4665 lines
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Entry
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- *604712 - RIBONUCLEOTIDE REDUCTASE REGULATORY TP53 INDUCIBLE SUBUNIT M2B; RRM2B
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*604712</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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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/604712">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000048392;t=ENST00000251810" 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=50484" 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=604712" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000048392;t=ENST00000251810" 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_001172477,NM_001172478,NM_015713" 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_015713" 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=604712" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
|
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=05276&isoform_id=05276_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/RRM2B" 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/7023557,7229086,7229115,27769295,42544136,42794058,42794060,45259565,45259569,45268714,50949848,52545612,63055293,74727333,80473666,109659128,119612246,119612247,119612248,120660296,194385642,289177074,289177076" 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/Q7LG56" 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=50484" 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=ENSG00000048392;t=ENST00000251810" 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=RRM2B" 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=RRM2B" 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+50484" 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/RRM2B" 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:50484" 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/50484" 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=chr8&hgg_gene=ENST00000251810.8&hgg_start=102204501&hgg_end=102238961&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://medlineplus.gov/genetics/gene/rrm2b" 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=604712[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=604712[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/RRM2B/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/ENSG00000048392" 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=RRM2B" 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=RRM2B" 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=RRM2B" 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=RRM2B&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/PA34866" 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:17296" 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/FBgn0011704.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:2155865" 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/RRM2B#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:2155865" 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/50484/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=50484" 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=WBGene00004392;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-030616-614" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:50484" 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=RRM2B&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 765100000<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
604712
|
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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>
|
|
<span class="mim-font">
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RIBONUCLEOTIDE REDUCTASE REGULATORY TP53 INDUCIBLE SUBUNIT M2B; RRM2B
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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>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
RIBONUCLEOTIDE REDUCTASE, M2 B<br />
|
|
RIBONUCLEOTIDE REDUCTASE SMALL SUBUNIT 2-LIKE, p53-INDUCIBLE; P53R2<br />
|
|
p53-INDUCIBLE AND RIBONUCLEOTIDE REDUCTASE SMALL SUBUNIT 2-LIKE
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=RRM2B" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">RRM2B</a></em></strong>
|
|
</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/8/452?start=-3&limit=10&highlight=452">8q22.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr8:102204501-102238961&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'})">8:102,204,501-102,238,961</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
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|
|
</span>
|
|
</p>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=612075,612075,613077,268315" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/8/452?start=-3&limit=10&highlight=452">
|
|
8q22.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy)
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/612075"> 612075 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
|
</td>
|
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</tr>
|
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|
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|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Mitochondrial DNA depletion syndrome 8B (MNGIE type)
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/612075"> 612075 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
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<p>The RRM2B gene encodes the small subunit of p53 (<a href="/entry/191170">191170</a>)-inducible ribonucleotide reductase, a heterotetrameric enzyme responsible for de novo conversion of ribonucleoside diphosphates into the corresponding deoxyribonucleoside diphosphates that are essential for DNA synthesis (<a href="#2" class="mim-tip-reference" title="Bourdon, A., Minai, L., Serre, V., Jais, J.-P., Sarzi, E., Aubert, S., Chretien, D., de Lonlay, P., Paquis-Flucklinger, V., Arakawa, H., Nakamura, Y., Munnich, A., Rotig, A. <strong>Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. (Letter)</strong> Nature Genet. 39: 776-780, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17486094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17486094</a>] [<a href="https://doi.org/10.1038/ng2040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17486094">Bourdon et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17486094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The p53 gene is frequently inactivated in human cancers. By using differential display to examine mRNAs in a human colon cancer cell line carrying a highly regulated wildtype p53 expression system, <a href="#11" class="mim-tip-reference" title="Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., Nakamura, Y. <strong>A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage.</strong> Nature 404: 42-49, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10716435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10716435</a>] [<a href="https://doi.org/10.1038/35003506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10716435">Tanaka et al. (2000)</a> detected a 5.5-kb transcript that was inducible by wildtype p53 but not mutant p53. Using the differential display fragment representing this transcript as a probe to screen a skeletal muscle cDNA library, they isolated a cDNA sequence that incorporated an open reading frame of 351 amino acids with 80% identity to the small subunit of human ribonucleotide reductase (R2; <a href="/entry/180390">180390</a>). Comparison of this sequence, which they called p53R2 for 'p53-inducible ribonucleotide reductase small subunit 2 homolog,' with those of yeast RNR2 and RNR4 revealed 60% and 40% identity, respectively. <a href="#11" class="mim-tip-reference" title="Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., Nakamura, Y. <strong>A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage.</strong> Nature 404: 42-49, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10716435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10716435</a>] [<a href="https://doi.org/10.1038/35003506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10716435">Tanaka et al. (2000)</a> considered p53R2 to be a human counterpart of yeast RNR2. The protein has a ribonucleotide reductase small subunit signature and 2 putative nuclear localization signal sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10716435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="mim-changed mim-change"><p><a href="#11" class="mim-tip-reference" title="Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., Nakamura, Y. <strong>A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage.</strong> Nature 404: 42-49, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10716435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10716435</a>] [<a href="https://doi.org/10.1038/35003506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10716435">Tanaka et al. (2000)</a> found that the p53R2 gene has 9 exons and spans a 30-kb genomic region. Electromobility shift assays identified a 20-nucleotide region in intron 1 as the p53 binding site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10716435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><a href="#11" class="mim-tip-reference" title="Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., Nakamura, Y. <strong>A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage.</strong> Nature 404: 42-49, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10716435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10716435</a>] [<a href="https://doi.org/10.1038/35003506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10716435">Tanaka et al. (2000)</a> mapped the p53R2 gene to chromosome 8q23.1 by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10716435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 03/01/2022."None>Stumpf (2022)</a> mapped the RRM2B gene to chromosome 8q22.3 based on an alignment of the RRM2B sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC117496" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC117496</a>) with the genomic sequence (GRCh38).</p>
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<p><a href="#11" class="mim-tip-reference" title="Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., Nakamura, Y. <strong>A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage.</strong> Nature 404: 42-49, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10716435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10716435</a>] [<a href="https://doi.org/10.1038/35003506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10716435">Tanaka et al. (2000)</a> found that expression of p53R2, but not R2, was induced by ultraviolet and gamma-irradiation and adriamycin treatment in a wildtype p53-dependent manner. Induction of p53R2 in p53-deficient cells caused G2/M arrest and protected cells from death in response to adriamycin. Inhibition of endogenous p53R2 expression in cells that had an intact p53-dependent DNA damage checkpoint reduced ribonucleotide reductase activity, DNA repair, and cell survival after exposure to various genotoxins. <a href="#11" class="mim-tip-reference" title="Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., Nakamura, Y. <strong>A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage.</strong> Nature 404: 42-49, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10716435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10716435</a>] [<a href="https://doi.org/10.1038/35003506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10716435">Tanaka et al. (2000)</a> demonstrated nuclear accumulation of p53R2 protein in response to genotoxic stress induced by gamma-irradiation. <a href="#11" class="mim-tip-reference" title="Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., Nakamura, Y. <strong>A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage.</strong> Nature 404: 42-49, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10716435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10716435</a>] [<a href="https://doi.org/10.1038/35003506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10716435">Tanaka et al. (2000)</a> concluded that p53R2 encodes a ribonucleotide reductase that is directly involved in the p53 checkpoint for repair of damaged DNA. The discovery of p53R2 clarified a relationship between a ribonucleotide reductase activity involved in repair of damaged DNA and tumor suppression by p53. <a href="#11" class="mim-tip-reference" title="Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., Nakamura, Y. <strong>A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage.</strong> Nature 404: 42-49, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10716435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10716435</a>] [<a href="https://doi.org/10.1038/35003506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10716435">Tanaka et al. (2000)</a> proposed that inactivation of p53 directly interferes with the transcription of p53R2 in response to DNA damage, with the result that ribonucleotide reductase activity is insufficient for normal DNA repair. Faulty regulation of p53R2 might also enhance misincorporation of deoxyribonucleotide triphosphates (dNTPs) and dysregulation of DNA repair machinery and thereby increase the frequency of mutations. <a href="#11" class="mim-tip-reference" title="Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., Nakamura, Y. <strong>A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage.</strong> Nature 404: 42-49, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10716435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10716435</a>] [<a href="https://doi.org/10.1038/35003506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10716435">Tanaka et al. (2000)</a> suggested that the genomic instability often seen in tumors lacking wildtype p53 may reflect dysfunction of ribonucleotide reductase due to the failure of p53R2 induction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10716435" 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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In 7 patients from 4 families with severe autosomal recessive mitochondrial DNA (mtDNA) depletion syndrome-8A (MTDPS8A; <a href="/entry/612075">612075</a>), associated with renal tubulopathy, <a href="#2" class="mim-tip-reference" title="Bourdon, A., Minai, L., Serre, V., Jais, J.-P., Sarzi, E., Aubert, S., Chretien, D., de Lonlay, P., Paquis-Flucklinger, V., Arakawa, H., Nakamura, Y., Munnich, A., Rotig, A. <strong>Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. (Letter)</strong> Nature Genet. 39: 776-780, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17486094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17486094</a>] [<a href="https://doi.org/10.1038/ng2040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17486094">Bourdon et al. (2007)</a> identified homozygous or compound heterozygous mutations in the RRM2B gene (see, e.g., <a href="#0001">604712.0001</a>-<a href="#0005">604712.0005</a>). All patients had 1 to 2% residual mtDNA in skeletal muscle and died in the first months of life with severe lactic acidosis. Respiratory chain complex activities were severely decreased in muscle from these patients. The findings indicated that RRM2B plays a crucial role in dNTP supply, especially for the synthesis of mtDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17486094" 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 male infant, born to consanguineous Latino parents, with MTDPS8A, <a href="#6" class="mim-tip-reference" title="Penque, B. A., Su, L., Wang, J., Ji, W., Bale, A., Luh, F., Fulbright, R. K., Fulbright, R. K., Sarmast, U., Sega, A. G., Konstantino, M., Spencer-Manzon, M., Pierce, R., Yen, Y., Lakhani, S. A. <strong>A homozygous variant in RRM2B is associated with severe metabolic acidosis and early neonatal death.</strong> Europ. J. Med. Genet. 62: 103574, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30439532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30439532</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.11.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30439532">Penque et al. (2019)</a> identified a homozygous missense mutation in the RRM2B gene (N221S; <a href="#0015">604712.0015</a>). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Molecular modeling suggested that the mutation disrupts a conserved alpha helix region of the protein by altering intramolecular interactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30439532" 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>Mitochondrial DNA Depletion Syndrome 8B (MNGIE Type)</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Shaibani, A., Shchelochkov, O. A., Zhang, S., Katsonis, P., Lichtarge, O., Wong, L.-J., Shinawi, M. <strong>Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B.</strong> Arch. Neurol. 66: 1028-1032, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19667227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19667227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19667227[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/10.1001/archneurol.2009.139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19667227">Shaibani et al. (2009)</a> identified compound heterozygosity for 2 mutations in the RRM2B gene (R110H, <a href="#0008">604712.0008</a>; R121H, <a href="#0009">604712.0009</a>) in a 42-year-old woman with mtDNA depletion syndrome-8B, manifest as a neurogastrointestinal encephalopathy (see <a href="/entry/612075">612075</a>). The authors stated that this was the oldest reported patient with RRM2B mutations and that her clinical course was different from that reported previously in patients with MNGIE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19667227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Autosomal Dominant Progressive External Ophthalmoplegia 5</em></strong></p><p>
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By linkage analysis followed by candidate gene sequencing in a large North American family with mild autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; <a href="/entry/613077">613077</a>), <a href="#12" class="mim-tip-reference" title="Tyynismaa, H., Ylikallio, E., Patel, M., Molnar, M. J., Haller, R. G., Suomalainen, A. <strong>A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions.</strong> Am. J. Hum. Genet. 85: 290-295, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19664747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19664747</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19664747[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.2009.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19664747">Tyynismaa et al. (2009)</a> identified a heterozygous mutation in the RRM2B gene (R327X; <a href="#0006">604712.0006</a>) that segregated with the disorder. Affected members of an unrelated Hungarian family carried the same mutation, but there was no evidence of a common origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19664747" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By direct sequencing of the RRM2B gene in 75 unrelated probands with PEO in whom mutations in other known PEO-related genes had been excluded, <a href="#3" class="mim-tip-reference" title="Fratter, C., Raman, P., Alston, C. L., Blakely, E. L., Craig, K., Smith, C., Evans, J., Seller, A., Czermin, B., Hanna, M. G., Poulton, J., Brierley, C., Staunton, T. G., Turnpenny, P. D., Schaefer, A. M., Chinnery, P. F., Horvath, R., Turnbull, D. M., Gorman, G. S., Taylor, R. W. <strong>RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions.</strong> Neurology 76: 2032-2034, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21646632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21646632</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31821e558b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21646632">Fratter et al. (2011)</a> identified 3 different heterozygous truncating mutations in the RRM2B gene (see, e.g., <a href="#0010">604712.0010</a> and <a href="#0011">604712.0011</a>) in 7 (9.3%) patients. The findings suggested that truncating RRM2B mutations are rather frequent in familial PEO with mtDNA deletions. Three additional patients were found to carry 3 different heterozygous missense variants, but the pathogenicity of the variants was considered provisional in the absence of further supporting evidence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21646632" 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>Rod-Cone Dystrophy, Sensorineural Deafness, and Fanconi-Type Renal Dysfunction</em></strong></p><p>
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In 6 patients from 5 Afrikaner families with rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction (RCDFRD; <a href="/entry/268315">268315</a>), <a href="#7" class="mim-tip-reference" title="Roberts, L., Julius, S., Dawlat, S., Yildiz, S., Rebello, G., Meldau, S., Pillay, K., Esterhuizen, A., Vorster, A., Benefeld, G., da Rocha, J., Beighton, P., Sellars, S. L., Thandrayen, K., Pettifor, J. M., Ramesar, R. S. <strong>Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B.</strong> Hum. Mutat. 41: 1871-1876, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32827185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32827185</a>] [<a href="https://doi.org/10.1002/humu.24094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32827185">Roberts et al. (2020)</a> identified homozygosity for a missense mutation in the RRM2B gene (E262D; <a href="#0016">604712.0016</a>) that segregated with disease in each family and was not found in Afrikaner controls or in public variant databases. Haplotype analysis suggested a probable founder effect in the Afrikaner population. Evaluation of a patient muscle biopsy showed no evidence of mtDNA deletions or depletion, but microscopy was consistent with a mild mitochondrial abnormality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32827185" 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>To determine whether ribonucleotide reductase is involved in DNA repair by supplying deoxyribonucleotides (dNTPs) for resting cells in vivo, <a href="#4" class="mim-tip-reference" title="Kimura, T., Takeda, S., Sagiya, Y., Gotoh, M., Nakamura, Y., Arakawa, H. <strong>Impaired function of p53R2 in Rrm2b-null mice causes severe renal failure through attenuation of dNTP pools.</strong> Nature Genet. 34: 440-445, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12858174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12858174</a>] [<a href="https://doi.org/10.1038/ng1212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12858174">Kimura et al. (2003)</a> generated a strain of mice lacking Rrm2b. These mice developed normally until they were weaned but from then on had growth retardation and early mortality. Pathologic examination indicated that multiple organs had failed, and all Rrm2b-null mice died from severe renal failure by the age of 14 weeks. TUNEL staining showed a greater number of apoptotic cells in kidneys of 8-week-old null mice relative to wildtype. p53 (<a href="/entry/191170">191170</a>) was activated in kidney tissues of the null mice, leading to transcriptional induction of p53 target genes. Embryonic fibroblasts from null mice became immortal much earlier than wildtype embryonic fibroblasts. dNTP pools were severely attenuated in embryonic fibroblasts from null mice under oxidative stress. Rrm2b deficiency caused higher rates of spontaneous mutation in the kidneys of null mice. The results suggested that p53R2 has a pivotal role in maintaining dNTP levels for repair of DNA in resting cells. Impairment of this pathway may enhance spontaneous mutation frequency and activate p53-dependent apoptotic pathways in vivo, causing severe renal failure, growth retardation, and early mortality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12858174" 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="Bourdon, A., Minai, L., Serre, V., Jais, J.-P., Sarzi, E., Aubert, S., Chretien, D., de Lonlay, P., Paquis-Flucklinger, V., Arakawa, H., Nakamura, Y., Munnich, A., Rotig, A. <strong>Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. (Letter)</strong> Nature Genet. 39: 776-780, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17486094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17486094</a>] [<a href="https://doi.org/10.1038/ng2040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17486094">Bourdon et al. (2007)</a> found that 12-week-old Rrm2b-null mice had markedly decreased mtDNA content in kidney (5.57% of controls), muscle (5.24%), and liver (21%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17486094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=604712[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918307 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918307;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/rs121918307?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=rs121918307" 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=rs121918307" 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 sibs, born of consanguineous Moroccan parents, with mitochondrial DNA depletion syndrome-8A (MTDPS8A; <a href="/entry/612075">612075</a>), manifest as encephalomyopathy and renal tubulopathy, <a href="#2" class="mim-tip-reference" title="Bourdon, A., Minai, L., Serre, V., Jais, J.-P., Sarzi, E., Aubert, S., Chretien, D., de Lonlay, P., Paquis-Flucklinger, V., Arakawa, H., Nakamura, Y., Munnich, A., Rotig, A. <strong>Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. (Letter)</strong> Nature Genet. 39: 776-780, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17486094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17486094</a>] [<a href="https://doi.org/10.1038/ng2040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17486094">Bourdon et al. (2007)</a> identified a homozygous 850C-T transition in the RRM2B gene, resulting in a gln284-to-ter (Q284X) substitution. The substitution resulted in the deletion of the last 68 C-terminal residues of the protein, including part of the an alpha-helix as well as the heptapeptide involved in the binding to R1. The sibs had hypotonia and lactic acidosis and died within the first months of life. Severe mtDNA depletion (less than 1% of controls) was found in muscle of 1 the sibs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17486094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 French infants with mitochondrial DNA depletion syndrome-8A (MTDPS8A; <a href="/entry/612075">612075</a>), manifest as encephalomyopathy with renal tubulopathy, <a href="#2" class="mim-tip-reference" title="Bourdon, A., Minai, L., Serre, V., Jais, J.-P., Sarzi, E., Aubert, S., Chretien, D., de Lonlay, P., Paquis-Flucklinger, V., Arakawa, H., Nakamura, Y., Munnich, A., Rotig, A. <strong>Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. (Letter)</strong> Nature Genet. 39: 776-780, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17486094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17486094</a>] [<a href="https://doi.org/10.1038/ng2040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17486094">Bourdon et al. (2007)</a> identified compound heterozygosity for 2 mutations in the RRM2B gene: an A-to-G transition in intron 3 and E194K (<a href="#0003">604712.0003</a>). The sibs had lactic acidemia, hypotonia, tubulopathy, and seizures. Only 2% of normal mtDNA levels was detected in the muscle of 1 of the sibs. Both died at 2 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17486094" 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 MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY)</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> rs121918308 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918308;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/rs121918308?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=rs121918308" 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=rs121918308" 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=RCV000005719 OR RCV000118999" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005719, RCV000118999" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005719...</a>
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<p>In 2 French infants with mitochondrial DNA depletion syndrome-8A (MTDPS8A; <a href="/entry/612075">612075</a>), manifest as encephalomyopathy with renal tubulopathy, <a href="#2" class="mim-tip-reference" title="Bourdon, A., Minai, L., Serre, V., Jais, J.-P., Sarzi, E., Aubert, S., Chretien, D., de Lonlay, P., Paquis-Flucklinger, V., Arakawa, H., Nakamura, Y., Munnich, A., Rotig, A. <strong>Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. (Letter)</strong> Nature Genet. 39: 776-780, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17486094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17486094</a>] [<a href="https://doi.org/10.1038/ng2040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17486094">Bourdon et al. (2007)</a> identified compound heterozygosity for 2 mutations in the RRM2B gene: a 580G-A transition, resulting in a glu194-to-lys (E194K) substitution, and a splice site mutation (<a href="#0002">604712.0002</a>). Residue 194 is involved in iron binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17486094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY)</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> rs515726184 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726184;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/rs515726184?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=rs515726184" 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=rs515726184" 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=RCV000005720 OR RCV000118988 OR RCV000186558 OR RCV000413797 OR RCV002483199" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005720, RCV000118988, RCV000186558, RCV000413797, RCV002483199" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005720...</a>
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<p>In a French infant with severe mitochondrial DNA depletion with renal tubulopathy (<a href="/entry/612075">612075</a>), <a href="#2" class="mim-tip-reference" title="Bourdon, A., Minai, L., Serre, V., Jais, J.-P., Sarzi, E., Aubert, S., Chretien, D., de Lonlay, P., Paquis-Flucklinger, V., Arakawa, H., Nakamura, Y., Munnich, A., Rotig, A. <strong>Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. (Letter)</strong> Nature Genet. 39: 776-780, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17486094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17486094</a>] [<a href="https://doi.org/10.1038/ng2040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17486094">Bourdon et al. (2007)</a> identified compound heterozygosity for 2 mutations in the RRM2B gene: a 3-bp deletion (253delGAG), resulting in an in-frame deletion of glu85, and C236F (<a href="#0005">604712.0005</a>). The patient had neonatal hypotonia and increased plasma and CSF lactate; she died at age 3 months. Muscle histology showed ragged-red fibers, and mtDNA content was about 1% of normal. The deletion of glu85 was predicted to disrupt the local subdomain structure and the dimerization interface between R1 and R2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17486094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY)</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">rs121918309 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918309;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=rs121918309" 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=rs121918309" 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=RCV000005721 OR RCV000119007" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005721, RCV000119007" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005721...</a>
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<p>In a French infant with severe mitochondrial DNA depletion with renal tubulopathy (<a href="/entry/612075">612075</a>), <a href="#2" class="mim-tip-reference" title="Bourdon, A., Minai, L., Serre, V., Jais, J.-P., Sarzi, E., Aubert, S., Chretien, D., de Lonlay, P., Paquis-Flucklinger, V., Arakawa, H., Nakamura, Y., Munnich, A., Rotig, A. <strong>Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. (Letter)</strong> Nature Genet. 39: 776-780, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17486094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17486094</a>] [<a href="https://doi.org/10.1038/ng2040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17486094">Bourdon et al. (2007)</a> identified compound heterozygosity for 2 mutations in the RRM2B gene: a 707G-T transversion, resulting in a cys236-to-phe (C236F) substitution, and a 3-bp deletion (<a href="#0004">604712.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17486094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 5</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">rs121918310 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918310;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=rs121918310" 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=rs121918310" 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=RCV000005722 OR RCV000119016 OR RCV000197531" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005722, RCV000119016, RCV000197531" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005722...</a>
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<p>In affected members of 2 unrelated families with autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; <a href="/entry/613077">613077</a>), <a href="#12" class="mim-tip-reference" title="Tyynismaa, H., Ylikallio, E., Patel, M., Molnar, M. J., Haller, R. G., Suomalainen, A. <strong>A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions.</strong> Am. J. Hum. Genet. 85: 290-295, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19664747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19664747</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19664747[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.2009.07.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19664747">Tyynismaa et al. (2009)</a> identified a heterozygous 979C-T transition in the last exon of the RRM2B gene, resulting in an arg327-to-ter (R327X) substitution. The substitution was predicted to result in a protein lacking the last 25 amino acids. One family was North American of European origin, and the second was Hungarian. The mutation was not observed in 380 control European chromosomes, and there was no evidence of a founder effect. The phenotype was characterized by late-onset of mild ophthalmoplegia and mild muscle weakness. Skeletal muscle biopsies showed mtDNA deletions, but normal mtDNA copy numbers. RNA studies showed that the R328X mRNA escaped nonsense-mediated decay, and that the mutant protein was expressed and stable. The findings suggested that the mutant RRM2B protein can compete with wildtype in binding to ribonucleotide reductase, causing a dominant-negative or gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19664747" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY)</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> rs121918311 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918311;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/rs121918311?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=rs121918311" 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=rs121918311" 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=RCV000005723 OR RCV000119005 OR RCV001818139" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005723, RCV000119005, RCV001818139" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005723...</a>
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<p>In 2 Sudanese brothers, born of consanguineous parents, with encephalomyopathic mitochondrial DNA depletion syndrome (MTDPS8A; <a href="/entry/612075">612075</a>), <a href="#5" class="mim-tip-reference" title="Kollberg, G., Darin, N., Benan, K., Moslemi, A.-R., Lindal, S., Tulinius, M., Oldfors, A., Holme, E. <strong>A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion.</strong> Neuromusc. Disord. 19: 147-150, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19138848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19138848</a>] [<a href="https://doi.org/10.1016/j.nmd.2008.11.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19138848">Kollberg et al. (2009)</a> identified a homozygous 686G-T transversion in exon 7 of the RRM2B gene, resulting in a gly229-to-val (G229V) substitution in the diferric iron center of the protein. Each unaffected parent was heterozygous for the mutation. The phenotype was severe, with hypotonia, seizures, poor visual contact, and lactic acidosis, and both patients died by 5 months of age. One boy developed a proximal renal tubulopathy. Southern blot analysis of patient cells showed severe mtDNA depletion, about 1 to 4% of normal controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19138848" 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> rs267607025 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607025;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/rs267607025?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=rs267607025" 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=rs267607025" 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=RCV000005724 OR RCV000118992 OR RCV001596931 OR RCV003147275" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005724, RCV000118992, RCV001596931, RCV003147275" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005724...</a>
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<p>In a 42-year-old woman with mitochondrial DNA depletion syndrome-8B, manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE; see <a href="/entry/612075">612075</a>), <a href="#8" class="mim-tip-reference" title="Shaibani, A., Shchelochkov, O. A., Zhang, S., Katsonis, P., Lichtarge, O., Wong, L.-J., Shinawi, M. <strong>Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B.</strong> Arch. Neurol. 66: 1028-1032, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19667227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19667227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19667227[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/10.1001/archneurol.2009.139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19667227">Shaibani et al. (2009)</a> identified compound heterozygosity for 2 mutations in the RRM2B gene: a 329G-A transition resulting in an arg110-to-his (R110H) substitution, and a 362G-A transition resulting in an arg121-to-his (R121H; <a href="#0009">604712.0009</a>) substitution. Both mutations occurred in highly conserved residues. The patient developed recurrent nausea, vomiting, and weight loss at age 30 years. At age 37, she developed restriction of eye movements, ptosis, dysarthria, unsteady gait, muscle weakness, and areflexia consistent with a peripheral neuropathy. Skeletal muscle showed mtDNA depletion (12% of controls). <a href="#8" class="mim-tip-reference" title="Shaibani, A., Shchelochkov, O. A., Zhang, S., Katsonis, P., Lichtarge, O., Wong, L.-J., Shinawi, M. <strong>Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B.</strong> Arch. Neurol. 66: 1028-1032, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19667227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19667227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19667227[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/10.1001/archneurol.2009.139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19667227">Shaibani et al. (2009)</a> noted that this was the oldest reported patient with RRM2B mutations and that her clinical course was different from that reported previously in patients with MNGIE. The findings also broadened the phenotype associated with RRM2B mutations to include an MNGIE-like picture. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19667227" 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 MITOCHONDRIAL DNA DEPLETION SYNDROME 8B (MNGIE TYPE)</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> rs267607024 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607024;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/rs267607024?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=rs267607024" 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=rs267607024" 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=RCV000005725 OR RCV000118994" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005725, RCV000118994" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005725...</a>
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<p>For discussion of the arg121-to-his (R121H) mutation in the RRM2B gene that was found in compound heterozygous state in a patient with mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE; see <a href="/entry/612075">612075</a>) by <a href="#8" class="mim-tip-reference" title="Shaibani, A., Shchelochkov, O. A., Zhang, S., Katsonis, P., Lichtarge, O., Wong, L.-J., Shinawi, M. <strong>Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B.</strong> Arch. Neurol. 66: 1028-1032, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19667227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19667227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19667227[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/10.1001/archneurol.2009.139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19667227">Shaibani et al. (2009)</a>, see <a href="#0008">604712.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19667227" 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 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 5</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">rs515726199 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726199;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=rs515726199" 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=rs515726199" 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=RCV000023385 OR RCV000119013 OR RCV000508947" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023385, RCV000119013, RCV000508947" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023385...</a>
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<p>In 3 unrelated patients with autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; <a href="/entry/613077">613077</a>), <a href="#3" class="mim-tip-reference" title="Fratter, C., Raman, P., Alston, C. L., Blakely, E. L., Craig, K., Smith, C., Evans, J., Seller, A., Czermin, B., Hanna, M. G., Poulton, J., Brierley, C., Staunton, T. G., Turnpenny, P. D., Schaefer, A. M., Chinnery, P. F., Horvath, R., Turnbull, D. M., Gorman, G. S., Taylor, R. W. <strong>RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions.</strong> Neurology 76: 2032-2034, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21646632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21646632</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31821e558b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21646632">Fratter et al. (2011)</a> identified a heterozygous 1-bp deletion (950delT) in the RRM2B gene, resulting in a frameshift and premature termination at leu317. The patients had onset at ages 30, 53, and 46 years, and all had a family history of the disorder. All had PEO and ptosis, but additional variable features in 2 patients included fatigue, ataxia, proximal myopathy, dysphagia, and glaucoma. Skeletal muscle biopsies of the probands showed a mosaic defect of cytochrome c oxidase activity and multiple mtDNA deletions. The mutation was not found in 352 control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21646632" 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 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 5</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">rs515726201 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726201;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=rs515726201" 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=rs515726201" 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=RCV000023386 OR RCV000119015" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023386, RCV000119015" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023386...</a>
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<p>In 3 unrelated patients with autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; <a href="/entry/613077">613077</a>), <a href="#3" class="mim-tip-reference" title="Fratter, C., Raman, P., Alston, C. L., Blakely, E. L., Craig, K., Smith, C., Evans, J., Seller, A., Czermin, B., Hanna, M. G., Poulton, J., Brierley, C., Staunton, T. G., Turnpenny, P. D., Schaefer, A. M., Chinnery, P. F., Horvath, R., Turnbull, D. M., Gorman, G. S., Taylor, R. W. <strong>RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions.</strong> Neurology 76: 2032-2034, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21646632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21646632</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31821e558b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21646632">Fratter et al. (2011)</a> identified a heterozygous 1-bp duplication (965dupA) in the RRM2B gene, resulting in a frameshift and premature termination. The patients had onset at ages 30, 54, and 26 years, and all had a family history of the disorder. All had PEO and fatigue, but additional features were variable and included diabetes, gastrointestinal symptoms, dysphagia, dysphonia, and proximal myopathy. Skeletal muscle biopsies of the probands showed a mosaic defect of cytochrome c oxidase activity and multiple mtDNA deletions. The mutation was not found in 352 control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21646632" 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">rs515726194 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs515726194;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=rs515726194" 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=rs515726194" 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=RCV000023387 OR RCV000119003" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023387, RCV000119003" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023387...</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to progressive external ophthalmoplegia (PEO) has not been confirmed.</p><p>In a 14-year-old patient with early-onset PEO at age 4 and hearing loss, <a href="#3" class="mim-tip-reference" title="Fratter, C., Raman, P., Alston, C. L., Blakely, E. L., Craig, K., Smith, C., Evans, J., Seller, A., Czermin, B., Hanna, M. G., Poulton, J., Brierley, C., Staunton, T. G., Turnpenny, P. D., Schaefer, A. M., Chinnery, P. F., Horvath, R., Turnbull, D. M., Gorman, G. S., Taylor, R. W. <strong>RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions.</strong> Neurology 76: 2032-2034, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21646632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21646632</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31821e558b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21646632">Fratter et al. (2011)</a> identified compound heterozygous changes in the RRM2B gene: a 606T-A transversion resulting in a phe202-to-leu (F202L) substitution, and an 817G-A transition resulting in a gly273-to-ser (G273S; <a href="#0013">604712.0013</a>) substitution. Functional studies of the variants were not performed. Skeletal muscle biopsy showed a mosaic defect of cytochrome c oxidase activity and multiple mtDNA deletions. Neither variant was found in 352 control alleles, and both occurred in conserved residues. There was no family history of a similar disorder, but information on the parents was not provided. The findings suggested recessive inheritance of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21646632" 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> rs387906891 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906891;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/rs387906891?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=rs387906891" 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=rs387906891" 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=RCV000023388 OR RCV000119008 OR RCV001582496" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023388, RCV000119008, RCV001582496" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023388...</a>
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<p>For discussion of the gly273-to-ser (G273S) mutation in the RRM2B gene that was found in compound heterozygous state in a patient with early-onset progressive external ophthalmoplegia (PEO) and hearing loss by <a href="#3" class="mim-tip-reference" title="Fratter, C., Raman, P., Alston, C. L., Blakely, E. L., Craig, K., Smith, C., Evans, J., Seller, A., Czermin, B., Hanna, M. G., Poulton, J., Brierley, C., Staunton, T. G., Turnpenny, P. D., Schaefer, A. M., Chinnery, P. F., Horvath, R., Turnbull, D. M., Gorman, G. S., Taylor, R. W. <strong>RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions.</strong> Neurology 76: 2032-2034, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21646632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21646632</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31821e558b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21646632">Fratter et al. (2011)</a> and classified as a variant of unknown significance, see <a href="#0012">604712.0012</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21646632" 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> rs387906892 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906892;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/rs387906892?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=rs387906892" 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=rs387906892" 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=RCV000023389 OR RCV000118993 OR RCV001852021 OR RCV002283445" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023389, RCV000118993, RCV001852021, RCV002283445" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023389...</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to progressive external ophthalmoplegia (PEO) has not been confirmed.</p><p>In a 43-year-old Japanese man, born of consanguineous parents, with adult-onset PEO, <a href="#10" class="mim-tip-reference" title="Takata, A., Kato, M., Nakamura, M., Yoshikawa, T., Kanba, S., Sano, A., Kato, T. <strong>Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia.</strong> Genome Biol. 12: R92, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21951382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21951382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21951382[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/gb-2011-12-9-r92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21951382">Takata et al. (2011)</a> identified a homozygous 341G-A transition in the RRM2B gene, resulting in a pro33-to-ser (P33S) substitution in a highly conserved residue in the N terminus. The variant was found by whole-exome sequencing in combination with runs of homozygosity analysis. Each unaffected parent was heterozygous for the mutation, which was found in 1 of 718 control chromosomes of Japanese origin. Functional studies of the variant were not performed. The patient presented with hearing loss at age 16 years, and later developed ptosis, ophthalmoplegia, and muscle weakness. He also had pigmentary degeneration of the retina and gonadal atrophy. Other features included depressed mood, anxiety, and hypochondriacal complaints. Muscle biopsy showed marked variation of fiber size, ragged-red fibers, COX-negative fibers, and multiple mtDNA deletions. There was no family history of a similar disorder. Mutations in other candidate genes were excluded. <a href="#10" class="mim-tip-reference" title="Takata, A., Kato, M., Nakamura, M., Yoshikawa, T., Kanba, S., Sano, A., Kato, T. <strong>Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia.</strong> Genome Biol. 12: R92, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21951382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21951382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21951382[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/gb-2011-12-9-r92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21951382">Takata et al. (2011)</a> suggested that this was the first case of recessive inheritance of PEO due to RRM2B mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21951382" 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 MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY)</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> rs863224193 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863224193;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/rs863224193?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=rs863224193" 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=rs863224193" 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=RCV000196496 OR RCV000680084 OR RCV000714482" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000196496, RCV000680084, RCV000714482" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000196496...</a>
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<p>In a male infant, born to consanguineous Latino parents, with mitochondrial DNA depletion syndrome-8A (MTDPS8A; <a href="/entry/612075">612075</a>), <a href="#6" class="mim-tip-reference" title="Penque, B. A., Su, L., Wang, J., Ji, W., Bale, A., Luh, F., Fulbright, R. K., Fulbright, R. K., Sarmast, U., Sega, A. G., Konstantino, M., Spencer-Manzon, M., Pierce, R., Yen, Y., Lakhani, S. A. <strong>A homozygous variant in RRM2B is associated with severe metabolic acidosis and early neonatal death.</strong> Europ. J. Med. Genet. 62: 103574, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30439532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30439532</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.11.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30439532">Penque et al. (2019)</a> identified homozygosity for a c.662A-G transition (c.662A-G, NM_015713) in the RRM2B gene, resulting in an asn221-to-ser (N221S) substitution at a conserved residue in a highly conserved alpha helix region close to 2 known iron-binding sites. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was present in 1 of 250,000 alleles in the gnomAD database. Molecular modeling suggested that the mutation disrupts the conserved alpha helix region by altering intramolecular interactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30439532" 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 ROD-CONE DYSTROPHY, SENSORINEURAL DEAFNESS, AND FANCONI-TYPE RENAL DYSFUNCTION</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">rs1810682433 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1810682433;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=rs1810682433" 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=rs1810682433" 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=RCV001254943 OR RCV001841197 OR RCV001879920" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001254943, RCV001841197, RCV001879920" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001254943...</a>
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<p>In 6 patients from 5 unrelated Afrikaner families with rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction (RCDFRD; <a href="/entry/268315">268315</a>), including 2 sisters who were originally reported by <a href="#1" class="mim-tip-reference" title="Beighton, P., Bartmann, L., Bingham, G., Sellars, S. <strong>Rod-cone dystrophy, sensorineural deafness, and renal dysfunction: an autosomal recessive syndrome.</strong> Am. J. Med. Genet. 47: 832-836, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8279480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8279480</a>] [<a href="https://doi.org/10.1002/ajmg.1320470607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8279480">Beighton et al. (1993)</a> as patients 1 and 2, <a href="#7" class="mim-tip-reference" title="Roberts, L., Julius, S., Dawlat, S., Yildiz, S., Rebello, G., Meldau, S., Pillay, K., Esterhuizen, A., Vorster, A., Benefeld, G., da Rocha, J., Beighton, P., Sellars, S. L., Thandrayen, K., Pettifor, J. M., Ramesar, R. S. <strong>Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B.</strong> Hum. Mutat. 41: 1871-1876, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32827185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32827185</a>] [<a href="https://doi.org/10.1002/humu.24094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32827185">Roberts et al. (2020)</a> identified homozygosity for a c.786G-T transversion (c.786G-T, NM_015713.4) in exon 7 of the RRM2B gene, resulting in a glu262-to-asp (E262D) substitution at a highly conserved residue within helix G of the p53R2 monomer. The mutation segregated with disease in the families and was not found in 34 healthy Afrikaner controls or in the 1000 Genomes Project, ExAC, or gnomAD v2.11 databases. Haplotype analysis suggested a probable founder effect in the Afrikaner population. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8279480+32827185" 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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Beighton, P., Bartmann, L., Bingham, G., Sellars, S.
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<strong>Rod-cone dystrophy, sensorineural deafness, and renal dysfunction: an autosomal recessive syndrome.</strong>
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Am. J. Med. Genet. 47: 832-836, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8279480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8279480</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8279480" 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.1320470607" target="_blank">Full Text</a>]
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Bourdon, A., Minai, L., Serre, V., Jais, J.-P., Sarzi, E., Aubert, S., Chretien, D., de Lonlay, P., Paquis-Flucklinger, V., Arakawa, H., Nakamura, Y., Munnich, A., Rotig, A.
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Nature Genet. 39: 776-780, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17486094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17486094</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17486094" 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/ng2040" target="_blank">Full Text</a>]
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<strong>RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions.</strong>
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Neurology 76: 2032-2034, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21646632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21646632</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21646632" 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.0b013e31821e558b" target="_blank">Full Text</a>]
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Kimura, T., Takeda, S., Sagiya, Y., Gotoh, M., Nakamura, Y., Arakawa, H.
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<strong>Impaired function of p53R2 in Rrm2b-null mice causes severe renal failure through attenuation of dNTP pools.</strong>
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Nature Genet. 34: 440-445, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12858174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12858174</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12858174" 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/ng1212" target="_blank">Full Text</a>]
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<strong>A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19138848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19138848</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19138848" 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.nmd.2008.11.014" target="_blank">Full Text</a>]
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Penque, B. A., Su, L., Wang, J., Ji, W., Bale, A., Luh, F., Fulbright, R. K., Fulbright, R. K., Sarmast, U., Sega, A. G., Konstantino, M., Spencer-Manzon, M., Pierce, R., Yen, Y., Lakhani, S. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30439532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30439532</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30439532" 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.ejmg.2018.11.008" target="_blank">Full Text</a>]
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Roberts, L., Julius, S., Dawlat, S., Yildiz, S., Rebello, G., Meldau, S., Pillay, K., Esterhuizen, A., Vorster, A., Benefeld, G., da Rocha, J., Beighton, P., Sellars, S. L., Thandrayen, K., Pettifor, J. M., Ramesar, R. S.
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<strong>Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B.</strong>
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Hum. Mutat. 41: 1871-1876, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32827185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32827185</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32827185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.24094" target="_blank">Full Text</a>]
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Shaibani, A., Shchelochkov, O. A., Zhang, S., Katsonis, P., Lichtarge, O., Wong, L.-J., Shinawi, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19667227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19667227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19667227[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=19667227" 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/10.1001/archneurol.2009.139" target="_blank">Full Text</a>]
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Stumpf, A. M.
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Baltimore, Md. 03/01/2022.
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Takata, A., Kato, M., Nakamura, M., Yoshikawa, T., Kanba, S., Sano, A., Kato, T.
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<strong>Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21951382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21951382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21951382[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=21951382" 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/gb-2011-12-9-r92" target="_blank">Full Text</a>]
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Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., Nakamura, Y.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10716435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10716435</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10716435" 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/10.1038/35003506" target="_blank">Full Text</a>]
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Tyynismaa, H., Ylikallio, E., Patel, M., Molnar, M. J., Haller, R. G., Suomalainen, A.
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<strong>A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19664747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19664747</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19664747[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=19664747" 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.2009.07.009" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 12/28/2020<br>Cassandra L. Kniffin - updated : 4/19/2012<br>Cassandra L. Kniffin - updated : 12/15/2009<br>Cassandra L. Kniffin - updated : 11/3/2009<br>Cassandra L. Kniffin - updated : 10/12/2009<br>Cassandra L. Kniffin - updated : 7/27/2007<br>Victor A. McKusick - updated : 7/30/2003
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 01/22/2025
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alopez : 03/01/2022<br>carol : 12/29/2020<br>carol : 12/28/2020<br>mcolton : 07/29/2015<br>alopez : 4/23/2015<br>mcolton : 4/21/2015<br>carol : 9/24/2013<br>carol : 1/7/2013<br>carol : 6/5/2012<br>terry : 4/30/2012<br>carol : 4/27/2012<br>ckniffin : 4/19/2012<br>carol : 12/17/2010<br>ckniffin : 12/9/2010<br>carol : 12/23/2009<br>ckniffin : 12/15/2009<br>wwang : 11/19/2009<br>ckniffin : 11/3/2009<br>wwang : 10/16/2009<br>ckniffin : 10/12/2009<br>wwang : 5/28/2008<br>ckniffin : 5/22/2008<br>alopez : 8/8/2007<br>ckniffin : 7/27/2007<br>alopez : 7/31/2003<br>terry : 7/30/2003<br>alopez : 1/17/2002<br>alopez : 3/22/2000
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<span class="mim-font">
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<strong>*</strong> 604712
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</span>
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</h3>
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<h3>
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<span class="mim-font">
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RIBONUCLEOTIDE REDUCTASE REGULATORY TP53 INDUCIBLE SUBUNIT M2B; RRM2B
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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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<h4>
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<span class="mim-font">
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RIBONUCLEOTIDE REDUCTASE, M2 B<br />
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RIBONUCLEOTIDE REDUCTASE SMALL SUBUNIT 2-LIKE, p53-INDUCIBLE; P53R2<br />
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p53-INDUCIBLE AND RIBONUCLEOTIDE REDUCTASE SMALL SUBUNIT 2-LIKE
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: RRM2B</em></strong>
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</span>
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</p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 765100000;
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<strong>
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<em>
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Cytogenetic location: 8q22.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 8:102,204,501-102,238,961 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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</th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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8q22.3
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<span class="mim-font">
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Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy)
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<span class="mim-font">
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612075
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<span class="mim-font">
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Mitochondrial DNA depletion syndrome 8B (MNGIE type)
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<span class="mim-font">
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612075
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<span class="mim-font">
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Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5
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<span class="mim-font">
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613077
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction
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<span class="mim-font">
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268315
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<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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<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 RRM2B gene encodes the small subunit of p53 (191170)-inducible ribonucleotide reductase, a heterotetrameric enzyme responsible for de novo conversion of ribonucleoside diphosphates into the corresponding deoxyribonucleoside diphosphates that are essential for DNA synthesis (Bourdon et al., 2007). </p>
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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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</h4>
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</div>
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<span class="mim-text-font">
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<p>The p53 gene is frequently inactivated in human cancers. By using differential display to examine mRNAs in a human colon cancer cell line carrying a highly regulated wildtype p53 expression system, Tanaka et al. (2000) detected a 5.5-kb transcript that was inducible by wildtype p53 but not mutant p53. Using the differential display fragment representing this transcript as a probe to screen a skeletal muscle cDNA library, they isolated a cDNA sequence that incorporated an open reading frame of 351 amino acids with 80% identity to the small subunit of human ribonucleotide reductase (R2; 180390). Comparison of this sequence, which they called p53R2 for 'p53-inducible ribonucleotide reductase small subunit 2 homolog,' with those of yeast RNR2 and RNR4 revealed 60% and 40% identity, respectively. Tanaka et al. (2000) considered p53R2 to be a human counterpart of yeast RNR2. The protein has a ribonucleotide reductase small subunit signature and 2 putative nuclear localization signal sequences. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Tanaka et al. (2000) found that the p53R2 gene has 9 exons and spans a 30-kb genomic region. Electromobility shift assays identified a 20-nucleotide region in intron 1 as the p53 binding site. </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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<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>Tanaka et al. (2000) mapped the p53R2 gene to chromosome 8q23.1 by fluorescence in situ hybridization. </p><p>Stumpf (2022) mapped the RRM2B gene to chromosome 8q22.3 based on an alignment of the RRM2B sequence (GenBank BC117496) with the genomic sequence (GRCh38).</p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Tanaka et al. (2000) found that expression of p53R2, but not R2, was induced by ultraviolet and gamma-irradiation and adriamycin treatment in a wildtype p53-dependent manner. Induction of p53R2 in p53-deficient cells caused G2/M arrest and protected cells from death in response to adriamycin. Inhibition of endogenous p53R2 expression in cells that had an intact p53-dependent DNA damage checkpoint reduced ribonucleotide reductase activity, DNA repair, and cell survival after exposure to various genotoxins. Tanaka et al. (2000) demonstrated nuclear accumulation of p53R2 protein in response to genotoxic stress induced by gamma-irradiation. Tanaka et al. (2000) concluded that p53R2 encodes a ribonucleotide reductase that is directly involved in the p53 checkpoint for repair of damaged DNA. The discovery of p53R2 clarified a relationship between a ribonucleotide reductase activity involved in repair of damaged DNA and tumor suppression by p53. Tanaka et al. (2000) proposed that inactivation of p53 directly interferes with the transcription of p53R2 in response to DNA damage, with the result that ribonucleotide reductase activity is insufficient for normal DNA repair. Faulty regulation of p53R2 might also enhance misincorporation of deoxyribonucleotide triphosphates (dNTPs) and dysregulation of DNA repair machinery and thereby increase the frequency of mutations. Tanaka et al. (2000) suggested that the genomic instability often seen in tumors lacking wildtype p53 may reflect dysfunction of ribonucleotide reductase due to the failure of p53R2 induction. </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>Mitochondrial DNA Depletion Syndrome 8A (Encephalomyopathic Type with Renal Tubulopathy)</em></strong></p><p>
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In 7 patients from 4 families with severe autosomal recessive mitochondrial DNA (mtDNA) depletion syndrome-8A (MTDPS8A; 612075), associated with renal tubulopathy, Bourdon et al. (2007) identified homozygous or compound heterozygous mutations in the RRM2B gene (see, e.g., 604712.0001-604712.0005). All patients had 1 to 2% residual mtDNA in skeletal muscle and died in the first months of life with severe lactic acidosis. Respiratory chain complex activities were severely decreased in muscle from these patients. The findings indicated that RRM2B plays a crucial role in dNTP supply, especially for the synthesis of mtDNA. </p><p>In a male infant, born to consanguineous Latino parents, with MTDPS8A, Penque et al. (2019) identified a homozygous missense mutation in the RRM2B gene (N221S; 604712.0015). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Molecular modeling suggested that the mutation disrupts a conserved alpha helix region of the protein by altering intramolecular interactions. </p><p><strong><em>Mitochondrial DNA Depletion Syndrome 8B (MNGIE Type)</em></strong></p><p>
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Shaibani et al. (2009) identified compound heterozygosity for 2 mutations in the RRM2B gene (R110H, 604712.0008; R121H, 604712.0009) in a 42-year-old woman with mtDNA depletion syndrome-8B, manifest as a neurogastrointestinal encephalopathy (see 612075). The authors stated that this was the oldest reported patient with RRM2B mutations and that her clinical course was different from that reported previously in patients with MNGIE. </p><p><strong><em>Autosomal Dominant Progressive External Ophthalmoplegia 5</em></strong></p><p>
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By linkage analysis followed by candidate gene sequencing in a large North American family with mild autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; 613077), Tyynismaa et al. (2009) identified a heterozygous mutation in the RRM2B gene (R327X; 604712.0006) that segregated with the disorder. Affected members of an unrelated Hungarian family carried the same mutation, but there was no evidence of a common origin. </p><p>By direct sequencing of the RRM2B gene in 75 unrelated probands with PEO in whom mutations in other known PEO-related genes had been excluded, Fratter et al. (2011) identified 3 different heterozygous truncating mutations in the RRM2B gene (see, e.g., 604712.0010 and 604712.0011) in 7 (9.3%) patients. The findings suggested that truncating RRM2B mutations are rather frequent in familial PEO with mtDNA deletions. Three additional patients were found to carry 3 different heterozygous missense variants, but the pathogenicity of the variants was considered provisional in the absence of further supporting evidence. </p><p><strong><em>Rod-Cone Dystrophy, Sensorineural Deafness, and Fanconi-Type Renal Dysfunction</em></strong></p><p>
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In 6 patients from 5 Afrikaner families with rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction (RCDFRD; 268315), Roberts et al. (2020) identified homozygosity for a missense mutation in the RRM2B gene (E262D; 604712.0016) that segregated with disease in each family and was not found in Afrikaner controls or in public variant databases. Haplotype analysis suggested a probable founder effect in the Afrikaner population. Evaluation of a patient muscle biopsy showed no evidence of mtDNA deletions or depletion, but microscopy was consistent with a mild mitochondrial abnormality. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>To determine whether ribonucleotide reductase is involved in DNA repair by supplying deoxyribonucleotides (dNTPs) for resting cells in vivo, Kimura et al. (2003) generated a strain of mice lacking Rrm2b. These mice developed normally until they were weaned but from then on had growth retardation and early mortality. Pathologic examination indicated that multiple organs had failed, and all Rrm2b-null mice died from severe renal failure by the age of 14 weeks. TUNEL staining showed a greater number of apoptotic cells in kidneys of 8-week-old null mice relative to wildtype. p53 (191170) was activated in kidney tissues of the null mice, leading to transcriptional induction of p53 target genes. Embryonic fibroblasts from null mice became immortal much earlier than wildtype embryonic fibroblasts. dNTP pools were severely attenuated in embryonic fibroblasts from null mice under oxidative stress. Rrm2b deficiency caused higher rates of spontaneous mutation in the kidneys of null mice. The results suggested that p53R2 has a pivotal role in maintaining dNTP levels for repair of DNA in resting cells. Impairment of this pathway may enhance spontaneous mutation frequency and activate p53-dependent apoptotic pathways in vivo, causing severe renal failure, growth retardation, and early mortality. </p><p>Bourdon et al. (2007) found that 12-week-old Rrm2b-null mice had markedly decreased mtDNA content in kidney (5.57% of controls), muscle (5.24%), and liver (21%). </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>16 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 MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY)</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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RRM2B, GLN284TER
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<br />
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SNP: rs121918307,
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gnomAD: rs121918307,
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ClinVar: RCV000005717, RCV000119010
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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 sibs, born of consanguineous Moroccan parents, with mitochondrial DNA depletion syndrome-8A (MTDPS8A; 612075), manifest as encephalomyopathy and renal tubulopathy, Bourdon et al. (2007) identified a homozygous 850C-T transition in the RRM2B gene, resulting in a gln284-to-ter (Q284X) substitution. The substitution resulted in the deletion of the last 68 C-terminal residues of the protein, including part of the an alpha-helix as well as the heptapeptide involved in the binding to R1. The sibs had hypotonia and lactic acidosis and died within the first months of life. Severe mtDNA depletion (less than 1% of controls) was found in muscle of 1 the sibs. </p>
|
|
</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 MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY)</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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RRM2B, IVS3AS, A-G, -2
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<br />
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SNP: rs515726185,
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|
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ClinVar: RCV000005718, RCV004700189
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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 French infants with mitochondrial DNA depletion syndrome-8A (MTDPS8A; 612075), manifest as encephalomyopathy with renal tubulopathy, Bourdon et al. (2007) identified compound heterozygosity for 2 mutations in the RRM2B gene: an A-to-G transition in intron 3 and E194K (604712.0003). The sibs had lactic acidemia, hypotonia, tubulopathy, and seizures. Only 2% of normal mtDNA levels was detected in the muscle of 1 of the sibs. Both died at 2 months of age. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0003 MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY)</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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RRM2B, GLU194LYS
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<br />
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SNP: rs121918308,
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gnomAD: rs121918308,
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ClinVar: RCV000005719, RCV000118999
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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 French infants with mitochondrial DNA depletion syndrome-8A (MTDPS8A; 612075), manifest as encephalomyopathy with renal tubulopathy, Bourdon et al. (2007) identified compound heterozygosity for 2 mutations in the RRM2B gene: a 580G-A transition, resulting in a glu194-to-lys (E194K) substitution, and a splice site mutation (604712.0002). Residue 194 is involved in iron binding. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY)</strong>
|
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</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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RRM2B, 3-BP DEL, 253GAG
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<br />
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SNP: rs515726184,
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|
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gnomAD: rs515726184,
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ClinVar: RCV000005720, RCV000118988, RCV000186558, RCV000413797, RCV002483199
|
|
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|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French infant with severe mitochondrial DNA depletion with renal tubulopathy (612075), Bourdon et al. (2007) identified compound heterozygosity for 2 mutations in the RRM2B gene: a 3-bp deletion (253delGAG), resulting in an in-frame deletion of glu85, and C236F (604712.0005). The patient had neonatal hypotonia and increased plasma and CSF lactate; she died at age 3 months. Muscle histology showed ragged-red fibers, and mtDNA content was about 1% of normal. The deletion of glu85 was predicted to disrupt the local subdomain structure and the dimerization interface between R1 and R2. </p>
|
|
</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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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
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RRM2B, CYS236PHE
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<br />
|
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|
|
SNP: rs121918309,
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|
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|
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ClinVar: RCV000005721, RCV000119007
|
|
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|
|
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</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a French infant with severe mitochondrial DNA depletion with renal tubulopathy (612075), Bourdon et al. (2007) identified compound heterozygosity for 2 mutations in the RRM2B gene: a 707G-T transversion, resulting in a cys236-to-phe (C236F) substitution, and a 3-bp deletion (604712.0004). </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
RRM2B, ARG327TER
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|
|
<br />
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|
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SNP: rs121918310,
|
|
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|
|
|
|
ClinVar: RCV000005722, RCV000119016, RCV000197531
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 unrelated families with autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; 613077), Tyynismaa et al. (2009) identified a heterozygous 979C-T transition in the last exon of the RRM2B gene, resulting in an arg327-to-ter (R327X) substitution. The substitution was predicted to result in a protein lacking the last 25 amino acids. One family was North American of European origin, and the second was Hungarian. The mutation was not observed in 380 control European chromosomes, and there was no evidence of a founder effect. The phenotype was characterized by late-onset of mild ophthalmoplegia and mild muscle weakness. Skeletal muscle biopsies showed mtDNA deletions, but normal mtDNA copy numbers. RNA studies showed that the R328X mRNA escaped nonsense-mediated decay, and that the mutant protein was expressed and stable. The findings suggested that the mutant RRM2B protein can compete with wildtype in binding to ribonucleotide reductase, causing a dominant-negative or gain-of-function effect. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RRM2B, GLY229VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918311,
|
|
|
|
|
|
gnomAD: rs121918311,
|
|
|
|
|
|
ClinVar: RCV000005723, RCV000119005, RCV001818139
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Sudanese brothers, born of consanguineous parents, with encephalomyopathic mitochondrial DNA depletion syndrome (MTDPS8A; 612075), Kollberg et al. (2009) identified a homozygous 686G-T transversion in exon 7 of the RRM2B gene, resulting in a gly229-to-val (G229V) substitution in the diferric iron center of the protein. Each unaffected parent was heterozygous for the mutation. The phenotype was severe, with hypotonia, seizures, poor visual contact, and lactic acidosis, and both patients died by 5 months of age. One boy developed a proximal renal tubulopathy. Southern blot analysis of patient cells showed severe mtDNA depletion, about 1 to 4% of normal controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 MITOCHONDRIAL DNA DEPLETION SYNDROME 8B (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RRM2B, ARG110HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607025,
|
|
|
|
|
|
gnomAD: rs267607025,
|
|
|
|
|
|
ClinVar: RCV000005724, RCV000118992, RCV001596931, RCV003147275
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 42-year-old woman with mitochondrial DNA depletion syndrome-8B, manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE; see 612075), Shaibani et al. (2009) identified compound heterozygosity for 2 mutations in the RRM2B gene: a 329G-A transition resulting in an arg110-to-his (R110H) substitution, and a 362G-A transition resulting in an arg121-to-his (R121H; 604712.0009) substitution. Both mutations occurred in highly conserved residues. The patient developed recurrent nausea, vomiting, and weight loss at age 30 years. At age 37, she developed restriction of eye movements, ptosis, dysarthria, unsteady gait, muscle weakness, and areflexia consistent with a peripheral neuropathy. Skeletal muscle showed mtDNA depletion (12% of controls). Shaibani et al. (2009) noted that this was the oldest reported patient with RRM2B mutations and that her clinical course was different from that reported previously in patients with MNGIE. The findings also broadened the phenotype associated with RRM2B mutations to include an MNGIE-like picture. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 MITOCHONDRIAL DNA DEPLETION SYNDROME 8B (MNGIE TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RRM2B, ARG121HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607024,
|
|
|
|
|
|
gnomAD: rs267607024,
|
|
|
|
|
|
ClinVar: RCV000005725, RCV000118994
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the arg121-to-his (R121H) mutation in the RRM2B gene that was found in compound heterozygous state in a patient with mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE; see 612075) by Shaibani et al. (2009), see 604712.0008. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RRM2B, 1-BP DEL, 950T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs515726199,
|
|
|
|
|
|
|
|
ClinVar: RCV000023385, RCV000119013, RCV000508947
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 unrelated patients with autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; 613077), Fratter et al. (2011) identified a heterozygous 1-bp deletion (950delT) in the RRM2B gene, resulting in a frameshift and premature termination at leu317. The patients had onset at ages 30, 53, and 46 years, and all had a family history of the disorder. All had PEO and ptosis, but additional variable features in 2 patients included fatigue, ataxia, proximal myopathy, dysphagia, and glaucoma. Skeletal muscle biopsies of the probands showed a mosaic defect of cytochrome c oxidase activity and multiple mtDNA deletions. The mutation was not found in 352 control alleles. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RRM2B, 1-BP DUP, 965A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs515726201,
|
|
|
|
|
|
|
|
ClinVar: RCV000023386, RCV000119015
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 unrelated patients with autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; 613077), Fratter et al. (2011) identified a heterozygous 1-bp duplication (965dupA) in the RRM2B gene, resulting in a frameshift and premature termination. The patients had onset at ages 30, 54, and 26 years, and all had a family history of the disorder. All had PEO and fatigue, but additional features were variable and included diabetes, gastrointestinal symptoms, dysphagia, dysphonia, and proximal myopathy. Skeletal muscle biopsies of the probands showed a mosaic defect of cytochrome c oxidase activity and multiple mtDNA deletions. The mutation was not found in 352 control alleles. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RRM2B, PHE202LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs515726194,
|
|
|
|
|
|
|
|
ClinVar: RCV000023387, RCV000119003
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant is classified as a variant of unknown significance because its contribution to progressive external ophthalmoplegia (PEO) has not been confirmed.</p><p>In a 14-year-old patient with early-onset PEO at age 4 and hearing loss, Fratter et al. (2011) identified compound heterozygous changes in the RRM2B gene: a 606T-A transversion resulting in a phe202-to-leu (F202L) substitution, and an 817G-A transition resulting in a gly273-to-ser (G273S; 604712.0013) substitution. Functional studies of the variants were not performed. Skeletal muscle biopsy showed a mosaic defect of cytochrome c oxidase activity and multiple mtDNA deletions. Neither variant was found in 352 control alleles, and both occurred in conserved residues. There was no family history of a similar disorder, but information on the parents was not provided. The findings suggested recessive inheritance of the disorder. </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">
|
|
|
|
RRM2B, GLY273SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906891,
|
|
|
|
|
|
gnomAD: rs387906891,
|
|
|
|
|
|
ClinVar: RCV000023388, RCV000119008, RCV001582496
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gly273-to-ser (G273S) mutation in the RRM2B gene that was found in compound heterozygous state in a patient with early-onset progressive external ophthalmoplegia (PEO) and hearing loss by Fratter et al. (2011) and classified as a variant of unknown significance, see 604712.0012. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
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<strong>.0014 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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RRM2B, PRO33SER
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<br />
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SNP: rs387906892,
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gnomAD: rs387906892,
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ClinVar: RCV000023389, RCV000118993, RCV001852021, RCV002283445
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<p>This variant is classified as a variant of unknown significance because its contribution to progressive external ophthalmoplegia (PEO) has not been confirmed.</p><p>In a 43-year-old Japanese man, born of consanguineous parents, with adult-onset PEO, Takata et al. (2011) identified a homozygous 341G-A transition in the RRM2B gene, resulting in a pro33-to-ser (P33S) substitution in a highly conserved residue in the N terminus. The variant was found by whole-exome sequencing in combination with runs of homozygosity analysis. Each unaffected parent was heterozygous for the mutation, which was found in 1 of 718 control chromosomes of Japanese origin. Functional studies of the variant were not performed. The patient presented with hearing loss at age 16 years, and later developed ptosis, ophthalmoplegia, and muscle weakness. He also had pigmentary degeneration of the retina and gonadal atrophy. Other features included depressed mood, anxiety, and hypochondriacal complaints. Muscle biopsy showed marked variation of fiber size, ragged-red fibers, COX-negative fibers, and multiple mtDNA deletions. There was no family history of a similar disorder. Mutations in other candidate genes were excluded. Takata et al. (2011) suggested that this was the first case of recessive inheritance of PEO due to RRM2B mutations. </p>
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<span class="mim-font">
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<strong>.0015 MITOCHONDRIAL DNA DEPLETION SYNDROME 8A (ENCEPHALOMYOPATHIC TYPE WITH RENAL TUBULOPATHY)</strong>
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RRM2B, ASN221SER
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<br />
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SNP: rs863224193,
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gnomAD: rs863224193,
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ClinVar: RCV000196496, RCV000680084, RCV000714482
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<p>In a male infant, born to consanguineous Latino parents, with mitochondrial DNA depletion syndrome-8A (MTDPS8A; 612075), Penque et al. (2019) identified homozygosity for a c.662A-G transition (c.662A-G, NM_015713) in the RRM2B gene, resulting in an asn221-to-ser (N221S) substitution at a conserved residue in a highly conserved alpha helix region close to 2 known iron-binding sites. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was present in 1 of 250,000 alleles in the gnomAD database. Molecular modeling suggested that the mutation disrupts the conserved alpha helix region by altering intramolecular interactions. </p>
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</span>
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<span class="mim-font">
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<strong>.0016 ROD-CONE DYSTROPHY, SENSORINEURAL DEAFNESS, AND FANCONI-TYPE RENAL DYSFUNCTION</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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RRM2B, GLU262ASP
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<br />
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SNP: rs1810682433,
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ClinVar: RCV001254943, RCV001841197, RCV001879920
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<p>In 6 patients from 5 unrelated Afrikaner families with rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction (RCDFRD; 268315), including 2 sisters who were originally reported by Beighton et al. (1993) as patients 1 and 2, Roberts et al. (2020) identified homozygosity for a c.786G-T transversion (c.786G-T, NM_015713.4) in exon 7 of the RRM2B gene, resulting in a glu262-to-asp (E262D) substitution at a highly conserved residue within helix G of the p53R2 monomer. The mutation segregated with disease in the families and was not found in 34 healthy Afrikaner controls or in the 1000 Genomes Project, ExAC, or gnomAD v2.11 databases. Haplotype analysis suggested a probable founder effect in the Afrikaner population. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<ol>
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<li>
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<p class="mim-text-font">
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Beighton, P., Bartmann, L., Bingham, G., Sellars, S.
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<strong>Rod-cone dystrophy, sensorineural deafness, and renal dysfunction: an autosomal recessive syndrome.</strong>
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Am. J. Med. Genet. 47: 832-836, 1993.
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[PubMed: 8279480]
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[Full Text: https://doi.org/10.1002/ajmg.1320470607]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bourdon, A., Minai, L., Serre, V., Jais, J.-P., Sarzi, E., Aubert, S., Chretien, D., de Lonlay, P., Paquis-Flucklinger, V., Arakawa, H., Nakamura, Y., Munnich, A., Rotig, A.
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<strong>Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. (Letter)</strong>
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Nature Genet. 39: 776-780, 2007.
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[PubMed: 17486094]
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[Full Text: https://doi.org/10.1038/ng2040]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Fratter, C., Raman, P., Alston, C. L., Blakely, E. L., Craig, K., Smith, C., Evans, J., Seller, A., Czermin, B., Hanna, M. G., Poulton, J., Brierley, C., Staunton, T. G., Turnpenny, P. D., Schaefer, A. M., Chinnery, P. F., Horvath, R., Turnbull, D. M., Gorman, G. S., Taylor, R. W.
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<strong>RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions.</strong>
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Neurology 76: 2032-2034, 2011.
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[PubMed: 21646632]
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[Full Text: https://doi.org/10.1212/WNL.0b013e31821e558b]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kimura, T., Takeda, S., Sagiya, Y., Gotoh, M., Nakamura, Y., Arakawa, H.
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<strong>Impaired function of p53R2 in Rrm2b-null mice causes severe renal failure through attenuation of dNTP pools.</strong>
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Nature Genet. 34: 440-445, 2003.
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[PubMed: 12858174]
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[Full Text: https://doi.org/10.1038/ng1212]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kollberg, G., Darin, N., Benan, K., Moslemi, A.-R., Lindal, S., Tulinius, M., Oldfors, A., Holme, E.
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<strong>A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion.</strong>
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Neuromusc. Disord. 19: 147-150, 2009.
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[PubMed: 19138848]
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[Full Text: https://doi.org/10.1016/j.nmd.2008.11.014]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Penque, B. A., Su, L., Wang, J., Ji, W., Bale, A., Luh, F., Fulbright, R. K., Fulbright, R. K., Sarmast, U., Sega, A. G., Konstantino, M., Spencer-Manzon, M., Pierce, R., Yen, Y., Lakhani, S. A.
|
|
<strong>A homozygous variant in RRM2B is associated with severe metabolic acidosis and early neonatal death.</strong>
|
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Europ. J. Med. Genet. 62: 103574, 2019. Note: Electronic Article.
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[PubMed: 30439532]
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[Full Text: https://doi.org/10.1016/j.ejmg.2018.11.008]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Roberts, L., Julius, S., Dawlat, S., Yildiz, S., Rebello, G., Meldau, S., Pillay, K., Esterhuizen, A., Vorster, A., Benefeld, G., da Rocha, J., Beighton, P., Sellars, S. L., Thandrayen, K., Pettifor, J. M., Ramesar, R. S.
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<strong>Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B.</strong>
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Hum. Mutat. 41: 1871-1876, 2020.
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[PubMed: 32827185]
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[Full Text: https://doi.org/10.1002/humu.24094]
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Shaibani, A., Shchelochkov, O. A., Zhang, S., Katsonis, P., Lichtarge, O., Wong, L.-J., Shinawi, M.
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<strong>Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B.</strong>
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Arch. Neurol. 66: 1028-1032, 2009.
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[PubMed: 19667227]
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[Full Text: https://doi.org/10.1001/archneurol.2009.139]
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<li>
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<p class="mim-text-font">
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 03/01/2022.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Takata, A., Kato, M., Nakamura, M., Yoshikawa, T., Kanba, S., Sano, A., Kato, T.
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<strong>Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia.</strong>
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Genome Biol. 12: R92, 2011. Note: Electronic Article.
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[PubMed: 21951382]
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[Full Text: https://doi.org/10.1186/gb-2011-12-9-r92]
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<p class="mim-text-font">
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Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., Nakamura, Y.
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<strong>A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage.</strong>
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Nature 404: 42-49, 2000.
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[PubMed: 10716435]
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[Full Text: https://doi.org/10.1038/35003506]
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<li>
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<p class="mim-text-font">
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Tyynismaa, H., Ylikallio, E., Patel, M., Molnar, M. J., Haller, R. G., Suomalainen, A.
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<strong>A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions.</strong>
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Am. J. Hum. Genet. 85: 290-295, 2009.
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[PubMed: 19664747]
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[Full Text: https://doi.org/10.1016/j.ajhg.2009.07.009]
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Marla J. F. O'Neill - updated : 03/01/2022<br>Hilary J. Vernon - updated : 12/28/2020<br>Cassandra L. Kniffin - updated : 4/19/2012<br>Cassandra L. Kniffin - updated : 12/15/2009<br>Cassandra L. Kniffin - updated : 11/3/2009<br>Cassandra L. Kniffin - updated : 10/12/2009<br>Cassandra L. Kniffin - updated : 7/27/2007<br>Victor A. McKusick - updated : 7/30/2003
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Ada Hamosh : 3/22/2000
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carol : 01/22/2025<br>alopez : 03/01/2022<br>carol : 12/29/2020<br>carol : 12/28/2020<br>mcolton : 07/29/2015<br>alopez : 4/23/2015<br>mcolton : 4/21/2015<br>carol : 9/24/2013<br>carol : 1/7/2013<br>carol : 6/5/2012<br>terry : 4/30/2012<br>carol : 4/27/2012<br>ckniffin : 4/19/2012<br>carol : 12/17/2010<br>ckniffin : 12/9/2010<br>carol : 12/23/2009<br>ckniffin : 12/15/2009<br>wwang : 11/19/2009<br>ckniffin : 11/3/2009<br>wwang : 10/16/2009<br>ckniffin : 10/12/2009<br>wwang : 5/28/2008<br>ckniffin : 5/22/2008<br>alopez : 8/8/2007<br>ckniffin : 7/27/2007<br>alopez : 7/31/2003<br>terry : 7/30/2003<br>alopez : 1/17/2002<br>alopez : 3/22/2000
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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