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- *606034 - RIBONUCLEASE H2, SUBUNIT A; RNASEH2A
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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">*606034</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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<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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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606034">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<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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<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 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="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=ENSG00000104889;t=ENST00000221486" 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=10535" 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=606034" 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 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=ENSG00000104889;t=ENST00000221486" 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_006397" 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_006397" 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=606034" 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=06914&isoform_id=06914_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/RNASEH2A" 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/3334761,15079910,20981704,34329831,38455391,48145799,119604719,189067523" 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/O75792" 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=10535" 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=ENSG00000104889;t=ENST00000221486" 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=RNASEH2A" 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=RNASEH2A" 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+10535" 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/RNASEH2A" 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:10535" 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/10535" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr19&hgg_gene=ENST00000221486.6&hgg_start=12806584&hgg_end=12813640&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:18518" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:18518" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/rnaseh2a" 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=606034[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=606034[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://gnomad.broadinstitute.org/gene/ENSG00000104889" 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=RNASEH2A" 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=RNASEH2A" 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=RNASEH2A" 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=RNASEH2A&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/PA38565" 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:18518" 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/FBgn0031252.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:1916974" 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/RNASEH2A#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:1916974" 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/10535/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=10535" 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=WBGene00004383;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-040426-976" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:10535" 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=RNASEH2A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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606034
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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RIBONUCLEASE H2, SUBUNIT A; RNASEH2A
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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RIBONUCLEASE H2, LARGE SUBUNIT<br />
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RIBONUCLEASE HI, LARGE SUBUNIT<br />
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RNase HI, LARGE SUBUNIT
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=RNASEH2A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">RNASEH2A</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/19/337?start=-3&limit=10&highlight=337">19p13.13</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:12806584-12813640&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">19:12,806,584-12,813,640</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/19/337?start=-3&limit=10&highlight=337">
|
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19p13.13
|
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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Aicardi-Goutieres syndrome 4
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/610333"> 610333 </a>
|
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/606034" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/606034" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<p>Ribonuclease (RNase) H enzymes specifically cleave ribonucleotides from RNA:DNA duplexes. Two classes of RNase H exist: type 1 (I) and 2 (II). RNase H2 is the major source of RNase H activity in mammalian cells and yeast. The protein complex is proposed to function in the removal of lagging-strand Okazaki fragment RNA primers during DNA replication and in the excision of single ribonucleotides from DNA:DNA duplexes. See also RNASEH2B (<a href="/entry/610326">610326</a>) and RNASEH2C (<a href="/entry/610330">610330</a>). The 3 homologs in S. cerevisiae are known as Rnh2Ap, Rnh2Bp, and RNh2Cp, respectively (<a href="#2" class="mim-tip-reference" title="Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., Ali, M., Semple, C., Aicardi, J., Babul-Hirji, R., Baumann, C., Baxter, P., and 33 others. <strong>Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection.</strong> Nature Genet. 38: 910-916, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16845400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16845400</a>] [<a href="https://doi.org/10.1038/ng1842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16845400">Crow et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16845400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By biochemical purification of the 32-kD subunit of calf thymus RNase HI, microsequence analysis, EST database searching, and PCR with degenerate primers on an erythroleukemia cDNA library, <a href="#3" class="mim-tip-reference" title="Frank, P., Braunshofer-Reiter, C., Wintersberger, U., Grimm, R., Busen, W. <strong>Cloning of the cDNA encoding the large subunit of human RNase HI, a homologue of the prokaryotic RNase HII.</strong> Proc. Nat. Acad. Sci. 95: 12872-12877, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9789007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9789007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9789007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.22.12872" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9789007">Frank et al. (1998)</a> obtained a cDNA encoding the large subunit of human RNase HI. The deduced 299-amino acid protein appeared to lack RNA- and DNA-binding domains. Genomic database comparisons revealed homologies between the large subunit of mammalian RNase HI and prokaryotic RNase HII. Western blot analysis showed expression of a 33-kD recombinant protein, close to the predicted size. Northern blot analysis detected a 1.2-kb transcript in a kidney cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9789007" 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 RNASEH2A gene contains 8 exons (<a href="#2" class="mim-tip-reference" title="Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., Ali, M., Semple, C., Aicardi, J., Babul-Hirji, R., Baumann, C., Baxter, P., and 33 others. <strong>Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection.</strong> Nature Genet. 38: 910-916, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16845400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16845400</a>] [<a href="https://doi.org/10.1038/ng1842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16845400">Crow et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16845400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., Ali, M., Semple, C., Aicardi, J., Babul-Hirji, R., Baumann, C., Baxter, P., and 33 others. <strong>Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection.</strong> Nature Genet. 38: 910-916, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16845400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16845400</a>] [<a href="https://doi.org/10.1038/ng1842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16845400">Crow et al. (2006)</a> mapped the RNASEH2A gene to chromosome 19p13.13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16845400" 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>RNase HI is involved in DNA replication and participates with FEN1 (<a href="/entry/600393">600393</a>) in DNA repair. The smaller RNase HII is associated with transcription (<a href="#3" class="mim-tip-reference" title="Frank, P., Braunshofer-Reiter, C., Wintersberger, U., Grimm, R., Busen, W. <strong>Cloning of the cDNA encoding the large subunit of human RNase HI, a homologue of the prokaryotic RNase HII.</strong> Proc. Nat. Acad. Sci. 95: 12872-12877, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9789007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9789007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9789007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.22.12872" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9789007">Frank et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9789007" 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 transient expression in HEK293T cells, <a href="#2" class="mim-tip-reference" title="Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., Ali, M., Semple, C., Aicardi, J., Babul-Hirji, R., Baumann, C., Baxter, P., and 33 others. <strong>Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection.</strong> Nature Genet. 38: 910-916, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16845400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16845400</a>] [<a href="https://doi.org/10.1038/ng1842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16845400">Crow et al. (2006)</a> showed that the human RNASEH2A, RNASEH2B, and RNASEH2C genes interact with each other and form an enzymatic protein complex with RNase H2 activity. The complex was able to recognize and cleave a single ribonucleotide embedded in a DNA-DNA complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16845400" 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>RNase H2 is specialized to remove single ribonucleotides (ribonucleoside monophosphates, or rNMPs) from duplex DNA, and its absence in budding yeast has been associated with the accumulation of deletions within short tandem repeats. <a href="#4" class="mim-tip-reference" title="Kim, N., Huang, S. N., Williams, J. S., Li, Y. C., Clark, A. B., Cho, J.-E., Kunkel, T. A., Pommier, Y., Jinks-Robertson, S. <strong>Mutagenic processing of ribonucleotides in DNA by yeast topoisomerase I.</strong> Science 332: 1561-1564, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700875</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700875[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1205016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700875">Kim et al. (2011)</a> demonstrated that rNMP-associated deletion formation requires the activity of Top1 (<a href="/entry/126420">126420</a>), a topoisomerase that relaxes supercoils by reversibly nicking duplex DNA. The reported studies extended the role of Top1 to include the processing of rNMPs in genomic DNA into irreversible single-strand breaks, an activity that can have distinct mutagenic consequences and may be relevant to human disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21700875" 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 expressing fluorescence-tagged RNASEH2 subunits individually or together in HeLa cells, <a href="#5" class="mim-tip-reference" title="Kind, B., Muster, B., Staroske, W., Herce, H. D., Sachse, R., Rapp, A., Schmidt, F., Koss, S., Cardoso, M. C., Lee-Kirsch, M. A. <strong>Altered spatio-temporal dynamics of RNase H2 complex assembly at replication and repair sites in Aicardi-Goutieres syndrome.</strong> Hum. Molec. Genet. 23: 5950-5960, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24986920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24986920</a>] [<a href="https://doi.org/10.1093/hmg/ddu319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24986920">Kind et al. (2014)</a> determined that the B subunit was required for nuclear expression of the A and C subunits. Mutation analysis revealed that the C terminus of the C subunit, but not a catalytically active A subunit, was also required for formation of a stable nuclear complex. Ring-shaped trimeric PCNA (<a href="/entry/176740">176740</a>) functions as a 'sliding clamp' along DNA that guides assembly of factors involved in DNA replication and repair. PCNA recruited RNASEH2 to sites of DNA damage, and the PIP-box motif of subunit B was required for interaction of RNASEH2 with PCNA and accumulation of RNASEH2 to sites of DNA damage. In addition, a catalytically active A subunit bound more tightly than a catalytically inactive A subunit to sites of DNA replication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24986920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using CRISPR screens to identify genes and pathways that mediate cellular resistance to olaparib, a clinically approved PARP (<a href="/entry/173870">173870</a>) inhibitor, <a href="#10" class="mim-tip-reference" title="Zimmermann, M., Murina, O., Reijns, M. A. M., Agathanggelou, A., Challis, R., Tarnauskaite, Z., Muir, M., Fluteau, A., Aregger, M., McEwan, A., Yuan, W., Clarke, M., and 12 others. <strong>CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions.</strong> Nature 559: 285-289, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29973717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29973717</a>] [<a href="https://doi.org/10.1038/s41586-018-0291-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29973717">Zimmermann et al. (2018)</a> identified a high-confidence set of 73 genes that when mutated cause increased sensitivity to PARP inhibitors. In addition to an expected enrichment for genes related to homologous recombination, <a href="#10" class="mim-tip-reference" title="Zimmermann, M., Murina, O., Reijns, M. A. M., Agathanggelou, A., Challis, R., Tarnauskaite, Z., Muir, M., Fluteau, A., Aregger, M., McEwan, A., Yuan, W., Clarke, M., and 12 others. <strong>CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions.</strong> Nature 559: 285-289, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29973717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29973717</a>] [<a href="https://doi.org/10.1038/s41586-018-0291-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29973717">Zimmermann et al. (2018)</a> discovered that mutations in all 3 genes encoding ribonuclease H2 (RNASEH2A; RNASEH2B, <a href="/entry/610326">610326</a>; and RNASEH2C, <a href="/entry/610330">610330</a>) sensitized cells to PARP inhibition and established that the underlying cause of the PARP-inhibitor hypersensitivity of cells deficient in ribonuclease H2 is impaired ribonucleotide excision repair. Embedded ribonucleotides, which are abundant in the genome of cells deficient in ribonucleotide excision repair, are substrates for cleavage by TOP1, resulting in PARP-trapping lesions that impede DNA replication and endanger genome integrity. <a href="#10" class="mim-tip-reference" title="Zimmermann, M., Murina, O., Reijns, M. A. M., Agathanggelou, A., Challis, R., Tarnauskaite, Z., Muir, M., Fluteau, A., Aregger, M., McEwan, A., Yuan, W., Clarke, M., and 12 others. <strong>CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions.</strong> Nature 559: 285-289, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29973717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29973717</a>] [<a href="https://doi.org/10.1038/s41586-018-0291-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29973717">Zimmermann et al. (2018)</a> concluded that genomic ribonucleotides are a hitherto unappreciated source of PARP-trapping DNA lesions, and that the frequent deletion of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukemia may provide an opportunity to exploit these findings therapeutically. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29973717" 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 children with Aicardi-Goutieres syndrome (AGS4; <a href="/entry/610333">610333</a>) from a consanguineous family of Spanish ancestry reported by <a href="#9" class="mim-tip-reference" title="Sanchis, A., Cervero, L., Bataller, A., Tortajada, J. L., Huguet, J., Crow, Y. J., Ali, M., Higuet, L. J., Martinez-Frias, M. L. <strong>Genetic syndromes mimic congenital infections.</strong> J. Pediat. 146: 701-705, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15870678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15870678</a>] [<a href="https://doi.org/10.1016/j.jpeds.2005.01.033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15870678">Sanchis et al. (2005)</a>, <a href="#2" class="mim-tip-reference" title="Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., Ali, M., Semple, C., Aicardi, J., Babul-Hirji, R., Baumann, C., Baxter, P., and 33 others. <strong>Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection.</strong> Nature Genet. 38: 910-916, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16845400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16845400</a>] [<a href="https://doi.org/10.1038/ng1842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16845400">Crow et al. (2006)</a> identified a homozygous mutation in the RNASEH2A gene (<a href="#0001">606034.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16845400+15870678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Rice, G., Patrick, T., Parmar, R., Taylor, C. F., Aeby, A., Aicardi, J., Artuch, R., Montalto, S. A., Bacino, C. A., Barroso, B., Baxter, P., Benko, W. S., and 106 others. <strong>Clinical and molecular phenotype of Aicardi-Goutieres syndrome.</strong> Am. J. Hum. Genet. 81: 713-725, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17846997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17846997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17846997[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/10.1086/521373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17846997">Rice et al. (2007)</a> found RNASEH2A mutations in 3 of 127 pedigrees with a clinical diagnosis of AGS. Four children in these 3 families had biallelic mutations. Four of 5 mutations, 1 of which occurred in homozygous form, were missense. In 1 family <a href="#8" class="mim-tip-reference" title="Rice, G., Patrick, T., Parmar, R., Taylor, C. F., Aeby, A., Aicardi, J., Artuch, R., Montalto, S. A., Bacino, C. A., Barroso, B., Baxter, P., Benko, W. S., and 106 others. <strong>Clinical and molecular phenotype of Aicardi-Goutieres syndrome.</strong> Am. J. Hum. Genet. 81: 713-725, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17846997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17846997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17846997[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/10.1086/521373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17846997">Rice et al. (2007)</a> identified a single mutation in RNASEH2A that had been inherited. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17846997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Rice, G. I., Reijns, M. A. M., Coffin, S. R., Forte, G. M. A., Anderson, B. H., Szynkiewicz, M., Gornall, H., Gent, D., Leitch, A., Botella, M. P., Fazzi, E., Gener, B., Lagae, L., Olivieri, I., Orcesi, S., Swoboda, K. J., Perrino, F. W., Jackson, A. P., Crow, Y. J. <strong>Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutieres syndrome.</strong> Hum. Mutat. 34: 1066-1070, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23592335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23592335</a>] [<a href="https://doi.org/10.1002/humu.22336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23592335">Rice et al. (2013)</a> studied 4 probands with AGS who had homozygous or compound heterozygous mutations in the RNASEH2A gene (<a href="#0002">606034.0002</a>-<a href="#0006">606034.0006</a>). All 4 patients carried at least 1 synonymous RNASEH2A mutation; functional analysis confirmed the pathogenicity of the synonymous mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23592335" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Pokatayev, V., Hasin, N., Chon, H., Cerritelli, S. M., Sakhuja, K., Ward, J. M., Morris, H. D., Yan, N., Crouch, R. J. <strong>RNase H2 catalytic core Aicardi-Goutieres syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice.</strong> J. Exp. Med. 213: 329-336, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26880576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26880576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26880576[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/10.1084/jem.20151464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26880576">Pokatayev et al. (2016)</a> found that knockin mice homozygous for the gly37-to-ser (G37S; <a href="#0001">606034.0001</a>) mutation in the Rnaseh2a gene exhibited perinatal lethality. The G37S mutation led to increased expression of interferon-stimulated genes dependent on Cgas (MB21D1; <a href="/entry/613973">613973</a>)-Sting (TMEM173; <a href="/entry/612374">612374</a>) signaling. Ablation of Sting in G37S mice resulted in partial rescue of perinatal lethality, with viable mice exhibiting white spotting on their ventral surface. <a href="#6" class="mim-tip-reference" title="Pokatayev, V., Hasin, N., Chon, H., Cerritelli, S. M., Sakhuja, K., Ward, J. M., Morris, H. D., Yan, N., Crouch, R. J. <strong>RNase H2 catalytic core Aicardi-Goutieres syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice.</strong> J. Exp. Med. 213: 329-336, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26880576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26880576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26880576[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/10.1084/jem.20151464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26880576">Pokatayev et al. (2016)</a> proposed that this mouse model may facilitate study of RNASEH2-associated autoimmune diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26880576" 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 brothers with Aicardi-Goutieres syndrome-4 (AGS4; <a href="/entry/610333">610333</a>) from a consanguineous family of Spanish ancestry reported by <a href="#9" class="mim-tip-reference" title="Sanchis, A., Cervero, L., Bataller, A., Tortajada, J. L., Huguet, J., Crow, Y. J., Ali, M., Higuet, L. J., Martinez-Frias, M. L. <strong>Genetic syndromes mimic congenital infections.</strong> J. Pediat. 146: 701-705, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15870678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15870678</a>] [<a href="https://doi.org/10.1016/j.jpeds.2005.01.033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15870678">Sanchis et al. (2005)</a>, <a href="#2" class="mim-tip-reference" title="Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., Ali, M., Semple, C., Aicardi, J., Babul-Hirji, R., Baumann, C., Baxter, P., and 33 others. <strong>Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection.</strong> Nature Genet. 38: 910-916, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16845400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16845400</a>] [<a href="https://doi.org/10.1038/ng1842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16845400">Crow et al. (2006)</a> identified a homozygous 109G-A transition in exon 1 of the RNASEH2A gene, resulting in a gly37-to-ser (G37S) substitution at the end of the first beta-sheet in the floor of the predicted substrate-binding cleft near the catalytic site. This amino acid is conserved across all 3 major phylogenetic divisions (archea, eubacteria, eukaryotes). In vitro functional expression studies showed that the G37S mutant protein resulted in markedly reduced protein activity. The mutation was not detected in 178 European control alleles, and both parents were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16845400+15870678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 7-year-old Belgian girl with Aicardi-Goutieres syndrome-4 (AGS4; <a href="/entry/610333">610333</a>), <a href="#7" class="mim-tip-reference" title="Rice, G. I., Reijns, M. A. M., Coffin, S. R., Forte, G. M. A., Anderson, B. H., Szynkiewicz, M., Gornall, H., Gent, D., Leitch, A., Botella, M. P., Fazzi, E., Gener, B., Lagae, L., Olivieri, I., Orcesi, S., Swoboda, K. J., Perrino, F. W., Jackson, A. P., Crow, Y. J. <strong>Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutieres syndrome.</strong> Hum. Mutat. 34: 1066-1070, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23592335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23592335</a>] [<a href="https://doi.org/10.1002/humu.22336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23592335">Rice et al. (2013)</a> identified homozygosity for a c.75C-T transition in exon 1 of the RNASEH2A gene, resulting in an arg25-to-arg (R25R) substitution. Her unaffected parents were heterozygous for the variant. The mutation was predicted to create a new donor splice site within exon 1; sequencing of the smaller RT-PCR product obtained from patient cell lines confirmed preferential usage of the new donor splice site. The aberrant transcript had a 54-bp in-frame deletion, resulting in an 18-amino acid internal deletion (del26-43) in the RNASEH2A protein. Coexpression of the mutant RNASEH2A with the B and C subunits in E. coli showed that although a mutant trimeric complex was formed, it exhibited no detectable catalytic activity, consistent with the loss of key metal-binding residues asp34 and glu35 in the mutant enzyme. However, a small amount of full-length transcript was also detected and confirmed by quantitative RT-PCR analysis of patient cells and peripheral whole blood, and residual levels of cellular RNase H2 activity were confirmed using a fluorometric assay on whole cell lysates from patient fibroblasts and lymphoblastoid cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23592335" 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=RCV000056303 OR RCV003155061" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056303, RCV003155061" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056303...</a>
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<p>In a 12-year-old Spanish girl with Aicardi-Goutieres syndrome-4 (AGS4; <a href="/entry/610333">610333</a>) and her affected sister, <a href="#7" class="mim-tip-reference" title="Rice, G. I., Reijns, M. A. M., Coffin, S. R., Forte, G. M. A., Anderson, B. H., Szynkiewicz, M., Gornall, H., Gent, D., Leitch, A., Botella, M. P., Fazzi, E., Gener, B., Lagae, L., Olivieri, I., Orcesi, S., Swoboda, K. J., Perrino, F. W., Jackson, A. P., Crow, Y. J. <strong>Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutieres syndrome.</strong> Hum. Mutat. 34: 1066-1070, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23592335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23592335</a>] [<a href="https://doi.org/10.1002/humu.22336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23592335">Rice et al. (2013)</a> identified compound heterozygosity for 2 mutations in the RNASEH2A gene: a synonymous R25R substitution (<a href="#0002">606034.0002</a>), and a c.704G-A transition in exon 7, resulting in an arg235-to-gln (R235Q) substitution at a highly conserved residue. Their unaffected parents were each heterozygous for 1 of the mutations. <a href="#1" class="mim-tip-reference" title="Coffin, S. R., Hollis, T., Perrino, F. W. <strong>Functional consequences of the RNase H2A subunit mutations that cause Aicardi-Goutieres syndrome.</strong> J. Biol. Chem. 286: 16984-16991, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21454563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21454563</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21454563[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.228833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21454563">Coffin et al. (2011)</a> performed kinetic analysis of wildtype and R235Q mutant RNASEH2A and observed that the mutant showed dramatically reduced activity, measured at 1/370, 1/600, and 1/750 relative to wildtype, as well as reduced binding affinity, measured at 1/4, 1/4, and 1/10 relative to wildtype, using polynucleotide substrates containing 1, 4, and 20 ribonucleotides, respectively. Catalytic efficiency with the R235Q mutant was 1/800 of the efficiency of the wildtype protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21454563+23592335" 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> rs397515480 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515480;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/rs397515480?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=rs397515480" 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=rs397515480" 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=RCV000056304 OR RCV001731349 OR RCV002307387" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056304, RCV001731349, RCV002307387" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056304...</a>
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<p>In an Italian boy with Aicardi-Goutieres syndrome-4 (AGS4; <a href="/entry/610333">610333</a>) who died at 3.5 years of age, <a href="#7" class="mim-tip-reference" title="Rice, G. I., Reijns, M. A. M., Coffin, S. R., Forte, G. M. A., Anderson, B. H., Szynkiewicz, M., Gornall, H., Gent, D., Leitch, A., Botella, M. P., Fazzi, E., Gener, B., Lagae, L., Olivieri, I., Orcesi, S., Swoboda, K. J., Perrino, F. W., Jackson, A. P., Crow, Y. J. <strong>Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutieres syndrome.</strong> Hum. Mutat. 34: 1066-1070, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23592335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23592335</a>] [<a href="https://doi.org/10.1002/humu.22336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23592335">Rice et al. (2013)</a> identified compound heterozygosity for 2 mutations in the RNASEH2A gene. The first mutation was a c.69G-A transition in exon 1, resulting in a val23-to-val (V23V) substitution and predicted to create a new donor splice site; sequencing confirmed an out-of-frame deletion and insertion of 20 amino acids followed by a premature stop codon at residue 42. The second mutation was a c.556C-T transition in exon 6, resulting in an arg186-to-trp (R186W; <a href="#0005">606034.0005</a>) substitution at a highly conserved residue. His unaffected parents were each heterozygous for 1 of the mutations. <a href="#1" class="mim-tip-reference" title="Coffin, S. R., Hollis, T., Perrino, F. W. <strong>Functional consequences of the RNase H2A subunit mutations that cause Aicardi-Goutieres syndrome.</strong> J. Biol. Chem. 286: 16984-16991, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21454563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21454563</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21454563[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.228833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21454563">Coffin et al. (2011)</a> performed kinetic analysis of wildtype and R186W mutant RNASEH2A and observed that the mutant showed dramatically reduced activity, measured at 1/160, 1/9, and 1/8 relative to wildtype, as well as reduced binding affinity, measured at 1/8, 1/25, and 1/100 relative to wildtype, using polynucleotide substrates containing 1, 4, and 20 ribonucleotides, respectively. Catalytic efficiency with the R186W mutant was 1/56 of the efficiency of the wildtype protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21454563+23592335" 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> rs77103971 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77103971;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/rs77103971?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=rs77103971" 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=rs77103971" 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=RCV000056305 OR RCV000610608 OR RCV003894911" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056305, RCV000610608, RCV003894911" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056305...</a>
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<p>For discussion of the arg186-to-trp (R186W) mutation in the RNASEH2A gene that was found in compound heterozygous state in a patient with Aicardi-Goutieres syndrome-4 (AGS4; <a href="/entry/610333">610333</a>) by <a href="#7" class="mim-tip-reference" title="Rice, G. I., Reijns, M. A. M., Coffin, S. R., Forte, G. M. A., Anderson, B. H., Szynkiewicz, M., Gornall, H., Gent, D., Leitch, A., Botella, M. P., Fazzi, E., Gener, B., Lagae, L., Olivieri, I., Orcesi, S., Swoboda, K. J., Perrino, F. W., Jackson, A. P., Crow, Y. J. <strong>Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutieres syndrome.</strong> Hum. Mutat. 34: 1066-1070, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23592335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23592335</a>] [<a href="https://doi.org/10.1002/humu.22336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23592335">Rice et al. (2013)</a>, see <a href="#0004">606034.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23592335" 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=RCV000056306 OR RCV004700358" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056306, RCV004700358" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056306...</a>
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<p>In an 11-year-old Caucasian boy with Aicardi-Goutieres syndrome-4 (AGS4; <a href="/entry/610333">610333</a>), <a href="#7" class="mim-tip-reference" title="Rice, G. I., Reijns, M. A. M., Coffin, S. R., Forte, G. M. A., Anderson, B. H., Szynkiewicz, M., Gornall, H., Gent, D., Leitch, A., Botella, M. P., Fazzi, E., Gener, B., Lagae, L., Olivieri, I., Orcesi, S., Swoboda, K. J., Perrino, F. W., Jackson, A. P., Crow, Y. J. <strong>Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutieres syndrome.</strong> Hum. Mutat. 34: 1066-1070, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23592335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23592335</a>] [<a href="https://doi.org/10.1002/humu.22336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23592335">Rice et al. (2013)</a> identified compound heterozygosity for 2 mutations in the RNASEH2A gene: a synonymous V23V mutation (<a href="#0004">606034.0004</a>), and a c.635A-T transversion in exon 6, resulting in an asn212-to-ile (N212I) substitution at a conserved residue. His unaffected parents were each heterozygous for 1 of the mutations. RNase H2 enzyme activity was strongly reduced in cell lysates from the patient, whereas enzyme activity in parental cells was similar to control levels. <a href="#1" class="mim-tip-reference" title="Coffin, S. R., Hollis, T., Perrino, F. W. <strong>Functional consequences of the RNase H2A subunit mutations that cause Aicardi-Goutieres syndrome.</strong> J. Biol. Chem. 286: 16984-16991, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21454563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21454563</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21454563[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M111.228833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21454563">Coffin et al. (2011)</a> performed kinetic analysis of wildtype and N212I mutant RNASEH2A and observed that although activity and catalytic efficiency were comparable to wildtype, the mutant showed reduced binding affinity, measured at 1/2 and 1/3 relative to wildtype, using polynucleotide substrates containing 4 and 20 ribonucleotides, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21454563+23592335" 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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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21454563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21454563</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21454563[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=21454563" 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/10.1074/jbc.M111.228833" target="_blank">Full Text</a>]
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</p>
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<a id="2" class="mim-anchor"></a>
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<a id="Crow2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., Ali, M., Semple, C., Aicardi, J., Babul-Hirji, R., Baumann, C., Baxter, P., and 33 others.
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<strong>Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16845400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16845400</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16845400" 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/ng1842" target="_blank">Full Text</a>]
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</p>
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<a id="3" class="mim-anchor"></a>
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<a id="Frank1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Frank, P., Braunshofer-Reiter, C., Wintersberger, U., Grimm, R., Busen, W.
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<strong>Cloning of the cDNA encoding the large subunit of human RNase HI, a homologue of the prokaryotic RNase HII.</strong>
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[<a href="https://doi.org/10.1073/pnas.95.22.12872" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Kim2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Kim, N., Huang, S. N., Williams, J. S., Li, Y. C., Clark, A. B., Cho, J.-E., Kunkel, T. A., Pommier, Y., Jinks-Robertson, S.
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<strong>Mutagenic processing of ribonucleotides in DNA by yeast topoisomerase I.</strong>
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Science 332: 1561-1564, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700875</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700875[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=21700875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1205016" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="5" class="mim-anchor"></a>
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<a id="Kind2014" class="mim-anchor"></a>
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Kind, B., Muster, B., Staroske, W., Herce, H. D., Sachse, R., Rapp, A., Schmidt, F., Koss, S., Cardoso, M. C., Lee-Kirsch, M. A.
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<strong>Altered spatio-temporal dynamics of RNase H2 complex assembly at replication and repair sites in Aicardi-Goutieres syndrome.</strong>
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Hum. Molec. Genet. 23: 5950-5960, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24986920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24986920</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24986920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddu319" target="_blank">Full Text</a>]
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<a id="Pokatayev2016" class="mim-anchor"></a>
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Pokatayev, V., Hasin, N., Chon, H., Cerritelli, S. M., Sakhuja, K., Ward, J. M., Morris, H. D., Yan, N., Crouch, R. J.
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<strong>RNase H2 catalytic core Aicardi-Goutieres syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice.</strong>
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J. Exp. Med. 213: 329-336, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26880576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26880576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26880576[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=26880576" 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/10.1084/jem.20151464" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Rice2013" class="mim-anchor"></a>
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Rice, G. I., Reijns, M. A. M., Coffin, S. R., Forte, G. M. A., Anderson, B. H., Szynkiewicz, M., Gornall, H., Gent, D., Leitch, A., Botella, M. P., Fazzi, E., Gener, B., Lagae, L., Olivieri, I., Orcesi, S., Swoboda, K. J., Perrino, F. W., Jackson, A. P., Crow, Y. J.
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<strong>Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutieres syndrome.</strong>
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Hum. Mutat. 34: 1066-1070, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23592335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23592335</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23592335" 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.22336" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Rice2007" class="mim-anchor"></a>
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<div class="">
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Rice, G., Patrick, T., Parmar, R., Taylor, C. F., Aeby, A., Aicardi, J., Artuch, R., Montalto, S. A., Bacino, C. A., Barroso, B., Baxter, P., Benko, W. S., and 106 others.
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<strong>Clinical and molecular phenotype of Aicardi-Goutieres syndrome.</strong>
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Am. J. Hum. Genet. 81: 713-725, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17846997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17846997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17846997[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=17846997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/521373" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Sanchis2005" class="mim-anchor"></a>
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<div class="">
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Sanchis, A., Cervero, L., Bataller, A., Tortajada, J. L., Huguet, J., Crow, Y. J., Ali, M., Higuet, L. J., Martinez-Frias, M. L.
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<strong>Genetic syndromes mimic congenital infections.</strong>
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J. Pediat. 146: 701-705, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15870678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15870678</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15870678" 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.jpeds.2005.01.033" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Zimmermann2018" class="mim-anchor"></a>
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<div class="">
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Zimmermann, M., Murina, O., Reijns, M. A. M., Agathanggelou, A., Challis, R., Tarnauskaite, Z., Muir, M., Fluteau, A., Aregger, M., McEwan, A., Yuan, W., Clarke, M., and 12 others.
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<strong>CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions.</strong>
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Nature 559: 285-289, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29973717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29973717</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29973717" 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/s41586-018-0291-z" target="_blank">Full Text</a>]
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</ol>
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<br />
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 09/14/2018
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Paul J. Converse - updated : 07/07/2016<br>Patricia A. Hartz - updated : 6/8/2015<br>Marla J. F. O'Neill - updated : 10/8/2013<br>Ada Hamosh - updated : 8/4/2011<br>Victor A. McKusick - updated : 10/3/2007<br>Cassandra L. Kniffin - updated : 8/18/2006<br>Victor A. McKusick - updated : 8/15/2006
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<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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<span class="mim-text-font">
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Paul J. Converse : 6/19/2001
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<span class="mim-text-font">
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carol : 07/20/2020
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<span class="mim-text-font">
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alopez : 09/14/2018<br>mgross : 07/07/2016<br>mgross : 7/13/2015<br>mcolton : 6/8/2015<br>carol : 10/8/2013<br>tpirozzi : 10/8/2013<br>alopez : 8/15/2011<br>terry : 8/4/2011<br>alopez : 10/8/2007<br>alopez : 10/8/2007<br>alopez : 10/8/2007<br>terry : 10/3/2007<br>carol : 8/18/2006<br>ckniffin : 8/17/2006<br>ckniffin : 8/17/2006<br>terry : 8/15/2006<br>mgross : 8/30/2002<br>mgross : 6/19/2001<br>mgross : 6/19/2001
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<span class="mim-font">
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<strong>*</strong> 606034
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<h3>
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RIBONUCLEASE H2, SUBUNIT A; RNASEH2A
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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RIBONUCLEASE H2, LARGE SUBUNIT<br />
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RIBONUCLEASE HI, LARGE SUBUNIT<br />
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RNase HI, LARGE SUBUNIT
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</span>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: RNASEH2A</em></strong>
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<strong>
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<em>
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Cytogenetic location: 19p13.13
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:12,806,584-12,813,640 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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19p13.13
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</span>
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</td>
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<td>
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<span class="mim-font">
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Aicardi-Goutieres syndrome 4
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</span>
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</td>
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<td>
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<span class="mim-font">
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610333
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ribonuclease (RNase) H enzymes specifically cleave ribonucleotides from RNA:DNA duplexes. Two classes of RNase H exist: type 1 (I) and 2 (II). RNase H2 is the major source of RNase H activity in mammalian cells and yeast. The protein complex is proposed to function in the removal of lagging-strand Okazaki fragment RNA primers during DNA replication and in the excision of single ribonucleotides from DNA:DNA duplexes. See also RNASEH2B (610326) and RNASEH2C (610330). The 3 homologs in S. cerevisiae are known as Rnh2Ap, Rnh2Bp, and RNh2Cp, respectively (Crow et al., 2006). </p>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By biochemical purification of the 32-kD subunit of calf thymus RNase HI, microsequence analysis, EST database searching, and PCR with degenerate primers on an erythroleukemia cDNA library, Frank et al. (1998) obtained a cDNA encoding the large subunit of human RNase HI. The deduced 299-amino acid protein appeared to lack RNA- and DNA-binding domains. Genomic database comparisons revealed homologies between the large subunit of mammalian RNase HI and prokaryotic RNase HII. Western blot analysis showed expression of a 33-kD recombinant protein, close to the predicted size. Northern blot analysis detected a 1.2-kb transcript in a kidney cell line. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The RNASEH2A gene contains 8 exons (Crow et al., 2006). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Crow et al. (2006) mapped the RNASEH2A gene to chromosome 19p13.13. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>RNase HI is involved in DNA replication and participates with FEN1 (600393) in DNA repair. The smaller RNase HII is associated with transcription (Frank et al., 1998). </p><p>By transient expression in HEK293T cells, Crow et al. (2006) showed that the human RNASEH2A, RNASEH2B, and RNASEH2C genes interact with each other and form an enzymatic protein complex with RNase H2 activity. The complex was able to recognize and cleave a single ribonucleotide embedded in a DNA-DNA complex. </p><p>RNase H2 is specialized to remove single ribonucleotides (ribonucleoside monophosphates, or rNMPs) from duplex DNA, and its absence in budding yeast has been associated with the accumulation of deletions within short tandem repeats. Kim et al. (2011) demonstrated that rNMP-associated deletion formation requires the activity of Top1 (126420), a topoisomerase that relaxes supercoils by reversibly nicking duplex DNA. The reported studies extended the role of Top1 to include the processing of rNMPs in genomic DNA into irreversible single-strand breaks, an activity that can have distinct mutagenic consequences and may be relevant to human disease. </p><p>By expressing fluorescence-tagged RNASEH2 subunits individually or together in HeLa cells, Kind et al. (2014) determined that the B subunit was required for nuclear expression of the A and C subunits. Mutation analysis revealed that the C terminus of the C subunit, but not a catalytically active A subunit, was also required for formation of a stable nuclear complex. Ring-shaped trimeric PCNA (176740) functions as a 'sliding clamp' along DNA that guides assembly of factors involved in DNA replication and repair. PCNA recruited RNASEH2 to sites of DNA damage, and the PIP-box motif of subunit B was required for interaction of RNASEH2 with PCNA and accumulation of RNASEH2 to sites of DNA damage. In addition, a catalytically active A subunit bound more tightly than a catalytically inactive A subunit to sites of DNA replication. </p><p>Using CRISPR screens to identify genes and pathways that mediate cellular resistance to olaparib, a clinically approved PARP (173870) inhibitor, Zimmermann et al. (2018) identified a high-confidence set of 73 genes that when mutated cause increased sensitivity to PARP inhibitors. In addition to an expected enrichment for genes related to homologous recombination, Zimmermann et al. (2018) discovered that mutations in all 3 genes encoding ribonuclease H2 (RNASEH2A; RNASEH2B, 610326; and RNASEH2C, 610330) sensitized cells to PARP inhibition and established that the underlying cause of the PARP-inhibitor hypersensitivity of cells deficient in ribonuclease H2 is impaired ribonucleotide excision repair. Embedded ribonucleotides, which are abundant in the genome of cells deficient in ribonucleotide excision repair, are substrates for cleavage by TOP1, resulting in PARP-trapping lesions that impede DNA replication and endanger genome integrity. Zimmermann et al. (2018) concluded that genomic ribonucleotides are a hitherto unappreciated source of PARP-trapping DNA lesions, and that the frequent deletion of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukemia may provide an opportunity to exploit these findings therapeutically. </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>In 2 children with Aicardi-Goutieres syndrome (AGS4; 610333) from a consanguineous family of Spanish ancestry reported by Sanchis et al. (2005), Crow et al. (2006) identified a homozygous mutation in the RNASEH2A gene (606034.0001). </p><p>Rice et al. (2007) found RNASEH2A mutations in 3 of 127 pedigrees with a clinical diagnosis of AGS. Four children in these 3 families had biallelic mutations. Four of 5 mutations, 1 of which occurred in homozygous form, were missense. In 1 family Rice et al. (2007) identified a single mutation in RNASEH2A that had been inherited. </p><p>Rice et al. (2013) studied 4 probands with AGS who had homozygous or compound heterozygous mutations in the RNASEH2A gene (606034.0002-606034.0006). All 4 patients carried at least 1 synonymous RNASEH2A mutation; functional analysis confirmed the pathogenicity of the synonymous mutations. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Pokatayev et al. (2016) found that knockin mice homozygous for the gly37-to-ser (G37S; 606034.0001) mutation in the Rnaseh2a gene exhibited perinatal lethality. The G37S mutation led to increased expression of interferon-stimulated genes dependent on Cgas (MB21D1; 613973)-Sting (TMEM173; 612374) signaling. Ablation of Sting in G37S mice resulted in partial rescue of perinatal lethality, with viable mice exhibiting white spotting on their ventral surface. Pokatayev et al. (2016) proposed that this mouse model may facilitate study of RNASEH2-associated autoimmune diseases. </p>
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</span>
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<div>
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</div>
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<div>
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<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>6 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 AICARDI-GOUTIERES SYNDROME 4</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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RNASEH2A, GLY37SER
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<br />
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SNP: rs76857106,
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ClinVar: RCV000004904
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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 brothers with Aicardi-Goutieres syndrome-4 (AGS4; 610333) from a consanguineous family of Spanish ancestry reported by Sanchis et al. (2005), Crow et al. (2006) identified a homozygous 109G-A transition in exon 1 of the RNASEH2A gene, resulting in a gly37-to-ser (G37S) substitution at the end of the first beta-sheet in the floor of the predicted substrate-binding cleft near the catalytic site. This amino acid is conserved across all 3 major phylogenetic divisions (archea, eubacteria, eukaryotes). In vitro functional expression studies showed that the G37S mutant protein resulted in markedly reduced protein activity. The mutation was not detected in 178 European control alleles, and both parents were heterozygous for the mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 AICARDI-GOUTIERES SYNDROME 4</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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RNASEH2A, ARG25ARG
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<br />
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SNP: rs397515479,
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ClinVar: RCV000056302
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 7-year-old Belgian girl with Aicardi-Goutieres syndrome-4 (AGS4; 610333), Rice et al. (2013) identified homozygosity for a c.75C-T transition in exon 1 of the RNASEH2A gene, resulting in an arg25-to-arg (R25R) substitution. Her unaffected parents were heterozygous for the variant. The mutation was predicted to create a new donor splice site within exon 1; sequencing of the smaller RT-PCR product obtained from patient cell lines confirmed preferential usage of the new donor splice site. The aberrant transcript had a 54-bp in-frame deletion, resulting in an 18-amino acid internal deletion (del26-43) in the RNASEH2A protein. Coexpression of the mutant RNASEH2A with the B and C subunits in E. coli showed that although a mutant trimeric complex was formed, it exhibited no detectable catalytic activity, consistent with the loss of key metal-binding residues asp34 and glu35 in the mutant enzyme. However, a small amount of full-length transcript was also detected and confirmed by quantitative RT-PCR analysis of patient cells and peripheral whole blood, and residual levels of cellular RNase H2 activity were confirmed using a fluorometric assay on whole cell lysates from patient fibroblasts and lymphoblastoid cells. </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 AICARDI-GOUTIERES SYNDROME 4</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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RNASEH2A, ARG235GLN
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<br />
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SNP: rs75718910,
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gnomAD: rs75718910,
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ClinVar: RCV000056303, RCV003155061
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 12-year-old Spanish girl with Aicardi-Goutieres syndrome-4 (AGS4; 610333) and her affected sister, Rice et al. (2013) identified compound heterozygosity for 2 mutations in the RNASEH2A gene: a synonymous R25R substitution (606034.0002), and a c.704G-A transition in exon 7, resulting in an arg235-to-gln (R235Q) substitution at a highly conserved residue. Their unaffected parents were each heterozygous for 1 of the mutations. Coffin et al. (2011) performed kinetic analysis of wildtype and R235Q mutant RNASEH2A and observed that the mutant showed dramatically reduced activity, measured at 1/370, 1/600, and 1/750 relative to wildtype, as well as reduced binding affinity, measured at 1/4, 1/4, and 1/10 relative to wildtype, using polynucleotide substrates containing 1, 4, and 20 ribonucleotides, respectively. Catalytic efficiency with the R235Q mutant was 1/800 of the efficiency of the wildtype protein. </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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<h4>
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<span class="mim-font">
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<strong>.0004 AICARDI-GOUTIERES SYNDROME 4</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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RNASEH2A, VAL23VAL
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<br />
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SNP: rs397515480,
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gnomAD: rs397515480,
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ClinVar: RCV000056304, RCV001731349, RCV002307387
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an Italian boy with Aicardi-Goutieres syndrome-4 (AGS4; 610333) who died at 3.5 years of age, Rice et al. (2013) identified compound heterozygosity for 2 mutations in the RNASEH2A gene. The first mutation was a c.69G-A transition in exon 1, resulting in a val23-to-val (V23V) substitution and predicted to create a new donor splice site; sequencing confirmed an out-of-frame deletion and insertion of 20 amino acids followed by a premature stop codon at residue 42. The second mutation was a c.556C-T transition in exon 6, resulting in an arg186-to-trp (R186W; 606034.0005) substitution at a highly conserved residue. His unaffected parents were each heterozygous for 1 of the mutations. Coffin et al. (2011) performed kinetic analysis of wildtype and R186W mutant RNASEH2A and observed that the mutant showed dramatically reduced activity, measured at 1/160, 1/9, and 1/8 relative to wildtype, as well as reduced binding affinity, measured at 1/8, 1/25, and 1/100 relative to wildtype, using polynucleotide substrates containing 1, 4, and 20 ribonucleotides, respectively. Catalytic efficiency with the R186W mutant was 1/56 of the efficiency of the wildtype protein. </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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<h4>
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<span class="mim-font">
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<strong>.0005 AICARDI-GOUTIERES SYNDROME 4</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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RNASEH2A, ARG186TRP
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<br />
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SNP: rs77103971,
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gnomAD: rs77103971,
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ClinVar: RCV000056305, RCV000610608, RCV003894911
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the arg186-to-trp (R186W) mutation in the RNASEH2A gene that was found in compound heterozygous state in a patient with Aicardi-Goutieres syndrome-4 (AGS4; 610333) by Rice et al. (2013), see 606034.0004. </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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<h4>
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<span class="mim-font">
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<strong>.0006 AICARDI-GOUTIERES SYNDROME 4</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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RNASEH2A, ASN212ILE
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<br />
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SNP: rs377244188,
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gnomAD: rs377244188,
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ClinVar: RCV000056306, RCV004700358
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an 11-year-old Caucasian boy with Aicardi-Goutieres syndrome-4 (AGS4; 610333), Rice et al. (2013) identified compound heterozygosity for 2 mutations in the RNASEH2A gene: a synonymous V23V mutation (606034.0004), and a c.635A-T transversion in exon 6, resulting in an asn212-to-ile (N212I) substitution at a conserved residue. His unaffected parents were each heterozygous for 1 of the mutations. RNase H2 enzyme activity was strongly reduced in cell lysates from the patient, whereas enzyme activity in parental cells was similar to control levels. Coffin et al. (2011) performed kinetic analysis of wildtype and N212I mutant RNASEH2A and observed that although activity and catalytic efficiency were comparable to wildtype, the mutant showed reduced binding affinity, measured at 1/2 and 1/3 relative to wildtype, using polynucleotide substrates containing 4 and 20 ribonucleotides, respectively. </p>
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</span>
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</div>
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<div>
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</div>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Coffin, S. R., Hollis, T., Perrino, F. W.
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<strong>Functional consequences of the RNase H2A subunit mutations that cause Aicardi-Goutieres syndrome.</strong>
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Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., Ali, M., Semple, C., Aicardi, J., Babul-Hirji, R., Baumann, C., Baxter, P., and 33 others.
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<strong>Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection.</strong>
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Frank, P., Braunshofer-Reiter, C., Wintersberger, U., Grimm, R., Busen, W.
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<strong>Cloning of the cDNA encoding the large subunit of human RNase HI, a homologue of the prokaryotic RNase HII.</strong>
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Kim, N., Huang, S. N., Williams, J. S., Li, Y. C., Clark, A. B., Cho, J.-E., Kunkel, T. A., Pommier, Y., Jinks-Robertson, S.
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<strong>Mutagenic processing of ribonucleotides in DNA by yeast topoisomerase I.</strong>
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Science 332: 1561-1564, 2011.
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<p class="mim-text-font">
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Kind, B., Muster, B., Staroske, W., Herce, H. D., Sachse, R., Rapp, A., Schmidt, F., Koss, S., Cardoso, M. C., Lee-Kirsch, M. A.
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<strong>Altered spatio-temporal dynamics of RNase H2 complex assembly at replication and repair sites in Aicardi-Goutieres syndrome.</strong>
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Hum. Molec. Genet. 23: 5950-5960, 2014.
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Pokatayev, V., Hasin, N., Chon, H., Cerritelli, S. M., Sakhuja, K., Ward, J. M., Morris, H. D., Yan, N., Crouch, R. J.
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<strong>RNase H2 catalytic core Aicardi-Goutieres syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice.</strong>
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J. Exp. Med. 213: 329-336, 2016.
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[Full Text: https://doi.org/10.1084/jem.20151464]
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Rice, G. I., Reijns, M. A. M., Coffin, S. R., Forte, G. M. A., Anderson, B. H., Szynkiewicz, M., Gornall, H., Gent, D., Leitch, A., Botella, M. P., Fazzi, E., Gener, B., Lagae, L., Olivieri, I., Orcesi, S., Swoboda, K. J., Perrino, F. W., Jackson, A. P., Crow, Y. J.
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<strong>Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutieres syndrome.</strong>
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Hum. Mutat. 34: 1066-1070, 2013.
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[PubMed: 23592335]
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[Full Text: https://doi.org/10.1002/humu.22336]
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Rice, G., Patrick, T., Parmar, R., Taylor, C. F., Aeby, A., Aicardi, J., Artuch, R., Montalto, S. A., Bacino, C. A., Barroso, B., Baxter, P., Benko, W. S., and 106 others.
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<strong>Clinical and molecular phenotype of Aicardi-Goutieres syndrome.</strong>
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Am. J. Hum. Genet. 81: 713-725, 2007.
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[Full Text: https://doi.org/10.1086/521373]
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Sanchis, A., Cervero, L., Bataller, A., Tortajada, J. L., Huguet, J., Crow, Y. J., Ali, M., Higuet, L. J., Martinez-Frias, M. L.
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<strong>Genetic syndromes mimic congenital infections.</strong>
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J. Pediat. 146: 701-705, 2005.
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[PubMed: 15870678]
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[Full Text: https://doi.org/10.1016/j.jpeds.2005.01.033]
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Zimmermann, M., Murina, O., Reijns, M. A. M., Agathanggelou, A., Challis, R., Tarnauskaite, Z., Muir, M., Fluteau, A., Aregger, M., McEwan, A., Yuan, W., Clarke, M., and 12 others.
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<strong>CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions.</strong>
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Nature 559: 285-289, 2018.
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[PubMed: 29973717]
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[Full Text: https://doi.org/10.1038/s41586-018-0291-z]
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Contributors:
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<span class="mim-text-font">
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Ada Hamosh - updated : 09/14/2018<br>Paul J. Converse - updated : 07/07/2016<br>Patricia A. Hartz - updated : 6/8/2015<br>Marla J. F. O'Neill - updated : 10/8/2013<br>Ada Hamosh - updated : 8/4/2011<br>Victor A. McKusick - updated : 10/3/2007<br>Cassandra L. Kniffin - updated : 8/18/2006<br>Victor A. McKusick - updated : 8/15/2006
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Paul J. Converse : 6/19/2001
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