-<a href="#0004">606834.0004</a>). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Three of the mutations occurred de novo, and 1 was inherited (family F4). Analysis of cells from 2 unrelated patients showed that the mutations resulted in nonsense-mediated mRNA decay and haploinsufficiency. The 4 probands were part of a cohort of 31 patients with dystonia who underwent genetic studies. <a href="#13" class="mim-tip-reference" title="Zech, M., Boesch, S., Maier, E. M., Borggraefe, I., Vill, K., Laccone, F., Pilshofer, V., Ceballos-Baumann, A., Alhaddad, B., Berutti, R., Poewe, W., Haack, T. B., Haslinger, B., Strom, T. M., Winkelmann, J. <strong>Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia.</strong> Am. J. Hum. Genet. 99: 1377-1387, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27839873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27839873</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27839873[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.2016.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27839873">Zech et al. (2016)</a> noted that some patients with heterozygous deletion of chromosome 19p13 (<a href="/entry/613026">613026</a>) that includes the KMT2B gene have dystonia, supporting haploinsufficiency of this gene and defects in histone modification in the pathogenesis of this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27839873" 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 17 probands with DYT28, <a href="#9" class="mim-tip-reference" title="Meyer, E., Carss, K. J., Rankin, J., Nichols, J. M. E., Grozeva, D., Joseph, A. P., Mencacci, N. E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., and 61 others. <strong>Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.</strong> Nature Genet. 49: 223-237, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27992417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27992417</a>] [<a href="https://doi.org/10.1038/ng.3740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27992417">Meyer et al. (2017)</a> identified heterozygous mutations in the KMT2B gene (see, e.g., <a href="#0005">606834.0005</a>-<a href="#0008">606834.0008</a>). There were 7 frameshift mutations, 2 nonsense mutations, 1 splice site mutation, and 7 missense mutations. The mutations were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing. Most of the mutations occurred de novo, but the mutation was maternally inherited in 3 cases, and 2 of these mothers were asymptomatic, suggesting incomplete penetrance. Functional studies of the variants were not performed, but studies of some patient cells showed decreased expression of KMT2B, suggesting haploinsufficiency. However, patient cells did not show differences in histone H3K4 methylation compared to controls. Fibroblasts derived from 3 patients showed reduced transcript levels of THAP1 (<a href="/entry/609520">609520</a>) and TOR1A (<a href="/entry/605204">605204</a>) compared to controls, and immunoblot studies showed decreased THAP1 protein expression in these cells, but only 1 patient had decreased TOR1A protein expression. These findings suggested that the KMT2B mutations may affect the expression profiles of specific genes involved in dystonia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27992417" 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="Cif, L., Demailly, D., Lin, J.-P., Barwick, K. E., Sa, M., Abela, L., Malhotra, S., Chong, W. K., Steel, D., Sanchis-Juan, A., Ngoh, A., Trump, N., and 103 others. <strong>KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.</strong> Brain 143: 3242-3261, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33150406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33150406</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33150406[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/brain/awaa304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33150406">Cif et al. (2020)</a> identified heterozygous mutations in the KMT2B gene in 44 patients (patients 1-44) with DYT28 and in 9 patients (patients 45-53) with MRD68 (<a href="/entry/619934">619934</a>). The patients were ascertained through international collaborative efforts after genetic analysis identified heterozygous KMT2B mutations. The mutations in patients with DYT28, which were identified by a combination of microarray and gene panel, whole-exome, whole-genome, or Sanger sequencing, included truncating, missense, splicing, and chromosome microdeletions. Twenty-nine patients had de novo mutations; a few inherited the mutation from a symptomatic parent, and the inheritance pattern was unknown in the other patients. Missense variants showed slightly reduced penetrance compared to protein-truncating variants. The protein-truncating mutations occurred throughout the gene, whereas missense variants clustered in putative functional domains. Functional studies of the variants were not performed, and the authors noted that missense variants should be interpreted with caution. It was postulated that haploinsufficiency or dysfunction of KMT2B affects the downstream expression of key genes regulating neurodevelopment and motor control. There were several instances of discordant phenotypes associated with a particular mutation that resulted in both DYT28 and MRD68: 2 sibs (patients 18 and 47) carried a frameshift mutation (<a href="#0011">606834.0011</a>), and 2 unrelated patients (patients 25 and 50) shared an R1597W mutation (<a href="#0010">606834.0010</a>). Moreover, P17, who had DYT28, inherited a KMT2B frameshift mutation from his 57-year-old mother (P46), who did not have dystonia but was noted to have intellectual disability and short stature, consistent with MRD68. The finding of the same mutation in individuals with discordant phenotypes illustrated the phenotypic spectrum that can result from KMT2B mutations. The authors suggested that disease manifestations may be influenced by other genetic, epigenetic, or environmental factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33150406" 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>Autosomal Dominant Intellectual Developmental Disorder 68</em></strong></p><p>
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In an 11-year-old girl with autosomal dominant intellectual developmental disorder-68 (MRD68; <a href="/entry/619934">619934</a>), <a href="#3" class="mim-tip-reference" title="Faundes, V., Newman, W. G., Bernardini, L., Canham, N., Clayton-Smith, J., Dallapiccola, B., Davies, S. J., Demos, M. K., Goldman, A., Gill, H., Horton, R., Kerr, B., and 11 others. <strong>Histone lysine methylases and demethylases in the landscape of human developmental disorders.</strong> Am. J. Hum. Genet. 102: 175-187, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29276005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29276005</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29276005[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.2017.11.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29276005">Faundes et al. (2018)</a> identified a de novo heterozygous 1-bp duplication in the KMT2B gene (c.1808dupC; <a href="/entry/610881#0009">610881.0009</a>). The patient was ascertained from a cohort of 4,293 trios from the Deciphering Developmental Disorders (DDD) study who underwent exome sequencing. The KMT2B gene was chosen for study through a pathway-based approach focusing on candidate genes involved in histone lysine methylation/demethylation. The variant was filtered against several large databases, including ExAC, the 1000 Genomes Project, and the Exome Sequencing Project. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29276005" 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="Cif, L., Demailly, D., Lin, J.-P., Barwick, K. E., Sa, M., Abela, L., Malhotra, S., Chong, W. K., Steel, D., Sanchis-Juan, A., Ngoh, A., Trump, N., and 103 others. <strong>KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.</strong> Brain 143: 3242-3261, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33150406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33150406</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33150406[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/brain/awaa304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33150406">Cif et al. (2020)</a> reported 9 patients (patients 45-53) with MRD68 identified through collaborative efforts after heterozygous KMT2B mutations were found. Mutations in patients with MRD68, which were identified by gene panel, whole-exome, or Sanger sequencing, included 6 truncating (see, e.g., <a href="#0012">606834.0012</a>) and 3 missense. There were some instances of discordant phenotypes associated with a particular mutation that resulted in both DYT28 and MRD68 (see, e.g., <a href="#0010">606834.0010</a> and <a href="#0011">606834.0011</a>). The finding of the same mutation in individuals with discordant phenotypes illustrated the phenotypic spectrum that can result from KMT2B mutations. The authors suggested that disease manifestations may be influenced by other genetic, epigenetic, or environmental factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33150406" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Glaser, S., Lubitz, S., Loveland, K. L., Ohbo, K., Robb, L., Schwenk, F., Seibler, J., Roellig, D., Kranz, A., Anastassiadis, K., Stewart, A. F. <strong>The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis.</strong> Epigenetics Chromatin 2: 5, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19348672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19348672</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19348672[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/10.1186/1756-8935-2-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19348672">Glaser et al. (2009)</a> found that, although Mll2 knockout in utero resulted in lethality before embryonic day (E) 10.5, adult mice with conditional knockout of Mll2 appeared normal compared to controls. The mutant mice showed only slight abnormalities, had normal weight and blood profiles, lived as long as their littermates, and were not prone to tumorigenesis or any other notable pathology. Using tamoxifen induction in conditional knockout mice, <a href="#5" class="mim-tip-reference" title="Glaser, S., Lubitz, S., Loveland, K. L., Ohbo, K., Robb, L., Schwenk, F., Seibler, J., Roellig, D., Kranz, A., Anastassiadis, K., Stewart, A. F. <strong>The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis.</strong> Epigenetics Chromatin 2: 5, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19348672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19348672</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19348672[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/10.1186/1756-8935-2-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19348672">Glaser et al. (2009)</a> showed that Mll2 is required only in a brief developmental window between E7.5 and E10.5, and not for further development or somatic homeostasis. However, Mll2 knockout male and female mice were infertile. In male mice, loss of Mll2 led to blockage of spermatogenic differentiation and apoptosis of spermatogonia, although spermatogonia A persisted, indicating that Mll2 is required in the germ cell lineage. In addition, quantitative RT-PCR of total testis RNA revealed alterations in gene expression in Mll2 knockout adult mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19348672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519278 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519278;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=rs1057519278" 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=rs1057519278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 31-year-old woman of Austrian descent (family F1) with childhood-onset dystonia-28 (DYT28; <a href="/entry/617284">617284</a>), <a href="#13" class="mim-tip-reference" title="Zech, M., Boesch, S., Maier, E. M., Borggraefe, I., Vill, K., Laccone, F., Pilshofer, V., Ceballos-Baumann, A., Alhaddad, B., Berutti, R., Poewe, W., Haack, T. B., Haslinger, B., Strom, T. M., Winkelmann, J. <strong>Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia.</strong> Am. J. Hum. Genet. 99: 1377-1387, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27839873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27839873</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27839873[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.2016.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27839873">Zech et al. (2016)</a> identified a de novo heterozygous 1-bp deletion (c.6406delC, NM_014727.2) in exon 28 of the KMT2B gene, resulting in a frameshift and premature termination (Leu2136SerfsTer17). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 142) or ExAC (v.0.3.1) databases, or in 7,900 in-house control exomes. Analysis of patient cells showed that the mutation resulted in nonsense-mediated mRNA and haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27839873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an 11-year-old girl of German descent (family F2) with childhood-onset dystonia-28 (DYT28; <a href="/entry/617284">617284</a>), <a href="#13" class="mim-tip-reference" title="Zech, M., Boesch, S., Maier, E. M., Borggraefe, I., Vill, K., Laccone, F., Pilshofer, V., Ceballos-Baumann, A., Alhaddad, B., Berutti, R., Poewe, W., Haack, T. B., Haslinger, B., Strom, T. M., Winkelmann, J. <strong>Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia.</strong> Am. J. Hum. Genet. 99: 1377-1387, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27839873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27839873</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27839873[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.2016.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27839873">Zech et al. (2016)</a> identified a de novo heterozygous c.1633C-T transition (c.1633C-T, NM_014727.2) in exon 3 of the KMT2B gene, resulting in an arg545-to-ter (R545X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 142) or ExAC (v.0.3.1) databases, or in 7,900 in-house control exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27839873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519280 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519280;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=rs1057519280" 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=rs1057519280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 15-year-old boy of German descent (family F3) with childhood-onset dystonia-28 (DYT28; <a href="/entry/617284">617284</a>), <a href="#13" class="mim-tip-reference" title="Zech, M., Boesch, S., Maier, E. M., Borggraefe, I., Vill, K., Laccone, F., Pilshofer, V., Ceballos-Baumann, A., Alhaddad, B., Berutti, R., Poewe, W., Haack, T. B., Haslinger, B., Strom, T. M., Winkelmann, J. <strong>Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia.</strong> Am. J. Hum. Genet. 99: 1377-1387, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27839873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27839873</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27839873[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.2016.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27839873">Zech et al. (2016)</a> identified a de novo heterozygous A-to-G transition in intron 29 of the KMT2B gene (c.7050-2A-G, NM_014727.2), resulting in a splice site alteration and a complex pattern of incorrect splicing causing a frameshift and premature termination (Phe2321SerfsTer93). The mutation, which was confirmed by Sanger sequencing, was not found in the ExAC database (v.0.3.1) or in 7,900 in-house control exomes. Analysis of patient cells showed that the mutation resulted in nonsense-mediated mRNA and haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27839873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519281 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519281;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=rs1057519281" 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=rs1057519281" 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=RCV000415591" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415591" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415591</a>
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<p>In a 6-year-old girl, her father, and her paternal grandfather of Austrian descent (family F4) with childhood-onset dystonia-28 (DYT28; <a href="/entry/617284">617284</a>), <a href="#13" class="mim-tip-reference" title="Zech, M., Boesch, S., Maier, E. M., Borggraefe, I., Vill, K., Laccone, F., Pilshofer, V., Ceballos-Baumann, A., Alhaddad, B., Berutti, R., Poewe, W., Haack, T. B., Haslinger, B., Strom, T. M., Winkelmann, J. <strong>Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia.</strong> Am. J. Hum. Genet. 99: 1377-1387, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27839873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27839873</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27839873[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.2016.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27839873">Zech et al. (2016)</a> identified a de novo heterozygous c.2428C-T transition (c.2428C-T, NM_014727.2) in exon 3 of the KMT2B gene, resulting in a gln810-to-ter (Q810X) substitution. The mutation, which was confirmed by Sanger sequencing, was not found in the ExAC database (v.0.3.1) or in 7,900 in-house control exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27839873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 DYSTONIA 28, CHILDHOOD-ONSET</strong>
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KMT2B, 1-BP DUP, NT402
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519282 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519282;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=rs1057519282" 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=rs1057519282" 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=RCV000415532" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415532" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415532</a>
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<p>In a 25-year-old woman (patient 11) with childhood-onset dystonia-28 (DYT28; <a href="/entry/617284">617284</a>), <a href="#9" class="mim-tip-reference" title="Meyer, E., Carss, K. J., Rankin, J., Nichols, J. M. E., Grozeva, D., Joseph, A. P., Mencacci, N. E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., and 61 others. <strong>Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.</strong> Nature Genet. 49: 223-237, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27992417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27992417</a>] [<a href="https://doi.org/10.1038/ng.3740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27992417">Meyer et al. (2017)</a> identified a de novo heterozygous 1-bp duplication (c.402dup, NM_014727.2) in the KMT2B gene, resulting in a frameshift and premature termination (Ser135GlnfsTer23). Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in haploinsufficiency. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27992417" 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 class="mim-font">
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<strong>.0006 DYSTONIA 28, CHILDHOOD-ONSET</strong>
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KMT2B, ARG564TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519283 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519283;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=rs1057519283" 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=rs1057519283" 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=RCV000415564" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415564" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415564</a>
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<p>In a 6-year-old girl (patient 12) with childhood-onset dystonia-28 (DYT28; <a href="/entry/617284">617284</a>), <a href="#9" class="mim-tip-reference" title="Meyer, E., Carss, K. J., Rankin, J., Nichols, J. M. E., Grozeva, D., Joseph, A. P., Mencacci, N. E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., and 61 others. <strong>Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.</strong> Nature Genet. 49: 223-237, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27992417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27992417</a>] [<a href="https://doi.org/10.1038/ng.3740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27992417">Meyer et al. (2017)</a> identified a de novo heterozygous c.1690C-T transition (c.1690C-T, NM_014727.2) in exon 3 of the KMT2B gene, resulting in an arg564-to-ter (R564X) substitution. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in haploinsufficiency. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27992417" 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="0007" class="mim-anchor"></a>
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<strong>.0007 DYSTONIA 28, CHILDHOOD-ONSET</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519284 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519284;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=rs1057519284" 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=rs1057519284" 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=RCV000415597 OR RCV002251741" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415597, RCV002251741" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415597...</a>
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<span class="mim-text-font">
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<p>In a 20-year-old woman (patient 15) with childhood-onset dystonia-28 (DYT28; <a href="/entry/617284">617284</a>), <a href="#9" class="mim-tip-reference" title="Meyer, E., Carss, K. J., Rankin, J., Nichols, J. M. E., Grozeva, D., Joseph, A. P., Mencacci, N. E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., and 61 others. <strong>Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.</strong> Nature Genet. 49: 223-237, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27992417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27992417</a>] [<a href="https://doi.org/10.1038/ng.3740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27992417">Meyer et al. (2017)</a> identified a de novo heterozygous c.4545C-A transversion (c.4545C-A, NM_014727.2) in exon 19 of the KMT2B gene, resulting in a tyr1515-to-ter (Y1515X) substitution. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in haploinsufficiency. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27992417" 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="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 DYSTONIA 28, CHILDHOOD-ONSET</strong>
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KMT2B, ARG2517TRP
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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> rs1057519285 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519285;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/rs1057519285?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=rs1057519285" 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=rs1057519285" 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=RCV000415537" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415537" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415537</a>
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<p>In a mother and son (patients 26a and 26b) with childhood-onset dystonia-28 (DYT28; <a href="/entry/617284">617284</a>), <a href="#9" class="mim-tip-reference" title="Meyer, E., Carss, K. J., Rankin, J., Nichols, J. M. E., Grozeva, D., Joseph, A. P., Mencacci, N. E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., and 61 others. <strong>Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.</strong> Nature Genet. 49: 223-237, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27992417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27992417</a>] [<a href="https://doi.org/10.1038/ng.3740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27992417">Meyer et al. (2017)</a> identified a heterozygous c.7549C-T transition (c.7549C-T, NM_014727.2) in exon 33 of the KMT2B gene, resulting in an arg2517-to-trp (R2517W) substitution at a highly conserved residue. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to interrupt protein-protein interactions and result in a loss of function. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27992417" 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="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 68</strong>
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KMT2B, 1-BP DUP, 1808C
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<p>In an 11-year-old girl with autosomal dominant intellectual developmental disorder-68 (MRD68; <a href="/entry/619934">619934</a>), <a href="#3" class="mim-tip-reference" title="Faundes, V., Newman, W. G., Bernardini, L., Canham, N., Clayton-Smith, J., Dallapiccola, B., Davies, S. J., Demos, M. K., Goldman, A., Gill, H., Horton, R., Kerr, B., and 11 others. <strong>Histone lysine methylases and demethylases in the landscape of human developmental disorders.</strong> Am. J. Hum. Genet. 102: 175-187, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29276005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29276005</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29276005[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.2017.11.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29276005">Faundes et al. (2018)</a> identified a de novo heterozygous 1-bp duplication (c.1808dupC, NM_014727.2) in the KMT2B gene, resulting in a frameshift and premature termination (Leu604ProfsTer72). The patient was ascertained from a cohort of 4,293 trios from the Deciphering Developmental Disorders (DDD) study who underwent exome sequencing. The KMT2B gene was chosen for study through a pathway-based approach focusing on candidate genes involved in histone lysine methylation/demethylation. The variant was filtered against several large databases, including ExAC, the 1000 Genomes Project, and the Exome Sequencing Project. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and haploinsufficiency. The patient had severe global developmental delay, poor growth, and microcephaly (-3.34 SD). Additional features included delayed walking at age 6.5 years, poor speech, hand stereotypies, nystagmus, urinary incontinence, poor feeding requiring gastrostomy tube, and dysmorphic facial features, such as sparse hair, large mouth, high palate, and absent ear lobes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29276005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 DYSTONIA 28, CHILDHOOD-ONSET</strong>
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INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 68, INCLUDED
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KMT2B, ARG1597TRP
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<p>In 2 unrelated patients, a 22-year-old woman (P25) with onset of dystonia-28 (DYT28; <a href="/entry/617284">617284</a>) at age 7, and a 12.3-year-old girl (P50) with autosomal dominant intellectual developmental disorder-68 (MRD68; <a href="/entry/619934">619934</a>), <a href="#1" class="mim-tip-reference" title="Cif, L., Demailly, D., Lin, J.-P., Barwick, K. E., Sa, M., Abela, L., Malhotra, S., Chong, W. K., Steel, D., Sanchis-Juan, A., Ngoh, A., Trump, N., and 103 others. <strong>KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.</strong> Brain 143: 3242-3261, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33150406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33150406</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33150406[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/brain/awaa304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33150406">Cif et al. (2020)</a> identified the same de novo heterozygous c.4789C-T transition (c.4789C-T, NM_014727.2) in the KMT2B gene, resulting in an arg1597-to-trp (R1597W) substitution. The mutation was found by diagnostic or research whole-exome sequencing. Functional studies of the variant were not performed, but molecular modeling predicted disruption of a functional domain of the protein. P25, with DYT28, did not have developmental delay or intellectual disability, but did manifest behavioral issues. P50, with MRD68, did not have dystonia. The finding of the same mutation in unrelated individuals with a discordant phenotype illustrated the phenotypic spectrum that can result from KMT2B mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33150406" 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>.0011 DYSTONIA 28, CHILDHOOD-ONSET</strong>
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INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 68, INCLUDED
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KMT2B, 1-BP DEL, 3325C
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<p>In 2 sibs, a 33-year-old man (P18) with onset of dystonia-28 (DYT28; <a href="/entry/617284">617284</a>) at age 5, and a 29-year-old woman (P47) with autosomal dominant intellectual developmental disorder-68 (MRD68; <a href="/entry/619934">619934</a>), <a href="#1" class="mim-tip-reference" title="Cif, L., Demailly, D., Lin, J.-P., Barwick, K. E., Sa, M., Abela, L., Malhotra, S., Chong, W. K., Steel, D., Sanchis-Juan, A., Ngoh, A., Trump, N., and 103 others. <strong>KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.</strong> Brain 143: 3242-3261, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33150406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33150406</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33150406[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/brain/awaa304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33150406">Cif et al. (2020)</a> identified a heterozygous 1-bp deletion (c.3325delC, NM_014727.2) in the KMT2B gene, predicted to result in a frameshift and premature termination (Arg1109GlufsTer73). The mutation was identified through a diagnostic gene panel; the inheritance pattern could not be determined. Functional studies of the variant were not performed, but it was predicted to result in a loss of function. P18, with dystonia, did not have intellectual disability. P47, with MRD68, had developmental delay and impaired intellectual development without evidence of dystonia. The finding of the same mutation in 2 with a discordant phenotype illustrated the phenotype spectrum that can result from KMT2B mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33150406" 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>.0012 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 68</strong>
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KMT2B, TRP1295TER
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<p>In a 12-year-old girl (P49) with autosomal dominant intellectual developmental disorder-68 (MRD68; <a href="/entry/619934">619934</a>), <a href="#1" class="mim-tip-reference" title="Cif, L., Demailly, D., Lin, J.-P., Barwick, K. E., Sa, M., Abela, L., Malhotra, S., Chong, W. K., Steel, D., Sanchis-Juan, A., Ngoh, A., Trump, N., and 103 others. <strong>KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.</strong> Brain 143: 3242-3261, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33150406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33150406</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33150406[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/brain/awaa304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33150406">Cif et al. (2020)</a> identified a de novo heterozygous c.3885G-A transition (c.3885G-A, NM_014727.2) in the KMT2B gene, resulting in a trp1295-to-ter (W1295X) substitution. The mutation was found by whole-exome sequencing. Functional studies of the variant were not performed. The patient had global developmental delay, impaired intellectual development, autism spectrum disorder, and ADHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33150406" 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 id="Cif2020" class="mim-anchor"></a>
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Cif, L., Demailly, D., Lin, J.-P., Barwick, K. E., Sa, M., Abela, L., Malhotra, S., Chong, W. K., Steel, D., Sanchis-Juan, A., Ngoh, A., Trump, N., and 103 others.
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<strong>KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.</strong>
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Brain 143: 3242-3261, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33150406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33150406</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33150406[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=33150406" 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/brain/awaa304" target="_blank">Full Text</a>]
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Demers, C., Chaturvedi, C.-P., Ranish, J. A., Juban, G., Lai, P., Morle, F., Aebersold, R., Dilworth, F. J., Groudine, M., Brand, M.
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<strong>Activator-mediated recruitment of the MLL2 methyltransferase complex to the beta-globin locus.</strong>
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Molec. Cell 27: 573-584, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17707229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17707229</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17707229[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=17707229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2007.06.022" target="_blank">Full Text</a>]
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<a id="Faundes2018" class="mim-anchor"></a>
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Faundes, V., Newman, W. G., Bernardini, L., Canham, N., Clayton-Smith, J., Dallapiccola, B., Davies, S. J., Demos, M. K., Goldman, A., Gill, H., Horton, R., Kerr, B., and 11 others.
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<strong>Histone lysine methylases and demethylases in the landscape of human developmental disorders.</strong>
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Am. J. Hum. Genet. 102: 175-187, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29276005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29276005</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29276005[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=29276005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2017.11.013" target="_blank">Full Text</a>]
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FitzGerald, K. T., Diaz, M. O.
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<strong>MLL2: a new mammalian member of the trx/MLL family of genes.</strong>
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Genomics 59: 187-192, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10409430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10409430</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10409430" 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/10.1006/geno.1999.5860" target="_blank">Full Text</a>]
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Glaser, S., Lubitz, S., Loveland, K. L., Ohbo, K., Robb, L., Schwenk, F., Seibler, J., Roellig, D., Kranz, A., Anastassiadis, K., Stewart, A. F.
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<strong>The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis.</strong>
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Epigenetics Chromatin 2: 5, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19348672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19348672</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19348672[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=19348672" 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/10.1186/1756-8935-2-5" target="_blank">Full Text</a>]
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<a id="Huntsman1999" class="mim-anchor"></a>
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Huntsman, D. G., Chin, S.-F., Muleris, M., Batley, S. J., Collins, V. P., Wiedemann, L. M., Aparicio, S., Caldas, C.
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<strong>MLL2, the second human homolog of the Drosophila trithorax gene, maps to 19q31.1 and is amplified in solid tumor cell lines.</strong>
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Oncogene 18: 7975-7984, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10637508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10637508</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10637508" 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/sj.onc.1203291" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Ladopoulos2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ladopoulos, V., Hofemeister, H., Hoogenkamp, M., Riggs, A. D., Stewart, A. F., Bonifer, C.
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<strong>The histone methyltransferase KMT2B is required for RNA polymerase II association and protection from DNA methylation at the MagohB CpG island promoter.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23358417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23358417</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23358417[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=23358417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/MCB.01721-12" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Li2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Li, Y., Han, J., Zhang, Y., Cao, F., Liu, Z., Li, S., Wu, J., Hu, C., Wang, Y., Shuai, J., Chen, J., Cao, L., Li, D., Shi, P., Tian, C., Zhang, J., Dou, Y., Li, G., Chen, Y., Lei, M.
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<strong>Structural basis for activity regulation of MLL family methyltransferases.</strong>
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Nature 530: 447-452, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26886794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26886794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26886794[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=26886794" 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/nature16952" target="_blank">Full Text</a>]
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Meyer2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Meyer, E., Carss, K. J., Rankin, J., Nichols, J. M. E., Grozeva, D., Joseph, A. P., Mencacci, N. E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., and 61 others.
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<strong>Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.</strong>
|
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Nature Genet. 49: 223-237, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27992417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27992417</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27992417" 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.3740" target="_blank">Full Text</a>]
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Nagase1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nagase, T., Ishikawa, I., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., O'Hara, O.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9205841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9205841</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9205841" 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/dnares/4.2.141" target="_blank">Full Text</a>]
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Santos2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Santos, M. A., Faryabi, R. B., Ergen, A. V., Day, A. M., Malhowski, A., Canela, A., Onozawa, M., Lee, J.-E., Callen, E., Gutierrez-Martinez, P., Chen, H.-T., Wong, N., and 9 others.
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<strong>DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier.</strong>
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Nature 514: 107-111, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25079327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25079327</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25079327[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=25079327" 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/nature13483" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
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<a id="Shao2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shao, G.-B., Chen, J.-C., Zhang, L.-P., Huang, P., Lu, H.-Y., Jin, J., Gong, A.-H., Sang, J.-R.
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<strong>Dynamic patterns of histone H3 lysine 4 methyltransferases and demethylases during mouse preimplantation development.</strong>
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In Vitro Cell. Dev. Biol. Anim. 50: 603-613, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24619213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24619213</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24619213" 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/10.1007/s11626-014-9741-6" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
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<a id="Zech2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zech, M., Boesch, S., Maier, E. M., Borggraefe, I., Vill, K., Laccone, F., Pilshofer, V., Ceballos-Baumann, A., Alhaddad, B., Berutti, R., Poewe, W., Haack, T. B., Haslinger, B., Strom, T. M., Winkelmann, J.
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<strong>Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia.</strong>
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Am. J. Hum. Genet. 99: 1377-1387, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27839873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27839873</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27839873[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=27839873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2016.10.010" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 06/30/2022
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 06/21/2022<br>Bao Lige - updated : 09/29/2021<br>Cassandra L. Kniffin - updated : 09/07/2018<br>Cassandra L. Kniffin - updated : 01/04/2017<br>Ada Hamosh - updated : 12/19/2016<br>Ada Hamosh - updated : 12/2/2014<br>Matthew B. Gross - updated : 3/14/2014<br>Ada Hamosh - updated : 9/29/2010
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 4/5/2002
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/12/2022
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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ckniffin : 06/30/2022<br>carol : 06/29/2022<br>alopez : 09/29/2021<br>alopez : 09/29/2021<br>carol : 09/10/2018<br>ckniffin : 09/07/2018<br>mgross : 11/27/2017<br>alopez : 06/20/2017<br>carol : 02/01/2017<br>mgross : 01/12/2017<br>carol : 01/07/2017<br>carol : 01/06/2017<br>ckniffin : 01/04/2017<br>alopez : 12/19/2016<br>carol : 08/23/2016<br>mcolton : 01/30/2015<br>alopez : 12/2/2014<br>mgross : 3/14/2014<br>mgross : 3/14/2014<br>mgross : 2/5/2013<br>alopez : 10/5/2010<br>terry : 9/29/2010<br>mgross : 10/5/2007<br>mgross : 4/5/2002
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606834
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</span>
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<div>
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<h3>
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<span class="mim-font">
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LYSINE-SPECIFIC METHYLTRANSFERASE 2B; KMT2B
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div >
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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MYELOID/LYMPHOID OR MIXED-LINEAGE LEUKEMIA 4; MLL4<br />
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MYELOID/LYMPHOID OR MIXED-LINEAGE LEUKEMIA 2; MLL2<br />
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TRITHORAX, DROSOPHILA, HOMOLOG OF, 2; TRX2<br />
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KIAA0304
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: KMT2B</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>SNOMEDCT:</strong> 1281844004;
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</span>
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<br />
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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: 19q13.12
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:35,718,003-35,738,878 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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19q13.12
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</span>
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</td>
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<td>
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<span class="mim-font">
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Dystonia 28, childhood-onset
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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617284
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Intellectual developmental disorder, autosomal dominant 68
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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|
619934
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Methylation of histone H3 (see 602810) lys4 (H3K4) is an important epigenetic modification involved in gene activation. H3K4 di- and trimethylation (H3K4me2 and H3K4me3, respectively) residues mark the transcription start sites of actively transcribed genes, whereas a high level of H3K4 monomethylation (H3K4me1) is associated with enhancer sequences. Members of the SET/MLL protein family, including KMT2B, are responsible for the generation of H3K4me1, H3K4me2, and H3K4me3 marks to induce gene activation and are essential for normal development (summary by Shao et al., 2014). </p>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>By searching for cDNA sequences encoding large proteins expressed in brain, Nagase et al. (1997) identified a partial cDNA encoding MLL4, which they called KIAA0304. The deduced 1,529-amino acid protein was predicted to be 36% homologous to the mouse Hrx zinc finger protein (MLL; 159555). RT-PCR analysis detected wide expression that was strongest in kidney, thymus, liver, small intestine, testis, ovary, and prostate. Expression was weak or undetectable in heart, skeletal muscle, and pancreas. </p><p>By PCR on placenta and bone marrow cDNA libraries using primers for putative exons in a chromosome 19 clone with similarity to MLL, FitzGerald and Diaz (1999) isolated partial cDNAs encoding different domains of MLL4, which they termed MLL2. MLL4 has higher similarity to MLL than do Drosophila Trx or human ALR (KMT2D; 602113). Northern blot analysis revealed expression of a 9.0-kb transcript in all tissues tested, including pancreas, heart, and muscle. </p><p>By EST database searching with MLL as the probe, followed by screening of a testis cDNA library and RT-PCR, Huntsman et al. (1999) assembled a cDNA encoding MLL4, which they also designated MLL2. Depending on the exact initiation codon used, Huntsman et al. (1999) predicted that the MLL4 protein contains 2,605 or 2,716 amino acids with all the domains identified in MLL. Northern blot analysis detected ubiquitous expression that was most prominent in testis. FISH and slot-blot analysis detected amplified expression in some pancreatic carcinoma and glioblastoma cell lines. </p><p>By PCR analysis, Meyer et al. (2017) found expression of KMT2B in a variety of fetal and adult human tissues. It was ubiquitously expressed in brain, with highest expression in the cerebellum. </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>FitzGerald and Diaz (1999) noted that MLL4 did not compensate for loss of Mll1 in mice, suggesting that their functions do not totally overlap. </p><p>Demers et al. (2007) showed that a complex containing Mll4, which they called Mll2, associated with the hematopoietic activator Nfe2 (601490) in mouse erythroid cells. Mll4 was recruited to the beta-globin (HBB; 141900) locus in a Nfe2-dependent manner and was important for H3K4 trimethylation and maximal transcription at the beta-globin locus. Although recruitment of the Mll4 complex was limited to the beta-globin locus control region located 38 kb upstream of the active major beta-globin gene, the Mll4 protein spread across the beta-globin locus, and spreading increased during erythroid differentiation. Mll4 was fully activated only when it reached the coding region of the active major beta-globin gene, because H3K4 trimethylation was restricted to this part of the locus. </p><p>Shao et al. (2014) examined the changes of H3K4me and its key regulators in mouse oocytes and preimplantation embryos. They observed increased levels of H3K4me2 and H3K4me3 at the 1- to 2-cell stages, corresponding to the period of embryonic genome activation. The H3K4me2 level dramatically decreased at the 4-cell stage and remained low until the blastocyst stage. In contrast, the H3K4me3 level transiently decreased in 4-cell embryos but steadily increased to peak in blastocysts. Quantitative real-time PCR and immunofluorescence analyses showed that the high level of H3K4me2 during embryonic genome activation coincided with peak expression of its methyltransferase, Ash2l (604782), and a concomitant decrease in its demethylases, Kdm5b (605393) and Kdm1a (609132). H3K4me3 correlated with expression of its methyltransferase, Kmt2b, and demethylase, Kdm5a (180202). Shao et al. (2014) proposed that these enzymes function in embryonic genome activation and first lineage segregation in preimplantation mouse embryos. </p><p>Santos et al. (2014) showed that the histone methyltransferase MLL4, a suppressor of B-cell lymphoma, is required for stem cell activity and an aggressive form of acute myeloid leukemia (AML; 601626) harboring the MLL-AF9 oncogene. Deletion of MLL4 enhances myelopoiesis and myeloid differentiation of leukemic blasts, which protects mice from death related to AML. MLL4 exerts its function by regulating transcriptional programs associated with the antioxidant response. Addition of reactive oxygen species scavengers or ectopic expression of FOXO3 (602681) protects MLL4-null MLL-AF9 cells from DNA damage and inhibits myeloid maturation. Similar to MLL4 deficiency, loss of ATM (607585) or BRCA1 (113705) sensitizes transformed cells to differentiation, suggesting that myeloid differentiation is promoted by loss of genome integrity. Santos et al. (2014) showed that restriction enzyme-induced double-strand breaks are sufficient to induce differentiation of MLL-AF9 blasts, which requires cyclin-dependent kinase inhibitor p21 (CDKN1A; 116899) activity. The authors concluded that they had uncovered an unexpected tumor-promoting role of genome guardians in enforcing the oncogene-induced differentiation blockade in AML. </p><p>Li et al. (2016) demonstrated that a minimized human RBBP5 (600697)-ASH2L heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases (MLL1, 159555; MLL2, 602113; MLL3; MLL4; SET1A, 611052; SET1B, 611055). Their structural, biochemical, and computational analyses revealed a 2-step activation mechanism of MLL family proteins. Li et al. (2016) concluded that their findings provided unprecedented insights into the common theme and functional plasticity in complex assembly and activity regulation of MLL family methyltransferases, and also suggested a universal regulation mechanism for most histone methyltransferases. </p><p>Using conditional knockout of Mll2 in mouse embryonic stem (ES) cells, Glaser et al. (2009) demonstrated that Mll2 regulates the expression of MagohB (619552), which they termed Magoh2. Mll2 repressed the Magoh2 promoter as its direct target, and the repression of the Magoh2 promoter was further accompanied by DNA methylation. Loss of Mll2 caused loss of H3K4me3 at the Magoh2 promoter and concomitant gain of opposing histone methylation at H3K27me3. </p><p>Using RT-qPCR analysis, Ladopoulos et al. (2013) showed that MagohB expression was abolished in Mll2 -/- mouse ES cells, suggesting that MagohB expression absolutely requires Mll2 expression. Conditional knockout of Mll2 in mouse ES cells indicated that MagohB was transcriptionally silenced 4 days after Mll2 deletion. Examination of the entire MagohB gene revealed that the main element driving the expression of MagohB was its CpG island promoter. Mll2 was required for maintenance of the activating histone mark H3K4me3 and a stable RNA polymerase II association on the MagohB promoter. Consequently, chromatin structure of the MagohB promoter was perturbed after Mll2 depletion in ES cells, altering the nuclease accessibility on the MagohB promoter and surrounding region. After Mll2 depletion and soon after subsequent transcriptional silencing of MagohB, rapid DNA methylation of the MagohB CpG island promoter was seen. However, at that time, the H3K4me3 and H3K9ac histone marks along with RNA polymerase II were already removed and transcription was ceased, suggesting that DNA methylation was not responsible for initiating MagohB silencing. RNA polymerase II recruitment on the MagohB promoter and transcription were not required for maintenance of the H3K4me3 mark and for protection from DNA methylation, indicating that the presence of Mll2 and/or the H3K4me3 mark was sufficient to protect the MagohB promoter from the action of DNA methyltransferases. DNA methylation did not permanently lock the MagohB promoter in the inactive state, as reactivation of endogenous Mll2 alleles was sufficient to reestablish the normal H3K4me3 pattern and revert MagohB to its active state. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Huntsman et al. (1999) determined that the MLL4 gene has 37 exons and spans 20 kb. </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>Using radiation hybrid analysis, Nagase et al. (1997) mapped the KIAA0304 gene to chromosome 19. By genomic sequence analysis and FISH, respectively, FitzGerald and Diaz (1999) and Huntsman et al. (1999) localized the MLL4 gene to chromosome 19q13.1. </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>Nomenclature</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>The KMT2B and KMT2D (602113) genes have both been referred to as MLL2 and MLL4 in the literature.</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>Dystonia 28, Childhood-Onset</em></strong></p><p>
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In 4 unrelated probands with childhood-onset dystonia-28 (DYT28; 617284), Zech et al. (2016) identified 4 different heterozygous loss-of-function mutations in the KMT2B gene (606834.0001-606834.0004). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Three of the mutations occurred de novo, and 1 was inherited (family F4). Analysis of cells from 2 unrelated patients showed that the mutations resulted in nonsense-mediated mRNA decay and haploinsufficiency. The 4 probands were part of a cohort of 31 patients with dystonia who underwent genetic studies. Zech et al. (2016) noted that some patients with heterozygous deletion of chromosome 19p13 (613026) that includes the KMT2B gene have dystonia, supporting haploinsufficiency of this gene and defects in histone modification in the pathogenesis of this disorder. </p><p>In 17 probands with DYT28, Meyer et al. (2017) identified heterozygous mutations in the KMT2B gene (see, e.g., 606834.0005-606834.0008). There were 7 frameshift mutations, 2 nonsense mutations, 1 splice site mutation, and 7 missense mutations. The mutations were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing. Most of the mutations occurred de novo, but the mutation was maternally inherited in 3 cases, and 2 of these mothers were asymptomatic, suggesting incomplete penetrance. Functional studies of the variants were not performed, but studies of some patient cells showed decreased expression of KMT2B, suggesting haploinsufficiency. However, patient cells did not show differences in histone H3K4 methylation compared to controls. Fibroblasts derived from 3 patients showed reduced transcript levels of THAP1 (609520) and TOR1A (605204) compared to controls, and immunoblot studies showed decreased THAP1 protein expression in these cells, but only 1 patient had decreased TOR1A protein expression. These findings suggested that the KMT2B mutations may affect the expression profiles of specific genes involved in dystonia. </p><p>Cif et al. (2020) identified heterozygous mutations in the KMT2B gene in 44 patients (patients 1-44) with DYT28 and in 9 patients (patients 45-53) with MRD68 (619934). The patients were ascertained through international collaborative efforts after genetic analysis identified heterozygous KMT2B mutations. The mutations in patients with DYT28, which were identified by a combination of microarray and gene panel, whole-exome, whole-genome, or Sanger sequencing, included truncating, missense, splicing, and chromosome microdeletions. Twenty-nine patients had de novo mutations; a few inherited the mutation from a symptomatic parent, and the inheritance pattern was unknown in the other patients. Missense variants showed slightly reduced penetrance compared to protein-truncating variants. The protein-truncating mutations occurred throughout the gene, whereas missense variants clustered in putative functional domains. Functional studies of the variants were not performed, and the authors noted that missense variants should be interpreted with caution. It was postulated that haploinsufficiency or dysfunction of KMT2B affects the downstream expression of key genes regulating neurodevelopment and motor control. There were several instances of discordant phenotypes associated with a particular mutation that resulted in both DYT28 and MRD68: 2 sibs (patients 18 and 47) carried a frameshift mutation (606834.0011), and 2 unrelated patients (patients 25 and 50) shared an R1597W mutation (606834.0010). Moreover, P17, who had DYT28, inherited a KMT2B frameshift mutation from his 57-year-old mother (P46), who did not have dystonia but was noted to have intellectual disability and short stature, consistent with MRD68. The finding of the same mutation in individuals with discordant phenotypes illustrated the phenotypic spectrum that can result from KMT2B mutations. The authors suggested that disease manifestations may be influenced by other genetic, epigenetic, or environmental factors. </p><p><strong><em>Autosomal Dominant Intellectual Developmental Disorder 68</em></strong></p><p>
|
|
In an 11-year-old girl with autosomal dominant intellectual developmental disorder-68 (MRD68; 619934), Faundes et al. (2018) identified a de novo heterozygous 1-bp duplication in the KMT2B gene (c.1808dupC; 610881.0009). The patient was ascertained from a cohort of 4,293 trios from the Deciphering Developmental Disorders (DDD) study who underwent exome sequencing. The KMT2B gene was chosen for study through a pathway-based approach focusing on candidate genes involved in histone lysine methylation/demethylation. The variant was filtered against several large databases, including ExAC, the 1000 Genomes Project, and the Exome Sequencing Project. </p><p>Cif et al. (2020) reported 9 patients (patients 45-53) with MRD68 identified through collaborative efforts after heterozygous KMT2B mutations were found. Mutations in patients with MRD68, which were identified by gene panel, whole-exome, or Sanger sequencing, included 6 truncating (see, e.g., 606834.0012) and 3 missense. There were some instances of discordant phenotypes associated with a particular mutation that resulted in both DYT28 and MRD68 (see, e.g., 606834.0010 and 606834.0011). The finding of the same mutation in individuals with discordant phenotypes illustrated the phenotypic spectrum that can result from KMT2B mutations. The authors suggested that disease manifestations may be influenced by other genetic, epigenetic, or environmental factors. </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>Glaser et al. (2009) found that, although Mll2 knockout in utero resulted in lethality before embryonic day (E) 10.5, adult mice with conditional knockout of Mll2 appeared normal compared to controls. The mutant mice showed only slight abnormalities, had normal weight and blood profiles, lived as long as their littermates, and were not prone to tumorigenesis or any other notable pathology. Using tamoxifen induction in conditional knockout mice, Glaser et al. (2009) showed that Mll2 is required only in a brief developmental window between E7.5 and E10.5, and not for further development or somatic homeostasis. However, Mll2 knockout male and female mice were infertile. In male mice, loss of Mll2 led to blockage of spermatogenic differentiation and apoptosis of spermatogonia, although spermatogonia A persisted, indicating that Mll2 is required in the germ cell lineage. In addition, quantitative RT-PCR of total testis RNA revealed alterations in gene expression in Mll2 knockout adult mice. </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>12 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 DYSTONIA 28, CHILDHOOD-ONSET</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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KMT2B, 1-BP DEL, 6406C
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<br />
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SNP: rs1057519278,
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ClinVar: RCV000415586
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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 31-year-old woman of Austrian descent (family F1) with childhood-onset dystonia-28 (DYT28; 617284), Zech et al. (2016) identified a de novo heterozygous 1-bp deletion (c.6406delC, NM_014727.2) in exon 28 of the KMT2B gene, resulting in a frameshift and premature termination (Leu2136SerfsTer17). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 142) or ExAC (v.0.3.1) databases, or in 7,900 in-house control exomes. Analysis of patient cells showed that the mutation resulted in nonsense-mediated mRNA and haploinsufficiency. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 DYSTONIA 28, CHILDHOOD-ONSET</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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KMT2B, ARG545TER
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<br />
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SNP: rs1057519279,
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ClinVar: RCV000415516
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an 11-year-old girl of German descent (family F2) with childhood-onset dystonia-28 (DYT28; 617284), Zech et al. (2016) identified a de novo heterozygous c.1633C-T transition (c.1633C-T, NM_014727.2) in exon 3 of the KMT2B gene, resulting in an arg545-to-ter (R545X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 142) or ExAC (v.0.3.1) databases, or in 7,900 in-house control exomes. </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 DYSTONIA 28, CHILDHOOD-ONSET</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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KMT2B, IVS29AS, A-G, -2
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<br />
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SNP: rs1057519280,
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ClinVar: RCV000415558
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an 15-year-old boy of German descent (family F3) with childhood-onset dystonia-28 (DYT28; 617284), Zech et al. (2016) identified a de novo heterozygous A-to-G transition in intron 29 of the KMT2B gene (c.7050-2A-G, NM_014727.2), resulting in a splice site alteration and a complex pattern of incorrect splicing causing a frameshift and premature termination (Phe2321SerfsTer93). The mutation, which was confirmed by Sanger sequencing, was not found in the ExAC database (v.0.3.1) or in 7,900 in-house control exomes. Analysis of patient cells showed that the mutation resulted in nonsense-mediated mRNA and haploinsufficiency. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 DYSTONIA 28, CHILDHOOD-ONSET</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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KMT2B, GLN810TER
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<br />
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SNP: rs1057519281,
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ClinVar: RCV000415591
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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 6-year-old girl, her father, and her paternal grandfather of Austrian descent (family F4) with childhood-onset dystonia-28 (DYT28; 617284), Zech et al. (2016) identified a de novo heterozygous c.2428C-T transition (c.2428C-T, NM_014727.2) in exon 3 of the KMT2B gene, resulting in a gln810-to-ter (Q810X) substitution. The mutation, which was confirmed by Sanger sequencing, was not found in the ExAC database (v.0.3.1) or in 7,900 in-house control exomes. </p>
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</span>
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</div>
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<div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 DYSTONIA 28, CHILDHOOD-ONSET</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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KMT2B, 1-BP DUP, NT402
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<br />
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SNP: rs1057519282,
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ClinVar: RCV000415532
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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 25-year-old woman (patient 11) with childhood-onset dystonia-28 (DYT28; 617284), Meyer et al. (2017) identified a de novo heterozygous 1-bp duplication (c.402dup, NM_014727.2) in the KMT2B gene, resulting in a frameshift and premature termination (Ser135GlnfsTer23). Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in haploinsufficiency. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 DYSTONIA 28, CHILDHOOD-ONSET</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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KMT2B, ARG564TER
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<br />
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SNP: rs1057519283,
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ClinVar: RCV000415564
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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 6-year-old girl (patient 12) with childhood-onset dystonia-28 (DYT28; 617284), Meyer et al. (2017) identified a de novo heterozygous c.1690C-T transition (c.1690C-T, NM_014727.2) in exon 3 of the KMT2B gene, resulting in an arg564-to-ter (R564X) substitution. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in haploinsufficiency. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 DYSTONIA 28, CHILDHOOD-ONSET</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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KMT2B, TYR1515TER
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<br />
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SNP: rs1057519284,
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ClinVar: RCV000415597, RCV002251741
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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 20-year-old woman (patient 15) with childhood-onset dystonia-28 (DYT28; 617284), Meyer et al. (2017) identified a de novo heterozygous c.4545C-A transversion (c.4545C-A, NM_014727.2) in exon 19 of the KMT2B gene, resulting in a tyr1515-to-ter (Y1515X) substitution. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in haploinsufficiency. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0008 DYSTONIA 28, CHILDHOOD-ONSET</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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KMT2B, ARG2517TRP
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<br />
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SNP: rs1057519285,
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gnomAD: rs1057519285,
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ClinVar: RCV000415537
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a mother and son (patients 26a and 26b) with childhood-onset dystonia-28 (DYT28; 617284), Meyer et al. (2017) identified a heterozygous c.7549C-T transition (c.7549C-T, NM_014727.2) in exon 33 of the KMT2B gene, resulting in an arg2517-to-trp (R2517W) substitution at a highly conserved residue. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to interrupt protein-protein interactions and result in a loss of function. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. </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>
|
|
<span class="mim-font">
|
|
<strong>.0009 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 68</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
KMT2B, 1-BP DUP, 1808C
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|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 11-year-old girl with autosomal dominant intellectual developmental disorder-68 (MRD68; 619934), Faundes et al. (2018) identified a de novo heterozygous 1-bp duplication (c.1808dupC, NM_014727.2) in the KMT2B gene, resulting in a frameshift and premature termination (Leu604ProfsTer72). The patient was ascertained from a cohort of 4,293 trios from the Deciphering Developmental Disorders (DDD) study who underwent exome sequencing. The KMT2B gene was chosen for study through a pathway-based approach focusing on candidate genes involved in histone lysine methylation/demethylation. The variant was filtered against several large databases, including ExAC, the 1000 Genomes Project, and the Exome Sequencing Project. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function and haploinsufficiency. The patient had severe global developmental delay, poor growth, and microcephaly (-3.34 SD). Additional features included delayed walking at age 6.5 years, poor speech, hand stereotypies, nystagmus, urinary incontinence, poor feeding requiring gastrostomy tube, and dysmorphic facial features, such as sparse hair, large mouth, high palate, and absent ear lobes. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 DYSTONIA 28, CHILDHOOD-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 68, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KMT2B, ARG1597TRP
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients, a 22-year-old woman (P25) with onset of dystonia-28 (DYT28; 617284) at age 7, and a 12.3-year-old girl (P50) with autosomal dominant intellectual developmental disorder-68 (MRD68; 619934), Cif et al. (2020) identified the same de novo heterozygous c.4789C-T transition (c.4789C-T, NM_014727.2) in the KMT2B gene, resulting in an arg1597-to-trp (R1597W) substitution. The mutation was found by diagnostic or research whole-exome sequencing. Functional studies of the variant were not performed, but molecular modeling predicted disruption of a functional domain of the protein. P25, with DYT28, did not have developmental delay or intellectual disability, but did manifest behavioral issues. P50, with MRD68, did not have dystonia. The finding of the same mutation in unrelated individuals with a discordant phenotype illustrated the phenotypic spectrum that can result from KMT2B mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 DYSTONIA 28, CHILDHOOD-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 68, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KMT2B, 1-BP DEL, 3325C
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs, a 33-year-old man (P18) with onset of dystonia-28 (DYT28; 617284) at age 5, and a 29-year-old woman (P47) with autosomal dominant intellectual developmental disorder-68 (MRD68; 619934), Cif et al. (2020) identified a heterozygous 1-bp deletion (c.3325delC, NM_014727.2) in the KMT2B gene, predicted to result in a frameshift and premature termination (Arg1109GlufsTer73). The mutation was identified through a diagnostic gene panel; the inheritance pattern could not be determined. Functional studies of the variant were not performed, but it was predicted to result in a loss of function. P18, with dystonia, did not have intellectual disability. P47, with MRD68, had developmental delay and impaired intellectual development without evidence of dystonia. The finding of the same mutation in 2 with a discordant phenotype illustrated the phenotype spectrum that can result from KMT2B mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 68</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KMT2B, TRP1295TER
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 12-year-old girl (P49) with autosomal dominant intellectual developmental disorder-68 (MRD68; 619934), Cif et al. (2020) identified a de novo heterozygous c.3885G-A transition (c.3885G-A, NM_014727.2) in the KMT2B gene, resulting in a trp1295-to-ter (W1295X) substitution. The mutation was found by whole-exome sequencing. Functional studies of the variant were not performed. The patient had global developmental delay, impaired intellectual development, autism spectrum disorder, and ADHD. </p>
|
|
</span>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Cif, L., Demailly, D., Lin, J.-P., Barwick, K. E., Sa, M., Abela, L., Malhotra, S., Chong, W. K., Steel, D., Sanchis-Juan, A., Ngoh, A., Trump, N., and 103 others.
|
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<strong>KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.</strong>
|
|
Brain 143: 3242-3261, 2020.
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[PubMed: 33150406]
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[Full Text: https://doi.org/10.1093/brain/awaa304]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Demers, C., Chaturvedi, C.-P., Ranish, J. A., Juban, G., Lai, P., Morle, F., Aebersold, R., Dilworth, F. J., Groudine, M., Brand, M.
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<strong>Activator-mediated recruitment of the MLL2 methyltransferase complex to the beta-globin locus.</strong>
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Molec. Cell 27: 573-584, 2007.
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[PubMed: 17707229]
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[Full Text: https://doi.org/10.1016/j.molcel.2007.06.022]
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<li>
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<p class="mim-text-font">
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Faundes, V., Newman, W. G., Bernardini, L., Canham, N., Clayton-Smith, J., Dallapiccola, B., Davies, S. J., Demos, M. K., Goldman, A., Gill, H., Horton, R., Kerr, B., and 11 others.
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<strong>Histone lysine methylases and demethylases in the landscape of human developmental disorders.</strong>
|
|
Am. J. Hum. Genet. 102: 175-187, 2018.
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[PubMed: 29276005]
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[Full Text: https://doi.org/10.1016/j.ajhg.2017.11.013]
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</p>
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<li>
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<p class="mim-text-font">
|
|
FitzGerald, K. T., Diaz, M. O.
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<strong>MLL2: a new mammalian member of the trx/MLL family of genes.</strong>
|
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Genomics 59: 187-192, 1999.
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[PubMed: 10409430]
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[Full Text: https://doi.org/10.1006/geno.1999.5860]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Glaser, S., Lubitz, S., Loveland, K. L., Ohbo, K., Robb, L., Schwenk, F., Seibler, J., Roellig, D., Kranz, A., Anastassiadis, K., Stewart, A. F.
|
|
<strong>The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis.</strong>
|
|
Epigenetics Chromatin 2: 5, 2009.
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[PubMed: 19348672]
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[Full Text: https://doi.org/10.1186/1756-8935-2-5]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Huntsman, D. G., Chin, S.-F., Muleris, M., Batley, S. J., Collins, V. P., Wiedemann, L. M., Aparicio, S., Caldas, C.
|
|
<strong>MLL2, the second human homolog of the Drosophila trithorax gene, maps to 19q31.1 and is amplified in solid tumor cell lines.</strong>
|
|
Oncogene 18: 7975-7984, 1999.
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[PubMed: 10637508]
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[Full Text: https://doi.org/10.1038/sj.onc.1203291]
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</p>
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<li>
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<p class="mim-text-font">
|
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Ladopoulos, V., Hofemeister, H., Hoogenkamp, M., Riggs, A. D., Stewart, A. F., Bonifer, C.
|
|
<strong>The histone methyltransferase KMT2B is required for RNA polymerase II association and protection from DNA methylation at the MagohB CpG island promoter.</strong>
|
|
Molec. Cell. Biol. 33: 1383-1393, 2013.
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[PubMed: 23358417]
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[Full Text: https://doi.org/10.1128/MCB.01721-12]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Li, Y., Han, J., Zhang, Y., Cao, F., Liu, Z., Li, S., Wu, J., Hu, C., Wang, Y., Shuai, J., Chen, J., Cao, L., Li, D., Shi, P., Tian, C., Zhang, J., Dou, Y., Li, G., Chen, Y., Lei, M.
|
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<strong>Structural basis for activity regulation of MLL family methyltransferases.</strong>
|
|
Nature 530: 447-452, 2016.
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[PubMed: 26886794]
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[Full Text: https://doi.org/10.1038/nature16952]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Meyer, E., Carss, K. J., Rankin, J., Nichols, J. M. E., Grozeva, D., Joseph, A. P., Mencacci, N. E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., and 61 others.
|
|
<strong>Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.</strong>
|
|
Nature Genet. 49: 223-237, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.
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[PubMed: 27992417]
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[Full Text: https://doi.org/10.1038/ng.3740]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Santos, M. A., Faryabi, R. B., Ergen, A. V., Day, A. M., Malhowski, A., Canela, A., Onozawa, M., Lee, J.-E., Callen, E., Gutierrez-Martinez, P., Chen, H.-T., Wong, N., and 9 others.
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Zech, M., Boesch, S., Maier, E. M., Borggraefe, I., Vill, K., Laccone, F., Pilshofer, V., Ceballos-Baumann, A., Alhaddad, B., Berutti, R., Poewe, W., Haack, T. B., Haslinger, B., Strom, T. M., Winkelmann, J.
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