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Entry
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- *602900 - DNA METHYLTRANSFERASE 3B; DNMT3B
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- OMIM
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</form>
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<div id="mimAlertBanner">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*602900</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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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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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602900">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000088305;t=ENST00000328111" 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=1789" 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=602900" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000088305;t=ENST00000328111" 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_001207055,NM_001207056,NM_001424351,NM_001424352,NM_001424353,NM_001424354,NM_001424355,NM_001424356,NM_001424357,NM_001424358,NM_001424359,NM_001424360,NM_006892,NM_175848,NM_175849,NM_175850,XM_047439946,XM_047439949,XM_047439950,XM_047439955,XM_047439956,XM_047439959,XM_047439960" 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_006892" 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=602900" 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=04209&isoform_id=04209_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/DNMT3B" 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/4877789,4877791,4877793,5823166,5823168,5901940,6118092,17375667,18033255,28559061,28559063,28559065,62087340,83945102,119596756,119596757,119596758,119596759,119596760,119596761,119596762,193785499,194374785,194379666,194389396,194389448,194389584,333440487,333440489,1084352781,2078124488,2217334611,2217334617,2217334619,2217334630,2217334632,2217334639,2217334641,2462579691,2462579697,2462579699,2462579711,2462579713,2462579721,2462579723,2580012571,2580012573,2580012576,2580012581,2580012592,2580012605,2580012613,2580012617,2580853929,2580853931" 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/Q9UBC3" 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=1789" 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=ENSG00000088305;t=ENST00000328111" 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=DNMT3B" 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=DNMT3B" 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+1789" 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/DNMT3B" 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:1789" 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/1789" 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=chr20&hgg_gene=ENST00000328111.6&hgg_start=32762385&hgg_end=32809356&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:2979" 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=602900[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=602900[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/DNMT3B/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/ENSG00000088305" 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=DNMT3B" 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=DNMT3B" 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=DNMT3B" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://structure.bmc.lu.se/idbase/DNMT3Bbase/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=DNMT3B&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/PA27446" 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:2979" 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://www.mousephenotype.org/data/genes/MGI:1261819" 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/DNMT3B#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:1261819" 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/1789/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=1789" 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-050314-1" 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="mimCellLines">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:602900" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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:1789" 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=DNMT3B&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
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602900
|
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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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DNA METHYLTRANSFERASE 3B; DNMT3B
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</span>
|
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</h3>
|
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=DNMT3B" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DNMT3B</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/20/203?start=-3&limit=10&highlight=203">20q11.21</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr20:32762385-32809356&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'})">20:32,762,385-32,809,356</a> </span>
|
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</em>
|
|
</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>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<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">
|
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<thead>
|
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<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=619478,242860" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</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/20/203?start=-3&limit=10&highlight=203">
|
|
20q11.21
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Facioscapulohumeral muscular dystrophy 4, digenic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619478"> 619478 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Digenic dominant">DD</abbr>
|
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|
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</span>
|
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<p>Mammalian cells can epigenetically modify their genomes via DNA methylation. DNA methylation plays important roles in genomic imprinting and X chromosome inactivation and is essential for mammalian development. DNMT3B appears to function as a de novo methyltransferase, since it can methylate unmethylated and hemimethylated DNA with equal efficiencies (<a href="#40" class="mim-tip-reference" title="Yanagisawa, Y., Ito, E., Yuasa, Y., Maruyama, K. <strong>The human DNA methyltransferases DNMT3A and DNMT3B have two types of promoters with different CpG contents.</strong> Biochim. Biophys. Acta 1577: 457-465, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12359337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12359337</a>] [<a href="https://doi.org/10.1016/s0167-4781(02)00482-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12359337">Yanagisawa et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12359337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By searching an EST database using full-length bacterial type II cytosine-5 methyltransferase sequences as queries, followed by isolation and sequencing of overlapping cDNA clones, <a href="#25" class="mim-tip-reference" title="Okano, M., Xie, S., Li, E. <strong>Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. (Letter)</strong> Nature Genet. 19: 219-220, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662389</a>] [<a href="https://doi.org/10.1038/890" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662389">Okano et al. (1998)</a> identified 2 homologous genes in both human and mouse that contained the highly conserved cytosine-5 methyltransferase motifs. The mouse genes, termed Dnmt3a (<a href="/entry/602769">602769</a>) and Dnmt3b, showed little sequence similarity to mouse Dnmt1 (<a href="/entry/126375">126375</a>) and Dnmt2 (<a href="/entry/602478">602478</a>), and masc1 from Ascobolus. The Dnmt3b cDNA encodes a protein of 859 amino acids. The Dnmt3b gene encodes at least 2 shorter polypeptides of 840 and 777 amino acid residues through alternative splicing. The human DNMT3A and DNMT3B cDNAs were highly homologous to the mouse genes. Dnmt3a and Dnmt3b transcripts were abundantly expressed in undifferentiated ES cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9662389" 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="#38" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. <strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong> Nature 402: 187-191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>] [<a href="https://doi.org/10.1038/46052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647011">Xu et al. (1999)</a> showed that expression of the 4.3-kb human DNMT3B mRNA was restricted mostly to testis and thymus. Levels of mRNA expression in adult tissues were far less than levels of DNMT1. The C-terminal region contains 5 of the most highly conserved DNA methyltransferase motifs, whose functions in the transmethylation reaction are known from crystallography data. The N-terminal region of DNMT3B contains a cysteine-rich domain that is distinct from the zinc-binding domain of DNMT1, but is closely related to a region of the putative DNA helicase ATRX (<a href="/entry/300032">300032</a>). Closer to the N terminus of DNMT3B is a PWWP domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647011" 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="#29" class="mim-tip-reference" title="Robertson, K. D., Uzvolgyi, E., Liang, G., Talmadge, C., Sumegi, J., Gonzales, F. A., Jones, P. A. <strong>The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors.</strong> Nucleic Acids Res. 27: 2291-2298, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10325416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10325416</a>] [<a href="https://doi.org/10.1093/nar/27.11.2291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10325416">Robertson et al. (1999)</a> detected DNMT3B expression in most adult and fetal tissues examined by Northern blot analysis, although DNMT3B expression was weaker than that of DNMT1 or DNMT3A. Highest expression was detected in fetal liver, followed by adult heart, skeletal muscle, thymus, kidney, liver, placenta, and peripheral blood mononuclear cells. Semiquantitative RT-PCR detected ubiquitous DNMT3B expression. Expression of DNMT1, DNMT3A, and DNMT3B appeared to be coregulated in most tissues, since they frequently had a similar pattern of expression. RT-PCR detected 4 DNMT3B splice variants that were expected to alter the reading frame. These variants were expressed in a tissue-specific manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10325416" 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 RNA in situ hybridization, <a href="#30" class="mim-tip-reference" title="Shah, M. Y., Vasanthakumar, A., Barnes, N. Y., Figueroa, M. E., Kamp, A., Hendrick, C., Ostler, K. R., Davis, E. M., Lin, S., Anastasi, J., Le Beau, M. M., Moskowitz, I. P., Melnick, A., Pytel, P., Godley, L. A. <strong>DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis.</strong> Cancer Res. 70: 5840-5850, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20587527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20587527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20587527[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/10.1158/0008-5472.CAN-10-0847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20587527">Shah et al. (2010)</a> demonstrated that Dnmt3b7, an isoform consisting of the first 360 N-terminal amino acids of Dnmt3b, is expressed dynamically during mouse embryogenesis, with a low and widespread expression at earlier development to a high and more restricted expression during advanced development. Dnmt3b expression was also observed in adult mouse lymphoid tissues, brain, and testis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20587527" 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="#25" class="mim-tip-reference" title="Okano, M., Xie, S., Li, E. <strong>Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. (Letter)</strong> Nature Genet. 19: 219-220, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662389</a>] [<a href="https://doi.org/10.1038/890" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662389">Okano et al. (1998)</a> performed experiments suggesting that mouse Dnmt3a and Dnmt3b encode the long-sought de novo DNA methyltransferases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9662389" 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="#28" class="mim-tip-reference" title="Rhee, I., Bachman, K. E., Park, B. H., Jair, K.-W., Yen, R.-W. C., Schuebel, K. E., Cui, H., Feinberg, A. P., Lengauer, C., Kinzler, K. W., Baylin, S. B., Vogelstein, B. <strong>DNMT1 and DNMT3b cooperate to silence genes in human cancer cells.</strong> Nature 416: 552-556, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11932749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11932749</a>] [<a href="https://doi.org/10.1038/416552a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11932749">Rhee et al. (2002)</a> disrupted the human DNMT3B gene in a colorectal cancer cell line. This deletion reduced global DNA methylation by less than 3%. Surprisingly, however, genetic disruption of both DNMT1 and DNMT3B nearly eliminated methyltransferase activity, and reduced genomic DNA methylation by greater than 95%. These marked changes resulted in demethylation of repeated sequences, loss of insulin-like growth factor II imprinting, abrogation of silencing of the tumor suppressor gene p16 (INK4A; <a href="/entry/600160">600160</a>), and growth suppression. <a href="#28" class="mim-tip-reference" title="Rhee, I., Bachman, K. E., Park, B. H., Jair, K.-W., Yen, R.-W. C., Schuebel, K. E., Cui, H., Feinberg, A. P., Lengauer, C., Kinzler, K. W., Baylin, S. B., Vogelstein, B. <strong>DNMT1 and DNMT3b cooperate to silence genes in human cancer cells.</strong> Nature 416: 552-556, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11932749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11932749</a>] [<a href="https://doi.org/10.1038/416552a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11932749">Rhee et al. (2002)</a> demonstrated that these 2 enzymes cooperatively maintain DNA methylation and gene silencing in human cancer cells, and provide compelling evidence that such methylation is essential for optimal neoplastic proliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11932749" 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 coimmunoprecipitation of recombinant proteins expressed in insect cells and COS-7 cells, <a href="#22" class="mim-tip-reference" title="Kim, G.-D., Ni, J., Kelesoglu, N., Roberts, R. J., Pradhan, S. <strong>Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases.</strong> EMBO J. 21: 4183-4195, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145218/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145218</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12145218[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/emboj/cdf401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12145218">Kim et al. (2002)</a> identified interaction between DNMT1, DNMT3A, and DNMT3B. DNMT3A and DNMT3B were also able to form complexes in the absence of DNMT1. By mutation analysis, they localized the interacting domains to the N termini of the proteins. Immunocytochemical staining revealed mostly nuclear colocalization of fluorescence-labeled proteins, except for DNMT3A, which was found either exclusively in the cytoplasm or in both the cytoplasm and nucleus. In vivo coexpression of DNMT1 and DNMT3A and/or DNMT3B led to methylation spreading in the genome, suggesting cooperation between them. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12145218" 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 isotype-specific antisense inhibitors, <a href="#3" class="mim-tip-reference" title="Beaulieu, N., Morin, S., Chute, I. C., Robert, M.-F., Nguyen, H., MacLeod, A. R. <strong>An essential role for DNA methyltransferase DNMT3B in cancer cell survival.</strong> J. Biol. Chem. 277: 28176-28181, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12015329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12015329</a>] [<a href="https://doi.org/10.1074/jbc.M204734200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12015329">Beaulieu et al. (2002)</a> depleted expression of select DNMT genes in human cancer cell lines. They found that depletion of DNMT3B, but not DNMT3A, induced apoptosis in human cancer cells but not in normal cells. Depletion reactivated methylation-silenced gene expression but did not induce global or juxtacentromeric satellite demethylation, as did depletion of DNMT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12015329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#16" class="mim-tip-reference" title="Hansen, R. S. <strong>X inactivation-specific methylation of LINE-1 elements by DNMT3B: implications for the Lyon repeat hypothesis.</strong> Hum. Molec. Genet. 12: 2559-2567, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12925568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12925568</a>] [<a href="https://doi.org/10.1093/hmg/ddg268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12925568">Hansen (2003)</a> demonstrated that X-linked LINE-1 elements (L1s) are normally hypermethylated on both the active and inactive X chromosomes. In contrast, cells from patients with ICF syndrome cells have L1s that are hypomethylated on the inactive X, but not on the active X or autosomes. DNMT3B activity, therefore, is required for methylation of L1 CpG islands on the inactive X, whereas methylation of the corresponding L1 loci on the active X, as well as most autosomal L1s, is accomplished by another DNA methyltransferase. The ICF inactive X is able to form a Barr body, associates with XIST (<a href="/entry/314670">314670</a>) RNA, replicates late, and carries X-inactivated genes that are mostly silent. Because the unmethylated state of the ICF inactive X L1s probably reflects their methylation status at the time of X inactivation, <a href="#16" class="mim-tip-reference" title="Hansen, R. S. <strong>X inactivation-specific methylation of LINE-1 elements by DNMT3B: implications for the Lyon repeat hypothesis.</strong> Hum. Molec. Genet. 12: 2559-2567, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12925568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12925568</a>] [<a href="https://doi.org/10.1093/hmg/ddg268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12925568">Hansen (2003)</a> suggested that unmethylated L1 elements, but not methylated L1s, may have a role in the spreading of X chromosome inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12925568" 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="#27" class="mim-tip-reference" title="Paz, M. F., Wei, S., Cigudosa, J. C., Rodriguez-Perales, S., Peinado, M. A., Huang, T. H.-M., Esteller, M. <strong>Genetic unmasking of epigenetically silenced tumor suppressor genes in colon cancer cells deficient in DNA methyltransferases.</strong> Hum. Molec. Genet. 12: 2209-2219, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915469</a>] [<a href="https://doi.org/10.1093/hmg/ddg226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915469">Paz et al. (2003)</a> searched for hypermethylated CpG islands in the colorectal cancer cell line HCT-116, in which 2 major DNA methyltransferases, DNMT1 (<a href="/entry/126375">126375</a>) and DNMT3B, have been genetically disrupted (DKO cells). The authors found that DKO cells, but not the single DNMT1 or DNMT3B knockouts, had a massive loss of hypermethylated CpG islands that induced reactivation of the contiguous genes. A substantial number of these CpG island-associated genes had potentially important roles in tumorigenesis. For other genes whose role in transformation was not characterized, their reintroduction in DKO cells inhibited colony formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915469" 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 a biochemical strategy in HeLa cells, <a href="#12" class="mim-tip-reference" title="Geiman, T. M., Sankpal, U. T., Robertson, A. K., Chen, Y., Mazumdar, M., Heale, J. T., Schmiesing, J. A., Kim, W., Yokomori, K., Zhao, Y., Robertson, K. D. <strong>Isolation and characterization of a novel DNA methyltransferase complex linking DNMT3B with components of the mitotic chromosome condensation machinery.</strong> Nucleic Acids Res. 32: 2716-2729, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15148359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15148359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15148359[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/nar/gkh589" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15148359">Geiman et al. (2004)</a> found that endogenous DNMT3B interacts with components of the mitotic chromosome condensation machinery, and that the DNMT3B complex possesses DNA methyltransferase activity. DNMT3B interacted with HDAC1 (<a href="/entry/601241">601241</a>), SIN3A (<a href="/entry/607776">607776</a>), and SNF2H (<a href="/entry/603375">603375</a>). Coimmunoprecipitation experiments confirmed these results and demonstrated that DNMT3B is capable of interacting with the condensin complex and KIF4A (<a href="/entry/300521">300521</a>). A GST pull-down assay revealed that the interactions occur in the N-terminal regulatory domain of DNMT3B. Immunofluorescence microscopy showed that DNMT3B and its associated proteins colocalize in the cytoplasm and the interphase nuclei. DNMT3B colocalizes with the condensin complex, KIF4A, and SNF2H on condensed chromosomes throughout mitosis. ChIP assay demonstrated that DNMT3B-associated proteins bind to the known DNMT3B target sequences that are methylated by DNMT3B in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15148359" 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="#8" class="mim-tip-reference" title="Dodge, J. E., Okano, M., Dick, F., Tsujimoto, N., Chen, T., Wang, S., Ueda, Y., Dyson, N., Li, E. <strong>Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization.</strong> J. Biol. Chem. 280: 17986-17991, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15757890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15757890</a>] [<a href="https://doi.org/10.1074/jbc.M413246200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15757890">Dodge et al. (2005)</a> found that inactivation of Dnmt3b in mouse embryonic fibroblasts (MEFs) resulted in global demethylation and defects in cell growth, and caused either premature senescence or spontaneous immortalization. Reexpression of Dnmt3b in the MEFs restored DNA methylation and inhibited cellular proliferation. Metaphase analysis revealed that the loss of Dnmt3b was associated with chromosomal abnormalities, including aneuploidy and polyploidy, chromosomal breaks, and fusions. Examination of the function of the G1- to S-phase checkpoint in the MEF cells showed that inactivation of Dnmt3b resulted in increased levels of p21 protein; however, demethylation of the p21 promoter CpG island was found not to be the underlying mechanism of the p21 induction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15757890" 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="#34" class="mim-tip-reference" title="Vire, E., Brenner, C., Deplus, R., Blanchon, L., Fraga, M., Didelot, C., Morey, L., Van Eynde, A., Bernard, D., Vanderwinden, J.-M., Bollen, M., Esteller, M., Di Croce, L., de Launoit, Y., Fuks, F. <strong>The polycomb group protein EZH2 directly controls DNA methylation.</strong> Nature 439: 871-874, 2006. Note: Erratum: Nature 446: 824 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16357870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16357870</a>] [<a href="https://doi.org/10.1038/nature04431" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16357870">Vire et al. (2006)</a> showed that the silencing pathways of the polycomb group (PcG) and DNA methyltransferases systems are mechanically linked. They found that the PcG protein EZH2 (<a href="/entry/601573">601573</a>) interacts--within the context of the Polycomb repressive complexes 2 and 3 (PRC2/3)--with DNMT1, DNMT3A, and DNMT3B and associates with DNMT activity in vivo. Chromatin immunoprecipitations indicated that binding of DNMTs to several EZH2-repressed genes depends on the presence of EZH2. Using bisulfite genomic sequencing, <a href="#34" class="mim-tip-reference" title="Vire, E., Brenner, C., Deplus, R., Blanchon, L., Fraga, M., Didelot, C., Morey, L., Van Eynde, A., Bernard, D., Vanderwinden, J.-M., Bollen, M., Esteller, M., Di Croce, L., de Launoit, Y., Fuks, F. <strong>The polycomb group protein EZH2 directly controls DNA methylation.</strong> Nature 439: 871-874, 2006. Note: Erratum: Nature 446: 824 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16357870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16357870</a>] [<a href="https://doi.org/10.1038/nature04431" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16357870">Vire et al. (2006)</a> showed that EZH2 is required for DNA methylation of EZH2-target promoters. <a href="#34" class="mim-tip-reference" title="Vire, E., Brenner, C., Deplus, R., Blanchon, L., Fraga, M., Didelot, C., Morey, L., Van Eynde, A., Bernard, D., Vanderwinden, J.-M., Bollen, M., Esteller, M., Di Croce, L., de Launoit, Y., Fuks, F. <strong>The polycomb group protein EZH2 directly controls DNA methylation.</strong> Nature 439: 871-874, 2006. Note: Erratum: Nature 446: 824 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16357870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16357870</a>] [<a href="https://doi.org/10.1038/nature04431" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16357870">Vire et al. (2006)</a> concluded that EZH2 serves as a recruitment platform for DNA methyltransferases, demonstrating a direct connection between 2 key epigenetic repression systems. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16357870" 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 mass spectrometry, <a href="#26" class="mim-tip-reference" title="Ooi, S. K. T., Qiu, C., Bernstein, E., Li, K., Jia, D., Yang, Z., Erdjument-Bromage, H., Tempst, P., Lin, S.-P., Allis, C. D., Cheng, X., Bestor, T. H. <strong>DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA.</strong> Nature 448: 714-717, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17687327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17687327</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17687327[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/nature05987" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17687327">Ooi et al. (2007)</a> identified the main proteins that interacted in vivo with the product of an epitope-tagged allele of the endogenous DNMT3L (<a href="/entry/606588">606588</a>) gene as DNMT3A2 (<a href="/entry/602769">602769</a>), DNMT3B, and the 4 core histones. Various studies indicated that DNMT3L recognizes histone H3 tails that are unmethylated at lysine-4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17687327" 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 microRNAs MIRN29A (<a href="/entry/610782">610782</a>), MIRN29B (see MIRN29B1; <a href="/entry/610783">610783</a>), and MIRN29C (<a href="/entry/610784">610784</a>) are downregulated in lung cancer. <a href="#10" class="mim-tip-reference" title="Fabbri, M., Garzon, R., Cimmino, A., Liu, Z., Zanesi, N., Callegari, E., Liu, S., Alder, H., Costinean, S., Fernandez-Cymering, C., Volinia, S., Guler, G., Morrison, C. D., Chan, K. K., Marcucci, G., Calin, G. A., Huebner, K., Croce, C. M. <strong>MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B.</strong> Proc. Nat. Acad. Sci. 104: 15805-15810, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17890317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17890317</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17890317[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0707628104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17890317">Fabbri et al. (2007)</a> identified complementarity sites for the MIRN29s in the 3-prime UTRs of DNMT3A and DNMT3B, which are frequently upregulated in lung cancers with poor prognosis. Expression of the MIRN29s was inversely correlated with levels of DNMT3A and DNMT3B in lung cancer tissues, and the MIRN29s directly targeted DNMT3A and DNMT3B. Enforced expression of MIRN29s in lung cancer cell lines restored normal patterns of DNA methylation, induced reexpression of methylation-silenced tumor suppressor genes, and inhibited tumorigenicity in vitro and in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17890317" 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 ELISA, <a href="#1" class="mim-tip-reference" title="Balada, E., Ordi-Ros, J., Serrano-Acedo, S., Martinez-Lostao, L., Rosa-Leyva, M., Vilardell-Tarres, M. <strong>Transcript levels of DNA methyltransferases DNMT1, DNMT3A and DNMT3B in CD4+ T cells from patients with systemic lupus erythematosus.</strong> Immunology 124: 339-347, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18194272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18194272</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18194272[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/10.1111/j.1365-2567.2007.02771.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18194272">Balada et al. (2008)</a> determined that the DNA deoxymethylcytosine content of purified CD4 (<a href="/entry/186940">186940</a>)-positive T cells was lower in patients with systemic lupus erythematosus (SLE; <a href="/entry/152700">152700</a>) than in controls. RT-PCR analysis detected no differences in DNMT1, DNMT3A, or DNMT3B transcript levels between SLE patients and controls. However, simultaneous association of low complement counts with lymphopenia, high titers of anti-double-stranded DNA, or a high SLE disease activity index resulted in an increase in at least 1 of the DNMTs. <a href="#1" class="mim-tip-reference" title="Balada, E., Ordi-Ros, J., Serrano-Acedo, S., Martinez-Lostao, L., Rosa-Leyva, M., Vilardell-Tarres, M. <strong>Transcript levels of DNA methyltransferases DNMT1, DNMT3A and DNMT3B in CD4+ T cells from patients with systemic lupus erythematosus.</strong> Immunology 124: 339-347, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18194272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18194272</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18194272[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/10.1111/j.1365-2567.2007.02771.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18194272">Balada et al. (2008)</a> proposed that patients with active SLE and DNA hypomethylation have increased DNMT mRNA levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18194272" 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="#14" class="mim-tip-reference" title="Gopalakrishnan, S., Sullivan, B. A., Trazzi, S., Della Valle, G., Robertson, K. D. <strong>DNMT3B interacts with constitutive centromere protein CENP-C to modulate DNA methylation and the histone code at centromeric regions.</strong> Hum. Molec. Genet. 18: 3178-3193, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19482874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19482874</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19482874[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19482874">Gopalakrishnan et al. (2009)</a> used a yeast 2-hybrid screen to identify interaction between DNMT3B and constitutive centromere protein CENPC (CENPC1; <a href="/entry/117141">117141</a>). CENPC was itself essential for mitosis. CENPC recruited DNA methylation and DNMT3B to both centromeric and pericentromeric satellite repeats, and CENPC and DNMT3B regulated the histone code in these regions, including marks characteristic of centromeric chromatin. Loss of CENPC or DNMT3B led to elevated chromosome misalignment and segregation defects during mitosis and increased transcription of centromeric repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19482874" 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="#13" class="mim-tip-reference" title="Gendrel, A.-V., Apedaile, A., Coker, H., Termanis, A., Zvetkova, I., Godwin, J., Tang, Y. A., Huntley, D., Montana, G., Taylor, S., Giannoulatou, E., Heard, E., Stancheva, I., Brockdorff, N. <strong>Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome.</strong> Dev. Cell 23: 265-279, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22841499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22841499</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22841499[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.devcel.2012.06.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22841499">Gendrel et al. (2012)</a> identified 3 major classes of CpG islands on the inactive X chromosome (Xi) that showed rapid, intermediate, or slow methylation kinetics during X inactivation in mouse cells. A fourth class consisted of CpG islands on Xi for which methylation dynamics could not be assigned to any of the other classes. CpG islands with slow methylation kinetics were most common. CpG islands showing rapid or intermediate methylation kinetics had higher CpG density and GC content than those with slow methylation kinetics. Fast-methylating CpG islands were associated with fewer genes than slow-methylating CpG islands, and these genes were only weakly expressed in embryonic stem cells. Slow-methylating CpG islands were associated with low CpG density and higher levels of gene expression in embryonic stem cells than fast-methylating CpG islands. CpG islands with intermediate kinetics were located closer to the Xist locus relative to other classes. Use of knockout mouse embryonic fibroblasts revealed that Dnmt3b, but not Dnmt3a or Dnmt3l, was required for methylation of CpG islands of all classes. Smchd1 (<a href="/entry/614982">614982</a>) was required only for methylation of CpG islands with slow methylation kinetics. Smchd1 was not detected on Xi early during X inactivation, but was highly expressed throughout Xi late during X inactivation. Dnmt3b did not appear to be actively targeted to Xi. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22841499" 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="#18" class="mim-tip-reference" title="Huang, K., Shen, Y., Xue, Z., Bibikova, M., April, C., Liu, Z., Cheng, L., Nagy, A., Pellegrini, M., Fan, J. B., Fan, G. <strong>A panel of CpG methylation sites distinguishes human embryonic stem cells and induced pluripotent stem cells.</strong> Stem Cell Reports 2: 36-43, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24511466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24511466</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24511466[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.stemcr.2013.11.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24511466">Huang et al. (2014)</a> generated human induced pluripotent stem cells (hiPSCs) from skin fibroblasts of DNMT3B-deficient patients with ICF1 (<a href="/entry/242860">242860</a>) (see MOLECULAR GENETICS). Methylation profiling showed that DNMT3B contributed to the panel of methylation signatures that distinguished hiPSCs from human embryonic stem cells and somatic cells. Moreover, DNMT3B contributed directly to aberrant hypermethylation and silencing of TCERG1L (<a href="/entry/620498">620498</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24511466" 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="#32" class="mim-tip-reference" title="Torroglosa, A., Enguix-Riego, M. V., Fernandez, R. M., Roman-Rodriguez, F. J., Moya-Jimenez, M. J., de Agustin, J. C., Antinolo, G., Borrego, S. <strong>Involvement of DNMT3B in the pathogenesis of Hirschsprung disease and its possible role as a regulator of neurogenesis in the human enteric nervous system.</strong> Genet. Med. 16: 703-710, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24577265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24577265</a>] [<a href="https://doi.org/10.1038/gim.2014.17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24577265">Torroglosa et al. (2014)</a> compared the expression patterns of genes involved in human stem cell pluripotency between enteric precursors from controls and patients with Hirschsprung disease (HSCR1; <a href="/entry/142623">142623</a>). The authors further evaluated the role of DNMT3B in the context of Hirschsprung disease by immunocytochemistry, global DNA methylation assays, and mutational screening. Seven differentially expressed genes were identified, and 3 missense mutations were found in DNMT3B that could potentially be pathogenic. These mutations were present in conjunction with RET (<a href="/entry/164761">164761</a>) mutations in patients with long-segment Hirschsprung disease. <a href="#32" class="mim-tip-reference" title="Torroglosa, A., Enguix-Riego, M. V., Fernandez, R. M., Roman-Rodriguez, F. J., Moya-Jimenez, M. J., de Agustin, J. C., Antinolo, G., Borrego, S. <strong>Involvement of DNMT3B in the pathogenesis of Hirschsprung disease and its possible role as a regulator of neurogenesis in the human enteric nervous system.</strong> Genet. Med. 16: 703-710, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24577265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24577265</a>] [<a href="https://doi.org/10.1038/gim.2014.17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24577265">Torroglosa et al. (2014)</a> found that Hirschsprung disease neural precursors derived from neurosphere-like bodies (NLBs) had reduced levels of DNMT3B mRNA and protein compared to control cells. Additionally, methylation levels in Hirschsprung disease NLBs were lower than those of control NLBs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24577265" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Chen, C.-C., Wang, K.-Y., Shen, C.-K. J. <strong>The mammalian de novo DNA methyltransferases DNMT3A and DNMT3B are also DNA 5-hydroxymethylcytosine dehydroxymethylases.</strong> J. Biol. Chem. 287: 33116-33121, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22898819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22898819</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22898819[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/10.1074/jbc.C112.406975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22898819">Chen et al. (2012)</a> found that mouse de novo DNA methyltransferases Dnmt3a and Dnmt3b also possess redox-dependent DNA dehydroxymethylases to convert 5-hydroxymethyl cytosine (5-hmC) to C. Examination of the in vitro DNA dehydroxymethylation activity in nuclear extracts from 293T cells exogenously expressing Dnmt3a and Dnmt3b as well as their mutant forms with amino acid substitutions at the catalytic site of C methylation showed the requirement of intact DNA 5-mC catalytic sites of both enzymes for their dehydroxymethylase activities. Characterization of the methylation and dehydroxymethylation activities of recombinant human DNMT3A and mouse Dnmt3b demonstrated that both can function as dose-dependent DNA dehydroxymethylases. Although the dehydroxymethylation and methylation reactions likely utilize the same catalytic site, the redox state of the enzymes plays a crucial role in determining function as methyltransferases or dehydroxymethylases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22898819" 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="#30" class="mim-tip-reference" title="Shah, M. Y., Vasanthakumar, A., Barnes, N. Y., Figueroa, M. E., Kamp, A., Hendrick, C., Ostler, K. R., Davis, E. M., Lin, S., Anastasi, J., Le Beau, M. M., Moskowitz, I. P., Melnick, A., Pytel, P., Godley, L. A. <strong>DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis.</strong> Cancer Res. 70: 5840-5850, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20587527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20587527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20587527[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/10.1158/0008-5472.CAN-10-0847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20587527">Shah et al. (2010)</a> determined that the truncated Dnmt3b7 isoform can coimmunoprecipitate with full-length Dnmt3b. Dnmt3b7 expression led to increased numbers of chromosomal rearrangements of the pericentromeric region of chromosome 15 as well as hypomethylation of a repetitive element in this region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20587527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Dai, H.-Q., Wang, B.-A., Yang, L., Chen, J.-J., Zhu, G.-C., Sun, M.-L., Ge, H., Wang, R., Chapman, D. L., Tang, F., Sun, X., Xu, G.-L. <strong>TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling.</strong> Nature 538: 528-532, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27760115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27760115</a>] [<a href="https://doi.org/10.1038/nature20095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27760115">Dai et al. (2016)</a> demonstrated that inactivation of all 3 Tet genes (see TET1, <a href="/entry/607790">607790</a>) in mice leads to gastrulation phenotypes, including primitive streak patterning defects in association with impaired maturation of axial mesoderm and failed specification of paraxial mesoderm, mimicking phenotypes in embryos with gain-of-function Nodal (<a href="/entry/601265">601265</a>) signaling. Introduction of a single mutant allele of Nodal in the Tet mutant background partially restored patterning, suggesting that hyperactive Nodal signaling contributes to the gastrulation failure of Tet mutants. Increased Nodal signaling is probably due to diminished expression of the Lefty1 (<a href="/entry/603037">603037</a>) and Lefty2 (<a href="/entry/601877">601877</a>) genes, which encode inhibitors of Nodal signaling. Moreover, reduction in Lefty gene expression is linked to elevated DNA methylation, as both Lefty-Nodal signaling and normal morphogenesis are largely restored in Tet-deficient embryos when the Dnmt3a (<a href="/entry/602769">602769</a>) and Dnmt3b genes are disrupted. Additionally, a point mutation in Tet that specifically abolishes the dioxygenase activity causes similar morphologic and molecular abnormalities as the null mutation. <a href="#7" class="mim-tip-reference" title="Dai, H.-Q., Wang, B.-A., Yang, L., Chen, J.-J., Zhu, G.-C., Sun, M.-L., Ge, H., Wang, R., Chapman, D. L., Tang, F., Sun, X., Xu, G.-L. <strong>TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling.</strong> Nature 538: 528-532, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27760115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27760115</a>] [<a href="https://doi.org/10.1038/nature20095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27760115">Dai et al. (2016)</a> concluded that TET-mediated oxidation of 5-methylcytosine modulates Lefty-Nodal signaling by promoting demethylation in opposition to methylation by DNMT3A and DNMT3B. The authors also concluded that their findings revealed a fundamental epigenetic mechanism featuring dynamic DNA methylation and demethylation crucial to regulation of key signaling pathways in early body plan formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27760115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="mim-changed mim-change"><p>Using knockout analysis in mouse embryonic fibroblasts, <a href="#39" class="mim-tip-reference" title="Yagi, M., Kabata, M., Tanaka, A., Ukai, T., Ohta, S., Nakabayashi, K., Shimizu, M., Hata, K., Meissner, A., Yamamoto, T., Yamada, Y. <strong>Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development.</strong> Nature Commun. 11: 3199, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32581223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32581223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32581223[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-020-16989-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32581223">Yagi et al. (2020)</a> showed that Dnmt3a was exclusively required for de novo methylation at both transcription start site regions and gene bodies of PcG target developmental genes, whereas Dnmt3b had a predominant role on the X chromosome during X chromosome inactivation. Gene ontology analysis revealed that Dnmt3b-specific genes were involved in synaptonemal complex assembly, plasma membrane function, and cell proliferation in forebrain. By contrast, Dnmt3a-specific genes were involved in sequence-specific DNA binding, transcription, and pharyngeal system development. Dnmt3l was dispensable for Dnmt3a-mediated methylation at PcG target genes during embryonic development. Further analysis indicated that Dnmt3a-mediated DNA methylation played a role in stable silencing of a subset of PcG target developmental genes in a tissue-specific manner during development. Patients with DNMT3 mutations exhibited reduced DNA metylation at regions that were hypomethylated in mouse Dnmt3-knockout cells, suggesting that the region specificity of de novo methylation by DNMT3A and DNMT3B is essentially shared between mice and humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32581223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<div class="mim-changed mim-change"><p>Using a deep enzymology approach combined with cellular methylome profiling, <a href="#11" class="mim-tip-reference" title="Gao, L., Emperle, M., Guo, Y., Grimm, S. A., Ren, W., Adam, S., Uryu, H., Zhang, Z. M., Chen, D., Yin, J., Dukatz, M., Anteneh, H., Jurkowska, R. Z., Lu, J., Wang, Y., Bashtrykov, P., Wade, P. A., Wang, G. G., Jeltsch, A., Song, J. <strong>Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms.</strong> Nature Commun. 11: 3355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32620778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32620778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32620778[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-020-17109-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32620778">Gao et al. (2020)</a> characterized the flanking sequence preferences of DNMT3A and DNMT3B, which manifested more than 100-fold different methylation rates of CpG sites across different sequence contexts. Subsequently, the authors determined the crystal structures of DNMT3B in complex with both CpG and CpA DNA. A hydrogen bond in the catalytic loop of DNMT3B caused a lower CpG specificity than DNMT3A, whereas the interplay of target recognition domain and homodimeric interface fine-tuned the distinct target selection between the 2 enzymes, with lys777 of DNMT3B acting as a unique sensor of the +1 flanking base. The findings revealed distinctive substrate-readout mechanisms of the 2 enzymes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32620778" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><a href="#38" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. <strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong> Nature 402: 187-191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>] [<a href="https://doi.org/10.1038/46052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647011">Xu et al. (1999)</a> characterized the DNMT3B gene and found that it spans approximately 47 kb and contains 24 exons, 6 of which are subject to alternative splicing. There are 2 alternative 5-prime exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647011" 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="#40" class="mim-tip-reference" title="Yanagisawa, Y., Ito, E., Yuasa, Y., Maruyama, K. <strong>The human DNA methyltransferases DNMT3A and DNMT3B have two types of promoters with different CpG contents.</strong> Biochim. Biophys. Acta 1577: 457-465, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12359337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12359337</a>] [<a href="https://doi.org/10.1016/s0167-4781(02)00482-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12359337">Yanagisawa et al. (2002)</a> determined that the DNMT3B gene spans about 45.9 kb and contains 22 exons, including 2 alternative first exons (exons 1A and 1B). Both alternative first exons are associated with TATA-less promoter regions. The promoter region upstream of exon 1A is CpG rich, whereas that upstream of exon 1B is CpG poor. Translational start codons are located within exons 1B and 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12359337" 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="#37" class="mim-tip-reference" title="Xie, S., Wang, Z., Okano, M., Nogami, M., Li, Y., He, W.-W., Okumura, K., Li, E. <strong>Cloning, expression and chromosome locations of the human DNMT3 gene family.</strong> Gene 236: 87-95, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10433969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10433969</a>] [<a href="https://doi.org/10.1016/s0378-1119(99)00252-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10433969">Xie et al. (1999)</a> and <a href="#29" class="mim-tip-reference" title="Robertson, K. D., Uzvolgyi, E., Liang, G., Talmadge, C., Sumegi, J., Gonzales, F. A., Jones, P. A. <strong>The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors.</strong> Nucleic Acids Res. 27: 2291-2298, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10325416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10325416</a>] [<a href="https://doi.org/10.1093/nar/27.11.2291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10325416">Robertson et al. (1999)</a> independently mapped the DNMT3B gene to chromosome 20q11.2 using FISH. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10325416+10433969" 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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The immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome-1 (ICF1; <a href="/entry/242860">242860</a>) had been mapped to 20q11-q13 (<a href="#36" class="mim-tip-reference" title="Wijmenga, C., van den Heuvel, L. P. W. J., Strengman, E., Luyten, J. A. F. M., van der Burgt, I. J. A. M., de Groot, R., Smeets, D. F. C. M., Draaisma, J. M. T., van Dongen, J. J., De Abreu, R. A., Pearson, P. L., Sandkuijl, L. A., Weemaes, C. M. R. <strong>Localization of the ICF syndrome to chromosome 20 by homozygosity mapping.</strong> Am. J. Hum. Genet. 63: 803-809, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9718351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9718351</a>] [<a href="https://doi.org/10.1086/302021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9718351">Wijmenga et al., 1998</a>); <a href="#38" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. <strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong> Nature 402: 187-191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>] [<a href="https://doi.org/10.1038/46052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647011">Xu et al. (1999)</a> determined that this region contains the DNMT3B gene. <a href="#38" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. <strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong> Nature 402: 187-191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>] [<a href="https://doi.org/10.1038/46052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647011">Xu et al. (1999)</a> demonstrated mutations in homozygosity or compound heterozygosity in 5 unrelated patients with the ICF syndrome. The observation of mutations in DNMT3B in patients with ICF syndrome who have defective methylation of classical satellites 2 and 3 at juxtacentromeric regions of chromosomes 1, 9, and 16, which are heavily methylated at cytosine residues, suggests that cytosine methylation is essential for the organization and stabilization of a specific type of heterochromatin and that methylation appears to be carried out by an enzyme specialized for the purpose. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9718351+10647011" 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>DNA methylation studies have shown that the classical satellites 2 and 3, which are major components of constitutive heterochromatin, are hypomethylated in ICF syndrome, similar to the hypomethylation of centromeric minor satellite repeats in Dnmt3b -/- mutant mice. This observation, together with the genetic linkage data indicating that ICF syndrome maps to 20q11.2, raised the possibility that ICF syndrome may be associated with dysfunction of DNMT3B. To determine whether DNMT3B is indeed disrupted in this syndrome, <a href="#24" class="mim-tip-reference" title="Okano, M., Bell, D. W., Haber, D. A., Li, E. <strong>DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.</strong> Cell 99: 247-257, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10555141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10555141</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81656-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10555141">Okano et al. (1999)</a> analyzed immortalized lymphoblasts derived from an individual with ICF syndrome and her parents. They identified 2 mutations in the proband's DNMT3B gene, consistent with compound heterozygosity. One of these mutations, a splicing abnormality resulting in the insertion of 3 amino acids at codon 744 (<a href="#0009">602900.0009</a>), was de novo (not present in the parents), and both mutations were not found in 100 normal alleles. <a href="#24" class="mim-tip-reference" title="Okano, M., Bell, D. W., Haber, D. A., Li, E. <strong>DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.</strong> Cell 99: 247-257, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10555141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10555141</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81656-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10555141">Okano et al. (1999)</a> concluded that mutation in the DNMT3B gene is responsible for this form of ICF syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10555141" 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>Centromeric instability of chromosomes 1, 9, and 16 is associated with abnormal hypomethylation of CpG sites in the pericentromeric satellite regions. <a href="#15" class="mim-tip-reference" title="Hansen, R. S., Wijmenga, C., Luo, P., Stanek, A. M., Canfield, T. K., Weemaes, C. M. R., Gartler, S. M. <strong>The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome.</strong> Proc. Nat. Acad. Sci. 96: 14412-14417, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10588719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10588719</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10588719[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.25.14412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10588719">Hansen et al. (1999)</a> were able to complement this hypomethylation defect by somatic cell fusion to Chinese hamster ovary cells, suggesting that the ICF gene is conserved in the hamster and promotes de novo methylation. Following the mapping of the ICF gene to chromosome 20 by homozygosity mapping (<a href="#36" class="mim-tip-reference" title="Wijmenga, C., van den Heuvel, L. P. W. J., Strengman, E., Luyten, J. A. F. M., van der Burgt, I. J. A. M., de Groot, R., Smeets, D. F. C. M., Draaisma, J. M. T., van Dongen, J. J., De Abreu, R. A., Pearson, P. L., Sandkuijl, L. A., Weemaes, C. M. R. <strong>Localization of the ICF syndrome to chromosome 20 by homozygosity mapping.</strong> Am. J. Hum. Genet. 63: 803-809, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9718351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9718351</a>] [<a href="https://doi.org/10.1086/302021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9718351">Wijmenga et al., 1998</a>), <a href="#15" class="mim-tip-reference" title="Hansen, R. S., Wijmenga, C., Luo, P., Stanek, A. M., Canfield, T. K., Weemaes, C. M. R., Gartler, S. M. <strong>The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome.</strong> Proc. Nat. Acad. Sci. 96: 14412-14417, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10588719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10588719</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10588719[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.25.14412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10588719">Hansen et al. (1999)</a> sought homologies to known DNA methyltransferases in the critical region of chromosome 20 and identified a genomic sequence in the ICF region that contained the homolog of the mouse Dnmt3b methyltransferase gene. Using the human sequence to screen ICF kindreds, they discovered mutations in 4 patients from 3 families. Mutations included 2 missense substitutions and a 3-amino acid insertion resulting from the creation of a novel 3-prime splice acceptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9718351+10588719" 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="#35" class="mim-tip-reference" title="Wijmenga, C., Hansen, R. S., Gimelli, G., Bjorck, E. J., Davies, E. G., Valentine, D., Belohradsky, B. H., van Dongen, J. J., Smeets, D. F. C. M., van den Heuvel, L. P. W. J., Luyten, J. A. F. M., Strengman, E., Weemaes, C., Pearson, P. L. <strong>Genetic variation in ICF syndrome: evidence for genetic heterogeneity.</strong> Hum. Mutat. 16: 509-517, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11102980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11102980</a>] [<a href="https://doi.org/10.1002/1098-1004(200012)16:6<509::AID-HUMU8>3.0.CO;2-V" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11102980">Wijmenga et al. (2000)</a> found mutations in the DNMT3B gene in only 9 of 14 ICF patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11102980" 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>Deficiency of DNA methyltransferase 3B in the ICF syndrome leads to hypomethylation of satellites 2 and 3 in pericentric heterochromatin. This hypomethylation is associated with centromeric decondensation and chromosomal rearrangements, suggesting that these satellite repeats have an important structural role. In addition, the satellite regions may have functional roles in modifying gene expression. <a href="#17" class="mim-tip-reference" title="Hassan, K. M. A., Norwood, T., Gimelli, G., Gartler, S. M., Hansen, R. S. <strong>Satellite 2 methylation patterns in normal and ICF syndrome cells and association of hypomethylation with advanced replication.</strong> Hum. Genet. 109: 452-462, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11702227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11702227</a>] [<a href="https://doi.org/10.1007/s004390100590" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11702227">Hassan et al. (2001)</a> developed a bisulfite conversion-based method to determine the detailed cytosine methylation patterns at satellite 2 sequences in a quantitative manner for normal and ICF samples. The average level of methylation in normal lymphoblasts and in fibroblasts was 69%, compared with 20% in such cells from ICF patients with DNMT3B mutations and 29% in normal sperm. That satellite DNA is hypomethylated in gametes had been known for some time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11702227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Ehrlich, M., Buchanan, K. L., Tsien, F., Jiang, G., Sun, B., Uicker, W., Weemaes, C. M. R., Smeets, D., Sperling, K., Belohradsky, B. H., Tommerup, N., Misek, D. E., Rouillard, J.-M., Kuick, R., Hanash, S. M. <strong>DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes.</strong> Hum. Molec. Genet. 10: 2917-2931, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741835</a>] [<a href="https://doi.org/10.1093/hmg/10.25.2917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741835">Ehrlich et al. (2001)</a> performed microarray expression analysis on B-cell lymphoblastoid cell lines from 5 ICF patients with diverse DNMT3B mutations and on control lymphoblastoid cell lines. They employed oligonucleotide arrays for approximately 5,600 different genes, 510 of which showed a lymphoid lineage-restricted expression pattern among several different lineages tested. A set of 32 genes, half of which are thought to play a role in immune function, had consistent and significant ICF-specific changes in RNA levels. ICF-specific increases in immunoglobulin (Ig) heavy constant mu- and delta-RNA and cell surface IgM and IgD, decreases in Ig-gamma and Ig-alpha RNA, and surface IgG and IgA suggested inhibition of the later steps of lymphocyte maturation. ICF-specific increases were seen in RNA for RGS1 (<a href="/entry/600323">600323</a>), a B-cell specific inhibitor of G-protein signaling implicated in negative regulation of B-cell migration, and in RNA for the proapoptotic protein kinase C eta gene (<a href="/entry/605437">605437</a>). ICF-associated decreases were observed in RNAs encoding proteins involved in activation, migration, or survival of lymphoid cells, namely, transcription factor negative regulator ID3 (<a href="/entry/600277">600277</a>), the enhancer-binding MEF2C (<a href="/entry/600662">600662</a>), the iron regulatory TFRC (<a href="/entry/190010">190010</a>), integrin beta-7 (ITGB7; <a href="/entry/147559">147559</a>), the stress protein heme oxygenase (HMOX1; <a href="/entry/141250">141250</a>), and the lymphocyte-specific tumor necrosis factor receptor family members 7 and 17 (TNFRSF7, <a href="/entry/186711">186711</a>; TNFRSF17, <a href="/entry/109545">109545</a>). No differences in promoter methylation were seen between ICF and normal lymphoblastoid cell lines for 3 ICF upregulated genes and 1 downregulated gene by a quantitative methylation assay. The authors hypothesized that DNMT3B mutations in the ICF syndrome may cause lymphogenesis-associated gene dysregulation by indirect effects on gene expression that interfere with normal lymphocyte signaling, maturation, and migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741835" 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="#31" class="mim-tip-reference" title="Shirohzu, H., Kubota, T., Kumazawa, A., Sado, T., Chijiwa, T., Inagaki, K., Suetake, I., Tajima, S., Wakui, K., Miki, Y., Hayashi, M., Fukushima, Y., Sasaki, H. <strong>Three novel DNMT3B mutations in Japanese patients with ICF syndrome.</strong> Am. J. Med. Genet. 112: 31-37, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12239717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12239717</a>] [<a href="https://doi.org/10.1002/ajmg.10658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12239717">Shirohzu et al. (2002)</a> reported 3 Japanese cases of ICF syndrome from 2 unrelated families. All patients had typical facial dysmorphism and IgA deficiency, but none of them had apparent mental retardation. Cytogenetic analysis of peripheral blood lymphocytes showed chromosomal abnormalities, including multiradial configurations and a stretching of the pericentromeric heterochromatin of chromosomes 1 and 16. Hypomethylation of classical satellite-2 DNA was also observed. Three mutations in DNMT3B were found. One patient was a compound heterozygote for a gln42-to-ter (Q42X; <a href="#0011">602900.0011</a>) and an arg832-to-gln (R832Q; <a href="#0012">602900.0012</a>) mutation. The 2 patients from the second family were both homozygous for a ser282-to-pro (S282P; <a href="#0013">602900.0013</a>) mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12239717" 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>Some clinically diagnosed ICF patients do not carry a mutation in the catalytic domain of the DNMT3B gene. To characterize the heterogeneity in the ICF syndrome, <a href="#19" class="mim-tip-reference" title="Jiang, Y. L., Rigolet, M., Bourc'his, D., Nigon, F., Bokesoy, I., Fryns, J. P., Hulten, M., Jonveaux, P., Maraschio, P., Megarbane, A., Moncla, A., Viegas-Pequignot, E. <strong>DNMT3B mutations and DNA methylation defect define two types of ICF syndrome.</strong> Hum. Mutat. 25: 56-63, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15580563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15580563</a>] [<a href="https://doi.org/10.1002/humu.20113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15580563">Jiang et al. (2005)</a> analyzed 12 newly identified ICF patients by screening for mutations in the entire DNMT3B gene and also looking for possible mutations in the DNMT3A gene. In these 12 patients and 5 patients previously described by <a href="#38" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. <strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong> Nature 402: 187-191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>] [<a href="https://doi.org/10.1038/46052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647011">Xu et al. (1999)</a>, they correlated DNMT3B mutations with the methylation status of centromeric alpha satellites. Their observations led them to postulate that there are 2 types of ICF which harbor different genetic and epigenetic characteristics. ICF type 1 is characterized by DNMT3B mutations and normal methylation of the alpha satellites. ICF type 2 lacks DNMT3B mutations and shows hypomethylation of the alpha satellites. Both types are clinically diagnosed as ICF and share the characteristic heterochromatin abnormalities and undermethylation of classic satellites 2 and 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10647011+15580563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review of genetic disorders associated with aberrant chromatin structure, <a href="#4" class="mim-tip-reference" title="Bickmore, W. A., van der Maarel, S. M. <strong>Perturbations of chromatin structure in human genetic disease: recent advances.</strong> Hum. Molec. Genet. 12: R207-R213, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915455</a>] [<a href="https://doi.org/10.1093/hmg/ddg260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915455">Bickmore and van der Maarel (2003)</a> discussed altered heterochromatin structure, DNA methylation, and gene expression in ICF syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915455" 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>Facioscapulohumeral Dystrophy 4, Digenic</em></strong></p><p>
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In 5 members of 2 unrelated families with digenic facioscapulohumeral dystrophy-4 (FSHD4; <a href="/entry/619478">619478</a>), <a href="#33" class="mim-tip-reference" title="van den Boogaard, M. L., Lemmers, R. J. L. F., Balog, J., Wohlgemuth, M., Auranen, M., Mitsuhashi, S., van der Vliet, P. J., Straasheijm, K. R., van den Akker, R. F. P., Kriek, M., Laurense-Bik, M. E. Y., Raz, V., and 11 others. <strong>Mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of facioscapulohumeral dystrophy.</strong> Am. J. Hum. Genet. 98: 1020-1029, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27153398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27153398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27153398[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.2016.03.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27153398">van den Boogaard et al. (2016)</a> identified 2 different heterozygous missense mutations in the DNMT3B gene (C527R, <a href="#0014">602900.0014</a> and P691L, <a href="#0015">602900.0015</a>). The mutations, which were identified by whole-exome sequencing, were not found in public databases, including ExAC. The mutations segregated with hypomethylation of the D4Z4 repeat in the families, but not with clinical presentation. In family Rf210, 2 severely affected individuals carried a heterozygous C527R mutation in the DNMT3B gene that was associated with severe hypomethylation of D4Z4 (-29 and -30%). These patients also carried a 9-unit D4Z4 repeat in a permissive 4qA allele. A third family member with the DNMT3B mutation was clinically unaffected: this individual had hypomethylation at -29%, but the permissive 4qA allele contained 44 units, rather than 9. Two affected family members without the DNMT3B mutation had mild hypomethylation (-8%) on a permissive 4qA allele. There was another clinically unaffected family member with the 9-unit repeat and -6% hypomethylation, but without the DNMT3B mutation. In family Rf732, the clinically affected proband and his unaffected 74-year-old father both carried a heterozygous P691L mutation in the DNMT3B gene. In addition, both had a hypomethylated D4Z4 repeat (-22%) on a permissive 4qA allele with 13 D4Z4 units. The patient's 38-year-old unaffected brother, who did not carry the P691L mutation, had a 13-unit D4Z4 repeat and the permissive 4qA-S haplotype; his D4Z4 repeat was hypomethylated at -10%. These findings, which were consistent with incomplete penetrance in both families, implicated DNMT3B mutations as modifiers of FSHD. Fibroblasts isolated from a symptomatic FSHD4 patient with a DNMT3B mutation that were transdifferentiated into myotubes showed increased expression of DUX4 and DUX4 target genes compared to controls. <a href="#33" class="mim-tip-reference" title="van den Boogaard, M. L., Lemmers, R. J. L. F., Balog, J., Wohlgemuth, M., Auranen, M., Mitsuhashi, S., van der Vliet, P. J., Straasheijm, K. R., van den Akker, R. F. P., Kriek, M., Laurense-Bik, M. E. Y., Raz, V., and 11 others. <strong>Mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of facioscapulohumeral dystrophy.</strong> Am. J. Hum. Genet. 98: 1020-1029, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27153398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27153398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27153398[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.2016.03.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27153398">Van den Boogaard et al. (2016)</a> concluded that DNMT3B mutations confer increased penetrance of FSHD if other genetic factors are present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27153398" 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="#2" class="mim-tip-reference" title="Barau, J., Teissandier, A., Zamudio, N., Roy, S., Nalesso, V., Herault, Y., Guillou, F., Bourc'his, D. <strong>The DNA methyltransferase DNMT3C protects male germ cells from transposon activity.</strong> Science 354: 909-912, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27856912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27856912</a>] [<a href="https://doi.org/10.1126/science.aah5143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27856912">Barau et al. (2016)</a> described the discovery of Dnmt3C, a de novo DNA methyltransferase gene that evolved via a duplication of Dnmt3B in rodent genomes and previously had been annotated as a pseudogene. <a href="#2" class="mim-tip-reference" title="Barau, J., Teissandier, A., Zamudio, N., Roy, S., Nalesso, V., Herault, Y., Guillou, F., Bourc'his, D. <strong>The DNA methyltransferase DNMT3C protects male germ cells from transposon activity.</strong> Science 354: 909-912, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27856912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27856912</a>] [<a href="https://doi.org/10.1126/science.aah5143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27856912">Barau et al. (2016)</a> showed that Dnmt3c encodes the enzyme responsible for methylating the promoters of evolutionarily young retrotransposons in the male germline and that this specialized activity is required for mouse fertility. <a href="#2" class="mim-tip-reference" title="Barau, J., Teissandier, A., Zamudio, N., Roy, S., Nalesso, V., Herault, Y., Guillou, F., Bourc'his, D. <strong>The DNA methyltransferase DNMT3C protects male germ cells from transposon activity.</strong> Science 354: 909-912, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27856912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27856912</a>] [<a href="https://doi.org/10.1126/science.aah5143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27856912">Barau et al. (2016)</a> concluded that the function of Dnmt3c provides an example of the plasticity of the mammalian DNA methylation system and expands the scope of the mechanisms involved in the epigenetic control of retrotransposons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27856912" 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="#24" class="mim-tip-reference" title="Okano, M., Bell, D. W., Haber, D. A., Li, E. <strong>DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.</strong> Cell 99: 247-257, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10555141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10555141</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81656-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10555141">Okano et al. (1999)</a> generated mice with targeted disruption of the Dnmt3a (<a href="/entry/602769">602769</a>) and Dnmt3b genes. Inactivation of both genes blocked de novo methylation in embryonic stem cells and early embryos but had no effect on maintenance of imprinted methylation patterns. Dnmt3a -/- mice developed to term and appeared to be normal at birth. However, most homozygous mutant mice became runted and died at about 4 weeks of age. In contrast, no viable Dnmt3b -/- mice were recovered at birth. Dissection of embryos at different stages of development revealed that Dnmt3b -/- embryos had multiple developmental defects, including growth impairment and rostral neural tube defects with variable severity at later stages of development, though most of them appeared to develop normally before E9.5. Dnmt3a and Dnmt3b also exhibited nonoverlapping functions in development, with Dnmt3b specifically required for methylation of centromeric minor satellite repeats. These results indicated that both Dnmt3a and Dnmt3b are required for genomewide de novo methylation and are essential for mammalian development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10555141" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Kaneda, M., Okano, M., Hata, K., Sado, T., Tsujimoto, N., Li, E., Sasaki, H. <strong>Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting.</strong> Nature 429: 900-903, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15215868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15215868</a>] [<a href="https://doi.org/10.1038/nature02633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15215868">Kaneda et al. (2004)</a> reported the disruption of Dnmt3a and Dnmt3b in germ cells, with their preservation in somatic cells, by conditional knockout technology. Offspring from Dnmt3a conditional mutant females died in utero and lacked methylation and allele-specific expression at all maternally imprinted loci examined. Dnmt3a conditional mutant males showed impaired spermatogenesis and lacked methylation at 2 of 3 paternally imprinted loci examined in spermatogonia. By contrast, Dnmt3b conditional mutants and their offspring showed no apparent phenotype. The phenotype of Dnmt3a conditional mutants is indistinguishable from that of Dnmt3L knockout mice, except for the discrepancy in methylation at 1 locus (IG-DMR). <a href="#20" class="mim-tip-reference" title="Kaneda, M., Okano, M., Hata, K., Sado, T., Tsujimoto, N., Li, E., Sasaki, H. <strong>Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting.</strong> Nature 429: 900-903, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15215868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15215868</a>] [<a href="https://doi.org/10.1038/nature02633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15215868">Kaneda et al. (2004)</a> concluded that both Dnmt3a and Dnmt3L are required for methylation of most imprinted loci in germ cells, but other factors are probably involved. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15215868" 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="#23" class="mim-tip-reference" title="Miller, C. A., Sweatt, J. D. <strong>Covalent modification of DNA regulates memory formation.</strong> Neuron 53: 857-869, 2007. Note: Erratum: Neuron 59: 1051 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17359920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17359920</a>] [<a href="https://doi.org/10.1016/j.neuron.2007.02.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17359920">Miller and Sweatt (2007)</a> found that DNA methylation mediated by DNMTs was dynamically regulated during learning and memory consolidation in adult rats. Animals exposed to an associative context plus shock showed increased Dnmt3a and Dnmt3b mRNA in hippocampal area CA1 compared to context-only animals. Context plus shock rats showed increased methylation and decreased mRNA of the memory suppressor gene PP1C-beta (PPP1CB; <a href="/entry/600590">600590</a>) compared to shock-only controls, as well as increased demethylation and increased mRNA levels of reelin (RELN; <a href="/entry/600514">600514</a>), a gene involved in synaptic plasticity, compared to controls. The methylation levels of both these target genes returned to baseline within a day, indicating rapid and dynamic changes. Treatment with a DNMT inhibitor blocked the methylation changes and prevented memory consolidation of fear-conditioned learning, but the memory changes were plastic, and memory consolidation was reestablished after the inhibitor wore off. <a href="#23" class="mim-tip-reference" title="Miller, C. A., Sweatt, J. D. <strong>Covalent modification of DNA regulates memory formation.</strong> Neuron 53: 857-869, 2007. Note: Erratum: Neuron 59: 1051 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17359920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17359920</a>] [<a href="https://doi.org/10.1016/j.neuron.2007.02.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17359920">Miller and Sweatt (2007)</a> noted that DNA methylation has been viewed as having an exclusive role in development, but they emphasized that their findings indicated that rapid and dynamic alteration of DNA methylation can occur in the adult central nervous system in response to environmental stimuli during associative learning in the hippocampus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17359920" 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="#30" class="mim-tip-reference" title="Shah, M. Y., Vasanthakumar, A., Barnes, N. Y., Figueroa, M. E., Kamp, A., Hendrick, C., Ostler, K. R., Davis, E. M., Lin, S., Anastasi, J., Le Beau, M. M., Moskowitz, I. P., Melnick, A., Pytel, P., Godley, L. A. <strong>DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis.</strong> Cancer Res. 70: 5840-5850, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20587527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20587527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20587527[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/10.1158/0008-5472.CAN-10-0847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20587527">Shah et al. (2010)</a> engineered transgenic Dnmt3b7 mice and found that the mice had a smaller body size as well as craniofacial, cardiac, and immune defects. The mice exhibited lymphopenia and immunodeficiency, with lower numbers of total and mature B lymphocytes and lower IgA levels in the peripheral blood. Severity was greater in homozygous mice, who died prenatally or within hours of birth. Of 60 hemizygous mice followed for over 1 year, only 1 developed a spontaneous hematopoietic tumor. When transgenic Dnmt3b7 mice were bred with Emu-Myc transgenic mice, which model aggressive B-cell lymphoma, the frequency of the lymphomas increased. The lymphomas had more chromosomal rearrangements, increased global DNA methylation levels, and more locus-specific perturbations in DNA methylation patterns compared with Emu-Myc lymphomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20587527" 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 article by <a href="#21" class="mim-tip-reference" title="Kawasaki, H., Taira, K. <strong>Induction of DNA methylation and gene silencing by short interfering RNAs in human cells.</strong> Nature 431: 211-217, 2004. Note: Erratum: Nature 431: 878 only, 2004. Note: Retraction: Nature 441: 1176 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15311210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15311210</a>] [<a href="https://doi.org/10.1038/nature02889" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15311210">Kawasaki and Taira (2004)</a>, which presented evidence that disruption of the expression of DNMT1 or DNMT3B by specific short interfering RNAs (siRNAs) abolished the siRNA-mediated methylation of DNA, was retracted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15311210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient with ICF syndrome (ICF1; <a href="/entry/242860">242860</a>), <a href="#38" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. <strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong> Nature 402: 187-191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>] [<a href="https://doi.org/10.1038/46052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647011">Xu et al. (1999)</a> identified a homozygous A-to-G substitution in the DNMT3B gene resulting in an aspartic acid-to-glycine change at codon 809 (D809G). The consanguineous parents were both heterozygous for this mutation. None of 25 normal individuals screened by direct sequencing showed sequence alterations in this region, nor did the mutation occur in a further 30 individuals screened for the AflIII restriction site that is removed by the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908940 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908940;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/rs121908940?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=rs121908940" 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=rs121908940" 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=RCV000007126 OR RCV002512865" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007126, RCV002512865" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007126...</a>
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<p>In a patient with ICF syndrome (ICF1; <a href="/entry/242860">242860</a>), <a href="#38" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. <strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong> Nature 402: 187-191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>] [<a href="https://doi.org/10.1038/46052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647011">Xu et al. (1999)</a> identified a homozygous valine-to-methionine substitution at codon 810 (V810M) of the DNMT3B gene product. Each of the patient's consanguineous parents was heterozygous for this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 MOVED TO <a href="/entry/602900#0010">602900.0010</a></strong>
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<strong>.0004 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</strong>
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DNMT3B, GLY655SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908942 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908942;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=rs121908942" 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=rs121908942" 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=RCV000007128" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007128" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007128</a>
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<p>For discussion of the gly655-to-ser (G655S) mutation that was found in compound heterozygous state in a patient with ICF syndrome (ICF1; <a href="/entry/242860">242860</a>) by <a href="#38" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. <strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong> Nature 402: 187-191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>] [<a href="https://doi.org/10.1038/46052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647011">Xu et al. (1999)</a>, see <a href="#0010">602900.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647011" 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 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</strong>
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DNMT3B, LEU656THR
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007129" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007129" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007129</a>
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<p>In a patient with ICF syndrome (ICF1; <a href="/entry/242860">242860</a>), <a href="#38" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. <strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong> Nature 402: 187-191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>] [<a href="https://doi.org/10.1038/46052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647011">Xu et al. (1999)</a> found homozygosity for a leucine-to-threonine substitution at codon 656 (L656T) of the DNMT3B gene product. Each of the consanguineous parents was found to be a carrier. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</strong>
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DNMT3B, EX21-22DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007130" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007130" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007130</a>
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<p>In a patient with ICF syndrome (ICF1; <a href="/entry/242860">242860</a>) who was compound heterozygous for mutation in the DNMT3B gene, <a href="#38" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. <strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong> Nature 402: 187-191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>] [<a href="https://doi.org/10.1038/46052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647011">Xu et al. (1999)</a> determined that the maternal allele had an aberrant alternative splice that removed exons 21 and 22 and amino acids 737 to 798. Three intronic mutations existed that could have caused the alternative splicing. The paternal allele had a single nucleotide insertion at codon 53 that caused a frameshift and early termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</strong>
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DNMT3B, 1-BP INS, CODON 53
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007131" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007131" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007131</a>
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<p>For discussion of the 1-bp insertion in the DNMT3B gene that was found in compound heterozygous state in a patient with ICF syndrome (ICF1; <a href="/entry/242860">242860</a>) by <a href="#38" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. <strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong> Nature 402: 187-191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>] [<a href="https://doi.org/10.1038/46052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647011">Xu et al. (1999)</a>, see <a href="#0006">602900.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908943 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908943;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/rs121908943?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=rs121908943" 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=rs121908943" 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=RCV000007132 OR RCV002512866 OR RCV005031403" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007132, RCV002512866, RCV005031403" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007132...</a>
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<p>In a patient with ICF syndrome (ICF1; <a href="/entry/242860">242860</a>), <a href="#24" class="mim-tip-reference" title="Okano, M., Bell, D. W., Haber, D. A., Li, E. <strong>DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.</strong> Cell 99: 247-257, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10555141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10555141</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81656-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10555141">Okano et al. (1999)</a> found compound heterozygosity for 2 mutations in the DNMT3B gene. The first was a G-to-A transition at nucleotide 1807, resulting in an ala603-to-thr (A603T) substitution; this change was present in the proband and her mother. The mutation occurred in a region between motifs I and IV, within the catalytic domain of DNMT3B. The second mutation was a G-to-A transition within intron 22, located 11 nucleotides 5-prime of the normal splice acceptor site (<a href="#0009">602900.0009</a>). This mutation resulted in the generation of a novel splice acceptor site and a 9-bp insertion in the processed RNA, encoding 3 amino acids (serine, threonine, and proline) at codon 744. The insertion was within the conserved region of the catalytic domain, which is likely to be disrupted by the insertion of a proline residue. This mutation was de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10555141" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs547940069 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs547940069;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/rs547940069?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=rs547940069" 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=rs547940069" 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=RCV000007133 OR RCV001268751 OR RCV003593854" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007133, RCV001268751, RCV003593854" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007133...</a>
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<p>For discussion of the splice site mutation in the DNMT3B gene that was found in compound heterozygous state in a patient with ICF syndrome (ICF1; <a href="/entry/242860">242860</a>) by <a href="#24" class="mim-tip-reference" title="Okano, M., Bell, D. W., Haber, D. A., Li, E. <strong>DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.</strong> Cell 99: 247-257, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10555141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10555141</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81656-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10555141">Okano et al. (1999)</a>, see <a href="#0008">602900.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10555141" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Hansen, R. S., Wijmenga, C., Luo, P., Stanek, A. M., Canfield, T. K., Weemaes, C. M. R., Gartler, S. M. <strong>The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome.</strong> Proc. Nat. Acad. Sci. 96: 14412-14417, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10588719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10588719</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10588719[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.25.14412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10588719">Hansen et al. (1999)</a> described this mutation in homozygous state in 1 family and in compound heterozygous state in a second family in which it was combined with the A603T mutation (<a href="#0008">602900.0008</a>). <a href="#15" class="mim-tip-reference" title="Hansen, R. S., Wijmenga, C., Luo, P., Stanek, A. M., Canfield, T. K., Weemaes, C. M. R., Gartler, S. M. <strong>The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome.</strong> Proc. Nat. Acad. Sci. 96: 14412-14417, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10588719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10588719</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10588719[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.25.14412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10588719">Hansen et al. (1999)</a> referred to this mutation as IVS21-11G-A. It appeared that <a href="#24" class="mim-tip-reference" title="Okano, M., Bell, D. W., Haber, D. A., Li, E. <strong>DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.</strong> Cell 99: 247-257, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10555141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10555141</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81656-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10555141">Okano et al. (1999)</a> and <a href="#15" class="mim-tip-reference" title="Hansen, R. S., Wijmenga, C., Luo, P., Stanek, A. M., Canfield, T. K., Weemaes, C. M. R., Gartler, S. M. <strong>The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome.</strong> Proc. Nat. Acad. Sci. 96: 14412-14417, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10588719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10588719</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10588719[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.25.14412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10588719">Hansen et al. (1999)</a> were studying the same patient. The cells from the family were obtained by each investigator, apparently from the Coriell Cell Repositories in Camden, New Jersey (<a href="https://catalog.coriell.org/0/Sections/Search/Sample_Detail.aspx?Ref=GM08728&Product=CC" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'CCR\', \'domain\': \'ccr.coriell.org\'})">GM08728</a>), this being the family described by <a href="#5" class="mim-tip-reference" title="Carpenter, N. J., Filipovich, A., Blaese, R. M., Carey, T. L., Berkel, A. I. <strong>Variable immunodeficiency with abnormal condensation of the heterochromatin of chromosomes 1, 9, and 16.</strong> J. Pediat. 112: 757-760, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3361388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3361388</a>] [<a href="https://doi.org/10.1016/s0022-3476(88)80698-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3361388">Carpenter et al. (1988)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10555141+3361388+10588719" 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 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</strong>
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DNMT3B, VAL726GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908944 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908944;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=rs121908944" 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=rs121908944" 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=RCV000007134" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007134" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007134</a>
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<p>In a consanguineous family, 2 boys with ICF syndrome (ICF1; <a href="/entry/242860">242860</a>) were found by <a href="#15" class="mim-tip-reference" title="Hansen, R. S., Wijmenga, C., Luo, P., Stanek, A. M., Canfield, T. K., Weemaes, C. M. R., Gartler, S. M. <strong>The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome.</strong> Proc. Nat. Acad. Sci. 96: 14412-14417, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10588719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10588719</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10588719[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.25.14412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10588719">Hansen et al. (1999)</a> to be homozygous for a 2177T-G mutation in exon 19 of the DNMT3B gene, resulting in a val726-to-gly (V726G) missense mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10588719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with ICF1, <a href="#38" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. <strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong> Nature 402: 187-191, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>] [<a href="https://doi.org/10.1038/46052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10647011">Xu et al. (1999)</a> identified this mutation, which they reported as a val718-to-gly (V718G) mutation in compound heterozygous state with a gly655-to-ser (G655S; <a href="#0004">602900.0004</a>) mutation in the DNMT3B gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647011" 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"><span class="text-primary">●</span> rs121908945 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908945;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/rs121908945?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=rs121908945" 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=rs121908945" 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 20-year-old Japanese man with ICF syndrome (ICF1; <a href="/entry/242860">242860</a>), <a href="#31" class="mim-tip-reference" title="Shirohzu, H., Kubota, T., Kumazawa, A., Sado, T., Chijiwa, T., Inagaki, K., Suetake, I., Tajima, S., Wakui, K., Miki, Y., Hayashi, M., Fukushima, Y., Sasaki, H. <strong>Three novel DNMT3B mutations in Japanese patients with ICF syndrome.</strong> Am. J. Med. Genet. 112: 31-37, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12239717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12239717</a>] [<a href="https://doi.org/10.1002/ajmg.10658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12239717">Shirohzu et al. (2002)</a> identified compound heterozygosity for mutations in the DNMT3B gene: a C-to-T transition in exon 2 resulting in a gln42-to-ter (Q42X) substitution, and a G-to-A change in exon 23 resulting in an arg832-to-gln (R832Q; <a href="#0012">602900.0012</a>) substitution. The former mutation was inherited from the father and the latter from the mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12239717" 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 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908946 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908946;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/rs121908946?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=rs121908946" 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=rs121908946" 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=RCV000007136 OR RCV003593855" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007136, RCV003593855" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007136...</a>
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<p>For discussion of the arg832-to-gln (R832Q) mutation in the DNMT3B gene that was found in compound heterozygous state in a patient with ICF syndrome (ICF1; <a href="/entry/242860">242860</a>) by <a href="#31" class="mim-tip-reference" title="Shirohzu, H., Kubota, T., Kumazawa, A., Sado, T., Chijiwa, T., Inagaki, K., Suetake, I., Tajima, S., Wakui, K., Miki, Y., Hayashi, M., Fukushima, Y., Sasaki, H. <strong>Three novel DNMT3B mutations in Japanese patients with ICF syndrome.</strong> Am. J. Med. Genet. 112: 31-37, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12239717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12239717</a>] [<a href="https://doi.org/10.1002/ajmg.10658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12239717">Shirohzu et al. (2002)</a>, see <a href="#0011">602900.0011</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12239717" 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">rs121908947 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908947;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=rs121908947" 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=rs121908947" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 Japanese sibs with ICF syndrome (ICF1; <a href="/entry/242860">242860</a>), a 4-year-old girl and an 11-month-old boy, born to consanguineous healthy parents, <a href="#31" class="mim-tip-reference" title="Shirohzu, H., Kubota, T., Kumazawa, A., Sado, T., Chijiwa, T., Inagaki, K., Suetake, I., Tajima, S., Wakui, K., Miki, Y., Hayashi, M., Fukushima, Y., Sasaki, H. <strong>Three novel DNMT3B mutations in Japanese patients with ICF syndrome.</strong> Am. J. Med. Genet. 112: 31-37, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12239717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12239717</a>] [<a href="https://doi.org/10.1002/ajmg.10658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12239717">Shirohzu et al. (2002)</a> identified homozygosity for a T-to-C transition in exon 7 of the DNMT3B gene, resulting in a ser282-to-pro (S282P) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12239717" 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">rs2146029958 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2146029958;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=rs2146029958" 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=rs2146029958" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 members of a family (family Rf210) with digenic facioscapulohumeral dystrophy-4 (FSHD4; <a href="/entry/619478">619478</a>), <a href="#33" class="mim-tip-reference" title="van den Boogaard, M. L., Lemmers, R. J. L. F., Balog, J., Wohlgemuth, M., Auranen, M., Mitsuhashi, S., van der Vliet, P. J., Straasheijm, K. R., van den Akker, R. F. P., Kriek, M., Laurense-Bik, M. E. Y., Raz, V., and 11 others. <strong>Mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of facioscapulohumeral dystrophy.</strong> Am. J. Hum. Genet. 98: 1020-1029, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27153398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27153398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27153398[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.2016.03.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27153398">van den Boogaard et al. (2016)</a> identified a heterozygous c.1579T-C transition (c.1579T-C, NM_006892.3) in the DNMT3B gene, resulting in a cys527-to-arg (C527R) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing, was not present in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in an in-house database. The DNMT3B variant segregated with hypomethylation of the D4Z4 microsatellite repeat array, but not with disease presentation. Two of the individuals who carried the C527R mutation had severe disease and a 9-unit D4Z4 contracted allele, whereas the third individual with the C527R mutation was asymptomatic and had a 44-unit D4Z4 allele, clearly within the range of normal. All 3 individuals had a permissive haplotype (4qA-S). Four additional family members who did not carry the C527R mutation all had a contracted 9-unit D4Z4 allele and a permissive allele, but only 2 were clinically affected, which is typical for this borderline repeat array size and consistent with incomplete penetrance. <a href="#33" class="mim-tip-reference" title="van den Boogaard, M. L., Lemmers, R. J. L. F., Balog, J., Wohlgemuth, M., Auranen, M., Mitsuhashi, S., van der Vliet, P. J., Straasheijm, K. R., van den Akker, R. F. P., Kriek, M., Laurense-Bik, M. E. Y., Raz, V., and 11 others. <strong>Mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of facioscapulohumeral dystrophy.</strong> Am. J. Hum. Genet. 98: 1020-1029, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27153398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27153398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27153398[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.2016.03.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27153398">Van den Boogaard et al. (2016)</a> concluded that the DNMT3B mutation confers increased penetrance of FSHD if other genetic factors are present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27153398" 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"><span class="text-primary">●</span> rs889145646 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs889145646;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/rs889145646?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=rs889145646" 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=rs889145646" 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 45-year-old man (family Rf732) with digenic facioscapulohumeral muscular dystrophy-4 (FSHD4; <a href="/entry/619478">619478</a>) with a borderline contracted D4Z4 repeat (13 units) and a permissive 4qA haplotype, <a href="#33" class="mim-tip-reference" title="van den Boogaard, M. L., Lemmers, R. J. L. F., Balog, J., Wohlgemuth, M., Auranen, M., Mitsuhashi, S., van der Vliet, P. J., Straasheijm, K. R., van den Akker, R. F. P., Kriek, M., Laurense-Bik, M. E. Y., Raz, V., and 11 others. <strong>Mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of facioscapulohumeral dystrophy.</strong> Am. J. Hum. Genet. 98: 1020-1029, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27153398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27153398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27153398[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.2016.03.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27153398">van den Boogaard et al. (2016)</a> identified a heterozygous c.2072C-T transition (c.2072C-T, NM_006892.3) in the DNMT3B gene, resulting in a pro691-to-leu (P691L) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in an in-house database. The patient's D4Z4 repeat was hypomethylated. The proband's 74-year-old father was clinically unaffected, even though he had the same 13-unit D4Z4 repeat, a permissive 4qA haplotype, and carried the P691L mutation with similar hypomethylation of the D4Z4 repeat as his son. This finding was consistent with incomplete penetrance. The patient's 38-year-old unaffected brother, who did not carry the P691L mutation, had a 13-unit D4Z4 repeat and the permissive 4qA haplotype; his D4Z4 repeat was not as hypomethylated as the proband or their father. <a href="#33" class="mim-tip-reference" title="van den Boogaard, M. L., Lemmers, R. J. L. F., Balog, J., Wohlgemuth, M., Auranen, M., Mitsuhashi, S., van der Vliet, P. J., Straasheijm, K. R., van den Akker, R. F. P., Kriek, M., Laurense-Bik, M. E. Y., Raz, V., and 11 others. <strong>Mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of facioscapulohumeral dystrophy.</strong> Am. J. Hum. Genet. 98: 1020-1029, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27153398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27153398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27153398[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.2016.03.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27153398">Van den Boogaard et al. (2016)</a> concluded that the DNMT3B mutation confers increased penetrance of FSHD if other genetic factors are present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27153398" 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>Transcript levels of DNA methyltransferases DNMT1, DNMT3A and DNMT3B in CD4+ T cells from patients with systemic lupus erythematosus.</strong>
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Immunology 124: 339-347, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18194272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18194272</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18194272[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=18194272" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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van den Boogaard, M. L., Lemmers, R. J. L. F., Balog, J., Wohlgemuth, M., Auranen, M., Mitsuhashi, S., van der Vliet, P. J., Straasheijm, K. R., van den Akker, R. F. P., Kriek, M., Laurense-Bik, M. E. Y., Raz, V., and 11 others.
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<strong>Mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of facioscapulohumeral dystrophy.</strong>
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Am. J. Hum. Genet. 98: 1020-1029, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27153398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27153398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27153398[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=27153398" 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.2016.03.013" target="_blank">Full Text</a>]
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</p>
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<a id="34" class="mim-anchor"></a>
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<a id="Vire2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vire, E., Brenner, C., Deplus, R., Blanchon, L., Fraga, M., Didelot, C., Morey, L., Van Eynde, A., Bernard, D., Vanderwinden, J.-M., Bollen, M., Esteller, M., Di Croce, L., de Launoit, Y., Fuks, F.
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<strong>The polycomb group protein EZH2 directly controls DNA methylation.</strong>
|
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Nature 439: 871-874, 2006. Note: Erratum: Nature 446: 824 only, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16357870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16357870</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16357870" 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/nature04431" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="35" class="mim-anchor"></a>
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<a id="Wijmenga2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wijmenga, C., Hansen, R. S., Gimelli, G., Bjorck, E. J., Davies, E. G., Valentine, D., Belohradsky, B. H., van Dongen, J. J., Smeets, D. F. C. M., van den Heuvel, L. P. W. J., Luyten, J. A. F. M., Strengman, E., Weemaes, C., Pearson, P. L.
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<strong>Genetic variation in ICF syndrome: evidence for genetic heterogeneity.</strong>
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Hum. Mutat. 16: 509-517, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11102980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11102980</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11102980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/1098-1004(200012)16:6<509::AID-HUMU8>3.0.CO;2-V" target="_blank">Full Text</a>]
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<a id="36" class="mim-anchor"></a>
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<a id="Wijmenga1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wijmenga, C., van den Heuvel, L. P. W. J., Strengman, E., Luyten, J. A. F. M., van der Burgt, I. J. A. M., de Groot, R., Smeets, D. F. C. M., Draaisma, J. M. T., van Dongen, J. J., De Abreu, R. A., Pearson, P. L., Sandkuijl, L. A., Weemaes, C. M. R.
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<strong>Localization of the ICF syndrome to chromosome 20 by homozygosity mapping.</strong>
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Am. J. Hum. Genet. 63: 803-809, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9718351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9718351</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9718351" 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/10.1086/302021" target="_blank">Full Text</a>]
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<a id="37" class="mim-anchor"></a>
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<a id="Xie1999" class="mim-anchor"></a>
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Xie, S., Wang, Z., Okano, M., Nogami, M., Li, Y., He, W.-W., Okumura, K., Li, E.
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<strong>Cloning, expression and chromosome locations of the human DNMT3 gene family.</strong>
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Gene 236: 87-95, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10433969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10433969</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10433969" 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/s0378-1119(99)00252-8" target="_blank">Full Text</a>]
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<a id="38" class="mim-anchor"></a>
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<a id="Xu1999" class="mim-anchor"></a>
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<p class="mim-text-font">
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Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E.
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<strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong>
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Nature 402: 187-191, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647011" 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/10.1038/46052" target="_blank">Full Text</a>]
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<a id="Yagi2020" class="mim-anchor"></a>
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<p class="mim-text-font">
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Yagi, M., Kabata, M., Tanaka, A., Ukai, T., Ohta, S., Nakabayashi, K., Shimizu, M., Hata, K., Meissner, A., Yamamoto, T., Yamada, Y.
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<strong>Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development.</strong>
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Nature Commun. 11: 3199, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32581223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32581223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32581223[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=32581223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41467-020-16989-w" target="_blank">Full Text</a>]
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<a id="40" class="mim-anchor"></a>
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<a id="Yanagisawa2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yanagisawa, Y., Ito, E., Yuasa, Y., Maruyama, K.
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<strong>The human DNA methyltransferases DNMT3A and DNMT3B have two types of promoters with different CpG contents.</strong>
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Biochim. Biophys. Acta 1577: 457-465, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12359337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12359337</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12359337" 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/s0167-4781(02)00482-7" target="_blank">Full Text</a>]
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<br />
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 01/21/2025
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</span>
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</div>
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</div>
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<div class="row collapse" id="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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Bao Lige - updated : 08/31/2023<br>Cassandra L. Kniffin - updated : 08/12/2021<br>Ada Hamosh - updated : 05/13/2019<br>Bao Lige - updated : 01/28/2019<br>Ada Hamosh - updated : 03/15/2018<br>Cassandra L. Kniffin - updated : 06/14/2016<br>Ada Hamosh - updated : 10/13/2014<br>Patricia A. Hartz - updated : 12/14/2012<br>Paul J. Converse - updated : 8/3/2012<br>George E. Tiller - updated : 7/7/2010<br>Cassandra L. Kniffin - updated : 12/29/2009<br>Matthew B. Gross - updated : 10/8/2009<br>Patricia A. Hartz - updated : 9/17/2009<br>Patricia A. Hartz - updated : 3/24/2008<br>Ada Hamosh - updated : 8/28/2007<br>Ada Hamosh - updated : 12/6/2006<br>George E. Tiller - updated : 10/3/2005<br>George E. Tiller - updated : 9/12/2005<br>George E. Tiller - updated : 9/9/2005<br>Victor A. McKusick - updated : 2/4/2005<br>Ada Hamosh - updated : 9/29/2004<br>Ada Hamosh - updated : 7/22/2004<br>Patricia A. Hartz - updated : 1/23/2003<br>Patricia A. Hartz - updated : 11/5/2002<br>Victor A. McKusick - updated : 10/7/2002<br>George E. Tiller - updated : 8/15/2002<br>Ada Hamosh - updated : 4/9/2002<br>Victor A. McKusick - updated : 12/27/2001<br>Victor A. McKusick - updated : 1/11/2001<br>Victor A. McKusick - updated : 1/2/2001<br>Victor A. McKusick - updated : 1/3/2000<br>Stylianos E. Antonarakis - updated : 12/2/1999<br>Stylianos E. Antonarakis - updated : 11/12/1999<br>Ada Hamosh - updated : 11/11/1999
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 7/27/1998
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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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mgross : 01/21/2025
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 04/30/2024<br>mgross : 08/31/2023<br>carol : 08/20/2021<br>carol : 08/17/2021<br>carol : 08/16/2021<br>ckniffin : 08/12/2021<br>carol : 05/14/2019<br>alopez : 05/13/2019<br>carol : 01/29/2019<br>carol : 01/28/2019<br>alopez : 11/07/2018<br>alopez : 03/15/2018<br>ckniffin : 03/15/2018<br>ckniffin : 06/14/2016<br>carol : 5/12/2015<br>mcolton : 5/4/2015<br>alopez : 10/13/2014<br>mgross : 12/14/2012<br>terry : 12/14/2012<br>mgross : 8/3/2012<br>terry : 8/3/2012<br>wwang : 7/5/2011<br>wwang : 7/19/2010<br>terry : 7/7/2010<br>wwang : 1/13/2010<br>wwang : 1/13/2010<br>ckniffin : 12/29/2009<br>mgross : 10/8/2009<br>mgross : 10/8/2009<br>terry : 9/17/2009<br>mgross : 3/24/2008<br>alopez : 9/7/2007<br>terry : 8/28/2007<br>alopez : 4/27/2007<br>alopez : 12/20/2006<br>terry : 12/6/2006<br>alopez : 7/18/2006<br>alopez : 10/3/2005<br>alopez : 9/30/2005<br>terry : 9/12/2005<br>terry : 9/9/2005<br>wwang : 2/16/2005<br>wwang : 2/10/2005<br>terry : 2/4/2005<br>alopez : 10/20/2004<br>tkritzer : 10/5/2004<br>terry : 9/29/2004<br>alopez : 7/26/2004<br>terry : 7/22/2004<br>carol : 10/1/2003<br>mgross : 1/23/2003<br>mgross : 11/5/2002<br>tkritzer : 10/9/2002<br>tkritzer : 10/8/2002<br>terry : 10/7/2002<br>cwells : 8/15/2002<br>alopez : 4/11/2002<br>terry : 4/9/2002<br>cwells : 1/14/2002<br>cwells : 1/3/2002<br>terry : 12/27/2001<br>cwells : 1/11/2001<br>terry : 1/2/2001<br>terry : 10/4/2000<br>yemi : 2/18/2000<br>alopez : 1/10/2000<br>terry : 1/3/2000<br>mgross : 12/2/1999<br>terry : 12/2/1999<br>mgross : 11/12/1999<br>alopez : 11/11/1999<br>alopez : 11/11/1999<br>terry : 11/11/1999<br>alopez : 7/27/1998
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</span>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 602900
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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DNA METHYLTRANSFERASE 3B; DNMT3B
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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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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: DNMT3B</em></strong>
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</span>
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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: 20q11.21
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Genomic coordinates <span class="small">(GRCh38)</span> : 20:32,762,385-32,809,356 </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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<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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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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<span class="mim-font">
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20q11.21
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<span class="mim-font">
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Facioscapulohumeral muscular dystrophy 4, digenic
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<span class="mim-font">
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619478
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<span class="mim-font">
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Digenic dominant
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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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<span class="mim-font">
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Immunodeficiency-centromeric instability-facial anomalies syndrome 1
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<span class="mim-font">
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242860
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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</span>
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</tbody>
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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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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</h4>
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<span class="mim-text-font">
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<p>Mammalian cells can epigenetically modify their genomes via DNA methylation. DNA methylation plays important roles in genomic imprinting and X chromosome inactivation and is essential for mammalian development. DNMT3B appears to function as a de novo methyltransferase, since it can methylate unmethylated and hemimethylated DNA with equal efficiencies (Yanagisawa et al., 2002). </p>
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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 an EST database using full-length bacterial type II cytosine-5 methyltransferase sequences as queries, followed by isolation and sequencing of overlapping cDNA clones, Okano et al. (1998) identified 2 homologous genes in both human and mouse that contained the highly conserved cytosine-5 methyltransferase motifs. The mouse genes, termed Dnmt3a (602769) and Dnmt3b, showed little sequence similarity to mouse Dnmt1 (126375) and Dnmt2 (602478), and masc1 from Ascobolus. The Dnmt3b cDNA encodes a protein of 859 amino acids. The Dnmt3b gene encodes at least 2 shorter polypeptides of 840 and 777 amino acid residues through alternative splicing. The human DNMT3A and DNMT3B cDNAs were highly homologous to the mouse genes. Dnmt3a and Dnmt3b transcripts were abundantly expressed in undifferentiated ES cells. </p><p>Xu et al. (1999) showed that expression of the 4.3-kb human DNMT3B mRNA was restricted mostly to testis and thymus. Levels of mRNA expression in adult tissues were far less than levels of DNMT1. The C-terminal region contains 5 of the most highly conserved DNA methyltransferase motifs, whose functions in the transmethylation reaction are known from crystallography data. The N-terminal region of DNMT3B contains a cysteine-rich domain that is distinct from the zinc-binding domain of DNMT1, but is closely related to a region of the putative DNA helicase ATRX (300032). Closer to the N terminus of DNMT3B is a PWWP domain. </p><p>Robertson et al. (1999) detected DNMT3B expression in most adult and fetal tissues examined by Northern blot analysis, although DNMT3B expression was weaker than that of DNMT1 or DNMT3A. Highest expression was detected in fetal liver, followed by adult heart, skeletal muscle, thymus, kidney, liver, placenta, and peripheral blood mononuclear cells. Semiquantitative RT-PCR detected ubiquitous DNMT3B expression. Expression of DNMT1, DNMT3A, and DNMT3B appeared to be coregulated in most tissues, since they frequently had a similar pattern of expression. RT-PCR detected 4 DNMT3B splice variants that were expected to alter the reading frame. These variants were expressed in a tissue-specific manner. </p><p>Using RNA in situ hybridization, Shah et al. (2010) demonstrated that Dnmt3b7, an isoform consisting of the first 360 N-terminal amino acids of Dnmt3b, is expressed dynamically during mouse embryogenesis, with a low and widespread expression at earlier development to a high and more restricted expression during advanced development. Dnmt3b expression was also observed in adult mouse lymphoid tissues, brain, and testis. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Okano et al. (1998) performed experiments suggesting that mouse Dnmt3a and Dnmt3b encode the long-sought de novo DNA methyltransferases. </p><p>Rhee et al. (2002) disrupted the human DNMT3B gene in a colorectal cancer cell line. This deletion reduced global DNA methylation by less than 3%. Surprisingly, however, genetic disruption of both DNMT1 and DNMT3B nearly eliminated methyltransferase activity, and reduced genomic DNA methylation by greater than 95%. These marked changes resulted in demethylation of repeated sequences, loss of insulin-like growth factor II imprinting, abrogation of silencing of the tumor suppressor gene p16 (INK4A; 600160), and growth suppression. Rhee et al. (2002) demonstrated that these 2 enzymes cooperatively maintain DNA methylation and gene silencing in human cancer cells, and provide compelling evidence that such methylation is essential for optimal neoplastic proliferation. </p><p>Using coimmunoprecipitation of recombinant proteins expressed in insect cells and COS-7 cells, Kim et al. (2002) identified interaction between DNMT1, DNMT3A, and DNMT3B. DNMT3A and DNMT3B were also able to form complexes in the absence of DNMT1. By mutation analysis, they localized the interacting domains to the N termini of the proteins. Immunocytochemical staining revealed mostly nuclear colocalization of fluorescence-labeled proteins, except for DNMT3A, which was found either exclusively in the cytoplasm or in both the cytoplasm and nucleus. In vivo coexpression of DNMT1 and DNMT3A and/or DNMT3B led to methylation spreading in the genome, suggesting cooperation between them. </p><p>Using isotype-specific antisense inhibitors, Beaulieu et al. (2002) depleted expression of select DNMT genes in human cancer cell lines. They found that depletion of DNMT3B, but not DNMT3A, induced apoptosis in human cancer cells but not in normal cells. Depletion reactivated methylation-silenced gene expression but did not induce global or juxtacentromeric satellite demethylation, as did depletion of DNMT1. </p><p>Hansen (2003) demonstrated that X-linked LINE-1 elements (L1s) are normally hypermethylated on both the active and inactive X chromosomes. In contrast, cells from patients with ICF syndrome cells have L1s that are hypomethylated on the inactive X, but not on the active X or autosomes. DNMT3B activity, therefore, is required for methylation of L1 CpG islands on the inactive X, whereas methylation of the corresponding L1 loci on the active X, as well as most autosomal L1s, is accomplished by another DNA methyltransferase. The ICF inactive X is able to form a Barr body, associates with XIST (314670) RNA, replicates late, and carries X-inactivated genes that are mostly silent. Because the unmethylated state of the ICF inactive X L1s probably reflects their methylation status at the time of X inactivation, Hansen (2003) suggested that unmethylated L1 elements, but not methylated L1s, may have a role in the spreading of X chromosome inactivation. </p><p>Paz et al. (2003) searched for hypermethylated CpG islands in the colorectal cancer cell line HCT-116, in which 2 major DNA methyltransferases, DNMT1 (126375) and DNMT3B, have been genetically disrupted (DKO cells). The authors found that DKO cells, but not the single DNMT1 or DNMT3B knockouts, had a massive loss of hypermethylated CpG islands that induced reactivation of the contiguous genes. A substantial number of these CpG island-associated genes had potentially important roles in tumorigenesis. For other genes whose role in transformation was not characterized, their reintroduction in DKO cells inhibited colony formation. </p><p>Using a biochemical strategy in HeLa cells, Geiman et al. (2004) found that endogenous DNMT3B interacts with components of the mitotic chromosome condensation machinery, and that the DNMT3B complex possesses DNA methyltransferase activity. DNMT3B interacted with HDAC1 (601241), SIN3A (607776), and SNF2H (603375). Coimmunoprecipitation experiments confirmed these results and demonstrated that DNMT3B is capable of interacting with the condensin complex and KIF4A (300521). A GST pull-down assay revealed that the interactions occur in the N-terminal regulatory domain of DNMT3B. Immunofluorescence microscopy showed that DNMT3B and its associated proteins colocalize in the cytoplasm and the interphase nuclei. DNMT3B colocalizes with the condensin complex, KIF4A, and SNF2H on condensed chromosomes throughout mitosis. ChIP assay demonstrated that DNMT3B-associated proteins bind to the known DNMT3B target sequences that are methylated by DNMT3B in vivo. </p><p>Dodge et al. (2005) found that inactivation of Dnmt3b in mouse embryonic fibroblasts (MEFs) resulted in global demethylation and defects in cell growth, and caused either premature senescence or spontaneous immortalization. Reexpression of Dnmt3b in the MEFs restored DNA methylation and inhibited cellular proliferation. Metaphase analysis revealed that the loss of Dnmt3b was associated with chromosomal abnormalities, including aneuploidy and polyploidy, chromosomal breaks, and fusions. Examination of the function of the G1- to S-phase checkpoint in the MEF cells showed that inactivation of Dnmt3b resulted in increased levels of p21 protein; however, demethylation of the p21 promoter CpG island was found not to be the underlying mechanism of the p21 induction. </p><p>Vire et al. (2006) showed that the silencing pathways of the polycomb group (PcG) and DNA methyltransferases systems are mechanically linked. They found that the PcG protein EZH2 (601573) interacts--within the context of the Polycomb repressive complexes 2 and 3 (PRC2/3)--with DNMT1, DNMT3A, and DNMT3B and associates with DNMT activity in vivo. Chromatin immunoprecipitations indicated that binding of DNMTs to several EZH2-repressed genes depends on the presence of EZH2. Using bisulfite genomic sequencing, Vire et al. (2006) showed that EZH2 is required for DNA methylation of EZH2-target promoters. Vire et al. (2006) concluded that EZH2 serves as a recruitment platform for DNA methyltransferases, demonstrating a direct connection between 2 key epigenetic repression systems. </p><p>Using mass spectrometry, Ooi et al. (2007) identified the main proteins that interacted in vivo with the product of an epitope-tagged allele of the endogenous DNMT3L (606588) gene as DNMT3A2 (602769), DNMT3B, and the 4 core histones. Various studies indicated that DNMT3L recognizes histone H3 tails that are unmethylated at lysine-4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2. </p><p>The microRNAs MIRN29A (610782), MIRN29B (see MIRN29B1; 610783), and MIRN29C (610784) are downregulated in lung cancer. Fabbri et al. (2007) identified complementarity sites for the MIRN29s in the 3-prime UTRs of DNMT3A and DNMT3B, which are frequently upregulated in lung cancers with poor prognosis. Expression of the MIRN29s was inversely correlated with levels of DNMT3A and DNMT3B in lung cancer tissues, and the MIRN29s directly targeted DNMT3A and DNMT3B. Enforced expression of MIRN29s in lung cancer cell lines restored normal patterns of DNA methylation, induced reexpression of methylation-silenced tumor suppressor genes, and inhibited tumorigenicity in vitro and in vivo. </p><p>Using ELISA, Balada et al. (2008) determined that the DNA deoxymethylcytosine content of purified CD4 (186940)-positive T cells was lower in patients with systemic lupus erythematosus (SLE; 152700) than in controls. RT-PCR analysis detected no differences in DNMT1, DNMT3A, or DNMT3B transcript levels between SLE patients and controls. However, simultaneous association of low complement counts with lymphopenia, high titers of anti-double-stranded DNA, or a high SLE disease activity index resulted in an increase in at least 1 of the DNMTs. Balada et al. (2008) proposed that patients with active SLE and DNA hypomethylation have increased DNMT mRNA levels. </p><p>Gopalakrishnan et al. (2009) used a yeast 2-hybrid screen to identify interaction between DNMT3B and constitutive centromere protein CENPC (CENPC1; 117141). CENPC was itself essential for mitosis. CENPC recruited DNA methylation and DNMT3B to both centromeric and pericentromeric satellite repeats, and CENPC and DNMT3B regulated the histone code in these regions, including marks characteristic of centromeric chromatin. Loss of CENPC or DNMT3B led to elevated chromosome misalignment and segregation defects during mitosis and increased transcription of centromeric repeats. </p><p>Gendrel et al. (2012) identified 3 major classes of CpG islands on the inactive X chromosome (Xi) that showed rapid, intermediate, or slow methylation kinetics during X inactivation in mouse cells. A fourth class consisted of CpG islands on Xi for which methylation dynamics could not be assigned to any of the other classes. CpG islands with slow methylation kinetics were most common. CpG islands showing rapid or intermediate methylation kinetics had higher CpG density and GC content than those with slow methylation kinetics. Fast-methylating CpG islands were associated with fewer genes than slow-methylating CpG islands, and these genes were only weakly expressed in embryonic stem cells. Slow-methylating CpG islands were associated with low CpG density and higher levels of gene expression in embryonic stem cells than fast-methylating CpG islands. CpG islands with intermediate kinetics were located closer to the Xist locus relative to other classes. Use of knockout mouse embryonic fibroblasts revealed that Dnmt3b, but not Dnmt3a or Dnmt3l, was required for methylation of CpG islands of all classes. Smchd1 (614982) was required only for methylation of CpG islands with slow methylation kinetics. Smchd1 was not detected on Xi early during X inactivation, but was highly expressed throughout Xi late during X inactivation. Dnmt3b did not appear to be actively targeted to Xi. </p><p>Huang et al. (2014) generated human induced pluripotent stem cells (hiPSCs) from skin fibroblasts of DNMT3B-deficient patients with ICF1 (242860) (see MOLECULAR GENETICS). Methylation profiling showed that DNMT3B contributed to the panel of methylation signatures that distinguished hiPSCs from human embryonic stem cells and somatic cells. Moreover, DNMT3B contributed directly to aberrant hypermethylation and silencing of TCERG1L (620498). </p><p>Torroglosa et al. (2014) compared the expression patterns of genes involved in human stem cell pluripotency between enteric precursors from controls and patients with Hirschsprung disease (HSCR1; 142623). The authors further evaluated the role of DNMT3B in the context of Hirschsprung disease by immunocytochemistry, global DNA methylation assays, and mutational screening. Seven differentially expressed genes were identified, and 3 missense mutations were found in DNMT3B that could potentially be pathogenic. These mutations were present in conjunction with RET (164761) mutations in patients with long-segment Hirschsprung disease. Torroglosa et al. (2014) found that Hirschsprung disease neural precursors derived from neurosphere-like bodies (NLBs) had reduced levels of DNMT3B mRNA and protein compared to control cells. Additionally, methylation levels in Hirschsprung disease NLBs were lower than those of control NLBs. </p><p>Chen et al. (2012) found that mouse de novo DNA methyltransferases Dnmt3a and Dnmt3b also possess redox-dependent DNA dehydroxymethylases to convert 5-hydroxymethyl cytosine (5-hmC) to C. Examination of the in vitro DNA dehydroxymethylation activity in nuclear extracts from 293T cells exogenously expressing Dnmt3a and Dnmt3b as well as their mutant forms with amino acid substitutions at the catalytic site of C methylation showed the requirement of intact DNA 5-mC catalytic sites of both enzymes for their dehydroxymethylase activities. Characterization of the methylation and dehydroxymethylation activities of recombinant human DNMT3A and mouse Dnmt3b demonstrated that both can function as dose-dependent DNA dehydroxymethylases. Although the dehydroxymethylation and methylation reactions likely utilize the same catalytic site, the redox state of the enzymes plays a crucial role in determining function as methyltransferases or dehydroxymethylases. </p><p>Shah et al. (2010) determined that the truncated Dnmt3b7 isoform can coimmunoprecipitate with full-length Dnmt3b. Dnmt3b7 expression led to increased numbers of chromosomal rearrangements of the pericentromeric region of chromosome 15 as well as hypomethylation of a repetitive element in this region. </p><p>Dai et al. (2016) demonstrated that inactivation of all 3 Tet genes (see TET1, 607790) in mice leads to gastrulation phenotypes, including primitive streak patterning defects in association with impaired maturation of axial mesoderm and failed specification of paraxial mesoderm, mimicking phenotypes in embryos with gain-of-function Nodal (601265) signaling. Introduction of a single mutant allele of Nodal in the Tet mutant background partially restored patterning, suggesting that hyperactive Nodal signaling contributes to the gastrulation failure of Tet mutants. Increased Nodal signaling is probably due to diminished expression of the Lefty1 (603037) and Lefty2 (601877) genes, which encode inhibitors of Nodal signaling. Moreover, reduction in Lefty gene expression is linked to elevated DNA methylation, as both Lefty-Nodal signaling and normal morphogenesis are largely restored in Tet-deficient embryos when the Dnmt3a (602769) and Dnmt3b genes are disrupted. Additionally, a point mutation in Tet that specifically abolishes the dioxygenase activity causes similar morphologic and molecular abnormalities as the null mutation. Dai et al. (2016) concluded that TET-mediated oxidation of 5-methylcytosine modulates Lefty-Nodal signaling by promoting demethylation in opposition to methylation by DNMT3A and DNMT3B. The authors also concluded that their findings revealed a fundamental epigenetic mechanism featuring dynamic DNA methylation and demethylation crucial to regulation of key signaling pathways in early body plan formation. </p><p>Using knockout analysis in mouse embryonic fibroblasts, Yagi et al. (2020) showed that Dnmt3a was exclusively required for de novo methylation at both transcription start site regions and gene bodies of PcG target developmental genes, whereas Dnmt3b had a predominant role on the X chromosome during X chromosome inactivation. Gene ontology analysis revealed that Dnmt3b-specific genes were involved in synaptonemal complex assembly, plasma membrane function, and cell proliferation in forebrain. By contrast, Dnmt3a-specific genes were involved in sequence-specific DNA binding, transcription, and pharyngeal system development. Dnmt3l was dispensable for Dnmt3a-mediated methylation at PcG target genes during embryonic development. Further analysis indicated that Dnmt3a-mediated DNA methylation played a role in stable silencing of a subset of PcG target developmental genes in a tissue-specific manner during development. Patients with DNMT3 mutations exhibited reduced DNA metylation at regions that were hypomethylated in mouse Dnmt3-knockout cells, suggesting that the region specificity of de novo methylation by DNMT3A and DNMT3B is essentially shared between mice and humans. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using a deep enzymology approach combined with cellular methylome profiling, Gao et al. (2020) characterized the flanking sequence preferences of DNMT3A and DNMT3B, which manifested more than 100-fold different methylation rates of CpG sites across different sequence contexts. Subsequently, the authors determined the crystal structures of DNMT3B in complex with both CpG and CpA DNA. A hydrogen bond in the catalytic loop of DNMT3B caused a lower CpG specificity than DNMT3A, whereas the interplay of target recognition domain and homodimeric interface fine-tuned the distinct target selection between the 2 enzymes, with lys777 of DNMT3B acting as a unique sensor of the +1 flanking base. The findings revealed distinctive substrate-readout mechanisms of the 2 enzymes. </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>Xu et al. (1999) characterized the DNMT3B gene and found that it spans approximately 47 kb and contains 24 exons, 6 of which are subject to alternative splicing. There are 2 alternative 5-prime exons. </p><p>Yanagisawa et al. (2002) determined that the DNMT3B gene spans about 45.9 kb and contains 22 exons, including 2 alternative first exons (exons 1A and 1B). Both alternative first exons are associated with TATA-less promoter regions. The promoter region upstream of exon 1A is CpG rich, whereas that upstream of exon 1B is CpG poor. Translational start codons are located within exons 1B and 2. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Xie et al. (1999) and Robertson et al. (1999) independently mapped the DNMT3B gene to chromosome 20q11.2 using FISH. </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>Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome 1</em></strong></p><p>
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The immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome-1 (ICF1; 242860) had been mapped to 20q11-q13 (Wijmenga et al., 1998); Xu et al. (1999) determined that this region contains the DNMT3B gene. Xu et al. (1999) demonstrated mutations in homozygosity or compound heterozygosity in 5 unrelated patients with the ICF syndrome. The observation of mutations in DNMT3B in patients with ICF syndrome who have defective methylation of classical satellites 2 and 3 at juxtacentromeric regions of chromosomes 1, 9, and 16, which are heavily methylated at cytosine residues, suggests that cytosine methylation is essential for the organization and stabilization of a specific type of heterochromatin and that methylation appears to be carried out by an enzyme specialized for the purpose. </p><p>DNA methylation studies have shown that the classical satellites 2 and 3, which are major components of constitutive heterochromatin, are hypomethylated in ICF syndrome, similar to the hypomethylation of centromeric minor satellite repeats in Dnmt3b -/- mutant mice. This observation, together with the genetic linkage data indicating that ICF syndrome maps to 20q11.2, raised the possibility that ICF syndrome may be associated with dysfunction of DNMT3B. To determine whether DNMT3B is indeed disrupted in this syndrome, Okano et al. (1999) analyzed immortalized lymphoblasts derived from an individual with ICF syndrome and her parents. They identified 2 mutations in the proband's DNMT3B gene, consistent with compound heterozygosity. One of these mutations, a splicing abnormality resulting in the insertion of 3 amino acids at codon 744 (602900.0009), was de novo (not present in the parents), and both mutations were not found in 100 normal alleles. Okano et al. (1999) concluded that mutation in the DNMT3B gene is responsible for this form of ICF syndrome. </p><p>Centromeric instability of chromosomes 1, 9, and 16 is associated with abnormal hypomethylation of CpG sites in the pericentromeric satellite regions. Hansen et al. (1999) were able to complement this hypomethylation defect by somatic cell fusion to Chinese hamster ovary cells, suggesting that the ICF gene is conserved in the hamster and promotes de novo methylation. Following the mapping of the ICF gene to chromosome 20 by homozygosity mapping (Wijmenga et al., 1998), Hansen et al. (1999) sought homologies to known DNA methyltransferases in the critical region of chromosome 20 and identified a genomic sequence in the ICF region that contained the homolog of the mouse Dnmt3b methyltransferase gene. Using the human sequence to screen ICF kindreds, they discovered mutations in 4 patients from 3 families. Mutations included 2 missense substitutions and a 3-amino acid insertion resulting from the creation of a novel 3-prime splice acceptor. </p><p>Wijmenga et al. (2000) found mutations in the DNMT3B gene in only 9 of 14 ICF patients. </p><p>Deficiency of DNA methyltransferase 3B in the ICF syndrome leads to hypomethylation of satellites 2 and 3 in pericentric heterochromatin. This hypomethylation is associated with centromeric decondensation and chromosomal rearrangements, suggesting that these satellite repeats have an important structural role. In addition, the satellite regions may have functional roles in modifying gene expression. Hassan et al. (2001) developed a bisulfite conversion-based method to determine the detailed cytosine methylation patterns at satellite 2 sequences in a quantitative manner for normal and ICF samples. The average level of methylation in normal lymphoblasts and in fibroblasts was 69%, compared with 20% in such cells from ICF patients with DNMT3B mutations and 29% in normal sperm. That satellite DNA is hypomethylated in gametes had been known for some time. </p><p>Ehrlich et al. (2001) performed microarray expression analysis on B-cell lymphoblastoid cell lines from 5 ICF patients with diverse DNMT3B mutations and on control lymphoblastoid cell lines. They employed oligonucleotide arrays for approximately 5,600 different genes, 510 of which showed a lymphoid lineage-restricted expression pattern among several different lineages tested. A set of 32 genes, half of which are thought to play a role in immune function, had consistent and significant ICF-specific changes in RNA levels. ICF-specific increases in immunoglobulin (Ig) heavy constant mu- and delta-RNA and cell surface IgM and IgD, decreases in Ig-gamma and Ig-alpha RNA, and surface IgG and IgA suggested inhibition of the later steps of lymphocyte maturation. ICF-specific increases were seen in RNA for RGS1 (600323), a B-cell specific inhibitor of G-protein signaling implicated in negative regulation of B-cell migration, and in RNA for the proapoptotic protein kinase C eta gene (605437). ICF-associated decreases were observed in RNAs encoding proteins involved in activation, migration, or survival of lymphoid cells, namely, transcription factor negative regulator ID3 (600277), the enhancer-binding MEF2C (600662), the iron regulatory TFRC (190010), integrin beta-7 (ITGB7; 147559), the stress protein heme oxygenase (HMOX1; 141250), and the lymphocyte-specific tumor necrosis factor receptor family members 7 and 17 (TNFRSF7, 186711; TNFRSF17, 109545). No differences in promoter methylation were seen between ICF and normal lymphoblastoid cell lines for 3 ICF upregulated genes and 1 downregulated gene by a quantitative methylation assay. The authors hypothesized that DNMT3B mutations in the ICF syndrome may cause lymphogenesis-associated gene dysregulation by indirect effects on gene expression that interfere with normal lymphocyte signaling, maturation, and migration. </p><p>Shirohzu et al. (2002) reported 3 Japanese cases of ICF syndrome from 2 unrelated families. All patients had typical facial dysmorphism and IgA deficiency, but none of them had apparent mental retardation. Cytogenetic analysis of peripheral blood lymphocytes showed chromosomal abnormalities, including multiradial configurations and a stretching of the pericentromeric heterochromatin of chromosomes 1 and 16. Hypomethylation of classical satellite-2 DNA was also observed. Three mutations in DNMT3B were found. One patient was a compound heterozygote for a gln42-to-ter (Q42X; 602900.0011) and an arg832-to-gln (R832Q; 602900.0012) mutation. The 2 patients from the second family were both homozygous for a ser282-to-pro (S282P; 602900.0013) mutation. </p><p>Some clinically diagnosed ICF patients do not carry a mutation in the catalytic domain of the DNMT3B gene. To characterize the heterogeneity in the ICF syndrome, Jiang et al. (2005) analyzed 12 newly identified ICF patients by screening for mutations in the entire DNMT3B gene and also looking for possible mutations in the DNMT3A gene. In these 12 patients and 5 patients previously described by Xu et al. (1999), they correlated DNMT3B mutations with the methylation status of centromeric alpha satellites. Their observations led them to postulate that there are 2 types of ICF which harbor different genetic and epigenetic characteristics. ICF type 1 is characterized by DNMT3B mutations and normal methylation of the alpha satellites. ICF type 2 lacks DNMT3B mutations and shows hypomethylation of the alpha satellites. Both types are clinically diagnosed as ICF and share the characteristic heterochromatin abnormalities and undermethylation of classic satellites 2 and 3. </p><p>In a review of genetic disorders associated with aberrant chromatin structure, Bickmore and van der Maarel (2003) discussed altered heterochromatin structure, DNA methylation, and gene expression in ICF syndrome. </p><p><strong><em>Facioscapulohumeral Dystrophy 4, Digenic</em></strong></p><p>
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In 5 members of 2 unrelated families with digenic facioscapulohumeral dystrophy-4 (FSHD4; 619478), van den Boogaard et al. (2016) identified 2 different heterozygous missense mutations in the DNMT3B gene (C527R, 602900.0014 and P691L, 602900.0015). The mutations, which were identified by whole-exome sequencing, were not found in public databases, including ExAC. The mutations segregated with hypomethylation of the D4Z4 repeat in the families, but not with clinical presentation. In family Rf210, 2 severely affected individuals carried a heterozygous C527R mutation in the DNMT3B gene that was associated with severe hypomethylation of D4Z4 (-29 and -30%). These patients also carried a 9-unit D4Z4 repeat in a permissive 4qA allele. A third family member with the DNMT3B mutation was clinically unaffected: this individual had hypomethylation at -29%, but the permissive 4qA allele contained 44 units, rather than 9. Two affected family members without the DNMT3B mutation had mild hypomethylation (-8%) on a permissive 4qA allele. There was another clinically unaffected family member with the 9-unit repeat and -6% hypomethylation, but without the DNMT3B mutation. In family Rf732, the clinically affected proband and his unaffected 74-year-old father both carried a heterozygous P691L mutation in the DNMT3B gene. In addition, both had a hypomethylated D4Z4 repeat (-22%) on a permissive 4qA allele with 13 D4Z4 units. The patient's 38-year-old unaffected brother, who did not carry the P691L mutation, had a 13-unit D4Z4 repeat and the permissive 4qA-S haplotype; his D4Z4 repeat was hypomethylated at -10%. These findings, which were consistent with incomplete penetrance in both families, implicated DNMT3B mutations as modifiers of FSHD. Fibroblasts isolated from a symptomatic FSHD4 patient with a DNMT3B mutation that were transdifferentiated into myotubes showed increased expression of DUX4 and DUX4 target genes compared to controls. Van den Boogaard et al. (2016) concluded that DNMT3B mutations confer increased penetrance of FSHD if other genetic factors are present. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Evolution</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>Barau et al. (2016) described the discovery of Dnmt3C, a de novo DNA methyltransferase gene that evolved via a duplication of Dnmt3B in rodent genomes and previously had been annotated as a pseudogene. Barau et al. (2016) showed that Dnmt3c encodes the enzyme responsible for methylating the promoters of evolutionarily young retrotransposons in the male germline and that this specialized activity is required for mouse fertility. Barau et al. (2016) concluded that the function of Dnmt3c provides an example of the plasticity of the mammalian DNA methylation system and expands the scope of the mechanisms involved in the epigenetic control of retrotransposons. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Okano et al. (1999) generated mice with targeted disruption of the Dnmt3a (602769) and Dnmt3b genes. Inactivation of both genes blocked de novo methylation in embryonic stem cells and early embryos but had no effect on maintenance of imprinted methylation patterns. Dnmt3a -/- mice developed to term and appeared to be normal at birth. However, most homozygous mutant mice became runted and died at about 4 weeks of age. In contrast, no viable Dnmt3b -/- mice were recovered at birth. Dissection of embryos at different stages of development revealed that Dnmt3b -/- embryos had multiple developmental defects, including growth impairment and rostral neural tube defects with variable severity at later stages of development, though most of them appeared to develop normally before E9.5. Dnmt3a and Dnmt3b also exhibited nonoverlapping functions in development, with Dnmt3b specifically required for methylation of centromeric minor satellite repeats. These results indicated that both Dnmt3a and Dnmt3b are required for genomewide de novo methylation and are essential for mammalian development. </p><p>Kaneda et al. (2004) reported the disruption of Dnmt3a and Dnmt3b in germ cells, with their preservation in somatic cells, by conditional knockout technology. Offspring from Dnmt3a conditional mutant females died in utero and lacked methylation and allele-specific expression at all maternally imprinted loci examined. Dnmt3a conditional mutant males showed impaired spermatogenesis and lacked methylation at 2 of 3 paternally imprinted loci examined in spermatogonia. By contrast, Dnmt3b conditional mutants and their offspring showed no apparent phenotype. The phenotype of Dnmt3a conditional mutants is indistinguishable from that of Dnmt3L knockout mice, except for the discrepancy in methylation at 1 locus (IG-DMR). Kaneda et al. (2004) concluded that both Dnmt3a and Dnmt3L are required for methylation of most imprinted loci in germ cells, but other factors are probably involved. </p><p>Miller and Sweatt (2007) found that DNA methylation mediated by DNMTs was dynamically regulated during learning and memory consolidation in adult rats. Animals exposed to an associative context plus shock showed increased Dnmt3a and Dnmt3b mRNA in hippocampal area CA1 compared to context-only animals. Context plus shock rats showed increased methylation and decreased mRNA of the memory suppressor gene PP1C-beta (PPP1CB; 600590) compared to shock-only controls, as well as increased demethylation and increased mRNA levels of reelin (RELN; 600514), a gene involved in synaptic plasticity, compared to controls. The methylation levels of both these target genes returned to baseline within a day, indicating rapid and dynamic changes. Treatment with a DNMT inhibitor blocked the methylation changes and prevented memory consolidation of fear-conditioned learning, but the memory changes were plastic, and memory consolidation was reestablished after the inhibitor wore off. Miller and Sweatt (2007) noted that DNA methylation has been viewed as having an exclusive role in development, but they emphasized that their findings indicated that rapid and dynamic alteration of DNA methylation can occur in the adult central nervous system in response to environmental stimuli during associative learning in the hippocampus. </p><p>Shah et al. (2010) engineered transgenic Dnmt3b7 mice and found that the mice had a smaller body size as well as craniofacial, cardiac, and immune defects. The mice exhibited lymphopenia and immunodeficiency, with lower numbers of total and mature B lymphocytes and lower IgA levels in the peripheral blood. Severity was greater in homozygous mice, who died prenatally or within hours of birth. Of 60 hemizygous mice followed for over 1 year, only 1 developed a spontaneous hematopoietic tumor. When transgenic Dnmt3b7 mice were bred with Emu-Myc transgenic mice, which model aggressive B-cell lymphoma, the frequency of the lymphomas increased. The lymphomas had more chromosomal rearrangements, increased global DNA methylation levels, and more locus-specific perturbations in DNA methylation patterns compared with Emu-Myc lymphomas. </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>History</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 article by Kawasaki and Taira (2004), which presented evidence that disruption of the expression of DNMT1 or DNMT3B by specific short interfering RNAs (siRNAs) abolished the siRNA-mediated methylation of DNA, was retracted. </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>15 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 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</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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DNMT3B, ASP809GLY
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<br />
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SNP: rs121908939,
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ClinVar: RCV000007125
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with ICF syndrome (ICF1; 242860), Xu et al. (1999) identified a homozygous A-to-G substitution in the DNMT3B gene resulting in an aspartic acid-to-glycine change at codon 809 (D809G). The consanguineous parents were both heterozygous for this mutation. None of 25 normal individuals screened by direct sequencing showed sequence alterations in this region, nor did the mutation occur in a further 30 individuals screened for the AflIII restriction site that is removed by the mutation. </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 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</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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DNMT3B, VAL810MET
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<br />
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SNP: rs121908940,
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gnomAD: rs121908940,
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ClinVar: RCV000007126, RCV002512865
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with ICF syndrome (ICF1; 242860), Xu et al. (1999) identified a homozygous valine-to-methionine substitution at codon 810 (V810M) of the DNMT3B gene product. Each of the patient's consanguineous parents was heterozygous for this mutation. </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-text-font">
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<strong>.0003 MOVED TO 602900.0010</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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<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 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</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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DNMT3B, GLY655SER
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<br />
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SNP: rs121908942,
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ClinVar: RCV000007128
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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>For discussion of the gly655-to-ser (G655S) mutation that was found in compound heterozygous state in a patient with ICF syndrome (ICF1; 242860) by Xu et al. (1999), see 602900.0010. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</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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DNMT3B, LEU656THR
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<br />
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ClinVar: RCV000007129
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with ICF syndrome (ICF1; 242860), Xu et al. (1999) found homozygosity for a leucine-to-threonine substitution at codon 656 (L656T) of the DNMT3B gene product. Each of the consanguineous parents was found to be a carrier. </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 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</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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DNMT3B, EX21-22DEL
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<br />
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ClinVar: RCV000007130
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with ICF syndrome (ICF1; 242860) who was compound heterozygous for mutation in the DNMT3B gene, Xu et al. (1999) determined that the maternal allele had an aberrant alternative splice that removed exons 21 and 22 and amino acids 737 to 798. Three intronic mutations existed that could have caused the alternative splicing. The paternal allele had a single nucleotide insertion at codon 53 that caused a frameshift and early termination. </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 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</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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DNMT3B, 1-BP INS, CODON 53
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<br />
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ClinVar: RCV000007131
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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>For discussion of the 1-bp insertion in the DNMT3B gene that was found in compound heterozygous state in a patient with ICF syndrome (ICF1; 242860) by Xu et al. (1999), see 602900.0006. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0008 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</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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DNMT3B, ALA603THR
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<br />
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SNP: rs121908943,
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gnomAD: rs121908943,
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ClinVar: RCV000007132, RCV002512866, RCV005031403
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with ICF syndrome (ICF1; 242860), Okano et al. (1999) found compound heterozygosity for 2 mutations in the DNMT3B gene. The first was a G-to-A transition at nucleotide 1807, resulting in an ala603-to-thr (A603T) substitution; this change was present in the proband and her mother. The mutation occurred in a region between motifs I and IV, within the catalytic domain of DNMT3B. The second mutation was a G-to-A transition within intron 22, located 11 nucleotides 5-prime of the normal splice acceptor site (602900.0009). This mutation resulted in the generation of a novel splice acceptor site and a 9-bp insertion in the processed RNA, encoding 3 amino acids (serine, threonine, and proline) at codon 744. The insertion was within the conserved region of the catalytic domain, which is likely to be disrupted by the insertion of a proline residue. This mutation was de novo. </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>.0009 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</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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DNMT3B, IVS22AS, G-A, -11
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<br />
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SNP: rs547940069,
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gnomAD: rs547940069,
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ClinVar: RCV000007133, RCV001268751, RCV003593854
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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>For discussion of the splice site mutation in the DNMT3B gene that was found in compound heterozygous state in a patient with ICF syndrome (ICF1; 242860) by Okano et al. (1999), see 602900.0008. </p><p>Hansen et al. (1999) described this mutation in homozygous state in 1 family and in compound heterozygous state in a second family in which it was combined with the A603T mutation (602900.0008). Hansen et al. (1999) referred to this mutation as IVS21-11G-A. It appeared that Okano et al. (1999) and Hansen et al. (1999) were studying the same patient. The cells from the family were obtained by each investigator, apparently from the Coriell Cell Repositories in Camden, New Jersey (GM08728), this being the family described by Carpenter et al. (1988). </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</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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DNMT3B, VAL726GLY
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<br />
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SNP: rs121908944,
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ClinVar: RCV000007134
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a consanguineous family, 2 boys with ICF syndrome (ICF1; 242860) were found by Hansen et al. (1999) to be homozygous for a 2177T-G mutation in exon 19 of the DNMT3B gene, resulting in a val726-to-gly (V726G) missense mutation. </p><p>In a patient with ICF1, Xu et al. (1999) identified this mutation, which they reported as a val718-to-gly (V718G) mutation in compound heterozygous state with a gly655-to-ser (G655S; 602900.0004) mutation in the DNMT3B gene. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0011 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</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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DNMT3B, GLN42TER
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<br />
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SNP: rs121908945,
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gnomAD: rs121908945,
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ClinVar: RCV000007135
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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 Japanese man with ICF syndrome (ICF1; 242860), Shirohzu et al. (2002) identified compound heterozygosity for mutations in the DNMT3B gene: a C-to-T transition in exon 2 resulting in a gln42-to-ter (Q42X) substitution, and a G-to-A change in exon 23 resulting in an arg832-to-gln (R832Q; 602900.0012) substitution. The former mutation was inherited from the father and the latter from the mother. </p>
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</span>
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0012 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</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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DNMT3B, ARG832GLN
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<br />
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SNP: rs121908946,
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gnomAD: rs121908946,
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ClinVar: RCV000007136, RCV003593855
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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>For discussion of the arg832-to-gln (R832Q) mutation in the DNMT3B gene that was found in compound heterozygous state in a patient with ICF syndrome (ICF1; 242860) by Shirohzu et al. (2002), see 602900.0011. </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>.0013 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1</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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DNMT3B, SER282PRO
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<br />
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SNP: rs121908947,
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ClinVar: RCV000007137
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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 2 Japanese sibs with ICF syndrome (ICF1; 242860), a 4-year-old girl and an 11-month-old boy, born to consanguineous healthy parents, Shirohzu et al. (2002) identified homozygosity for a T-to-C transition in exon 7 of the DNMT3B gene, resulting in a ser282-to-pro (S282P) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0014 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 4, DIGENIC</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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DNMT3B, CYS527ARG
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<br />
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SNP: rs2146029958,
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ClinVar: RCV001568341
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 members of a family (family Rf210) with digenic facioscapulohumeral dystrophy-4 (FSHD4; 619478), van den Boogaard et al. (2016) identified a heterozygous c.1579T-C transition (c.1579T-C, NM_006892.3) in the DNMT3B gene, resulting in a cys527-to-arg (C527R) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing, was not present in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in an in-house database. The DNMT3B variant segregated with hypomethylation of the D4Z4 microsatellite repeat array, but not with disease presentation. Two of the individuals who carried the C527R mutation had severe disease and a 9-unit D4Z4 contracted allele, whereas the third individual with the C527R mutation was asymptomatic and had a 44-unit D4Z4 allele, clearly within the range of normal. All 3 individuals had a permissive haplotype (4qA-S). Four additional family members who did not carry the C527R mutation all had a contracted 9-unit D4Z4 allele and a permissive allele, but only 2 were clinically affected, which is typical for this borderline repeat array size and consistent with incomplete penetrance. Van den Boogaard et al. (2016) concluded that the DNMT3B mutation confers increased penetrance of FSHD if other genetic factors are present. </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>.0015 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 4, DIGENIC</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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DNMT3B, PRO691LEU
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<br />
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SNP: rs889145646,
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gnomAD: rs889145646,
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ClinVar: RCV001568342, RCV002234225
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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 45-year-old man (family Rf732) with digenic facioscapulohumeral muscular dystrophy-4 (FSHD4; 619478) with a borderline contracted D4Z4 repeat (13 units) and a permissive 4qA haplotype, van den Boogaard et al. (2016) identified a heterozygous c.2072C-T transition (c.2072C-T, NM_006892.3) in the DNMT3B gene, resulting in a pro691-to-leu (P691L) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in an in-house database. The patient's D4Z4 repeat was hypomethylated. The proband's 74-year-old father was clinically unaffected, even though he had the same 13-unit D4Z4 repeat, a permissive 4qA haplotype, and carried the P691L mutation with similar hypomethylation of the D4Z4 repeat as his son. This finding was consistent with incomplete penetrance. The patient's 38-year-old unaffected brother, who did not carry the P691L mutation, had a 13-unit D4Z4 repeat and the permissive 4qA haplotype; his D4Z4 repeat was not as hypomethylated as the proband or their father. Van den Boogaard et al. (2016) concluded that the DNMT3B mutation confers increased penetrance of FSHD if other genetic factors are present. </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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Balada, E., Ordi-Ros, J., Serrano-Acedo, S., Martinez-Lostao, L., Rosa-Leyva, M., Vilardell-Tarres, M.
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<strong>Transcript levels of DNA methyltransferases DNMT1, DNMT3A and DNMT3B in CD4+ T cells from patients with systemic lupus erythematosus.</strong>
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Immunology 124: 339-347, 2008.
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Barau, J., Teissandier, A., Zamudio, N., Roy, S., Nalesso, V., Herault, Y., Guillou, F., Bourc'his, D.
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Science 354: 909-912, 2016.
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Beaulieu, N., Morin, S., Chute, I. C., Robert, M.-F., Nguyen, H., MacLeod, A. R.
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<strong>An essential role for DNA methyltransferase DNMT3B in cancer cell survival.</strong>
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J. Biol. Chem. 277: 28176-28181, 2002.
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Bickmore, W. A., van der Maarel, S. M.
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Carpenter, N. J., Filipovich, A., Blaese, R. M., Carey, T. L., Berkel, A. I.
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Chen, C.-C., Wang, K.-Y., Shen, C.-K. J.
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<strong>The mammalian de novo DNA methyltransferases DNMT3A and DNMT3B are also DNA 5-hydroxymethylcytosine dehydroxymethylases.</strong>
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J. Biol. Chem. 287: 33116-33121, 2012.
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Dai, H.-Q., Wang, B.-A., Yang, L., Chen, J.-J., Zhu, G.-C., Sun, M.-L., Ge, H., Wang, R., Chapman, D. L., Tang, F., Sun, X., Xu, G.-L.
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<strong>TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling.</strong>
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Nature 538: 528-532, 2016.
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[PubMed: 27760115]
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Dodge, J. E., Okano, M., Dick, F., Tsujimoto, N., Chen, T., Wang, S., Ueda, Y., Dyson, N., Li, E.
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<strong>Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization.</strong>
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<p class="mim-text-font">
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Ehrlich, M., Buchanan, K. L., Tsien, F., Jiang, G., Sun, B., Uicker, W., Weemaes, C. M. R., Smeets, D., Sperling, K., Belohradsky, B. H., Tommerup, N., Misek, D. E., Rouillard, J.-M., Kuick, R., Hanash, S. M.
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<strong>DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes.</strong>
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Hum. Molec. Genet. 10: 2917-2931, 2001.
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<li>
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<p class="mim-text-font">
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Fabbri, M., Garzon, R., Cimmino, A., Liu, Z., Zanesi, N., Callegari, E., Liu, S., Alder, H., Costinean, S., Fernandez-Cymering, C., Volinia, S., Guler, G., Morrison, C. D., Chan, K. K., Marcucci, G., Calin, G. A., Huebner, K., Croce, C. M.
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<strong>MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B.</strong>
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Proc. Nat. Acad. Sci. 104: 15805-15810, 2007.
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[PubMed: 17890317]
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<p class="mim-text-font">
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Gao, L., Emperle, M., Guo, Y., Grimm, S. A., Ren, W., Adam, S., Uryu, H., Zhang, Z. M., Chen, D., Yin, J., Dukatz, M., Anteneh, H., Jurkowska, R. Z., Lu, J., Wang, Y., Bashtrykov, P., Wade, P. A., Wang, G. G., Jeltsch, A., Song, J.
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<strong>Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms.</strong>
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Nature Commun. 11: 3355, 2020.
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[PubMed: 32620778]
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<p class="mim-text-font">
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Geiman, T. M., Sankpal, U. T., Robertson, A. K., Chen, Y., Mazumdar, M., Heale, J. T., Schmiesing, J. A., Kim, W., Yokomori, K., Zhao, Y., Robertson, K. D.
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<strong>Isolation and characterization of a novel DNA methyltransferase complex linking DNMT3B with components of the mitotic chromosome condensation machinery.</strong>
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Nucleic Acids Res. 32: 2716-2729, 2004.
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[PubMed: 15148359]
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[Full Text: https://doi.org/10.1093/nar/gkh589]
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<li>
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<p class="mim-text-font">
|
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Gendrel, A.-V., Apedaile, A., Coker, H., Termanis, A., Zvetkova, I., Godwin, J., Tang, Y. A., Huntley, D., Montana, G., Taylor, S., Giannoulatou, E., Heard, E., Stancheva, I., Brockdorff, N.
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<strong>Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome.</strong>
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Dev. Cell 23: 265-279, 2012.
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[PubMed: 22841499]
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[Full Text: https://doi.org/10.1016/j.devcel.2012.06.011]
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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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Gopalakrishnan, S., Sullivan, B. A., Trazzi, S., Della Valle, G., Robertson, K. D.
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 01/21/2025<br>Bao Lige - updated : 08/31/2023<br>Cassandra L. Kniffin - updated : 08/12/2021<br>Ada Hamosh - updated : 05/13/2019<br>Bao Lige - updated : 01/28/2019<br>Ada Hamosh - updated : 03/15/2018<br>Cassandra L. Kniffin - updated : 06/14/2016<br>Ada Hamosh - updated : 10/13/2014<br>Patricia A. Hartz - updated : 12/14/2012<br>Paul J. Converse - updated : 8/3/2012<br>George E. Tiller - updated : 7/7/2010<br>Cassandra L. Kniffin - updated : 12/29/2009<br>Matthew B. Gross - updated : 10/8/2009<br>Patricia A. Hartz - updated : 9/17/2009<br>Patricia A. Hartz - updated : 3/24/2008<br>Ada Hamosh - updated : 8/28/2007<br>Ada Hamosh - updated : 12/6/2006<br>George E. Tiller - updated : 10/3/2005<br>George E. Tiller - updated : 9/12/2005<br>George E. Tiller - updated : 9/9/2005<br>Victor A. McKusick - updated : 2/4/2005<br>Ada Hamosh - updated : 9/29/2004<br>Ada Hamosh - updated : 7/22/2004<br>Patricia A. Hartz - updated : 1/23/2003<br>Patricia A. Hartz - updated : 11/5/2002<br>Victor A. McKusick - updated : 10/7/2002<br>George E. Tiller - updated : 8/15/2002<br>Ada Hamosh - updated : 4/9/2002<br>Victor A. McKusick - updated : 12/27/2001<br>Victor A. McKusick - updated : 1/11/2001<br>Victor A. McKusick - updated : 1/2/2001<br>Victor A. McKusick - updated : 1/3/2000<br>Stylianos E. Antonarakis - updated : 12/2/1999<br>Stylianos E. Antonarakis - updated : 11/12/1999<br>Ada Hamosh - updated : 11/11/1999
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</span>
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</div>
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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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Victor A. McKusick : 7/27/1998
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