3127 lines
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Entry
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- *601058 - H3 HISTONE, FAMILY 3B; H3F3B
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601058</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601058">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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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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<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=ENSG00000132475;t=ENST00000254810" 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=3021" 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=601058" 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=ENSG00000132475;t=ENST00000254810" 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_005324" 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_005324" 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=601058" 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=03036&isoform_id=03036_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/H3-3B" 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/761716,4885385,10441988,12654577,13676330,15215436,17028475,31873260,55977062,80477731,119609723,119609724,119609725,189053462,194388016,2462554800" 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/P84243" 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=3021" 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=ENSG00000132475;t=ENST00000254810" 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=H3-3B" 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=H3-3B" 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+3021" 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/H3-3B" 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:3021" 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/3021" 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=chr17&hgg_gene=ENST00000254810.8&hgg_start=75776434&hgg_end=75779779&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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601058[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 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=601058[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/H3-3B/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/ENSG00000132475" 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=H3-3B" 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=H3-3B" 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=H3-3B" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=H3-3B&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/PA29140" 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:4765" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0004828.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/search?q=MGI:1097686 MGI:1101768" 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/H3-3B#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/batch/summary?idType=MGI&ids=MGI:1097686 MGI:1101768" 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/3021/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=3021" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00001945;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00001945 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00001946;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00001946 </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 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:3021" 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=H3-3B&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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601058
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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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H3 HISTONE, FAMILY 3B; H3F3B
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
H3.3B
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=H3-3B" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">H3-3B</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/17/952?start=-3&limit=10&highlight=952">17q25.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr17:75776434-75779779&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'})">17:75,776,434-75,779,779</a> </span>
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</em>
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</strong>
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<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>
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</span>
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</div>
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<div>
|
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<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>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/17/952?start=-3&limit=10&highlight=952">
|
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17q25.1
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Bryant-Li-Bhoj neurodevelopmental syndrome 2
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<a href="/entry/619721"> 619721 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/601058" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/601058" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></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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<a id="text" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
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<div>
|
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<a id="description" class="mim-anchor"></a>
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<p>Histones are the basic nuclear proteins responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Five classes of histone genes have been reported, all of which are involved in chromosome structure. Some classes are expressed only during S phase, while others are replication independent. The latter are referred to as replacement histones and are expressed in quiescent or terminally differentiated cells. H3.3 is a replacement histone that is encoded by 2 distinct replication-independent genes, H3.3A (H3F3A; <a href="/entry/601128">601128</a>) and H3.3B (H3F3B). The proteins encoded by the H3.3A and H3.3B genes are identical (<a href="#1" class="mim-tip-reference" title="Albig, W., Bramlage, B., Gruber, K., Klobeck, H.-G., Kunz, J., Doenecke, D. <strong>The human replacement histone H3.3B gene (H3F3B).</strong> Genomics 30: 264-272, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8586426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8586426</a>] [<a href="https://doi.org/10.1006/geno.1995.9878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8586426">Albig et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8586426" 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>For additional background information on histones, histone gene clusters, and the H3 histone family, see HIST1H3A (<a href="/entry/602810">602810</a>).</p>
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<p><a href="#1" class="mim-tip-reference" title="Albig, W., Bramlage, B., Gruber, K., Klobeck, H.-G., Kunz, J., Doenecke, D. <strong>The human replacement histone H3.3B gene (H3F3B).</strong> Genomics 30: 264-272, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8586426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8586426</a>] [<a href="https://doi.org/10.1006/geno.1995.9878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8586426">Albig et al. (1995)</a> used a histone H1 probe to identify a full-length cDNA, designated H3.3B by them, from a human testicular library. The amino acid sequence of H3.3B is identical to that of H3.3A, as well as to the amino acid sequences of H3.3 homologs in other species, including Drosophila. However, the nucleotide sequences of H3.3A and H3.3B differ substantially, especially in the 5-prime and 3-prime UTRs. Northern blot analysis detected 1.8- and 1.4-kb mRNAs, which differ due to alternative use of polyadenylation signals, in RNA from testis and the HEK293 embryonal kidney tumor cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8586426" 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 an RNase protections assay, <a href="#7" class="mim-tip-reference" title="Witt, O., Albig, W., Doenecke, D. <strong>Transcriptional regulation of the human replacement histone gene H3.3B.</strong> FEBS Lett. 408: 255-260, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9188772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9188772</a>] [<a href="https://doi.org/10.1016/s0014-5793(97)00436-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9188772">Witt et al. (1997)</a> showed variable expression of 1.4- and 1.8-kb H3.3B transcripts in human tissues and cell lines, with the 1.8-kb transcript predominating. They reported that H3.3a was basally expressed in mouse testis, whereas H3.3b was expressed in a stage-specific manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9188772" 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 Northern blot analysis, <a href="#4" class="mim-tip-reference" title="Frank, D., Doenecke, D., Albig, W. <strong>Differential expression of human replacement and cell cycle dependent H3 histone genes.</strong> Gene 312: 135-143, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12909349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12909349</a>] [<a href="https://doi.org/10.1016/s0378-1119(03)00609-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12909349">Frank et al. (2003)</a> assayed for expression of the replacement histones H3.3A and H3.3B and the cell cycle-dependent histone H3/m (HIST2H3C; <a href="/entry/142780">142780</a>) in human tissues and cell lines. All 6 cell lines expressed H3.3A, H3.3B, and H3/m at high levels. Conversely, fetal liver predominantly expressed H3/m, likely due to its rapid cell growth, whereas adult liver, kidney, and heart predominantly expressed H3.3A and H3.3B. The H3.3B transcript was detected at 1.4 and 1.8 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12909349" 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="#1" class="mim-tip-reference" title="Albig, W., Bramlage, B., Gruber, K., Klobeck, H.-G., Kunz, J., Doenecke, D. <strong>The human replacement histone H3.3B gene (H3F3B).</strong> Genomics 30: 264-272, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8586426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8586426</a>] [<a href="https://doi.org/10.1006/geno.1995.9878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8586426">Albig et al. (1995)</a> isolated the H3.3B gene and found that it spans approximately 2.5 kb. It has 4 exons, the first of which is noncoding, and exhibits features characteristic of a histone H3.3 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8586426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Witt, O., Albig, W., Doenecke, D. <strong>Transcriptional regulation of the human replacement histone gene H3.3B.</strong> FEBS Lett. 408: 255-260, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9188772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9188772</a>] [<a href="https://doi.org/10.1016/s0014-5793(97)00436-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9188772">Witt et al. (1997)</a> identified 6 CCAAT boxes, a conserved functional octamer element, a CRE/TRE element, and a TATA box within the proximal promoter region of the H3.3B gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9188772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Frank, D., Doenecke, D., Albig, W. <strong>Differential expression of human replacement and cell cycle dependent H3 histone genes.</strong> Gene 312: 135-143, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12909349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12909349</a>] [<a href="https://doi.org/10.1016/s0378-1119(03)00609-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12909349">Frank et al. (2003)</a> stated that the 3-prime end of the H3.3B gene contains 3 transcriptional termination signals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12909349" 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="#1" class="mim-tip-reference" title="Albig, W., Bramlage, B., Gruber, K., Klobeck, H.-G., Kunz, J., Doenecke, D. <strong>The human replacement histone H3.3B gene (H3F3B).</strong> Genomics 30: 264-272, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8586426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8586426</a>] [<a href="https://doi.org/10.1006/geno.1995.9878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8586426">Albig et al. (1995)</a> mapped the H3F3B gene by fluorescence in situ hybridization to chromosome 17q25. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8586426" 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>See H3F3A (<a href="/entry/601128">601128</a>) for functional information on H3.3 histone.</p><p>See HIST1H3A (<a href="/entry/602810">602810</a>) for functional information on the H3 histone family.</p>
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<a href="#2" class="mim-tip-reference" title="Behjati, S., Tarpey, P. S., Presneau, N., Scheipl, S., Pillay, N., Van Loo, P., Wedge, D. C., Cooke, S. L., Gundem, G., Davies, H., Nik-Zainal, S., Martin, S., and 17 others. <strong>Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone.</strong> Nature Genet. 45: 1479-1482, 2013. Note: Erratum: Nature Genet. 46: 316 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24162739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24162739</a>] [<a href="https://doi.org/10.1038/ng.2814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24162739">Behjati et al. (2013)</a> reported exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases (95%) of chondroblastoma, <a href="#2" class="mim-tip-reference" title="Behjati, S., Tarpey, P. S., Presneau, N., Scheipl, S., Pillay, N., Van Loo, P., Wedge, D. C., Cooke, S. L., Gundem, G., Davies, H., Nik-Zainal, S., Martin, S., and 17 others. <strong>Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone.</strong> Nature Genet. 45: 1479-1482, 2013. Note: Erratum: Nature Genet. 46: 316 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24162739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24162739</a>] [<a href="https://doi.org/10.1038/ng.2814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24162739">Behjati et al. (2013)</a> found K36M alterations predominantly encoded by H3F3B, which is 1 of 2 genes for histone H3.3. In contrast, in 92% (49 of 53) of giant cell tumors of bone, <a href="#2" class="mim-tip-reference" title="Behjati, S., Tarpey, P. S., Presneau, N., Scheipl, S., Pillay, N., Van Loo, P., Wedge, D. C., Cooke, S. L., Gundem, G., Davies, H., Nik-Zainal, S., Martin, S., and 17 others. <strong>Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone.</strong> Nature Genet. 45: 1479-1482, 2013. Note: Erratum: Nature Genet. 46: 316 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24162739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24162739</a>] [<a href="https://doi.org/10.1038/ng.2814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24162739">Behjati et al. (2013)</a> found histone H3.3 alterations exclusively in H3F3A (<a href="/entry/601128">601128</a>), leading to G34W or, in 1 case, G34L alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding K27M and G34R or G34V alterations in childhood brain tumors, a picture of tumor type specificity for histone H3.3 driver alterations emerged, indicating that histone H3.3 residues, mutations, and genes have distinct functions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24162739" 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>Bryant-Li-Bhoj Neurodevelopmental Syndrome 2</em></strong></p><p>
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In 13 unrelated patients with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; <a href="/entry/619721">619721</a>), <a href="#3" class="mim-tip-reference" title="Bryant, L., Li, D., Cox, S. G., Marchione, D., Joiner, E. F., Wilson, K., Janssen, K., Lee, P., March, M. E., Nair, D., Sherr, E., Fregeau, B., and 119 others. <strong>Histone H3.3 beyond cancer: germline mutations in histone 3 family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.</strong> Sci. Adv. 6: eabc9207, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33268356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33268356</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33268356[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/sciadv.abc9207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33268356">Bryant et al. (2020)</a> identified de novo heterozygous mutations in the H3F3B gene (see, e.g., <a href="#0001">601058.0001</a>-<a href="#0004">601058.0004</a>). The mutations, which were found by whole-exome or genome sequencing, occurred throughout the gene. All but 1 were missense variants, and all were absent from the gnomAD database. In vitro studies of lymphoblasts or fibroblasts derived from a subset of patients showed that the distribution of posttranslational modification (PTM) histone abundances was similar to controls. The overall histone PTM variation was slightly increased in controls compared to patients. Nonetheless, some histone PTMs were altered in patients compared to controls. The findings suggested that mutant histones can be incorporated into the nucleosome and cause local deregulation of the chromatin state with modest alterations in the control of histone modification. This could affect multiple histone functions, including gene expression, chromatin stability, DNA damage repair, and differentiation. RNA sequencing of a subset of pooled patient cells showed upregulation of genes involved in mitosis, and in vitro studies of pooled patient fibroblast lines showed increased cellular proliferation compared to controls; viability of patient cells was similar to controls. In silico molecular modeling of the mutations suggested 3 broad scenarios for the variants' impact: disruption of H3.3 DNA binding; disrupted formation of the histone octamer or binding with other histones; and disruption of histone-protein binding to chaperones or other interacting proteins. There were no genotype/phenotype correlations. None of the patients developed cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33268356" 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 6 unrelated patients with BRYLIB2, <a href="#6" class="mim-tip-reference" title="Okur, V., Chen, Z., Vossaert, L., Peacock, S., Rosenfeld, J., Zhao, L., Du, H., Calamaro, E., Gerard, A., Zhao, S., Kelsay, J., Lahr, A., and 26 others. <strong>De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.</strong> NPJ Genom. Med. 6: 104, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34876591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34876591</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34876591[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/s41525-021-00268-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34876591">Okur et al. (2021)</a> identified 6 different de novo heterozygous mutations at highly conserved residues in the H3F3B gene (see, e.g., <a href="#0001">601058.0001</a> and <a href="#0005">601058.0005</a>). The mutations, which were found by exome sequencing, were absent from the gnomAD database. Expression of a subset of variants in HEK293 cells showed that some resulted in decreased protein levels. The mutant proteins localized normally to the nucleus. Molecular modeling suggested that some, but not all, mutations might alter the PTMs of histone H3.3. The possible molecular pathomechanism of other mutations was unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34876591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Jang, C.-W., Shibata, Y., Starmer, J., Yee, D., Magnuson, T. <strong>Histone H3.3 maintains genome integrity during mammalian development.</strong> Genes Dev. 29: 1377-1392, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26159997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26159997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26159997[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/10.1101/gad.264150.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26159997">Jang et al. (2015)</a> reported that deletion of H3f3a or H3f3b in mice had no apparent deleterious impact on phenotype or fertility. However, knockout of both genes (H3.3 DKO) led to developmental retardation and embryonic lethality. H3.3 DKO embryos showed reduced cell proliferation and increased cell death. Embryonic stem cells from H3.3 DKO mice had mitotic defects. Growth retardation could be rescued by deletion of p53 (TP53; <a href="/entry/191170">191170</a>). RNA sequencing analysis revealed that p53 -/- H3.3 DKO embryos had only limited changes to the transcriptome. H3.3 DKO mouse embryonic fibroblasts lacking p53 proliferated but showed mitotic abnormalities associated with defects in chromosomal heterochromatic structures at telomeres, centromeres, and pericentromeric regions, as well as genome instability. Karyotypic abnormalities and DNA damage in H3.3 DKO mice led to p53 pathway activation. <a href="#5" class="mim-tip-reference" title="Jang, C.-W., Shibata, Y., Starmer, J., Yee, D., Magnuson, T. <strong>Histone H3.3 maintains genome integrity during mammalian development.</strong> Genes Dev. 29: 1377-1392, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26159997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26159997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26159997[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/10.1101/gad.264150.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26159997">Jang et al. (2015)</a> concluded that H3.3 supports chromosomal heterochromatic structures, thus maintaining genome integrity during mammalian development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26159997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601058[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2061653458 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2061653458;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=rs2061653458" 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=rs2061653458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 10-year-old boy (patient 34) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; <a href="/entry/619721">619721</a>) <a href="#3" class="mim-tip-reference" title="Bryant, L., Li, D., Cox, S. G., Marchione, D., Joiner, E. F., Wilson, K., Janssen, K., Lee, P., March, M. E., Nair, D., Sherr, E., Fregeau, B., and 119 others. <strong>Histone H3.3 beyond cancer: germline mutations in histone 3 family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.</strong> Sci. Adv. 6: eabc9207, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33268356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33268356</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33268356[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/sciadv.abc9207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33268356">Bryant et al. (2020)</a> identified a de novo heterozygous c.25C-T transition (c.25C-T, NM_005324.4) in the H3F3B gene, resulting in an arg9-to-cys (R9C) substitution in the nuclear localization signal. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this mutation would be described as ARG8CYS (R8C) according to standard histone nomenclature, which omits numbering the initiator methionine. Functional studies of the variant were not performed. The patient had global developmental delay, hypotonia, and dysmorphic features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33268356" 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 33-year-old woman (patient 6) with BRYLIB2, <a href="#6" class="mim-tip-reference" title="Okur, V., Chen, Z., Vossaert, L., Peacock, S., Rosenfeld, J., Zhao, L., Du, H., Calamaro, E., Gerard, A., Zhao, S., Kelsay, J., Lahr, A., and 26 others. <strong>De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.</strong> NPJ Genom. Med. 6: 104, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34876591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34876591</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34876591[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/s41525-021-00268-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34876591">Okur et al. (2021)</a> identified a de novo heterozygous R9C mutation at a conserved residue in the H3F3B gene. These authors stated that the substitution occurred in the core histone H3.3 domain. Functional studies were not performed, but molecular modeling predicted that it would alter posttranslational modifications of the protein. The patient had global developmental delay, short stature, seizures, hypothyroidism, type I diabetes mellitus, and dysmorphic features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34876591" 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 5-year-old girl (patient 37) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; <a href="/entry/619721">619721</a>), <a href="#3" class="mim-tip-reference" title="Bryant, L., Li, D., Cox, S. G., Marchione, D., Joiner, E. F., Wilson, K., Janssen, K., Lee, P., March, M. E., Nair, D., Sherr, E., Fregeau, B., and 119 others. <strong>Histone H3.3 beyond cancer: germline mutations in histone 3 family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.</strong> Sci. Adv. 6: eabc9207, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33268356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33268356</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33268356[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/sciadv.abc9207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33268356">Bryant et al. (2020)</a> identified a de novo heterozygous c.88G-C transversion (c.88G-C, NM_005324.4) in the H3F3B gene, resulting in an ala30-to-pro (A30P) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this mutation would be described as ALA29PRO (A29P) according to standard histone nomenclature, which omits numbering the initiator methionine. In vitro studies showed that the A30P mutation resulted in notable dysregulation of posttranslational modification (PTM) compared to controls. The patient had global developmental delay, inability to walk or speak, and early-onset seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33268356" 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">rs2143629995 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2143629995;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=rs2143629995" 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=rs2143629995" 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 unrelated patients (patients 43 and 44) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; <a href="/entry/619721">619721</a>), <a href="#3" class="mim-tip-reference" title="Bryant, L., Li, D., Cox, S. G., Marchione, D., Joiner, E. F., Wilson, K., Janssen, K., Lee, P., March, M. E., Nair, D., Sherr, E., Fregeau, B., and 119 others. <strong>Histone H3.3 beyond cancer: germline mutations in histone 3 family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.</strong> Sci. Adv. 6: eabc9207, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33268356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33268356</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33268356[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/sciadv.abc9207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33268356">Bryant et al. (2020)</a> identified a de novo heterozygous c.365C-G transversion (c.365C-G, NM_005324.4) in the H3F3B gene, resulting in a pro122-to-arg (P122R) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this mutation would be described as PRO121ARG (P121R) according to standard histone nomenclature, which omits numbering the initiator methionine. In vitro studies of pooled patient cells suggested that the mutation caused altered posttranslational modifications of the protein. The patients, who were 10 and 18 years of age, had global developmental delay, early-onset severe seizures, and spasticity. Neither could walk or speak. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33268356" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 BRYANT-LI-BHOJ NEURODEVELOPMENTAL SYNDROME 2</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">rs2143629984 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2143629984;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=rs2143629984" 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=rs2143629984" 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=RCV001823807 OR RCV003407831" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001823807, RCV003407831" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001823807...</a>
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<p>In a 4-year-old girl (patient 45) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; <a href="/entry/619721">619721</a>), <a href="#3" class="mim-tip-reference" title="Bryant, L., Li, D., Cox, S. G., Marchione, D., Joiner, E. F., Wilson, K., Janssen, K., Lee, P., March, M. E., Nair, D., Sherr, E., Fregeau, B., and 119 others. <strong>Histone H3.3 beyond cancer: germline mutations in histone 3 family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.</strong> Sci. Adv. 6: eabc9207, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33268356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33268356</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33268356[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/sciadv.abc9207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33268356">Bryant et al. (2020)</a> identified a de novo heterozygous c.377A-G transition (c.377A-G, NM_005324.4) in the H3F3B gene, resulting in a gln126-to-arg (Q126R) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this mutation would be described as GLN125ARG (Q125R) according to standard histone nomenclature, which omits numbering the initiator methionine. Functional studies of variant were not performed, but it was predicted to alter complex formation. The patient had global developmental delay, hypotonia, and dysmorphic features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33268356" 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">rs2143630846 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2143630846;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=rs2143630846" 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=rs2143630846" 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=RCV001541919 OR RCV001823781" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001541919, RCV001823781" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001541919...</a>
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<p>In a 5-year-old boy (patient 9) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; <a href="/entry/619721">619721</a>), <a href="#6" class="mim-tip-reference" title="Okur, V., Chen, Z., Vossaert, L., Peacock, S., Rosenfeld, J., Zhao, L., Du, H., Calamaro, E., Gerard, A., Zhao, S., Kelsay, J., Lahr, A., and 26 others. <strong>De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.</strong> NPJ Genom. Med. 6: 104, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34876591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34876591</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34876591[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/s41525-021-00268-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34876591">Okur et al. (2021)</a> identified a de novo heterozygous c.155T-A transversion (c.155T-A, NM_005324.5) in the H3F3B gene, resulting in an ile52-to-asn (I52N) substitution at a conserved residue in the core histone H3.3 domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Transfection of the mutation into HEK293 cells showed that it caused reduced protein levels compared to controls. Molecular modeling predicted that it would not have an effect on posttranslational modification. The patient had global developmental delay, hypotonia, and seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34876591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Albig1995" class="mim-anchor"></a>
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Albig, W., Bramlage, B., Gruber, K., Klobeck, H.-G., Kunz, J., Doenecke, D.
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<strong>The human replacement histone H3.3B gene (H3F3B).</strong>
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Genomics 30: 264-272, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8586426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8586426</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8586426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1995.9878" target="_blank">Full Text</a>]
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Behjati, S., Tarpey, P. S., Presneau, N., Scheipl, S., Pillay, N., Van Loo, P., Wedge, D. C., Cooke, S. L., Gundem, G., Davies, H., Nik-Zainal, S., Martin, S., and 17 others.
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<strong>Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone.</strong>
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Nature Genet. 45: 1479-1482, 2013. Note: Erratum: Nature Genet. 46: 316 only, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24162739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24162739</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24162739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.2814" target="_blank">Full Text</a>]
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Bryant, L., Li, D., Cox, S. G., Marchione, D., Joiner, E. F., Wilson, K., Janssen, K., Lee, P., March, M. E., Nair, D., Sherr, E., Fregeau, B., and 119 others.
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<strong>Histone H3.3 beyond cancer: germline mutations in histone 3 family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.</strong>
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Sci. Adv. 6: eabc9207, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33268356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33268356</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33268356[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=33268356" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/sciadv.abc9207" target="_blank">Full Text</a>]
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Frank, D., Doenecke, D., Albig, W.
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<strong>Differential expression of human replacement and cell cycle dependent H3 histone genes.</strong>
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Gene 312: 135-143, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12909349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12909349</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12909349" 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(03)00609-7" target="_blank">Full Text</a>]
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Jang, C.-W., Shibata, Y., Starmer, J., Yee, D., Magnuson, T.
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<strong>Histone H3.3 maintains genome integrity during mammalian development.</strong>
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Genes Dev. 29: 1377-1392, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26159997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26159997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26159997[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=26159997" 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/10.1101/gad.264150.115" target="_blank">Full Text</a>]
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Okur, V., Chen, Z., Vossaert, L., Peacock, S., Rosenfeld, J., Zhao, L., Du, H., Calamaro, E., Gerard, A., Zhao, S., Kelsay, J., Lahr, A., and 26 others.
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<strong>De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.</strong>
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NPJ Genom. Med. 6: 104, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34876591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34876591</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34876591[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=34876591" 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/s41525-021-00268-8" target="_blank">Full Text</a>]
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Witt, O., Albig, W., Doenecke, D.
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<strong>Transcriptional regulation of the human replacement histone gene H3.3B.</strong>
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FEBS Lett. 408: 255-260, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9188772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9188772</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9188772" 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/s0014-5793(97)00436-5" target="_blank">Full Text</a>]
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<a id="contributors" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 01/28/2022
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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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Paul J. Converse - updated : 04/06/2016<br>Ada Hamosh - updated : 1/14/2014<br>Patricia A. Hartz - updated : 2/6/2013<br>Matthew B. Gross - updated : 2/4/2013<br>Matthew B. Gross - updated : 5/17/2010<br>Rebekah S. Rasooly - updated : 7/8/1998
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Alan F. Scott : 2/11/1996
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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="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/02/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 02/01/2022<br>ckniffin : 01/28/2022<br>mgross : 04/06/2016<br>alopez : 4/1/2014<br>alopez : 1/14/2014<br>alopez : 1/14/2014<br>mgross : 2/6/2013<br>mgross : 2/5/2013<br>mgross : 2/4/2013<br>mgross : 5/17/2010<br>mgross : 5/17/2010<br>alopez : 4/14/2010<br>terry : 4/13/2010<br>alopez : 4/6/2010<br>alopez : 7/9/1998<br>alopez : 7/8/1998<br>alopez : 7/8/1998<br>mark : 9/22/1996<br>mark : 2/11/1996
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</span>
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</div>
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<div class="container visible-print-block">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 601058
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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H3 HISTONE, FAMILY 3B; H3F3B
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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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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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H3.3B
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: H3-3B</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 17q25.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 17:75,776,434-75,779,779 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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17q25.1
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</span>
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</td>
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<td>
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<span class="mim-font">
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Bryant-Li-Bhoj neurodevelopmental syndrome 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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619721
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<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>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Histones are the basic nuclear proteins responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Five classes of histone genes have been reported, all of which are involved in chromosome structure. Some classes are expressed only during S phase, while others are replication independent. The latter are referred to as replacement histones and are expressed in quiescent or terminally differentiated cells. H3.3 is a replacement histone that is encoded by 2 distinct replication-independent genes, H3.3A (H3F3A; 601128) and H3.3B (H3F3B). The proteins encoded by the H3.3A and H3.3B genes are identical (Albig et al., 1995). </p><p>For additional background information on histones, histone gene clusters, and the H3 histone family, see HIST1H3A (602810).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Albig et al. (1995) used a histone H1 probe to identify a full-length cDNA, designated H3.3B by them, from a human testicular library. The amino acid sequence of H3.3B is identical to that of H3.3A, as well as to the amino acid sequences of H3.3 homologs in other species, including Drosophila. However, the nucleotide sequences of H3.3A and H3.3B differ substantially, especially in the 5-prime and 3-prime UTRs. Northern blot analysis detected 1.8- and 1.4-kb mRNAs, which differ due to alternative use of polyadenylation signals, in RNA from testis and the HEK293 embryonal kidney tumor cell line. </p><p>Using an RNase protections assay, Witt et al. (1997) showed variable expression of 1.4- and 1.8-kb H3.3B transcripts in human tissues and cell lines, with the 1.8-kb transcript predominating. They reported that H3.3a was basally expressed in mouse testis, whereas H3.3b was expressed in a stage-specific manner. </p><p>Using Northern blot analysis, Frank et al. (2003) assayed for expression of the replacement histones H3.3A and H3.3B and the cell cycle-dependent histone H3/m (HIST2H3C; 142780) in human tissues and cell lines. All 6 cell lines expressed H3.3A, H3.3B, and H3/m at high levels. Conversely, fetal liver predominantly expressed H3/m, likely due to its rapid cell growth, whereas adult liver, kidney, and heart predominantly expressed H3.3A and H3.3B. The H3.3B transcript was detected at 1.4 and 1.8 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Albig et al. (1995) isolated the H3.3B gene and found that it spans approximately 2.5 kb. It has 4 exons, the first of which is noncoding, and exhibits features characteristic of a histone H3.3 gene. </p><p>Witt et al. (1997) identified 6 CCAAT boxes, a conserved functional octamer element, a CRE/TRE element, and a TATA box within the proximal promoter region of the H3.3B gene. </p><p>Frank et al. (2003) stated that the 3-prime end of the H3.3B gene contains 3 transcriptional termination signals. </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>Albig et al. (1995) mapped the H3F3B gene by fluorescence in situ hybridization to chromosome 17q25. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>See H3F3A (601128) for functional information on H3.3 histone.</p><p>See HIST1H3A (602810) for functional information on the H3 histone family.</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>Somatic Mutations</em></strong></p><p>
|
|
Behjati et al. (2013) reported exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases (95%) of chondroblastoma, Behjati et al. (2013) found K36M alterations predominantly encoded by H3F3B, which is 1 of 2 genes for histone H3.3. In contrast, in 92% (49 of 53) of giant cell tumors of bone, Behjati et al. (2013) found histone H3.3 alterations exclusively in H3F3A (601128), leading to G34W or, in 1 case, G34L alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding K27M and G34R or G34V alterations in childhood brain tumors, a picture of tumor type specificity for histone H3.3 driver alterations emerged, indicating that histone H3.3 residues, mutations, and genes have distinct functions. </p><p><strong><em>Bryant-Li-Bhoj Neurodevelopmental Syndrome 2</em></strong></p><p>
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|
In 13 unrelated patients with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; 619721), Bryant et al. (2020) identified de novo heterozygous mutations in the H3F3B gene (see, e.g., 601058.0001-601058.0004). The mutations, which were found by whole-exome or genome sequencing, occurred throughout the gene. All but 1 were missense variants, and all were absent from the gnomAD database. In vitro studies of lymphoblasts or fibroblasts derived from a subset of patients showed that the distribution of posttranslational modification (PTM) histone abundances was similar to controls. The overall histone PTM variation was slightly increased in controls compared to patients. Nonetheless, some histone PTMs were altered in patients compared to controls. The findings suggested that mutant histones can be incorporated into the nucleosome and cause local deregulation of the chromatin state with modest alterations in the control of histone modification. This could affect multiple histone functions, including gene expression, chromatin stability, DNA damage repair, and differentiation. RNA sequencing of a subset of pooled patient cells showed upregulation of genes involved in mitosis, and in vitro studies of pooled patient fibroblast lines showed increased cellular proliferation compared to controls; viability of patient cells was similar to controls. In silico molecular modeling of the mutations suggested 3 broad scenarios for the variants' impact: disruption of H3.3 DNA binding; disrupted formation of the histone octamer or binding with other histones; and disruption of histone-protein binding to chaperones or other interacting proteins. There were no genotype/phenotype correlations. None of the patients developed cancer. </p><p>In 6 unrelated patients with BRYLIB2, Okur et al. (2021) identified 6 different de novo heterozygous mutations at highly conserved residues in the H3F3B gene (see, e.g., 601058.0001 and 601058.0005). The mutations, which were found by exome sequencing, were absent from the gnomAD database. Expression of a subset of variants in HEK293 cells showed that some resulted in decreased protein levels. The mutant proteins localized normally to the nucleus. Molecular modeling suggested that some, but not all, mutations might alter the PTMs of histone H3.3. The possible molecular pathomechanism of other mutations was unclear. </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">
|
|
<strong>Animal Model</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Jang et al. (2015) reported that deletion of H3f3a or H3f3b in mice had no apparent deleterious impact on phenotype or fertility. However, knockout of both genes (H3.3 DKO) led to developmental retardation and embryonic lethality. H3.3 DKO embryos showed reduced cell proliferation and increased cell death. Embryonic stem cells from H3.3 DKO mice had mitotic defects. Growth retardation could be rescued by deletion of p53 (TP53; 191170). RNA sequencing analysis revealed that p53 -/- H3.3 DKO embryos had only limited changes to the transcriptome. H3.3 DKO mouse embryonic fibroblasts lacking p53 proliferated but showed mitotic abnormalities associated with defects in chromosomal heterochromatic structures at telomeres, centromeres, and pericentromeric regions, as well as genome instability. Karyotypic abnormalities and DNA damage in H3.3 DKO mice led to p53 pathway activation. Jang et al. (2015) concluded that H3.3 supports chromosomal heterochromatic structures, thus maintaining genome integrity during mammalian development. </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>5 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 BRYANT-LI-BHOJ NEURODEVELOPMENTAL SYNDROME 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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H3F3B, ARG9CYS
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<br />
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SNP: rs2061653458,
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ClinVar: RCV001266532, RCV001541916, RCV001823767
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 10-year-old boy (patient 34) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; 619721) Bryant et al. (2020) identified a de novo heterozygous c.25C-T transition (c.25C-T, NM_005324.4) in the H3F3B gene, resulting in an arg9-to-cys (R9C) substitution in the nuclear localization signal. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this mutation would be described as ARG8CYS (R8C) according to standard histone nomenclature, which omits numbering the initiator methionine. Functional studies of the variant were not performed. The patient had global developmental delay, hypotonia, and dysmorphic features. </p><p>In a 33-year-old woman (patient 6) with BRYLIB2, Okur et al. (2021) identified a de novo heterozygous R9C mutation at a conserved residue in the H3F3B gene. These authors stated that the substitution occurred in the core histone H3.3 domain. Functional studies were not performed, but molecular modeling predicted that it would alter posttranslational modifications of the protein. The patient had global developmental delay, short stature, seizures, hypothyroidism, type I diabetes mellitus, and dysmorphic features. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 BRYANT-LI-BHOJ NEURODEVELOPMENTAL SYNDROME 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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H3F3B, ALA30PRO
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<br />
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SNP: rs2143631293,
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ClinVar: RCV001823805
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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 5-year-old girl (patient 37) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; 619721), Bryant et al. (2020) identified a de novo heterozygous c.88G-C transversion (c.88G-C, NM_005324.4) in the H3F3B gene, resulting in an ala30-to-pro (A30P) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this mutation would be described as ALA29PRO (A29P) according to standard histone nomenclature, which omits numbering the initiator methionine. In vitro studies showed that the A30P mutation resulted in notable dysregulation of posttranslational modification (PTM) compared to controls. The patient had global developmental delay, inability to walk or speak, and early-onset seizures. </p>
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<strong>.0003 BRYANT-LI-BHOJ NEURODEVELOPMENTAL SYNDROME 2</strong>
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</span>
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</h4>
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H3F3B, PRO122ARG
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SNP: rs2143629995,
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ClinVar: RCV001823806
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<p>In 2 unrelated patients (patients 43 and 44) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; 619721), Bryant et al. (2020) identified a de novo heterozygous c.365C-G transversion (c.365C-G, NM_005324.4) in the H3F3B gene, resulting in a pro122-to-arg (P122R) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this mutation would be described as PRO121ARG (P121R) according to standard histone nomenclature, which omits numbering the initiator methionine. In vitro studies of pooled patient cells suggested that the mutation caused altered posttranslational modifications of the protein. The patients, who were 10 and 18 years of age, had global developmental delay, early-onset severe seizures, and spasticity. Neither could walk or speak. </p>
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<strong>.0004 BRYANT-LI-BHOJ NEURODEVELOPMENTAL SYNDROME 2</strong>
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</span>
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</h4>
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H3F3B, GLN126ARG
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<br />
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SNP: rs2143629984,
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ClinVar: RCV001823807, RCV003407831
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<span class="mim-text-font">
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<p>In a 4-year-old girl (patient 45) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; 619721), Bryant et al. (2020) identified a de novo heterozygous c.377A-G transition (c.377A-G, NM_005324.4) in the H3F3B gene, resulting in a gln126-to-arg (Q126R) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The authors noted that this mutation would be described as GLN125ARG (Q125R) according to standard histone nomenclature, which omits numbering the initiator methionine. Functional studies of variant were not performed, but it was predicted to alter complex formation. The patient had global developmental delay, hypotonia, and dysmorphic features. </p>
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<h4>
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<span class="mim-font">
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<strong>.0005 BRYANT-LI-BHOJ NEURODEVELOPMENTAL SYNDROME 2</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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H3F3B, ILE52ASN
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<br />
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SNP: rs2143630846,
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ClinVar: RCV001541919, RCV001823781
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</span>
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<span class="mim-text-font">
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<p>In a 5-year-old boy (patient 9) with Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2; 619721), Okur et al. (2021) identified a de novo heterozygous c.155T-A transversion (c.155T-A, NM_005324.5) in the H3F3B gene, resulting in an ile52-to-asn (I52N) substitution at a conserved residue in the core histone H3.3 domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Transfection of the mutation into HEK293 cells showed that it caused reduced protein levels compared to controls. Molecular modeling predicted that it would not have an effect on posttranslational modification. The patient had global developmental delay, hypotonia, and seizures. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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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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Albig, W., Bramlage, B., Gruber, K., Klobeck, H.-G., Kunz, J., Doenecke, D.
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<strong>The human replacement histone H3.3B gene (H3F3B).</strong>
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Genomics 30: 264-272, 1995.
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[PubMed: 8586426]
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[Full Text: https://doi.org/10.1006/geno.1995.9878]
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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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Behjati, S., Tarpey, P. S., Presneau, N., Scheipl, S., Pillay, N., Van Loo, P., Wedge, D. C., Cooke, S. L., Gundem, G., Davies, H., Nik-Zainal, S., Martin, S., and 17 others.
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<strong>Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone.</strong>
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Nature Genet. 45: 1479-1482, 2013. Note: Erratum: Nature Genet. 46: 316 only, 2014.
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[PubMed: 24162739]
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[Full Text: https://doi.org/10.1038/ng.2814]
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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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Bryant, L., Li, D., Cox, S. G., Marchione, D., Joiner, E. F., Wilson, K., Janssen, K., Lee, P., March, M. E., Nair, D., Sherr, E., Fregeau, B., and 119 others.
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|
<strong>Histone H3.3 beyond cancer: germline mutations in histone 3 family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.</strong>
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Sci. Adv. 6: eabc9207, 2020.
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[PubMed: 33268356]
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[Full Text: https://doi.org/10.1126/sciadv.abc9207]
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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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Frank, D., Doenecke, D., Albig, W.
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<strong>Differential expression of human replacement and cell cycle dependent H3 histone genes.</strong>
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Gene 312: 135-143, 2003.
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[PubMed: 12909349]
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[Full Text: https://doi.org/10.1016/s0378-1119(03)00609-7]
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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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Jang, C.-W., Shibata, Y., Starmer, J., Yee, D., Magnuson, T.
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<strong>Histone H3.3 maintains genome integrity during mammalian development.</strong>
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Genes Dev. 29: 1377-1392, 2015.
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[PubMed: 26159997]
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[Full Text: https://doi.org/10.1101/gad.264150.115]
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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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Okur, V., Chen, Z., Vossaert, L., Peacock, S., Rosenfeld, J., Zhao, L., Du, H., Calamaro, E., Gerard, A., Zhao, S., Kelsay, J., Lahr, A., and 26 others.
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<strong>De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.</strong>
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NPJ Genom. Med. 6: 104, 2021.
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[PubMed: 34876591]
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[Full Text: https://doi.org/10.1038/s41525-021-00268-8]
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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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Witt, O., Albig, W., Doenecke, D.
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<strong>Transcriptional regulation of the human replacement histone gene H3.3B.</strong>
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FEBS Lett. 408: 255-260, 1997.
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[PubMed: 9188772]
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[Full Text: https://doi.org/10.1016/s0014-5793(97)00436-5]
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</p>
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</li>
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</ol>
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<br />
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 01/28/2022<br>Paul J. Converse - updated : 04/06/2016<br>Ada Hamosh - updated : 1/14/2014<br>Patricia A. Hartz - updated : 2/6/2013<br>Matthew B. Gross - updated : 2/4/2013<br>Matthew B. Gross - updated : 5/17/2010<br>Rebekah S. Rasooly - updated : 7/8/1998
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<span class="mim-text-font">
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Alan F. Scott : 2/11/1996
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carol : 02/02/2022<br>alopez : 02/01/2022<br>ckniffin : 01/28/2022<br>mgross : 04/06/2016<br>alopez : 4/1/2014<br>alopez : 1/14/2014<br>alopez : 1/14/2014<br>mgross : 2/6/2013<br>mgross : 2/5/2013<br>mgross : 2/4/2013<br>mgross : 5/17/2010<br>mgross : 5/17/2010<br>alopez : 4/14/2010<br>terry : 4/13/2010<br>alopez : 4/6/2010<br>alopez : 7/9/1998<br>alopez : 7/8/1998<br>alopez : 7/8/1998<br>mark : 9/22/1996<br>mark : 2/11/1996
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