4673 lines
374 KiB
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4673 lines
374 KiB
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Entry
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- *614366 - POLYMERASE III, RNA, SUBUNIT B; POLR3B
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- OMIM
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<p>
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<span class="h4">*614366</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/614366">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<h4 class="panel-title">
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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 class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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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=ENSG00000013503;t=ENST00000228347" 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=55703" 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=614366" 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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<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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<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=ENSG00000013503;t=ENST00000228347" 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_001160708,NM_018082,XM_017019621" 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_018082" 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=614366" 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://www.proteinatlas.org/search/POLR3B" 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/7022241,7022389,24429617,28277230,29428029,31873396,119618186,119618187,158256702,193784141,193786878,193787264,238908503,238908505,672425696,1034580532,2462532947" 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/Q9NW08" 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=55703" 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=ENSG00000013503;t=ENST00000228347" 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=POLR3B" 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=POLR3B" 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+55703" 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/POLR3B" 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:55703" 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/55703" 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=chr12&hgg_gene=ENST00000228347.9&hgg_start=106357748&hgg_end=106510198&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 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://medlineplus.gov/genetics/gene/polr3b" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=614366[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=614366[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/POLR3B/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/ENSG00000013503" 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=POLR3B" 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=POLR3B" 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=POLR3B" 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=POLR3B&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/PA134867680" 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:30348" 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/FBgn0004463.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1917678" 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/POLR3B#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:1917678" 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/55703/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=55703" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00017300;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-2887" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:55703" 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=POLR3B&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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614366
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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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POLYMERASE III, RNA, SUBUNIT B; POLR3B
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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">
|
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RPC2<br />
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C128, S. CEREVISIAE, HOMOLOG OF; C128
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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=POLR3B" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">POLR3B</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/12/757?start=-3&limit=10&highlight=757">12q23.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:106357748-106510198&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'})">12:106,357,748-106,510,198</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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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=619742,614381" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
|
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
|
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</th>
|
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<th>
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
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|
|
<tr>
|
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<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/12/757?start=-3&limit=10&highlight=757">
|
|
12q23.3
|
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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">
|
|
Charcot-Marie-Tooth disease, demyelinating, type 1I
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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|
|
<a href="/entry/619742"> 619742 </a>
|
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|
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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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<tr>
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<td>
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<span class="mim-font">
|
|
Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism
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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/614381"> 614381 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/614366" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/614366" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</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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<p>The POLR3B gene encodes the second largest subunit of RNA polymerase (pol) III. RNA polymerase III consists of 17 subunits and is involved in the transcription of small noncoding RNAs, such as 5S ribosomal RNA (<a href="/entry/180420">180420</a>), U6 small nuclear RNA (see <a href="/entry/180692">180692</a>), and short interspersed nuclear elements (SINEs), as well as all transfer RNAs (summary by <a href="#8" class="mim-tip-reference" title="Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., Matsumoto, N. <strong>Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.</strong> Am. J. Hum. Genet. 89: 644-651, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036171[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036171">Saitsu et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using mass spectrometry to identify peptides obtained from purified HeLa cell RNA polymerase III complexes, followed by EST database analysis and PCR of a HeLa cell cDNA library, <a href="#6" class="mim-tip-reference" title="Hu, P., Wu, S., Sun, Y., Yuan, C.-C., Kobayashi, R., Myers, M. P., Hernandez, N. <strong>Characterization of human RNA polymerase III identifies orthologues for Saccharomyces cerevisiae RNA polymerase III subunits.</strong> Molec. Cell. Biol. 22: 8044-8055, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12391170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12391170</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12391170[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.22.22.8044-8055.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12391170">Hu et al. (2002)</a> cloned human POLR3B, which they called RPC2. The deduced 1,133-amino acid protein has a calculated molecular mass of 128 kD. It contains a zinc-binding domain near its C terminus that is predicted to form part of a clamp structure. Human RPC2 shares 63% amino acid identity with S. cerevisiae Rpc2 and 38% identity with the second largest subunit of human RNA polymerase II, RPB2 (POLR2B; <a href="/entry/180661">180661</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12391170" 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="Hartz, P. A. <strong>Personal Communication.</strong> Baltimore, Md. 11/29/2011."None>Hartz (2011)</a> mapped the POLR3B gene to chromosome 12q23.3. based on an alignment of the POLR3B sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AK001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AK001250</a>) with the genomic sequence (GRCh37).</p>
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<p><strong><em>Hypomyelinating Leukodystrophy 8</em></strong></p><p>
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Using whole-exome sequencing, <a href="#8" class="mim-tip-reference" title="Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., Matsumoto, N. <strong>Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.</strong> Am. J. Hum. Genet. 89: 644-651, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036171[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036171">Saitsu et al. (2011)</a> identified compound heterozygous mutations in the POLR3B gene (<a href="#0001">614366.0001</a>-<a href="#0004">614366.0004</a>) in 3 patients from 2 unrelated Japanese families with hypomyelinating leukodystrophy-8 (HLD8; <a href="/entry/614381">614381</a>). Two of the patients had hypogonadotropic hypogonadism, but none had hypodontia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036171" 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 3 unrelated patients of European descent with HLD8, <a href="#10" class="mim-tip-reference" title="Tetreault, M., Choquet, K., Orcesi, S., Tonduti, D., Balottin, U., Teichmann, M., Fribourg, S., Schiffmann, R., Brais, B., Vanderver, A., Bernard, G. <strong>Recessive mutations in POLR3B, encoding the second largest subunit of pol III, cause a rare hypomyelinating leukodystrophy.</strong> Am. J. Hum. Genet. 89: 652-655, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036172[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036172">Tetreault et al. (2011)</a> identified compound heterozygous mutations in the POLR3B gene (<a href="#0005">614366.0005</a>-<a href="#0008">614366.0008</a>). All had hypodontia and 2 developed hypogonadotropic hypogonadism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Daoud, H., Tetreault, M., Gibson, W., Guerrero, K., Cohen, A., Gburek-Augustat, J., Synofzik, M., Brais, B., Stevens, C. A., Sanchez-Carpintero, R., Goizet, C., Naidu, S., Vanderver, A., Bernard, G. <strong>Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism.</strong> J. Med. Genet. 50: 194-197, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23355746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23355746</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-101357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23355746">Daoud et al. (2013)</a> identified compound heterozygous mutations in the POLR3B gene in 7 patients with HLD8. Of the 8 mutations identified, 7 were novel (see, e.g., <a href="#0016">614366.0016</a>-<a href="#0018">614366.0018</a>). Six patients carried the previously identified V523E mutation (<a href="#0005">614366.0005</a>), which was located on a shared common haplotype in all 6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23355746" 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 15-year-old boy with HLD8, <a href="#4" class="mim-tip-reference" title="Ghoumid, J., Petit, F., Boute-Benejean, O., Frenois, F., Cartigny, M., Vanlerberghe, C., Smol, T., Caumes, R., de Roux, N., Manouvrier-Hanu, S. <strong>Cerebellar hypoplasia with endosteal sclerosis is a POLR3-related disorder.</strong> Europ. J. Hum. Genet. 25: 1011-1014, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28589944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28589944</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28589944[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2017.73" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28589944">Ghoumid et al. (2017)</a> identified compound heterozygous mutations in the POLR3B gene: the recurrent V523E mutation and a missense mutation (P925Q; <a href="#0015">614366.0015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28589944" 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 21-year-old woman with HLD8, <a href="#11" class="mim-tip-reference" title="Verberne, E. A., Dalen Meurs, L., Wolf, N. I., 4H leukodystrophy caused by a homozygous POLR3B mutation. <strong>further delineation of the phenotype.</strong> Am. J. Med. Genet. 182A: 1776-1779, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32319736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32319736</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32319736[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.61600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32319736">Verberne et al. (2020)</a> identified homozygosity for the recurrent V523E mutation in the POLR3B gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32319736" 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>Demyelinating Charcot-Marie-Tooth Disease Type 1I</em></strong></p><p>
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In 6 unrelated patients with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; <a href="/entry/619742">619742</a>), <a href="#3" class="mim-tip-reference" title="Djordjevic, D., Pinard, M., Gauthier, M.-S., Smith-Hicks, C., Hoffman, TL., Wolf, NI., Oegema, R., van Binsbergen, E., Baskin, B., Bernard, G., Fribourg, S., Coulombe, B., Yoon, G. <strong>De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy.</strong> Am. J. Hum. Genet. 108: 186-193, 2021. Note: Erratum: Am. J. Hum. Genet. 109: 759-763, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33417887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33417887</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33417887[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.12.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33417887">Djordjevic et al. (2021)</a> identified de novo heterozygous missense mutations in the POLR3B gene (see, e.g., <a href="#0009">614366.0009</a>-<a href="#0012">614366.0012</a>). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variants showed that 5 of the 6 impaired the association of POLR3B with one or more of the other RNA pol III subunits; the sixth variant showed disrupted association of POLR3B with multiple proteins. These findings suggested that the most of the mutations would render the enzyme inactive. All of the variants localized properly to the nucleus. Western blot analysis of fibroblasts from 1 patient showed normal protein expression. The authors postulated a dominant-negative effect, but noted that more studies were needed to confirm the pathogenetic mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33417887" 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 19-year-old Chinese man with CMT1I, <a href="#14" class="mim-tip-reference" title="Xue, Y.-Y., Cheng, H.-L., Dong, H.-L., Yin, H.-M., Yuan, Y., Meng, L.-C., Wu, Z.-Y., Yu, H. <strong>A de novo variant of POLR3B causes demyelinating Charcot-Marie-Tooth disease in a Chinese patient: a case report.</strong> BMC Neurol. 21: 402, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34666706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34666706</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34666706[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s12883-021-02399-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34666706">Xue et al. (2021)</a> identified a de novo heterozygous R1046H mutation at a highly conserved residue in the POLR3B gene. The mutation, which was found by exome sequencing, was absent from public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. He had normal cognition and no evidence of central nervous system involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34666706" 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>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between Wiedemann-Rautenstrauch syndrome (see <a href="/entry/264090">264090</a>) and variation in the POLR3B gene, see <a href="#0013">614366.0013</a>.</p>
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<p><a href="#7" class="mim-tip-reference" title="Michell-Robinson, M. A., Watt, K. E. N., Grouza, V., Macintosh, J., Pinard, M., Tuznik, M., Chen, X., Darbelli, L., Wu, C. L., Perrier, S., Chitsaz, D., Uccelli, N. A., Liu, H., Cox, T. C., Muller, C. W., Kennedy, T. E., Coulombe, B., Rudko, D. A., Trainor, P. A., Bernard, G. <strong>Hypomyelination, hypodontia and craniofacial abnormalities in a Polr3b mouse model of leukodystrophy.</strong> Brain 146: 5070-5085, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37635302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37635302</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37635302[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awad249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37635302">Michell-Robinson et al. (2023)</a> noted that a polr3b exon 10 deletion (delta-10) mutation was originally identified as the cause of a gut phenotype in zebrafish and was further studied for its effects on gut in mice. Using affinity purification-mass spectrometry and Western blot analysis, <a href="#7" class="mim-tip-reference" title="Michell-Robinson, M. A., Watt, K. E. N., Grouza, V., Macintosh, J., Pinard, M., Tuznik, M., Chen, X., Darbelli, L., Wu, C. L., Perrier, S., Chitsaz, D., Uccelli, N. A., Liu, H., Cox, T. C., Muller, C. W., Kennedy, T. E., Coulombe, B., Rudko, D. A., Trainor, P. A., Bernard, G. <strong>Hypomyelination, hypodontia and craniofacial abnormalities in a Polr3b mouse model of leukodystrophy.</strong> Brain 146: 5070-5085, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37635302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37635302</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37635302[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awad249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37635302">Michell-Robinson et al. (2023)</a> showed that expression of human POLR3B with the delta-10 mutation impaired RNA pol III complex assembly or stability and reduced wildtype POLR3B protein expression in human cells. They found that transgenic mice with homozygous inducible/conditional expression of Polr3b delta-10 had a recessive phenotype that recapitulated features of human HLD8, including reduced body size and weight, craniofacial and dental anomalies, reduced lifespan, and neurologic features including ataxia, tremor, and spontaneous seizures. Immunofluorescence analysis revealed significant hypomyelination in brains of delta-10 homozygotes. Hypomyelination was caused by defective proliferation and maturation of oligodendrocyte precursors, leading to a reduced number of myelinating cells in delta-10 homozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37635302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Borland, G., Wilkie, S. E., Thomson, J., Wang, Z., Tullet, J. M. A., Alic, N., Selman, C. <strong>Polr3b heterozygosity in mice induces both beneficial and deleterious effects on health during ageing with no effect on lifespan.</strong> Aging Cell 23: e14141, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38465473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38465473</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38465473[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/acel.14141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38465473">Borland et al. (2024)</a> found that Polr3b +/- mice exhibited sexually dimorphic, organ-specific effects that were both beneficial and detrimental. Female Polr3b +/- mice had improved bone health during aging, but their ability to maintain an effective gut barrier function was compromised, and they were susceptible to idiopathic dermatitis. Male Polr3b +/- mice were lighter than wildtype males and had significantly improved gut barrier function in old age. Several metabolic parameters were affected by both age and sex, but no genotype differences were detected. Neither male nor female Polr3b +/- mice were long-lived compared with wildtype. The findings showed that reduced pol III activity does not extend mouse lifespan but may have some potential organ- and sex-specific benefits for health in old age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38465473" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=614366[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA AND WITH HYPOGONADOTROPIC HYPOGONADISM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267608686 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608686;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267608686?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608686" 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=rs267608686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 Japanese adult sibs, born of unrelated parents, with hypomyelinating leukodystrophy-8 with hypogonadotropic hypogonadism (HLD8; <a href="/entry/614381">614381</a>), <a href="#8" class="mim-tip-reference" title="Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., Matsumoto, N. <strong>Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.</strong> Am. J. Hum. Genet. 89: 644-651, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036171[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036171">Saitsu et al. (2011)</a> identified compound heterozygosity for 2 mutations in the POLR3B gene: a paternally inherited A-to-C transversion in intron 17, resulting in a splice site mutation, and a maternally inherited 2303G-A transition in exon 21, resulting in an arg768-to-his (R768H; <a href="#0002">614366.0002</a>) substitution in a highly conserved residue. The splice site mutation was shown to cause a deletion of exon 18 and an in-frame 33-amino acid deletion (Asn620_Lys652del). Modeling with the yeast homolog of the pol II subunit indicated that the deletion would destroy a structural core of the protein, leading to loss of function. Yeast modeling also suggested that arg768 interacts with the main-chain carbonyl groups in other subunits, and that the R768H substitution would disturb these interactions and cause polymerase dysfunction. The R768H mutation was found in 1 of 540 Japanese control chromosomes, and the splice site mutation was not found in control chromosomes. After normal early infantile development, the patients presented with walking and exercise difficulties at age 3 years. They had mild intellectual disability but were able to finish high school. As adults, both had cerebellar signs, including ataxic speech, wide-based ataxic gait, dysdiadochokinesis, and dysmetria, hypotonia, and mild hyperreflexia without extensor plantar responses. Both also showed signs of hypogonadotropic hypogonadism, but did not have hypodontia. Other features included myopia, mild horizontal nystagmus, slowing of smooth-pursuit eye movements, and vertical gaze limitation. Brain MRI showed high-intensity areas in the white matter on T2-weighted images, consistent with diffuse cerebral hypomyelination, as well as cerebellar atrophy, and hypoplastic corpus callosum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA AND WITH HYPOGONADOTROPIC HYPOGONADISM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267608687 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608687;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267608687?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608687" 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=rs267608687" 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=RCV000024157 OR RCV001731314 OR RCV004549387 OR RCV004760342" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024157, RCV001731314, RCV004549387, RCV004760342" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024157...</a>
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<p>For discussion of the arg768-to-his (R768H) mutation in the POLR3B gene that was found in compound heterozygous state in 2 sibs with hypomyelinating leukodystrophy-8 with hypogonadotropic hypogonadism (HLD8; <a href="/entry/614381">614381</a>) by <a href="#8" class="mim-tip-reference" title="Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., Matsumoto, N. <strong>Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.</strong> Am. J. Hum. Genet. 89: 644-651, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036171[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036171">Saitsu et al. (2011)</a>, see <a href="#0001">614366.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA OR HYPOGONADOTROPIC HYPOGONADISM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267608688 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608688;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267608688?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608688" 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=rs267608688" 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 16-year-old Japanese girl with hypomyelinating leukodystrophy-8 (HLD8; <a href="/entry/614381">614381</a>), previously reported as patient 1 by <a href="#9" class="mim-tip-reference" title="Sasaki, M., Takanashi, J., Tada, H., Sakuma, H., Furushima, W., Sato, N. <strong>Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum.</strong> Brain Dev. 31: 582-587, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18851904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18851904</a>] [<a href="https://doi.org/10.1016/j.braindev.2008.09.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18851904">Sasaki et al. (2009)</a>, <a href="#8" class="mim-tip-reference" title="Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., Matsumoto, N. <strong>Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.</strong> Am. J. Hum. Genet. 89: 644-651, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036171[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036171">Saitsu et al. (2011)</a> identified compound heterozygosity for 2 mutations in the POLR3B gene: a paternally inherited 1648C-T transition in exon 16, resulting in an arg550-to-ter (R550X) substitution, and a maternally inherited 2778C-G transversion in exon 24, resulting in an asp926-to-glu (D926E; <a href="#0004">614366.0004</a>) substitution in a highly conserved residue. The R550X transcript was shown to undergo nonsense-mediated mRNA decay. Modeling with the yeast homolog of the pol II subunit suggested that asp926 interacts with the main-chain carbonyl groups in other subunits, and that the D926E substitution would disturb these interactions and cause polymerase dysfunction. Neither mutation was found in 540 Japanese control chromosomes. The patient began to walk unsteadily at age 11 months but retained her ability to walk as a teen. She had cerebellar signs, mild spasticity, slowing of smooth-pursuit eye movements, vertical gaze limitations, and intellectual disability. She did not have hypogonadism or hypodontia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22036171+18851904" 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">rs267608689 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608689;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=rs267608689" 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=rs267608689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the asp926-to-glu (D926E) mutation in the POLR3B gene that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 (HLD8; <a href="/entry/614381">614381</a>) by <a href="#8" class="mim-tip-reference" title="Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., Matsumoto, N. <strong>Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.</strong> Am. J. Hum. Genet. 89: 644-651, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036171[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036171">Saitsu et al. (2011)</a>, see <a href="#0003">614366.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs138249161 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs138249161;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs138249161?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs138249161" 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=rs138249161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 unrelated patients of European descent with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; <a href="/entry/614381">614381</a>), <a href="#10" class="mim-tip-reference" title="Tetreault, M., Choquet, K., Orcesi, S., Tonduti, D., Balottin, U., Teichmann, M., Fribourg, S., Schiffmann, R., Brais, B., Vanderver, A., Bernard, G. <strong>Recessive mutations in POLR3B, encoding the second largest subunit of pol III, cause a rare hypomyelinating leukodystrophy.</strong> Am. J. Hum. Genet. 89: 652-655, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036172[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036172">Tetreault et al. (2011)</a> identified compound heterozygous mutations in the POLR3B gene. All had a heterozygous 1568T-A transversion in exon 15, resulting in a val523-to-glu (V523E) substitution. The other POLR3B mutations found in compound heterozygosity with V523E were a 1508C-A transversion in exon 15, resulting in a thr503-to-lys (T503K; <a href="#0006">614366.0006</a>) substitution; a 1-bp deletion (1533delT; <a href="#0007">614366.0007</a>) predicted to result in a frameshift and premature stop codon; and a 2686A-T transversion in exon 23, resulting in a lys896-to-ter (K896X; <a href="#0008">614366.0008</a>) substitution. Based on electron microscopy structure, the V523E and T503K substitutions were predicted be located near the 'jaw' of pol III, where other subunits are localized. Thus these mutations would affect local structure and impair proper function of pol III. None of the mutations were found in 340 control chromosomes, except for V523E, which was found in 2 (0.5%) of 374 control chromosomes. All patients presented in early childhood with mild developmental delays and developed dysarthria as well as progressive motor difficulties, including cerebellar ataxia. Two showed progressive spasticity. Two individuals developed hypogonadotropic hypogonadism, whereas the third was too young to evaluate for endocrine dysfunction. All 3 individuals had teeth abnormalities, such as neonatal upper incisors, delayed eruption of deciduous teeth and permanent teeth, abnormal sequence of eruption, and malposition. Brain MRI showed thin corpus callosum, cerebellar atrophy, and hypomyelination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Wolf, N. I., Vanderver, A., van Spaendonk, R. M. L., Schiffmann, R., Brais, B., Bugiani, M., Sistermans, E., Catsman-Berrevoets, C., Kros, J. M., Soares Pinto, P., Pohl, D., Tirupathi, S., and 10 others. <strong>Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations.</strong> Neurology 83: 1898-1905, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25339210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25339210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25339210[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/10.1212/WNL.0000000000001002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25339210">Wolf et al. (2014)</a> reported that 51 of 62 patients with HLD8 were compound heterozygous for the V523E variant and another mutation in the POLR3B gene. Only 1 sib pair was homozygous for V523E, and the sibs had an exceptionally mild clinical course, with the older sib having no neurologic signs at age 21 years. Brain MRI in the sibs showed much better myelination in the 2 homozygous sibs than in the other patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25339210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated patients (patients 8 and 9) with HLD8, <a href="#2" class="mim-tip-reference" title="Daoud, H., Tetreault, M., Gibson, W., Guerrero, K., Cohen, A., Gburek-Augustat, J., Synofzik, M., Brais, B., Stevens, C. A., Sanchez-Carpintero, R., Goizet, C., Naidu, S., Vanderver, A., Bernard, G. <strong>Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism.</strong> J. Med. Genet. 50: 194-197, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23355746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23355746</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-101357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23355746">Daoud et al. (2013)</a> identified compound heterozygous mutations in the POLR3B gene: V523E and a c.2084-6A-G transition (IVS19-6A-G; <a href="#0016">614366.0016</a>) in intron 19, resulting in creation of a cryptic splice site and leading to a frameshift and premature termination (Gly695ValfsTer5). The mutations were identified by sequencing of the POLR3B gene. The V523E variant had an allele frequency of 0.5% in the dbSNP database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23355746" 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 15-year-old boy with HLD8, <a href="#4" class="mim-tip-reference" title="Ghoumid, J., Petit, F., Boute-Benejean, O., Frenois, F., Cartigny, M., Vanlerberghe, C., Smol, T., Caumes, R., de Roux, N., Manouvrier-Hanu, S. <strong>Cerebellar hypoplasia with endosteal sclerosis is a POLR3-related disorder.</strong> Europ. J. Hum. Genet. 25: 1011-1014, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28589944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28589944</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28589944[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2017.73" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28589944">Ghoumid et al. (2017)</a> identified compound heterozygous mutations in the POLR3B gene: V523E and a c.2274T-C transition resulting in a pro925-to-gln (P925Q; <a href="#0015">614366.0015</a>) substitution at a conserved site. The mutations were identified by Sanger sequencing of the POLR3B gene. The P925Q mutation was predicted to modify protein conformation. It was not present in the ExAC database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28589944" 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 21-year-old Dutch Caribbean woman with HLD8, <a href="#11" class="mim-tip-reference" title="Verberne, E. A., Dalen Meurs, L., Wolf, N. I., 4H leukodystrophy caused by a homozygous POLR3B mutation. <strong>further delineation of the phenotype.</strong> Am. J. Med. Genet. 182A: 1776-1779, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32319736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32319736</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32319736[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.61600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32319736">Verberne et al. (2020)</a> identified homozygosity for the V523E mutation. The mutation was found by sequencing of a gene panel of 761 genes associated with intellectual disability. Both parents were heterozygous for the mutation. The mutation was present in the gnomAD database at an allele frequency of 0.0003%. The patient had ataxia, developmental delay, and impaired intellectual development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32319736" 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>For discussion of the thr503-to-lys (T503K) mutation in the POLR3B gene that was found in compound heterozygous state in patients with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; <a href="/entry/614381">614381</a>) by <a href="#10" class="mim-tip-reference" title="Tetreault, M., Choquet, K., Orcesi, S., Tonduti, D., Balottin, U., Teichmann, M., Fribourg, S., Schiffmann, R., Brais, B., Vanderver, A., Bernard, G. <strong>Recessive mutations in POLR3B, encoding the second largest subunit of pol III, cause a rare hypomyelinating leukodystrophy.</strong> Am. J. Hum. Genet. 89: 652-655, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036172[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036172">Tetreault et al. (2011)</a>, see <a href="#0005">614366.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036172" 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">rs267608684 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608684;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=rs267608684" 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=rs267608684" 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=RCV000024161" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024161" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024161</a>
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<p>For discussion of the 1-bp deletion in the POLR3B gene (1533delT) that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; <a href="/entry/614381">614381</a>) by <a href="#10" class="mim-tip-reference" title="Tetreault, M., Choquet, K., Orcesi, S., Tonduti, D., Balottin, U., Teichmann, M., Fribourg, S., Schiffmann, R., Brais, B., Vanderver, A., Bernard, G. <strong>Recessive mutations in POLR3B, encoding the second largest subunit of pol III, cause a rare hypomyelinating leukodystrophy.</strong> Am. J. Hum. Genet. 89: 652-655, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036172[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036172">Tetreault et al. (2011)</a>, see <a href="#0005">614366.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH HYPODONTIA AND HYPOGONADOTROPIC HYPOGONADISM</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">rs267608685 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608685;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=rs267608685" 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=rs267608685" 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=RCV000032281" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032281" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032281</a>
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<p>For discussion of the lys896-to-ter (K896X) mutation in the POLR3B gene that was found in compound heterozygous state in patients with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; <a href="/entry/614381">614381</a>) by <a href="#10" class="mim-tip-reference" title="Tetreault, M., Choquet, K., Orcesi, S., Tonduti, D., Balottin, U., Teichmann, M., Fribourg, S., Schiffmann, R., Brais, B., Vanderver, A., Bernard, G. <strong>Recessive mutations in POLR3B, encoding the second largest subunit of pol III, cause a rare hypomyelinating leukodystrophy.</strong> Am. J. Hum. Genet. 89: 652-655, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036172[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036172">Tetreault et al. (2011)</a>, see <a href="#0005">614366.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1I</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">rs2037451945 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2037451945;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=rs2037451945" 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=rs2037451945" 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=RCV001353050 OR RCV001836991 OR RCV004548196" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001353050, RCV001836991, RCV004548196" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001353050...</a>
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<p>In a 16-year-old girl (patient 1) with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; <a href="/entry/619742">619742</a>), <a href="#3" class="mim-tip-reference" title="Djordjevic, D., Pinard, M., Gauthier, M.-S., Smith-Hicks, C., Hoffman, TL., Wolf, NI., Oegema, R., van Binsbergen, E., Baskin, B., Bernard, G., Fribourg, S., Coulombe, B., Yoon, G. <strong>De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy.</strong> Am. J. Hum. Genet. 108: 186-193, 2021. Note: Erratum: Am. J. Hum. Genet. 109: 759-763, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33417887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33417887</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33417887[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.12.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33417887">Djordjevic et al. (2021)</a> identified a de novo heterozygous c.1124A-T transversion (c.1124A-T, NM_018082.5) in the POLR3B gene, resulting in an asp375-to-val (D375V) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Western blot analysis of patient fibroblasts showed normal protein levels. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variant showed that it impaired the association of POLR3B with other RNA pol III subunits. These findings suggested that the variant would render the enzyme inactive; the authors postulated a dominant-negative effect. The patient had peripheral neuropathy, global developmental delay, ataxia, and progressive spasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33417887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1I</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">rs2038648611 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2038648611;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=rs2038648611" 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=rs2038648611" 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=RCV001353051 OR RCV001836992" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001353051, RCV001836992" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001353051...</a>
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<p>In a 11-year-old boy (patient 3) with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; <a href="/entry/619742">619742</a>), <a href="#3" class="mim-tip-reference" title="Djordjevic, D., Pinard, M., Gauthier, M.-S., Smith-Hicks, C., Hoffman, TL., Wolf, NI., Oegema, R., van Binsbergen, E., Baskin, B., Bernard, G., Fribourg, S., Coulombe, B., Yoon, G. <strong>De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy.</strong> Am. J. Hum. Genet. 108: 186-193, 2021. Note: Erratum: Am. J. Hum. Genet. 109: 759-763, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33417887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33417887</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33417887[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.12.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33417887">Djordjevic et al. (2021)</a> identified a de novo heterozygous c.3137G-A transition (c.3137G-A, NM_018082.5) in the POLR3B gene, resulting in an arg1046-to-his (R1046H) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variant showed that it impaired the association of POLR3B with other RNA pol III subunits. These findings suggested that the variant would render the enzyme inactive; the authors postulated a dominant-negative effect. The patient had peripheral sensorimotor neuropathy with no central nervous system involvement; development and cognition were normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33417887" 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 19-year-old Chinese man with CMT1I, <a href="#14" class="mim-tip-reference" title="Xue, Y.-Y., Cheng, H.-L., Dong, H.-L., Yin, H.-M., Yuan, Y., Meng, L.-C., Wu, Z.-Y., Yu, H. <strong>A de novo variant of POLR3B causes demyelinating Charcot-Marie-Tooth disease in a Chinese patient: a case report.</strong> BMC Neurol. 21: 402, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34666706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34666706</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34666706[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s12883-021-02399-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34666706">Xue et al. (2021)</a> identified a de novo heterozygous R1046H mutation at a highly conserved residue in the POLR3B gene. The mutation, which was found by exome sequencing, was absent from public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. The patient developed progressive muscle weakness and atrophy of the lower limbs starting at age 5 years. Electrophysiologic studies were consistent with a sensorimotor demyelinating polyneuropathy with secondary axonal loss, consistent with CMT. He had normal cognition and no evidence of central nervous system involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34666706" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1I</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">rs2037218302 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2037218302;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=rs2037218302" 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=rs2037218302" 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=RCV001249292 OR RCV001836975" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001249292, RCV001836975" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001249292...</a>
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<p>In a 22-year-old man (patient 4) with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; <a href="/entry/619742">619742</a>), <a href="#3" class="mim-tip-reference" title="Djordjevic, D., Pinard, M., Gauthier, M.-S., Smith-Hicks, C., Hoffman, TL., Wolf, NI., Oegema, R., van Binsbergen, E., Baskin, B., Bernard, G., Fribourg, S., Coulombe, B., Yoon, G. <strong>De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy.</strong> Am. J. Hum. Genet. 108: 186-193, 2021. Note: Erratum: Am. J. Hum. Genet. 109: 759-763, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33417887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33417887</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33417887[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.12.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33417887">Djordjevic et al. (2021)</a> identified a de novo heterozygous c.1094C-T transition (c.1094C-T, NM_018082.5) in the POLR3B gene, resulting in an ala365-to-val (A365V) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variant showed that it impaired the association of POLR3B with other RNA pol III subunits. These findings suggested that the variant would render the enzyme inactive; the authors postulated a dominant-negative effect. In addition to a peripheral neuropathy, the patient had global developmental delay, progressive spasticity, and early-onset refractory epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33417887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1I</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">rs2136937347 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2136937347;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=rs2136937347" 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=rs2136937347" 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=RCV001837163 OR RCV004797955" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001837163, RCV004797955" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001837163...</a>
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<p>In an 8-year-old girl (patient 5) with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; <a href="/entry/619742">619742</a>), <a href="#3" class="mim-tip-reference" title="Djordjevic, D., Pinard, M., Gauthier, M.-S., Smith-Hicks, C., Hoffman, TL., Wolf, NI., Oegema, R., van Binsbergen, E., Baskin, B., Bernard, G., Fribourg, S., Coulombe, B., Yoon, G. <strong>De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy.</strong> Am. J. Hum. Genet. 108: 186-193, 2021. Note: Erratum: Am. J. Hum. Genet. 109: 759-763, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33417887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33417887</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33417887[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.12.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33417887">Djordjevic et al. (2021)</a> identified a de novo heterozygous c.1087G-A transition (c.1087G-A, NM_018082.5) in the POLR3B gene, resulting in a glu363-to-lys (E363K) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variant showed that it impaired the association of POLR3B with multiple other proteins. The authors postulated a dominant-negative effect. The patient had peripheral neuropathy, global developmental delay, ataxia, and progressive spasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33417887" 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>.0013 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1183261043 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1183261043;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1183261043?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1183261043" 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=rs1183261043" 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=RCV001839436" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001839436" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001839436</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to Wiedemann-Rautenstrauch syndrome (see <a href="/entry/264090">264090</a>) has not been confirmed.</p><p>In a 6-year-old Italian boy diagnosed with Wiedemann-Rautenstrauch syndrome, <a href="#13" class="mim-tip-reference" title="Wu, S.-W., Li, L., Feng, F., Wang, L., Kong, Y.-Y., Liu, X.-W., Yin, C. <strong>Whole-exome sequencing reveals POLR3B variants associated with progeria-related Wiedemann-Rautenstrauch syndrome.</strong> Ital. J. Pediat. 47: 160, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34289880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34289880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34289880[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13052-021-01112-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34289880">Wu et al. (2021)</a> identified compound heterozygous mutations in the POLR3B gene: a c.2191G-C transversion (c.2191G-C, NM_018082.5), resulting in a glu731-to-gln (E731Q) substitution, and a c.3046G-A transition, resulting in a val1016-to-met (V1016M; <a href="#0014">614366.0014</a>) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were found in the carrier state in both parents. Neither mutation was present in the 1000 Genomes Project and gnomAD databases. Both mutations are located at highly conserved sites in the RNA_pol_Rpb2_6 domain. No functional studies were reported. The patient had progeroid features, micrognathia, triangular facies, macrocephaly, loss of subcutaneous fat, sparse hair, congenital dislocation of the hip, and hallux valgus. A subsequent sib pregnancy was terminated with the fetus having features of a lemon-shaped brain with a small frontal lobe. The fetus also was found to have the W731Q and V1016M mutations in the POLR3B gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34289880" 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>.0014 VARIANT OF UNKNOWN SIGNIFICANCE</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">rs2137084632 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2137084632;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=rs2137084632" 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=rs2137084632" 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=RCV001839437" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001839437" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001839437</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to Wiedemann-Rautenstrauch syndrome (see <a href="/entry/264090">264090</a>) has not been confirmed.</p><p>For discussion of the c.3046G-A transition (c.3046G-A, NM_018082.5) in the POLR3B gene, resulting in a val1016-to-met (V1016M) substitution, that was found in compound heterozygous state in a patient diagnosed with Wiedemann-Rautenstrauch syndrome by <a href="#13" class="mim-tip-reference" title="Wu, S.-W., Li, L., Feng, F., Wang, L., Kong, Y.-Y., Liu, X.-W., Yin, C. <strong>Whole-exome sequencing reveals POLR3B variants associated with progeria-related Wiedemann-Rautenstrauch syndrome.</strong> Ital. J. Pediat. 47: 160, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34289880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34289880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34289880[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13052-021-01112-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34289880">Wu et al. (2021)</a>, see <a href="#0013">614366.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34289880" 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>.0015 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA AND WITH HYPOGONADOTROPIC HYPOGONADISM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs775141057 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs775141057;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs775141057?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs775141057" 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=rs775141057" 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=RCV000498916" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000498916" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000498916</a>
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<p>For discussion of the c.2774C-A transversion (c.2774C-A, NM_018082.5) in the POLR3B gene, resulting in a pro925-to-gln (P925Q) substitution, that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; <a href="/entry/614381">614381</a>) by <a href="#4" class="mim-tip-reference" title="Ghoumid, J., Petit, F., Boute-Benejean, O., Frenois, F., Cartigny, M., Vanlerberghe, C., Smol, T., Caumes, R., de Roux, N., Manouvrier-Hanu, S. <strong>Cerebellar hypoplasia with endosteal sclerosis is a POLR3-related disorder.</strong> Europ. J. Hum. Genet. 25: 1011-1014, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28589944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28589944</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28589944[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2017.73" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28589944">Ghoumid et al. (2017)</a>, see <a href="#0005">614366.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28589944" 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>.0016 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA AND WITH HYPOGONADOTROPIC HYPOGONADISM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs747912710 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs747912710;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs747912710?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs747912710" 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=rs747912710" 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=RCV000484819 OR RCV001195929 OR RCV004691238" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000484819, RCV001195929, RCV004691238" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000484819...</a>
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<p>For discussion of the c.2084-6A-G mutation in the POLR3B gene, resulting in a frameshift and premature termination (Gly695fsTer5) that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; <a href="/entry/614381">614381</a>) by <a href="#2" class="mim-tip-reference" title="Daoud, H., Tetreault, M., Gibson, W., Guerrero, K., Cohen, A., Gburek-Augustat, J., Synofzik, M., Brais, B., Stevens, C. A., Sanchez-Carpintero, R., Goizet, C., Naidu, S., Vanderver, A., Bernard, G. <strong>Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism.</strong> J. Med. Genet. 50: 194-197, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23355746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23355746</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-101357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23355746">Daoud et al. (2013)</a>, see <a href="#0005">614366.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23355746" 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>.0017 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA AND WITH HYPOGONADOTROPIC HYPOGONADISM</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">rs2136887072 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2136887072;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=rs2136887072" 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=rs2136887072" 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=RCV001542038" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001542038" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001542038</a>
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<p>In a patient (patient 13) with hypodontia and hypogonadotropic hypogonadism (HLD8; <a href="/entry/614381">614381</a>), <a href="#2" class="mim-tip-reference" title="Daoud, H., Tetreault, M., Gibson, W., Guerrero, K., Cohen, A., Gburek-Augustat, J., Synofzik, M., Brais, B., Stevens, C. A., Sanchez-Carpintero, R., Goizet, C., Naidu, S., Vanderver, A., Bernard, G. <strong>Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism.</strong> J. Med. Genet. 50: 194-197, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23355746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23355746</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-101357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23355746">Daoud et al. (2013)</a> identified compound heterozygous mutations in the POLR3B gene: a c.312G-T transversion (c.312G-T, NM_018082) in exon 6, resulting in a leu104-to-phe (L104F) substitution, and a c.2570+1G-A transition (<a href="#0018">614366.0018</a>) in intron 22, resulting in a frameshift and premature termination (Gly818fsAlaTer13). Analysis of RNA from patient lymphoblastoid cells showed that the mutation resulted in skipping of exon 22. The mutations were identified by sequencing of the POLR3B gene. Neither mutation was present in the dbSNP database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23355746" 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>.0018 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA AND WITH HYPOGONADOTROPIC HYPOGONADISM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs753943393 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs753943393;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs753943393?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs753943393" 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=rs753943393" 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=RCV000760972 OR RCV001093430" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000760972, RCV001093430" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000760972...</a>
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<p>For discussion of the c.2570+1G-A transition (c.2570+1G-A, NM_018082) in intron 22 of the POLR3B gene, resulting in a frameshift and premature termination (Gly818fsTer13), that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; <a href="/entry/614381">614381</a>) by <a href="#2" class="mim-tip-reference" title="Daoud, H., Tetreault, M., Gibson, W., Guerrero, K., Cohen, A., Gburek-Augustat, J., Synofzik, M., Brais, B., Stevens, C. A., Sanchez-Carpintero, R., Goizet, C., Naidu, S., Vanderver, A., Bernard, G. <strong>Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism.</strong> J. Med. Genet. 50: 194-197, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23355746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23355746</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-101357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23355746">Daoud et al. (2013)</a>, see <a href="#0017">614366.0017</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23355746" 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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Borland, G., Wilkie, S. E., Thomson, J., Wang, Z., Tullet, J. M. A., Alic, N., Selman, C.
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<strong>Polr3b heterozygosity in mice induces both beneficial and deleterious effects on health during ageing with no effect on lifespan.</strong>
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Aging Cell 23: e14141, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38465473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38465473</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38465473[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=38465473" 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/10.1111/acel.14141" target="_blank">Full Text</a>]
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Daoud, H., Tetreault, M., Gibson, W., Guerrero, K., Cohen, A., Gburek-Augustat, J., Synofzik, M., Brais, B., Stevens, C. A., Sanchez-Carpintero, R., Goizet, C., Naidu, S., Vanderver, A., Bernard, G.
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<strong>Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism.</strong>
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J. Med. Genet. 50: 194-197, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23355746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23355746</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23355746" 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/10.1136/jmedgenet-2012-101357" target="_blank">Full Text</a>]
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Djordjevic, D., Pinard, M., Gauthier, M.-S., Smith-Hicks, C., Hoffman, TL., Wolf, NI., Oegema, R., van Binsbergen, E., Baskin, B., Bernard, G., Fribourg, S., Coulombe, B., Yoon, G.
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<strong>De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy.</strong>
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Am. J. Hum. Genet. 108: 186-193, 2021. Note: Erratum: Am. J. Hum. Genet. 109: 759-763, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33417887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33417887</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33417887[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=33417887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2020.12.002" target="_blank">Full Text</a>]
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Ghoumid, J., Petit, F., Boute-Benejean, O., Frenois, F., Cartigny, M., Vanlerberghe, C., Smol, T., Caumes, R., de Roux, N., Manouvrier-Hanu, S.
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<strong>Cerebellar hypoplasia with endosteal sclerosis is a POLR3-related disorder.</strong>
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Europ. J. Hum. Genet. 25: 1011-1014, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28589944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28589944</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28589944[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=28589944" 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/ejhg.2017.73" target="_blank">Full Text</a>]
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Hartz, P. A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 11/29/2011.
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Hu, P., Wu, S., Sun, Y., Yuan, C.-C., Kobayashi, R., Myers, M. P., Hernandez, N.
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<strong>Characterization of human RNA polymerase III identifies orthologues for Saccharomyces cerevisiae RNA polymerase III subunits.</strong>
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Molec. Cell. Biol. 22: 8044-8055, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12391170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12391170</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12391170[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=12391170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/MCB.22.22.8044-8055.2002" target="_blank">Full Text</a>]
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Michell-Robinson, M. A., Watt, K. E. N., Grouza, V., Macintosh, J., Pinard, M., Tuznik, M., Chen, X., Darbelli, L., Wu, C. L., Perrier, S., Chitsaz, D., Uccelli, N. A., Liu, H., Cox, T. C., Muller, C. W., Kennedy, T. E., Coulombe, B., Rudko, D. A., Trainor, P. A., Bernard, G.
|
|
<strong>Hypomyelination, hypodontia and craniofacial abnormalities in a Polr3b mouse model of leukodystrophy.</strong>
|
|
Brain 146: 5070-5085, 2023.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37635302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37635302</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37635302[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=37635302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awad249" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Saitsu2011" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., Matsumoto, N.
|
|
<strong>Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.</strong>
|
|
Am. J. Hum. Genet. 89: 644-651, 2011.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036171[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=22036171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2011.10.003" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Sasaki2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
|
Sasaki, M., Takanashi, J., Tada, H., Sakuma, H., Furushima, W., Sato, N.
|
|
<strong>Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum.</strong>
|
|
Brain Dev. 31: 582-587, 2009.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18851904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18851904</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18851904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.braindev.2008.09.003" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Tetreault2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Tetreault, M., Choquet, K., Orcesi, S., Tonduti, D., Balottin, U., Teichmann, M., Fribourg, S., Schiffmann, R., Brais, B., Vanderver, A., Bernard, G.
|
|
<strong>Recessive mutations in POLR3B, encoding the second largest subunit of pol III, cause a rare hypomyelinating leukodystrophy.</strong>
|
|
Am. J. Hum. Genet. 89: 652-655, 2011.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036172[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=22036172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2011.10.006" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Verberne2020" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
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|
Verberne, E. A., Dalen Meurs, L., Wolf, N. I., 4H leukodystrophy caused by a homozygous POLR3B mutation.
|
|
<strong>further delineation of the phenotype.</strong>
|
|
Am. J. Med. Genet. 182A: 1776-1779, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32319736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32319736</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32319736[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=32319736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.61600" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Wolf2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wolf, N. I., Vanderver, A., van Spaendonk, R. M. L., Schiffmann, R., Brais, B., Bugiani, M., Sistermans, E., Catsman-Berrevoets, C., Kros, J. M., Soares Pinto, P., Pohl, D., Tirupathi, S., and 10 others.
|
|
<strong>Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations.</strong>
|
|
Neurology 83: 1898-1905, 2014.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25339210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25339210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25339210[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=25339210" 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/10.1212/WNL.0000000000001002" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Wu2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, S.-W., Li, L., Feng, F., Wang, L., Kong, Y.-Y., Liu, X.-W., Yin, C.
|
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<strong>Whole-exome sequencing reveals POLR3B variants associated with progeria-related Wiedemann-Rautenstrauch syndrome.</strong>
|
|
Ital. J. Pediat. 47: 160, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34289880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34289880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34289880[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=34289880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1186/s13052-021-01112-6" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Xue2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xue, Y.-Y., Cheng, H.-L., Dong, H.-L., Yin, H.-M., Yuan, Y., Meng, L.-C., Wu, Z.-Y., Yu, H.
|
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<strong>A de novo variant of POLR3B causes demyelinating Charcot-Marie-Tooth disease in a Chinese patient: a case report.</strong>
|
|
BMC Neurol. 21: 402, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34666706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34666706</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34666706[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=34666706" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1186/s12883-021-02399-y" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 11/07/2024
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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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Hilary J. Vernon - updated : 03/04/2022<br>Hilary J. Vernon - updated : 02/25/2022<br>Cassandra L. Kniffin - updated : 02/10/2022<br>Marla J. F. O'Neill - updated : 07/09/2018<br>Cassandra L. Kniffin - updated : 12/7/2011
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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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Patricia A. Hartz : 11/29/2011
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 11/07/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/17/2022<br>carol : 03/04/2022<br>carol : 02/25/2022<br>alopez : 02/14/2022<br>ckniffin : 02/10/2022<br>alopez : 07/09/2018<br>carol : 07/08/2015<br>mcolton : 7/7/2015<br>carol : 6/20/2014<br>ckniffin : 6/19/2014<br>carol : 12/8/2011<br>ckniffin : 12/7/2011<br>mgross : 11/29/2011
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 614366
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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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POLYMERASE III, RNA, SUBUNIT B; POLR3B
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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RPC2<br />
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C128, S. CEREVISIAE, HOMOLOG OF; C128
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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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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: POLR3B</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: 12q23.3
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 12:106,357,748-106,510,198 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
12q23.3
|
|
</span>
|
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</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Charcot-Marie-Tooth disease, demyelinating, type 1I
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
619742
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
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|
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614381
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
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Autosomal recessive
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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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<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>The POLR3B gene encodes the second largest subunit of RNA polymerase (pol) III. RNA polymerase III consists of 17 subunits and is involved in the transcription of small noncoding RNAs, such as 5S ribosomal RNA (180420), U6 small nuclear RNA (see 180692), and short interspersed nuclear elements (SINEs), as well as all transfer RNAs (summary by Saitsu et al., 2011). </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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<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>Using mass spectrometry to identify peptides obtained from purified HeLa cell RNA polymerase III complexes, followed by EST database analysis and PCR of a HeLa cell cDNA library, Hu et al. (2002) cloned human POLR3B, which they called RPC2. The deduced 1,133-amino acid protein has a calculated molecular mass of 128 kD. It contains a zinc-binding domain near its C terminus that is predicted to form part of a clamp structure. Human RPC2 shares 63% amino acid identity with S. cerevisiae Rpc2 and 38% identity with the second largest subunit of human RNA polymerase II, RPB2 (POLR2B; 180661). </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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<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>Hartz (2011) mapped the POLR3B gene to chromosome 12q23.3. based on an alignment of the POLR3B sequence (GenBank AK001250) with the genomic sequence (GRCh37).</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>Hypomyelinating Leukodystrophy 8</em></strong></p><p>
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Using whole-exome sequencing, Saitsu et al. (2011) identified compound heterozygous mutations in the POLR3B gene (614366.0001-614366.0004) in 3 patients from 2 unrelated Japanese families with hypomyelinating leukodystrophy-8 (HLD8; 614381). Two of the patients had hypogonadotropic hypogonadism, but none had hypodontia. </p><p>In 3 unrelated patients of European descent with HLD8, Tetreault et al. (2011) identified compound heterozygous mutations in the POLR3B gene (614366.0005-614366.0008). All had hypodontia and 2 developed hypogonadotropic hypogonadism. </p><p>Daoud et al. (2013) identified compound heterozygous mutations in the POLR3B gene in 7 patients with HLD8. Of the 8 mutations identified, 7 were novel (see, e.g., 614366.0016-614366.0018). Six patients carried the previously identified V523E mutation (614366.0005), which was located on a shared common haplotype in all 6. </p><p>In a 15-year-old boy with HLD8, Ghoumid et al. (2017) identified compound heterozygous mutations in the POLR3B gene: the recurrent V523E mutation and a missense mutation (P925Q; 614366.0015). </p><p>In a 21-year-old woman with HLD8, Verberne et al. (2020) identified homozygosity for the recurrent V523E mutation in the POLR3B gene. </p><p><strong><em>Demyelinating Charcot-Marie-Tooth Disease Type 1I</em></strong></p><p>
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In 6 unrelated patients with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; 619742), Djordjevic et al. (2021) identified de novo heterozygous missense mutations in the POLR3B gene (see, e.g., 614366.0009-614366.0012). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variants showed that 5 of the 6 impaired the association of POLR3B with one or more of the other RNA pol III subunits; the sixth variant showed disrupted association of POLR3B with multiple proteins. These findings suggested that the most of the mutations would render the enzyme inactive. All of the variants localized properly to the nucleus. Western blot analysis of fibroblasts from 1 patient showed normal protein expression. The authors postulated a dominant-negative effect, but noted that more studies were needed to confirm the pathogenetic mechanism. </p><p>In a 19-year-old Chinese man with CMT1I, Xue et al. (2021) identified a de novo heterozygous R1046H mutation at a highly conserved residue in the POLR3B gene. The mutation, which was found by exome sequencing, was absent from public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. He had normal cognition and no evidence of central nervous system involvement. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between Wiedemann-Rautenstrauch syndrome (see 264090) and variation in the POLR3B gene, see 614366.0013.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Michell-Robinson et al. (2023) noted that a polr3b exon 10 deletion (delta-10) mutation was originally identified as the cause of a gut phenotype in zebrafish and was further studied for its effects on gut in mice. Using affinity purification-mass spectrometry and Western blot analysis, Michell-Robinson et al. (2023) showed that expression of human POLR3B with the delta-10 mutation impaired RNA pol III complex assembly or stability and reduced wildtype POLR3B protein expression in human cells. They found that transgenic mice with homozygous inducible/conditional expression of Polr3b delta-10 had a recessive phenotype that recapitulated features of human HLD8, including reduced body size and weight, craniofacial and dental anomalies, reduced lifespan, and neurologic features including ataxia, tremor, and spontaneous seizures. Immunofluorescence analysis revealed significant hypomyelination in brains of delta-10 homozygotes. Hypomyelination was caused by defective proliferation and maturation of oligodendrocyte precursors, leading to a reduced number of myelinating cells in delta-10 homozygotes. </p><p>Borland et al. (2024) found that Polr3b +/- mice exhibited sexually dimorphic, organ-specific effects that were both beneficial and detrimental. Female Polr3b +/- mice had improved bone health during aging, but their ability to maintain an effective gut barrier function was compromised, and they were susceptible to idiopathic dermatitis. Male Polr3b +/- mice were lighter than wildtype males and had significantly improved gut barrier function in old age. Several metabolic parameters were affected by both age and sex, but no genotype differences were detected. Neither male nor female Polr3b +/- mice were long-lived compared with wildtype. The findings showed that reduced pol III activity does not extend mouse lifespan but may have some potential organ- and sex-specific benefits for health in old age. </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>18 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 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA AND WITH HYPOGONADOTROPIC HYPOGONADISM</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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POLR3B, IVS17AS, A-C, -2
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<br />
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SNP: rs267608686,
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gnomAD: rs267608686,
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ClinVar: RCV000024156
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 Japanese adult sibs, born of unrelated parents, with hypomyelinating leukodystrophy-8 with hypogonadotropic hypogonadism (HLD8; 614381), Saitsu et al. (2011) identified compound heterozygosity for 2 mutations in the POLR3B gene: a paternally inherited A-to-C transversion in intron 17, resulting in a splice site mutation, and a maternally inherited 2303G-A transition in exon 21, resulting in an arg768-to-his (R768H; 614366.0002) substitution in a highly conserved residue. The splice site mutation was shown to cause a deletion of exon 18 and an in-frame 33-amino acid deletion (Asn620_Lys652del). Modeling with the yeast homolog of the pol II subunit indicated that the deletion would destroy a structural core of the protein, leading to loss of function. Yeast modeling also suggested that arg768 interacts with the main-chain carbonyl groups in other subunits, and that the R768H substitution would disturb these interactions and cause polymerase dysfunction. The R768H mutation was found in 1 of 540 Japanese control chromosomes, and the splice site mutation was not found in control chromosomes. After normal early infantile development, the patients presented with walking and exercise difficulties at age 3 years. They had mild intellectual disability but were able to finish high school. As adults, both had cerebellar signs, including ataxic speech, wide-based ataxic gait, dysdiadochokinesis, and dysmetria, hypotonia, and mild hyperreflexia without extensor plantar responses. Both also showed signs of hypogonadotropic hypogonadism, but did not have hypodontia. Other features included myopia, mild horizontal nystagmus, slowing of smooth-pursuit eye movements, and vertical gaze limitation. Brain MRI showed high-intensity areas in the white matter on T2-weighted images, consistent with diffuse cerebral hypomyelination, as well as cerebellar atrophy, and hypoplastic corpus callosum. </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 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA AND WITH HYPOGONADOTROPIC HYPOGONADISM</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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POLR3B, ARG768HIS
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<br />
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SNP: rs267608687,
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gnomAD: rs267608687,
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ClinVar: RCV000024157, RCV001731314, RCV004549387, RCV004760342
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the arg768-to-his (R768H) mutation in the POLR3B gene that was found in compound heterozygous state in 2 sibs with hypomyelinating leukodystrophy-8 with hypogonadotropic hypogonadism (HLD8; 614381) by Saitsu et al. (2011), see 614366.0001. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0003 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA OR HYPOGONADOTROPIC HYPOGONADISM</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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POLR3B, ARG550TER
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<br />
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SNP: rs267608688,
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gnomAD: rs267608688,
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ClinVar: RCV000024158, RCV002243660
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 16-year-old Japanese girl with hypomyelinating leukodystrophy-8 (HLD8; 614381), previously reported as patient 1 by Sasaki et al. (2009), Saitsu et al. (2011) identified compound heterozygosity for 2 mutations in the POLR3B gene: a paternally inherited 1648C-T transition in exon 16, resulting in an arg550-to-ter (R550X) substitution, and a maternally inherited 2778C-G transversion in exon 24, resulting in an asp926-to-glu (D926E; 614366.0004) substitution in a highly conserved residue. The R550X transcript was shown to undergo nonsense-mediated mRNA decay. Modeling with the yeast homolog of the pol II subunit suggested that asp926 interacts with the main-chain carbonyl groups in other subunits, and that the D926E substitution would disturb these interactions and cause polymerase dysfunction. Neither mutation was found in 540 Japanese control chromosomes. The patient began to walk unsteadily at age 11 months but retained her ability to walk as a teen. She had cerebellar signs, mild spasticity, slowing of smooth-pursuit eye movements, vertical gaze limitations, and intellectual disability. She did not have hypogonadism or hypodontia. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA OR HYPOGONADOTROPIC HYPOGONADISM</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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POLR3B, ASP926GLU
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<br />
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SNP: rs267608689,
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ClinVar: RCV000024159
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>For discussion of the asp926-to-glu (D926E) mutation in the POLR3B gene that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 (HLD8; 614381) by Saitsu et al. (2011), see 614366.0003. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH HYPODONTIA AND HYPOGONADOTROPIC HYPOGONADISM</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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POLR3B, VAL523GLU
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<br />
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SNP: rs138249161,
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gnomAD: rs138249161,
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ClinVar: RCV000032280, RCV000199616, RCV000442312, RCV000763295, RCV001095758, RCV001849282, RCV002251926, RCV002285009, RCV003334378, RCV004549388
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In 3 unrelated patients of European descent with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381), Tetreault et al. (2011) identified compound heterozygous mutations in the POLR3B gene. All had a heterozygous 1568T-A transversion in exon 15, resulting in a val523-to-glu (V523E) substitution. The other POLR3B mutations found in compound heterozygosity with V523E were a 1508C-A transversion in exon 15, resulting in a thr503-to-lys (T503K; 614366.0006) substitution; a 1-bp deletion (1533delT; 614366.0007) predicted to result in a frameshift and premature stop codon; and a 2686A-T transversion in exon 23, resulting in a lys896-to-ter (K896X; 614366.0008) substitution. Based on electron microscopy structure, the V523E and T503K substitutions were predicted be located near the 'jaw' of pol III, where other subunits are localized. Thus these mutations would affect local structure and impair proper function of pol III. None of the mutations were found in 340 control chromosomes, except for V523E, which was found in 2 (0.5%) of 374 control chromosomes. All patients presented in early childhood with mild developmental delays and developed dysarthria as well as progressive motor difficulties, including cerebellar ataxia. Two showed progressive spasticity. Two individuals developed hypogonadotropic hypogonadism, whereas the third was too young to evaluate for endocrine dysfunction. All 3 individuals had teeth abnormalities, such as neonatal upper incisors, delayed eruption of deciduous teeth and permanent teeth, abnormal sequence of eruption, and malposition. Brain MRI showed thin corpus callosum, cerebellar atrophy, and hypomyelination. </p><p>Wolf et al. (2014) reported that 51 of 62 patients with HLD8 were compound heterozygous for the V523E variant and another mutation in the POLR3B gene. Only 1 sib pair was homozygous for V523E, and the sibs had an exceptionally mild clinical course, with the older sib having no neurologic signs at age 21 years. Brain MRI in the sibs showed much better myelination in the 2 homozygous sibs than in the other patients. </p><p>In 2 unrelated patients (patients 8 and 9) with HLD8, Daoud et al. (2013) identified compound heterozygous mutations in the POLR3B gene: V523E and a c.2084-6A-G transition (IVS19-6A-G; 614366.0016) in intron 19, resulting in creation of a cryptic splice site and leading to a frameshift and premature termination (Gly695ValfsTer5). The mutations were identified by sequencing of the POLR3B gene. The V523E variant had an allele frequency of 0.5% in the dbSNP database. </p><p>In a 15-year-old boy with HLD8, Ghoumid et al. (2017) identified compound heterozygous mutations in the POLR3B gene: V523E and a c.2274T-C transition resulting in a pro925-to-gln (P925Q; 614366.0015) substitution at a conserved site. The mutations were identified by Sanger sequencing of the POLR3B gene. The P925Q mutation was predicted to modify protein conformation. It was not present in the ExAC database. </p><p>In a 21-year-old Dutch Caribbean woman with HLD8, Verberne et al. (2020) identified homozygosity for the V523E mutation. The mutation was found by sequencing of a gene panel of 761 genes associated with intellectual disability. Both parents were heterozygous for the mutation. The mutation was present in the gnomAD database at an allele frequency of 0.0003%. The patient had ataxia, developmental delay, and impaired intellectual development. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH HYPODONTIA AND HYPOGONADOTROPIC HYPOGONADISM</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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POLR3B, THR503LYS
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<br />
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SNP: rs267608683,
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ClinVar: RCV000032279
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the thr503-to-lys (T503K) mutation in the POLR3B gene that was found in compound heterozygous state in patients with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381) by Tetreault et al. (2011), see 614366.0005. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH HYPODONTIA AND HYPOGONADOTROPIC HYPOGONADISM</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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POLR3B, 1-BP DEL, 1533T
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|
<br />
|
|
|
|
SNP: rs267608684,
|
|
|
|
|
|
|
|
ClinVar: RCV000024161
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion in the POLR3B gene (1533delT) that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381) by Tetreault et al. (2011), see 614366.0005. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH HYPODONTIA AND HYPOGONADOTROPIC HYPOGONADISM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3B, LYS896TER
|
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|
|
|
<br />
|
|
|
|
SNP: rs267608685,
|
|
|
|
|
|
|
|
ClinVar: RCV000032281
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the lys896-to-ter (K896X) mutation in the POLR3B gene that was found in compound heterozygous state in patients with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381) by Tetreault et al. (2011), see 614366.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3B, ASP375VAL
|
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|
|
|
<br />
|
|
|
|
SNP: rs2037451945,
|
|
|
|
|
|
|
|
ClinVar: RCV001353050, RCV001836991, RCV004548196
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 16-year-old girl (patient 1) with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; 619742), Djordjevic et al. (2021) identified a de novo heterozygous c.1124A-T transversion (c.1124A-T, NM_018082.5) in the POLR3B gene, resulting in an asp375-to-val (D375V) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Western blot analysis of patient fibroblasts showed normal protein levels. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variant showed that it impaired the association of POLR3B with other RNA pol III subunits. These findings suggested that the variant would render the enzyme inactive; the authors postulated a dominant-negative effect. The patient had peripheral neuropathy, global developmental delay, ataxia, and progressive spasticity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3B, ARG1046HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2038648611,
|
|
|
|
|
|
|
|
ClinVar: RCV001353051, RCV001836992
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 11-year-old boy (patient 3) with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; 619742), Djordjevic et al. (2021) identified a de novo heterozygous c.3137G-A transition (c.3137G-A, NM_018082.5) in the POLR3B gene, resulting in an arg1046-to-his (R1046H) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variant showed that it impaired the association of POLR3B with other RNA pol III subunits. These findings suggested that the variant would render the enzyme inactive; the authors postulated a dominant-negative effect. The patient had peripheral sensorimotor neuropathy with no central nervous system involvement; development and cognition were normal. </p><p>In a 19-year-old Chinese man with CMT1I, Xue et al. (2021) identified a de novo heterozygous R1046H mutation at a highly conserved residue in the POLR3B gene. The mutation, which was found by exome sequencing, was absent from public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. The patient developed progressive muscle weakness and atrophy of the lower limbs starting at age 5 years. Electrophysiologic studies were consistent with a sensorimotor demyelinating polyneuropathy with secondary axonal loss, consistent with CMT. He had normal cognition and no evidence of central nervous system involvement. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3B, ALA365VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2037218302,
|
|
|
|
|
|
|
|
ClinVar: RCV001249292, RCV001836975
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 22-year-old man (patient 4) with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; 619742), Djordjevic et al. (2021) identified a de novo heterozygous c.1094C-T transition (c.1094C-T, NM_018082.5) in the POLR3B gene, resulting in an ala365-to-val (A365V) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variant showed that it impaired the association of POLR3B with other RNA pol III subunits. These findings suggested that the variant would render the enzyme inactive; the authors postulated a dominant-negative effect. In addition to a peripheral neuropathy, the patient had global developmental delay, progressive spasticity, and early-onset refractory epilepsy. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3B, GLU363LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2136937347,
|
|
|
|
|
|
|
|
ClinVar: RCV001837163, RCV004797955
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 8-year-old girl (patient 5) with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; 619742), Djordjevic et al. (2021) identified a de novo heterozygous c.1087G-A transition (c.1087G-A, NM_018082.5) in the POLR3B gene, resulting in a glu363-to-lys (E363K) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variant showed that it impaired the association of POLR3B with multiple other proteins. The authors postulated a dominant-negative effect. The patient had peripheral neuropathy, global developmental delay, ataxia, and progressive spasticity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3B, GLU731GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1183261043,
|
|
|
|
|
|
gnomAD: rs1183261043,
|
|
|
|
|
|
ClinVar: RCV001839436
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant is classified as a variant of unknown significance because its contribution to Wiedemann-Rautenstrauch syndrome (see 264090) has not been confirmed.</p><p>In a 6-year-old Italian boy diagnosed with Wiedemann-Rautenstrauch syndrome, Wu et al. (2021) identified compound heterozygous mutations in the POLR3B gene: a c.2191G-C transversion (c.2191G-C, NM_018082.5), resulting in a glu731-to-gln (E731Q) substitution, and a c.3046G-A transition, resulting in a val1016-to-met (V1016M; 614366.0014) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were found in the carrier state in both parents. Neither mutation was present in the 1000 Genomes Project and gnomAD databases. Both mutations are located at highly conserved sites in the RNA_pol_Rpb2_6 domain. No functional studies were reported. The patient had progeroid features, micrognathia, triangular facies, macrocephaly, loss of subcutaneous fat, sparse hair, congenital dislocation of the hip, and hallux valgus. A subsequent sib pregnancy was terminated with the fetus having features of a lemon-shaped brain with a small frontal lobe. The fetus also was found to have the W731Q and V1016M mutations in the POLR3B gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3B, VAL1016MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2137084632,
|
|
|
|
|
|
|
|
ClinVar: RCV001839437
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant is classified as a variant of unknown significance because its contribution to Wiedemann-Rautenstrauch syndrome (see 264090) has not been confirmed.</p><p>For discussion of the c.3046G-A transition (c.3046G-A, NM_018082.5) in the POLR3B gene, resulting in a val1016-to-met (V1016M) substitution, that was found in compound heterozygous state in a patient diagnosed with Wiedemann-Rautenstrauch syndrome by Wu et al. (2021), see 614366.0013. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA AND WITH HYPOGONADOTROPIC HYPOGONADISM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3B, PRO925GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs775141057,
|
|
|
|
|
|
gnomAD: rs775141057,
|
|
|
|
|
|
ClinVar: RCV000498916
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.2774C-A transversion (c.2774C-A, NM_018082.5) in the POLR3B gene, resulting in a pro925-to-gln (P925Q) substitution, that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381) by Ghoumid et al. (2017), see 614366.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA AND WITH HYPOGONADOTROPIC HYPOGONADISM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3B, IVS19AS, -6, A-G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs747912710,
|
|
|
|
|
|
gnomAD: rs747912710,
|
|
|
|
|
|
ClinVar: RCV000484819, RCV001195929, RCV004691238
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.2084-6A-G mutation in the POLR3B gene, resulting in a frameshift and premature termination (Gly695fsTer5) that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381) by Daoud et al. (2013), see 614366.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA AND WITH HYPOGONADOTROPIC HYPOGONADISM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3B, LEU104PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2136887072,
|
|
|
|
|
|
|
|
ClinVar: RCV001542038
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (patient 13) with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381), Daoud et al. (2013) identified compound heterozygous mutations in the POLR3B gene: a c.312G-T transversion (c.312G-T, NM_018082) in exon 6, resulting in a leu104-to-phe (L104F) substitution, and a c.2570+1G-A transition (614366.0018) in intron 22, resulting in a frameshift and premature termination (Gly818fsAlaTer13). Analysis of RNA from patient lymphoblastoid cells showed that the mutation resulted in skipping of exon 22. The mutations were identified by sequencing of the POLR3B gene. Neither mutation was present in the dbSNP database. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA AND WITH HYPOGONADOTROPIC HYPOGONADISM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3B, IVS22DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs753943393,
|
|
|
|
|
|
gnomAD: rs753943393,
|
|
|
|
|
|
ClinVar: RCV000760972, RCV001093430
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.2570+1G-A transition (c.2570+1G-A, NM_018082) in intron 22 of the POLR3B gene, resulting in a frameshift and premature termination (Gly818fsTer13), that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381) by Daoud et al. (2013), see 614366.0017. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
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|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Borland, G., Wilkie, S. E., Thomson, J., Wang, Z., Tullet, J. M. A., Alic, N., Selman, C.
|
|
<strong>Polr3b heterozygosity in mice induces both beneficial and deleterious effects on health during ageing with no effect on lifespan.</strong>
|
|
Aging Cell 23: e14141, 2024.
|
|
|
|
|
|
[PubMed: 38465473]
|
|
|
|
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[Full Text: https://doi.org/10.1111/acel.14141]
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</p>
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Daoud, H., Tetreault, M., Gibson, W., Guerrero, K., Cohen, A., Gburek-Augustat, J., Synofzik, M., Brais, B., Stevens, C. A., Sanchez-Carpintero, R., Goizet, C., Naidu, S., Vanderver, A., Bernard, G.
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<strong>Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism.</strong>
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J. Med. Genet. 50: 194-197, 2013.
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[PubMed: 23355746]
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[Full Text: https://doi.org/10.1136/jmedgenet-2012-101357]
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Djordjevic, D., Pinard, M., Gauthier, M.-S., Smith-Hicks, C., Hoffman, TL., Wolf, NI., Oegema, R., van Binsbergen, E., Baskin, B., Bernard, G., Fribourg, S., Coulombe, B., Yoon, G.
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<strong>De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy.</strong>
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Am. J. Hum. Genet. 108: 186-193, 2021. Note: Erratum: Am. J. Hum. Genet. 109: 759-763, 2022.
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[PubMed: 33417887]
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[Full Text: https://doi.org/10.1016/j.ajhg.2020.12.002]
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Ghoumid, J., Petit, F., Boute-Benejean, O., Frenois, F., Cartigny, M., Vanlerberghe, C., Smol, T., Caumes, R., de Roux, N., Manouvrier-Hanu, S.
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<strong>Cerebellar hypoplasia with endosteal sclerosis is a POLR3-related disorder.</strong>
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Europ. J. Hum. Genet. 25: 1011-1014, 2017.
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[PubMed: 28589944]
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[Full Text: https://doi.org/10.1038/ejhg.2017.73]
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</p>
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<p class="mim-text-font">
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Hartz, P. A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 11/29/2011.
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</p>
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Hu, P., Wu, S., Sun, Y., Yuan, C.-C., Kobayashi, R., Myers, M. P., Hernandez, N.
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<strong>Characterization of human RNA polymerase III identifies orthologues for Saccharomyces cerevisiae RNA polymerase III subunits.</strong>
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Molec. Cell. Biol. 22: 8044-8055, 2002.
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[PubMed: 12391170]
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[Full Text: https://doi.org/10.1128/MCB.22.22.8044-8055.2002]
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Michell-Robinson, M. A., Watt, K. E. N., Grouza, V., Macintosh, J., Pinard, M., Tuznik, M., Chen, X., Darbelli, L., Wu, C. L., Perrier, S., Chitsaz, D., Uccelli, N. A., Liu, H., Cox, T. C., Muller, C. W., Kennedy, T. E., Coulombe, B., Rudko, D. A., Trainor, P. A., Bernard, G.
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<strong>Hypomyelination, hypodontia and craniofacial abnormalities in a Polr3b mouse model of leukodystrophy.</strong>
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Brain 146: 5070-5085, 2023.
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[PubMed: 37635302]
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[Full Text: https://doi.org/10.1093/brain/awad249]
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Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., Matsumoto, N.
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<strong>Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.</strong>
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Am. J. Hum. Genet. 89: 644-651, 2011.
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[PubMed: 22036171]
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[Full Text: https://doi.org/10.1016/j.ajhg.2011.10.003]
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Sasaki, M., Takanashi, J., Tada, H., Sakuma, H., Furushima, W., Sato, N.
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<strong>Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum.</strong>
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Brain Dev. 31: 582-587, 2009.
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[PubMed: 18851904]
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[Full Text: https://doi.org/10.1016/j.braindev.2008.09.003]
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Tetreault, M., Choquet, K., Orcesi, S., Tonduti, D., Balottin, U., Teichmann, M., Fribourg, S., Schiffmann, R., Brais, B., Vanderver, A., Bernard, G.
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<strong>Recessive mutations in POLR3B, encoding the second largest subunit of pol III, cause a rare hypomyelinating leukodystrophy.</strong>
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Am. J. Hum. Genet. 89: 652-655, 2011.
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[PubMed: 22036172]
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[Full Text: https://doi.org/10.1016/j.ajhg.2011.10.006]
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Verberne, E. A., Dalen Meurs, L., Wolf, N. I., 4H leukodystrophy caused by a homozygous POLR3B mutation.
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<strong>further delineation of the phenotype.</strong>
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Am. J. Med. Genet. 182A: 1776-1779, 2020.
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[PubMed: 32319736]
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[Full Text: https://doi.org/10.1002/ajmg.a.61600]
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Wolf, N. I., Vanderver, A., van Spaendonk, R. M. L., Schiffmann, R., Brais, B., Bugiani, M., Sistermans, E., Catsman-Berrevoets, C., Kros, J. M., Soares Pinto, P., Pohl, D., Tirupathi, S., and 10 others.
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<strong>Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations.</strong>
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Neurology 83: 1898-1905, 2014.
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[PubMed: 25339210]
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[Full Text: https://doi.org/10.1212/WNL.0000000000001002]
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Wu, S.-W., Li, L., Feng, F., Wang, L., Kong, Y.-Y., Liu, X.-W., Yin, C.
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<strong>Whole-exome sequencing reveals POLR3B variants associated with progeria-related Wiedemann-Rautenstrauch syndrome.</strong>
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Ital. J. Pediat. 47: 160, 2021.
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[PubMed: 34289880]
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[Full Text: https://doi.org/10.1186/s13052-021-01112-6]
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Xue, Y.-Y., Cheng, H.-L., Dong, H.-L., Yin, H.-M., Yuan, Y., Meng, L.-C., Wu, Z.-Y., Yu, H.
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<strong>A de novo variant of POLR3B causes demyelinating Charcot-Marie-Tooth disease in a Chinese patient: a case report.</strong>
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BMC Neurol. 21: 402, 2021.
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[PubMed: 34666706]
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[Full Text: https://doi.org/10.1186/s12883-021-02399-y]
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