3235 lines
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3235 lines
264 KiB
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Entry
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- *179835 - REPLICATION PROTEIN A1, 70-KD; RPA1
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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">*179835</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<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/179835">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<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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<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 id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000132383;t=ENST00000254719" 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=6117" 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=179835" 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 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=ENSG00000132383;t=ENST00000254719" 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_001355120,NM_001355121,NM_002945" 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_002945" 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=179835" 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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</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=01565&isoform_id=01565_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/RPA1" 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/337489,1350579,4506583,17390283,33337952,46430939,62089044,119610980,158260431,1243057641,1243057643" 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/P27694" 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 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=6117" 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=ENSG00000132383;t=ENST00000254719" 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=RPA1" 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=RPA1" 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+6117" 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/RPA1" 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:6117" 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/6117" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr17&hgg_gene=ENST00000254719.10&hgg_start=1830005&hgg_end=1900082&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=179835[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 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=179835[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/ENSG00000132383" 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=RPA1" 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=RPA1" 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=RPA1" 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=RPA1&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/PA34651" 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:10289" 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/FBgn0010173.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:1915525" 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/RPA1#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:1915525" 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/6117/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=6117" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00017546;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00017546 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00019858;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00019858 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00019859;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00019859 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-030912-3" 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:6117" 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=RPA1&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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179835
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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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REPLICATION PROTEIN A1, 70-KD; RPA1
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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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RPA70<br />
|
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REPA1
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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=RPA1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">RPA1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/17/38?start=-3&limit=10&highlight=38">17p13.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr17:1830005-1900082&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">17:1,830,005-1,900,082</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
|
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/17/38?start=-3&limit=10&highlight=38">
|
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17p13.3
|
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</a>
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 6
|
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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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|
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<a href="/entry/619767"> 619767 </a>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/179835" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/179835" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p>Replication protein A (RPA) is a heterotrimeric single-strand DNA (ssDNA)-binding protein essential for DNA replication, repair, and recombination. It is composed of 70-kD (RPA1), 32-kD (RPA2; <a href="/entry/179836">179836</a>), and 14-kD (RPA3; <a href="/entry/179837">179837</a>) subunits. The RPA1 subunit is responsible for high-affinity ssDNA binding (summary by <a href="#7" class="mim-tip-reference" title="Haring, S. J., Mason, A. C., Binz, S. K., Wold, M. S. <strong>Cellular functions of human RPA1: multiple roles of domains in replication, repair, and checkpoints.</strong> J. Biol. Chem. 283: 19095-19111, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18469000[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.M800881200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469000">Haring et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18469000" 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="Erdile, L. F., Heyer, W.-D., Kolodner, R., Kelly, T. J. <strong>Characterization of a cDNA encoding the 70-kDa single-stranded DNA-binding subunit of human replication protein A and the role of the protein in DNA replication.</strong> J. Biol. Chem. 266: 12090-12098, 1991. Note: Erratum: J. Biol. Chem. 268: 2268 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2050703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2050703</a>]" pmid="2050703">Erdile et al. (1991)</a> reported the sequence of a cDNA encoding RPA1, the 70-kD RPA subunit. The human cDNA directed production in E. coli of a 70-kD protein that reacted with a monoclonal antibody directed against the 70-kD subunit of human RPA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2050703" 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="#5" class="mim-tip-reference" title="Gomes, X. V., Wold, M. S. <strong>Functional domains of the 70-kilodalton subunit of human replication protein A.</strong> Biochemistry 35: 10558-10568, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8756712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8756712</a>] [<a href="https://doi.org/10.1021/bi9607517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8756712">Gomes and Wold (1996)</a> stated that the human RPA1 protein contains 616 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8756712" 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="Haring, S. J., Mason, A. C., Binz, S. K., Wold, M. S. <strong>Cellular functions of human RPA1: multiple roles of domains in replication, repair, and checkpoints.</strong> J. Biol. Chem. 283: 19095-19111, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18469000[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.M800881200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469000">Haring et al. (2008)</a> stated that human RPA1 is made up of 4 oligonucleotide/oligosaccharide-binding (OB)-fold domains, also known as DNA-binding domains (DBDs). The N-terminal DBD-F domain is followed by the central DBD-A and DBD-B domains and the C-terminal DBD-C domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18469000" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using PCR amplification of genomic DNA from rodent-human cell lines, <a href="#14" class="mim-tip-reference" title="Umbricht, C. B., Erdile, L. F., Jabs, E. W., Kelly, T. J. <strong>Cloning, overexpression, and genomic mapping of the 14-kDa subunit of human replication protein A.</strong> J. Biol. Chem. 268: 6131-6138, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8454588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8454588</a>]" pmid="8454588">Umbricht et al. (1993)</a> mapped the RPA1 gene to chromosome 17. By the same method, they mapped the RPA2 and RPA3 genes to chromosomes 1 and 7, respectively. Using a combination of PCR amplification of somatic cell hybrids and radiation hybrids containing chromosome 17 fragments, <a href="#15" class="mim-tip-reference" title="Umbricht, C. B., Griffin, C. A., Hawkins, A. L., Grzeschik, K. H., O'Connell, P., Leach, R., Green, E. D., Kelly, T. J. <strong>High-resolution genomic mapping of the three human replication protein A genes (RPA1, RPA2, and RPA3).</strong> Genomics 20: 249-257, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8020972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8020972</a>] [<a href="https://doi.org/10.1006/geno.1994.1161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8020972">Umbricht et al. (1994)</a> mapped the RPA1 gene to chromosome 17p13.3. Loss of the 17p13.3 chromosomal region has repeatedly been implicated in various malignancies including colorectal cancers, breast cancers, lymphomas, and leukemias (<a href="#16" class="mim-tip-reference" title="Wang, Y., Putnam, C. D., Kane, M. F., Zhang, W., Edelmann, L., Russell, R., Carrion, D. V., Chin, L., Kucherlapati, R., Kolodner, R. D., Edelmann, W. <strong>Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice.</strong> Nature Genet. 37: 750-755, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15965476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15965476</a>] [<a href="https://doi.org/10.1038/ng1587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15965476">Wang et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15965476+8454588+8020972" 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 RPA complex was originally isolated as a factor essential for in vitro replication of the papovavirus SV40. <a href="#2" class="mim-tip-reference" title="Erdile, L. F., Heyer, W.-D., Kolodner, R., Kelly, T. J. <strong>Characterization of a cDNA encoding the 70-kDa single-stranded DNA-binding subunit of human replication protein A and the role of the protein in DNA replication.</strong> J. Biol. Chem. 266: 12090-12098, 1991. Note: Erratum: J. Biol. Chem. 268: 2268 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2050703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2050703</a>]" pmid="2050703">Erdile et al. (1991)</a> found that recombinant human RPA1, purified from bacteria, exhibited ssDNA-binding activity comparable to that of the complete RPA complex. RPA1 could substitute for the complete complex in stimulating the activity of DNA polymerase alpha-primase, but it could not substitute for the complete complex in SV40 DNA replication in vitro, suggesting an important functional role for the other subunits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2050703" 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="#5" class="mim-tip-reference" title="Gomes, X. V., Wold, M. S. <strong>Functional domains of the 70-kilodalton subunit of human replication protein A.</strong> Biochemistry 35: 10558-10568, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8756712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8756712</a>] [<a href="https://doi.org/10.1021/bi9607517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8756712">Gomes and Wold (1996)</a> constructed a series of N-terminal deletions of RPA70 to explore the function of the protein. Their data indicated that RPA70 is composed of 3 functional domains: an N-terminal domain that is not required for ssDNA binding or SV40 replication, a central DNA-binding domain, and a C-terminal domain that is essential for subunit interactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8756712" 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="#11" class="mim-tip-reference" title="Nakayama, M., Yasue, H., Yoshimura, M., Shimasaki, Y., Kugiyama, K., Ogawa, H., Motoyama, T., Saito, Y., Ogawa, Y., Miyamoto, Y., Nakao, K. <strong>T(-786)-C mutation in the 5-prime-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm.</strong> Circulation 99: 2864-2870, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10359729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10359729</a>] [<a href="https://doi.org/10.1161/01.cir.99.22.2864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10359729">Nakayama et al. (1999)</a> reported that a -786T-C mutation (<a href="/entry/163729#0002">163729.0002</a>) in the promoter region of the eNOS (NOS3; <a href="/entry/163729">163729</a>) gene reduced transcription of the gene and was strongly associated with coronary spastic angina and myocardial infarction. To elucidate the molecular mechanism for the reduced eNOS gene transcription, <a href="#10" class="mim-tip-reference" title="Miyamoto, Y., Saito, Y., Nakayama, M., Shimasaki, Y., Yoshimura, T., Yoshimura, M., Harada, M., Kajiyama, N., Kishimoto, I., Kuwahara, K., Hino, J., Ogawa, E., Hamanaka, I., Kamitani, S., Takahashi, N., Kawakami, R., Kangawa, K., Yasue, H., Nakao, K. <strong>Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786T-C mutation associated with coronary spastic angina.</strong> Hum. Molec. Genet. 9: 2629-2637, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11063722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11063722</a>] [<a href="https://doi.org/10.1093/hmg/9.18.2629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11063722">Miyamoto et al. (2000)</a> purified a protein that specifically bound the mutant allele in nuclear extracts from HeLa cells. The purified protein was identical to RPA1. In human umbilical vein endothelial cells, inhibition of RPA1 expression using antisense oligonucleotides restored transcription driven by the mutated promoter sequence, whereas overexpression of RPA1 further reduced it. Serum nitrite/nitrate levels among individuals carrying the -786T-C mutation were significantly lower than among those without the mutation. The authors concluded that RPA1 apparently functions as a repressor protein in the -786T-C mutation-related reduction of eNOS gene transcription associated with the development of coronary artery disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11063722+10359729" 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>The function of the ATR (<a href="/entry/601215">601215</a>)-ATRIP (<a href="/entry/606605">606605</a>) protein kinase complex is crucial for the cellular response to replication stress and DNA damage. <a href="#17" class="mim-tip-reference" title="Zou, L., Elledge, S. J. <strong>Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.</strong> Science 300: 1542-1548, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12791985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12791985</a>] [<a href="https://doi.org/10.1126/science.1083430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12791985">Zou and Elledge (2003)</a> demonstrated that the RPA complex was required for recruitment of ATR to sites of DNA damage and for ATR-mediated CHK1 (<a href="/entry/603078">603078</a>) activation in human cells. In vitro, RPA stimulated binding of ATRIP to ssDNA. Binding of ATRIP to RPA-coated ssDNA enabled the ATR-ATRIP complex to associate with DNA and stimulate phosphorylation of the RAD17 (<a href="/entry/603139">603139</a>) protein that was bound to DNA. Furthermore, Ddc2, the budding yeast homolog of ATRIP, was specifically recruited to double-stranded DNA breaks in an RPA-dependent manner. A checkpoint-deficient mutant of RPA, rfa1-t11, was defective for recruiting Ddc2 to ssDNA both in vivo and in vitro. <a href="#17" class="mim-tip-reference" title="Zou, L., Elledge, S. J. <strong>Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.</strong> Science 300: 1542-1548, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12791985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12791985</a>] [<a href="https://doi.org/10.1126/science.1083430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12791985">Zou and Elledge (2003)</a> concluded that RPA-coated ssDNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12791985" 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>Activation-induced cytidine deaminase (AID; <a href="/entry/605257">605257</a>) is an ssDNA deaminase required for somatic hypermutation and class switch recombination of immunoglobulin genes. Class switch recombination involves transcription through switch regions, which generates ssDNA within R loops. <a href="#1" class="mim-tip-reference" title="Chaudhuri, J., Khuong, C., Alt, F. W. <strong>Replication protein A interacts with AID to promote deamination of somatic hypermutation targets.</strong> Nature 430: 992-998, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15273694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15273694</a>] [<a href="https://doi.org/10.1038/nature02821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15273694">Chaudhuri et al. (2004)</a> characterized the mechanism of AID targeting to in vitro transcribed substrates harboring somatic hypermutation motifs. They showed that the targeting activity of AID was due to RPA. The 32-kD subunit of RPA interacted specifically with AID from activated B cells in a manner that seemed to be dependent on posttranslational AID modification. <a href="#1" class="mim-tip-reference" title="Chaudhuri, J., Khuong, C., Alt, F. W. <strong>Replication protein A interacts with AID to promote deamination of somatic hypermutation targets.</strong> Nature 430: 992-998, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15273694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15273694</a>] [<a href="https://doi.org/10.1038/nature02821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15273694">Chaudhuri et al. (2004)</a> concluded that RPA is implicated as a novel factor involved in immunoglobulin diversification and proposed that B cell-specific AID-RPA complexes preferentially bind to ssDNA of small transcription bubbles at somatic hypermutation hotspots, leading to AID-mediated deamination and RPA-mediated recruitment of DNA repair proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15273694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Maga, G., Villani, G., Crespan, E., Wimmer, U., Ferrari, E., Bertocci, B., Hubscher, U. <strong>8-oxo-guanine bypass by human DNA polymerases in the presence of auxiliary proteins.</strong> Nature 447: 606-608, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17507928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17507928</a>] [<a href="https://doi.org/10.1038/nature05843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17507928">Maga et al. (2007)</a> analyzed the effects of human proliferating cell nuclear antigen (PCNA; <a href="/entry/176740">176740</a>) and RPA on 6 different human DNA polymerases belonging to the B, Y, and X classes during in vitro bypass of different lesions. The mutagenic lesion 8-oxo-guanine has high miscoding potential. A major and specific effect was found for 8-oxo-G bypass with DNA pol-lambda (<a href="/entry/606343">606343</a>) and -eta (<a href="/entry/603968">603968</a>). PCNA and RPA allowed correct incorporation of dCTP opposite an 8-oxo-G template 1,200-fold more efficiently than the incorrect dATP by DNA pol-lambda, and 68-fold by DNA pol-eta, respectively. Experiments with DNA pol-gamma (<a href="/entry/174763">174763</a>)-null cell extracts suggested an important role for DNA pol-lambda. On the other hand, DNA pol-iota (<a href="/entry/605252">605252</a>) together with DNA pol-alpha (<a href="/entry/312040">312040</a>), -delta (<a href="/entry/174761">174761</a>), and -beta (<a href="/entry/174760">174760</a>), showed a much lower correct bypass efficiency. <a href="#9" class="mim-tip-reference" title="Maga, G., Villani, G., Crespan, E., Wimmer, U., Ferrari, E., Bertocci, B., Hubscher, U. <strong>8-oxo-guanine bypass by human DNA polymerases in the presence of auxiliary proteins.</strong> Nature 447: 606-608, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17507928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17507928</a>] [<a href="https://doi.org/10.1038/nature05843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17507928">Maga et al. (2007)</a> concluded that their findings showed the existence of an accurate mechanism to reduce the deleterious consequences of oxidative damage and, in addition, pointed to an important role for PCNA and RPA in determining a functional hierarchy among different DNA pols in lesion bypass. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17507928" 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="#6" class="mim-tip-reference" title="Gupta, R., Sharma, S., Sommers, J. A., Kenny, M. K., Cantor, S. B., Brosh, R. M., Jr. <strong>FANCJ (BACH1) helicase forms DNA damage inducible foci with replication protein A and interacts physically and functionally with the single-stranded DNA-binding protein.</strong> Blood 110: 2390-2398, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17596542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17596542</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17596542[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/10.1182/blood-2006-11-057273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17596542">Gupta et al. (2007)</a> found that FANCJ (BRIP1; <a href="/entry/605882">605882</a>) immunoprecipitated with RPA. FANCJ and RPA colocalized in nuclear foci after DNA damage or replication stress. FANCJ and RPA bound with high affinity via the RPA70 subunit. Although FANCJ showed limited ability to unwind even a 47-bp forked duplex, the presence of RPA enabled FANCJ to act as a much more processive helicase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17596542" 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="Haring, S. J., Mason, A. C., Binz, S. K., Wold, M. S. <strong>Cellular functions of human RPA1: multiple roles of domains in replication, repair, and checkpoints.</strong> J. Biol. Chem. 283: 19095-19111, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18469000[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.M800881200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469000">Haring et al. (2008)</a> stated that the N-terminal DBD-F domain of RPA1 is involved in protein interactions, the central DBD-A and DBD-B domains bind ssDNA, and the C-terminal DBD-C domain mediates interaction with RPA2 and RPA3. They found that knockdown of RPA1 in HeLa cells caused accumulation of cells in S and G2/M phases, followed by cell death. RPA1 was not required for stability of RPA2 or RPA3. Expression of various mutant RPA1 proteins in RPA1-depleted HeLa cells revealed that amino acids in DBD-A involved in polar interactions with ssDNA mediated DNA binding. However, only RPA1 with mutations at all 6 polar-interacting residues in DBD-A was defective in replication, foci formation at sites of DNA damage, and G2/M checkpoint. RPA1 with mutations at aromatic residues in DBD-A and DBD-B involved in nonpolar ssDNA interactions exhibited weak DNA binding, and its expression caused arrest of cells in G2/M. Expression of RPA1 with mutations in the N-terminal DBD-F domain or deletion of the DBD-F domain and adjacent linker region completely restored replication in RPA1-depleted cells, but these mutant RPA1 proteins exhibited defective responses to DNA damage. Deletion of the C-terminal DBD-C domain produced monomeric RPA1 mutants that bound DNA but were defective in replication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18469000" 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>Maintenance of telomeres requires both DNA replication and telomere capping by shelterin. These 2 processes use 2 ssDNA-binding proteins, RPA and protection of telomeres-1 (POT1; <a href="/entry/606478">606478</a>). POT1 ablation leads to activation of the ATR checkpoint kinase at telomeres, suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. Unexpectedly, <a href="#3" class="mim-tip-reference" title="Flynn, R. L., Centore, R. C., O'Sullivan, R. J., Rai, R., Tse, A., Songyang, Z., Chang, S., Karlseder, J., Zou, L. <strong>TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA.</strong> Nature 471: 532-536, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21399625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21399625</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21399625[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21399625">Flynn et al. (2011)</a> found that purified POT1 and its functional partner TPP1 (<a href="/entry/609377">609377</a>) are unable to prevent RPA binding to telomeric ssDNA efficiently. In cell extracts, they identified a novel activity that specifically displaces RPA, but not POT1, from telomeric ssDNA. Using purified protein, <a href="#3" class="mim-tip-reference" title="Flynn, R. L., Centore, R. C., O'Sullivan, R. J., Rai, R., Tse, A., Songyang, Z., Chang, S., Karlseder, J., Zou, L. <strong>TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA.</strong> Nature 471: 532-536, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21399625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21399625</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21399625[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21399625">Flynn et al. (2011)</a> showed that the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1; <a href="/entry/164017">164017</a>) recapitulates the RPA displacing activity. The RPA displacing activity is inhibited by the telomeric repeat-containing RNA (TERRA) in early S phase, but is then unleashed in late S phase when TERRA levels decline at telomeres. Interestingly, TERRA also promotes POT1 binding to telomeric ssDNA by removing hnRNPA1, suggesting that the reaccumulation of TERRA after S phase helps to complete the RPA-to-POT1 switch on telomeric ssDNA. <a href="#3" class="mim-tip-reference" title="Flynn, R. L., Centore, R. C., O'Sullivan, R. J., Rai, R., Tse, A., Songyang, Z., Chang, S., Karlseder, J., Zou, L. <strong>TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA.</strong> Nature 471: 532-536, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21399625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21399625</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21399625[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21399625">Flynn et al. (2011)</a> concluded that hnRNPA1, TERRA, and POT1 act in concert to displace RPA from telomeric ssDNA after DNA replication, and promote telomere capping to preserve genomic integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21399625" 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 small interfering RNA-mediated knockdown studies in human osteosarcoma cells, <a href="#8" class="mim-tip-reference" title="Hu, R., Wang, E., Peng, G., Dai, H., Lin, S.-Y. <strong>Zinc finger protein 668 interacts with Tip60 to promote H2AX acetylation after DNA damage.</strong> Cell Cycle 12: 2033-2041, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23777805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23777805</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23777805[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/10.4161/cc.25064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23777805">Hu et al. (2013)</a> showed that ZNF668 (<a href="/entry/617103">617103</a>) promoted RPA activation at ultraviolet-induced DNA damage sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23777805" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Flynn, R. L., Cox, K. E., Jeitany, M., Wakimoto, H., Bryll, A. R., Ganem, N. J., Bersani, F., Pineda, J. R., Suva, M. L., Benes, C. H., Haber, D. A., Boussin, F. D., Zou, L. <strong>Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.</strong> Science 347: 273-277, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25593184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25593184</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25593184[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.1257216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25593184">Flynn et al. (2015)</a> showed that loss of ATRX (<a href="/entry/300032">300032</a>) compromises cell-cycle regulation of the telomeric noncoding RNA TERRA and leads to persistent association of RPA with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of the protein kinase ATR, a critical regulator of recombination recruited by RPA, disrupts alternative lengthening of telomeres (ALT) and triggers chromosome fragmentation and apoptosis in ALT cells. The cell death induced by ATR inhibitors is highly selective for cancer cells that rely on ALT, suggesting that such inhibitors may be useful for treatment of ALT-positive cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25593184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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The folding of mRNA influences a diverse range of biologic events, such as mRNA splicing and processing and translational control and regulation. Because the structure of mRNA is determined by its nucleotide sequence and its environment, <a href="#13" class="mim-tip-reference" title="Shen, L. X., Basilion, J. P., Stanton, V. P., Jr. <strong>Single-nucleotide polymorphisms can cause different structural folds of mRNA.</strong> Proc. Nat. Acad. Sci. 96: 7871-7876, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10393914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10393914</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10393914[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.14.7871" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10393914">Shen et al. (1999)</a> examined whether the folding of mRNA could be influenced by the presence of single-nucleotide polymorphisms (SNPs). They reported marked differences in mRNA secondary structure associated with SNPs in the coding regions of 2 human mRNAs: alanyl-tRNA synthetase (<a href="/entry/601065">601065</a>) and RPA70. Enzymatic probing of SNP-containing fragments of the mRNAs revealed pronounced allelic differences in cleavage pattern at sites 14 or 18 nucleotides away from the SNP, suggesting that a single-nucleotide variation can give rise to different mRNA folds. By using oligodeoxyribonucleotides complementary to the region of different allelic structures in the RPA70 mRNA, but not extending to the SNP itself, they found that the SNP exerted an allele-specific effect on the accessibility of its flanking site in the endogenous human RPA70 mRNA. The results demonstrated the contribution of common genetic variation through structural diversity of mRNA and suggested a broader role than previously thought for the effects of SNPs on mRNA structure and, ultimately, biologic function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10393914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Telomere-Related Pulmonary Fibrosis And/Or Bone Marrow Failure Syndrome 6</em></strong></p><p>
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In 4 unrelated probands with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6; <a href="/entry/619767">619767</a>), <a href="#12" class="mim-tip-reference" title="Sharma, R., Sahoo, S. S., Honda, M., Granger, S. L., Goodings, C., Sanchez, L., Kunstner, A., Busch, H., Beier, F., Pruett-Miller, S. M., Valentine, M. B., Fernandez, A., and 21 others. <strong>Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.</strong> Blood 139: 1039-1051, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34767620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34767620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34767620[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/10.1182/blood.2021011980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34767620">Sharma et al. (2022)</a> identified heterozygous missense mutations in the RPA1 gene affecting residues in the DNA-binding domain-A (DBD-A) (E240K, <a href="#0001">179835.0001</a>; V227A, <a href="#0002">179835.0002</a>, and T270A, <a href="#0003">179835.0003</a>). The mutations, which were found by exome sequencing, were either absent from the gnomAD database or present at a very low frequency. Two mutations occurred de novo and 1 was inherited from an unaffected parent; familial segregation studies for patient 3 could not be determined. In vitro functional expression studies showed that the E240K and V227A variants had increased binding to ssDNA and telomeric DNA compared to controls, consistent with a gain-of-function effect. In contrast, T270A had binding properties similar to wildtype, but was postulated to have other detrimental effects. Expression of the E240K mutation into iPSC-derived hematopoietic cells resulted in shortened telomeres and impaired differentiation of hematopoietic progenitor cells, particularly of the erythroid and myeloid lineages, but also affecting CD34+ cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34767620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#16" class="mim-tip-reference" title="Wang, Y., Putnam, C. D., Kane, M. F., Zhang, W., Edelmann, L., Russell, R., Carrion, D. V., Chin, L., Kucherlapati, R., Kolodner, R. D., Edelmann, W. <strong>Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice.</strong> Nature Genet. 37: 750-755, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15965476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15965476</a>] [<a href="https://doi.org/10.1038/ng1587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15965476">Wang et al. (2005)</a> demonstrated that mice heterozygous for a missense mutation in one of the DNA-binding domains of Rpa1 develop lymphoid tumors and that their homozygous littermates succumb to early embryonic lethality. Array comparative genomic hybridization of the tumors identified large-scale chromosomal changes as well as segmental gains and losses. The Rpa1 mutation resulted in defects in DNA double-strand break repair and precipitated chromosomal breaks as well as aneuploidy in primary heterozygous mutant mouse embryonic fibroblasts. The equivalent mutation in yeast is hypomorphic and semidominant and enhanced the formation of gross chromosomal rearrangements in multiple genetic backgrounds. <a href="#16" class="mim-tip-reference" title="Wang, Y., Putnam, C. D., Kane, M. F., Zhang, W., Edelmann, L., Russell, R., Carrion, D. V., Chin, L., Kucherlapati, R., Kolodner, R. D., Edelmann, W. <strong>Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice.</strong> Nature Genet. 37: 750-755, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15965476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15965476</a>] [<a href="https://doi.org/10.1038/ng1587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15965476">Wang et al. (2005)</a> concluded that Rpa1 functions in DNA metabolism are essential for the maintenance of chromosomal stability and tumor suppression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15965476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0001 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 6</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs916648829 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs916648829;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs916648829" 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=rs916648829" 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=RCV001843384" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001843384" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001843384</a>
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<p>In a 28-year-old woman (P1) with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6; <a href="/entry/619767">619767</a>), <a href="#12" class="mim-tip-reference" title="Sharma, R., Sahoo, S. S., Honda, M., Granger, S. L., Goodings, C., Sanchez, L., Kunstner, A., Busch, H., Beier, F., Pruett-Miller, S. M., Valentine, M. B., Fernandez, A., and 21 others. <strong>Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.</strong> Blood 139: 1039-1051, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34767620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34767620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34767620[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/10.1182/blood.2021011980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34767620">Sharma et al. (2022)</a> identified a de novo heterozygous c.718G-A transition (c.718G-A, NM_002945.5) in exon 9 of the RPA1 gene, resulting in a glu240-to-lys (E240K) substitution in the DNA-binding domain-A (DBD-A). In vitro functional expression studies showed that the E240K variant had increased binding to ssDNA and telomeric DNA compared to controls. These findings suggested a gain-of-function effect. Expression of the E240K mutation into iPSC-derived hematopoietic cells resulted in shortened telomeres and impaired differentiation of hematopoietic progenitor cells, particularly of the erythroid and myeloid lineages, but also affecting CD34+ cells. These findings were consistent with the pancytopenia observed in the patient. She presented at 10 years of age with pancytopenia and hypoplastic bone marrow. Laboratory studies showed shortened telomeres. However, her clinical course was atypical due to stabilization of blood counts and mucocutaneous features without intervention over 18 years. Patient bone marrow analysis at age 13 showed reduced expression of the mutant E240K variant (27%) compared to fibroblasts (50%). Two somatic events were identified in the bone marrow that interfered with expression and proliferation of the mutant E240K allele: an RPA1 truncating (K579X) mutation at 10% allelic frequency and in cis with E240K, causing degradation of germline mutant RNA, and uniparental isodisomy of chromosome 17p, resulting in replacement of the germline variant with a wildtype allele. These allelic patterns were maintained over time and likely caused a rescue effect that coincided with the lack of progressive symptoms in the patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34767620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 6</strong>
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RPA1, VAL227ALA
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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> rs570041689 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs570041689;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/rs570041689?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=rs570041689" 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=rs570041689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001843385" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001843385" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001843385</a>
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<p>In 2 unrelated patients (P2 and P3) with heterogeneous manifestations of telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6; <a href="/entry/619767">619767</a>), <a href="#12" class="mim-tip-reference" title="Sharma, R., Sahoo, S. S., Honda, M., Granger, S. L., Goodings, C., Sanchez, L., Kunstner, A., Busch, H., Beier, F., Pruett-Miller, S. M., Valentine, M. B., Fernandez, A., and 21 others. <strong>Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.</strong> Blood 139: 1039-1051, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34767620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34767620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34767620[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/10.1182/blood.2021011980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34767620">Sharma et al. (2022)</a> identified a heterozygous c.680T-C transition (c.680T-C, NM_002945.5) in exon 8 of the RPA1 gene, resulting in a val227-to-ala (V227A) substitution at a highly conserved residue in the DNA-binding domain-A (DBD-A). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in 1 of 152,156 alleles in the gnomAD database and in 2 of 264,690 alleles in the TOPMed database. The RPA1 V227A mutation was also present in the unaffected father and sister of P2, suggesting incomplete penetrance. P3 had 2 deceased sisters with a similar phenotype, but DNA was not available from any family members to confirm segregation. In vitro functional expression studies showed that the V227A variant had increased binding to ssDNA and telomeric DNA compared to controls. These findings suggested a gain-of-function effect. Patient 2 presented at age 13 years with myelodysplastic syndrome (MDS) with excess blasts and a somatic NRAS mutation (G12D; <a href="/entry/164790#0007">164790.0007</a>) at 37% allelic frequency. She also had facial dysmorphism and mildly reduced restricted pulmonary function. She died of multiorgan failure after undergoing hematopoietic stem cell transplant. Patient 3 had early hair graying and onset of progressive pulmonary fibrosis at age 58 years. Telomere length was reduced in the blood cells of both patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34767620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 6</strong>
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RPA1, THR270ALA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2151286956 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2151286956;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2151286956" 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=rs2151286956" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001787404 OR RCV001843378" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001787404, RCV001843378" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001787404...</a>
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<p>In 3-year-old girl (patient 4) with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6; <a href="/entry/619767">619767</a>), <a href="#12" class="mim-tip-reference" title="Sharma, R., Sahoo, S. S., Honda, M., Granger, S. L., Goodings, C., Sanchez, L., Kunstner, A., Busch, H., Beier, F., Pruett-Miller, S. M., Valentine, M. B., Fernandez, A., and 21 others. <strong>Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.</strong> Blood 139: 1039-1051, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34767620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34767620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34767620[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/10.1182/blood.2021011980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34767620">Sharma et al. (2022)</a> identified a de novo heterozygous c.808A-G transition (c.808A-G, NM_002945.5) in exon 10 of the RPA1 gene, resulting in a thr270-to-ala (T270A) substitution at a conserved residue in the DNA-binding domain-A (DBD-A). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the T270A variant bound ssDNA with high affinity, although this binding and binding to telomeric DNA was similar to that of wildtype RPA1. The authors suggested that the variant may have other effects, including altering the interaction of RPA1 with other proteins. P4 was a 3-year-old girl who presented at birth with prematurity, failure to thrive, lymphopenia, and hypogammaglobulinemia. At age 3, she was stable on IgG replacement therapy. Telomere length was decreased in patient blood cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34767620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Chaudhuri2004" class="mim-anchor"></a>
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Chaudhuri, J., Khuong, C., Alt, F. W.
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<strong>Replication protein A interacts with AID to promote deamination of somatic hypermutation targets.</strong>
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Nature 430: 992-998, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15273694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15273694</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15273694" 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/nature02821" target="_blank">Full Text</a>]
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Erdile, L. F., Heyer, W.-D., Kolodner, R., Kelly, T. J.
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<strong>Characterization of a cDNA encoding the 70-kDa single-stranded DNA-binding subunit of human replication protein A and the role of the protein in DNA replication.</strong>
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J. Biol. Chem. 266: 12090-12098, 1991. Note: Erratum: J. Biol. Chem. 268: 2268 only, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2050703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2050703</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2050703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Flynn, R. L., Centore, R. C., O'Sullivan, R. J., Rai, R., Tse, A., Songyang, Z., Chang, S., Karlseder, J., Zou, L.
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<strong>TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA.</strong>
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Nature 471: 532-536, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21399625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21399625</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21399625[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=21399625" 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/nature09772" target="_blank">Full Text</a>]
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Flynn, R. L., Cox, K. E., Jeitany, M., Wakimoto, H., Bryll, A. R., Ganem, N. J., Bersani, F., Pineda, J. R., Suva, M. L., Benes, C. H., Haber, D. A., Boussin, F. D., Zou, L.
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<strong>Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.</strong>
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Science 347: 273-277, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25593184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25593184</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25593184[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=25593184" 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.1257216" target="_blank">Full Text</a>]
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Gomes, X. V., Wold, M. S.
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<strong>Functional domains of the 70-kilodalton subunit of human replication protein A.</strong>
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Biochemistry 35: 10558-10568, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8756712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8756712</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8756712" 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/10.1021/bi9607517" target="_blank">Full Text</a>]
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<strong>FANCJ (BACH1) helicase forms DNA damage inducible foci with replication protein A and interacts physically and functionally with the single-stranded DNA-binding protein.</strong>
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[<a href="https://doi.org/10.1182/blood-2006-11-057273" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M800881200" target="_blank">Full Text</a>]
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Hu, R., Wang, E., Peng, G., Dai, H., Lin, S.-Y.
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[<a href="https://doi.org/10.4161/cc.25064" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature05843" target="_blank">Full Text</a>]
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<strong>Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786T-C mutation associated with coronary spastic angina.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11063722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11063722</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11063722" 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/9.18.2629" target="_blank">Full Text</a>]
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<strong>T(-786)-C mutation in the 5-prime-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10359729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10359729</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10359729" 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/10.1161/01.cir.99.22.2864" target="_blank">Full Text</a>]
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<a id="Sharma2022" class="mim-anchor"></a>
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Sharma, R., Sahoo, S. S., Honda, M., Granger, S. L., Goodings, C., Sanchez, L., Kunstner, A., Busch, H., Beier, F., Pruett-Miller, S. M., Valentine, M. B., Fernandez, A., and 21 others.
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<strong>Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34767620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34767620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34767620[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=34767620" 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/10.1182/blood.2021011980" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.96.14.7871" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8020972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8020972</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8020972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1994.1161" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15965476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15965476</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15965476" 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/ng1587" target="_blank">Full Text</a>]
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<strong>Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.</strong>
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Science 300: 1542-1548, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12791985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12791985</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12791985" 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.1083430" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 02/25/2022
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Paul J. Converse - updated : 08/30/2016<br>Ada Hamosh - updated : 02/01/2016<br>Matthew B. Gross - updated : 3/13/2012<br>Patricia A. Hartz - updated : 1/26/2012<br>Ada Hamosh - updated : 5/9/2011<br>Patricia A. Hartz - updated : 6/19/2008<br>Ada Hamosh - updated : 6/15/2007<br>Victor A. McKusick - updated : 8/19/2005<br>Ada Hamosh - updated : 8/26/2004<br>Ada Hamosh - updated : 6/17/2003<br>George E. Tiller - updated : 1/25/2001<br>Lori M. Kelman - updated : 11/13/1996
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ckniffin : 05/08/2023<br>alopez : 03/03/2022<br>ckniffin : 02/25/2022<br>mgross : 08/30/2016<br>alopez : 02/01/2016<br>terry : 7/3/2012<br>mgross : 3/13/2012<br>mgross : 3/13/2012<br>mgross : 3/13/2012<br>terry : 1/26/2012<br>alopez : 5/12/2011<br>terry : 5/9/2011<br>carol : 3/17/2009<br>mgross : 6/19/2008<br>alopez : 6/21/2007<br>terry : 6/15/2007<br>wwang : 9/1/2005<br>wwang : 8/25/2005<br>terry : 8/19/2005<br>tkritzer : 8/27/2004<br>tkritzer : 8/27/2004<br>terry : 8/26/2004<br>alopez : 6/19/2003<br>terry : 6/17/2003<br>mcapotos : 2/1/2001<br>mcapotos : 1/25/2001<br>alopez : 8/23/1999<br>alopez : 8/23/1999<br>mark : 11/27/1996<br>jamie : 11/13/1996<br>mark : 10/21/1996<br>carol : 4/4/1994<br>carol : 9/24/1993<br>carol : 5/14/1993<br>supermim : 3/16/1992<br>carol : 10/7/1991<br>carol : 9/4/1991
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<span class="mim-font">
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<strong>*</strong> 179835
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</h3>
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<h3>
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<span class="mim-font">
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REPLICATION PROTEIN A1, 70-KD; RPA1
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</span>
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</h3>
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<span class="mim-font">
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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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RPA70<br />
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REPA1
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: RPA1</em></strong>
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<strong>
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Cytogenetic location: 17p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 17:1,830,005-1,900,082 </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 class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<td rowspan="1">
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<span class="mim-font">
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17p13.3
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<span class="mim-font">
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Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 6
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<td>
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<span class="mim-font">
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619767
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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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 class="mim-text-font">
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<p>Replication protein A (RPA) is a heterotrimeric single-strand DNA (ssDNA)-binding protein essential for DNA replication, repair, and recombination. It is composed of 70-kD (RPA1), 32-kD (RPA2; 179836), and 14-kD (RPA3; 179837) subunits. The RPA1 subunit is responsible for high-affinity ssDNA binding (summary by Haring et al., 2008). </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
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<p>Erdile et al. (1991) reported the sequence of a cDNA encoding RPA1, the 70-kD RPA subunit. The human cDNA directed production in E. coli of a 70-kD protein that reacted with a monoclonal antibody directed against the 70-kD subunit of human RPA. </p><p>Gomes and Wold (1996) stated that the human RPA1 protein contains 616 amino acids. </p><p>Haring et al. (2008) stated that human RPA1 is made up of 4 oligonucleotide/oligosaccharide-binding (OB)-fold domains, also known as DNA-binding domains (DBDs). The N-terminal DBD-F domain is followed by the central DBD-A and DBD-B domains and the C-terminal DBD-C domain. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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<span class="mim-text-font">
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<p>Using PCR amplification of genomic DNA from rodent-human cell lines, Umbricht et al. (1993) mapped the RPA1 gene to chromosome 17. By the same method, they mapped the RPA2 and RPA3 genes to chromosomes 1 and 7, respectively. Using a combination of PCR amplification of somatic cell hybrids and radiation hybrids containing chromosome 17 fragments, Umbricht et al. (1994) mapped the RPA1 gene to chromosome 17p13.3. Loss of the 17p13.3 chromosomal region has repeatedly been implicated in various malignancies including colorectal cancers, breast cancers, lymphomas, and leukemias (Wang et al., 2005). </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>The RPA complex was originally isolated as a factor essential for in vitro replication of the papovavirus SV40. Erdile et al. (1991) found that recombinant human RPA1, purified from bacteria, exhibited ssDNA-binding activity comparable to that of the complete RPA complex. RPA1 could substitute for the complete complex in stimulating the activity of DNA polymerase alpha-primase, but it could not substitute for the complete complex in SV40 DNA replication in vitro, suggesting an important functional role for the other subunits. </p><p>Gomes and Wold (1996) constructed a series of N-terminal deletions of RPA70 to explore the function of the protein. Their data indicated that RPA70 is composed of 3 functional domains: an N-terminal domain that is not required for ssDNA binding or SV40 replication, a central DNA-binding domain, and a C-terminal domain that is essential for subunit interactions. </p><p>Nakayama et al. (1999) reported that a -786T-C mutation (163729.0002) in the promoter region of the eNOS (NOS3; 163729) gene reduced transcription of the gene and was strongly associated with coronary spastic angina and myocardial infarction. To elucidate the molecular mechanism for the reduced eNOS gene transcription, Miyamoto et al. (2000) purified a protein that specifically bound the mutant allele in nuclear extracts from HeLa cells. The purified protein was identical to RPA1. In human umbilical vein endothelial cells, inhibition of RPA1 expression using antisense oligonucleotides restored transcription driven by the mutated promoter sequence, whereas overexpression of RPA1 further reduced it. Serum nitrite/nitrate levels among individuals carrying the -786T-C mutation were significantly lower than among those without the mutation. The authors concluded that RPA1 apparently functions as a repressor protein in the -786T-C mutation-related reduction of eNOS gene transcription associated with the development of coronary artery disease. </p><p>The function of the ATR (601215)-ATRIP (606605) protein kinase complex is crucial for the cellular response to replication stress and DNA damage. Zou and Elledge (2003) demonstrated that the RPA complex was required for recruitment of ATR to sites of DNA damage and for ATR-mediated CHK1 (603078) activation in human cells. In vitro, RPA stimulated binding of ATRIP to ssDNA. Binding of ATRIP to RPA-coated ssDNA enabled the ATR-ATRIP complex to associate with DNA and stimulate phosphorylation of the RAD17 (603139) protein that was bound to DNA. Furthermore, Ddc2, the budding yeast homolog of ATRIP, was specifically recruited to double-stranded DNA breaks in an RPA-dependent manner. A checkpoint-deficient mutant of RPA, rfa1-t11, was defective for recruiting Ddc2 to ssDNA both in vivo and in vitro. Zou and Elledge (2003) concluded that RPA-coated ssDNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling. </p><p>Activation-induced cytidine deaminase (AID; 605257) is an ssDNA deaminase required for somatic hypermutation and class switch recombination of immunoglobulin genes. Class switch recombination involves transcription through switch regions, which generates ssDNA within R loops. Chaudhuri et al. (2004) characterized the mechanism of AID targeting to in vitro transcribed substrates harboring somatic hypermutation motifs. They showed that the targeting activity of AID was due to RPA. The 32-kD subunit of RPA interacted specifically with AID from activated B cells in a manner that seemed to be dependent on posttranslational AID modification. Chaudhuri et al. (2004) concluded that RPA is implicated as a novel factor involved in immunoglobulin diversification and proposed that B cell-specific AID-RPA complexes preferentially bind to ssDNA of small transcription bubbles at somatic hypermutation hotspots, leading to AID-mediated deamination and RPA-mediated recruitment of DNA repair proteins. </p><p>Maga et al. (2007) analyzed the effects of human proliferating cell nuclear antigen (PCNA; 176740) and RPA on 6 different human DNA polymerases belonging to the B, Y, and X classes during in vitro bypass of different lesions. The mutagenic lesion 8-oxo-guanine has high miscoding potential. A major and specific effect was found for 8-oxo-G bypass with DNA pol-lambda (606343) and -eta (603968). PCNA and RPA allowed correct incorporation of dCTP opposite an 8-oxo-G template 1,200-fold more efficiently than the incorrect dATP by DNA pol-lambda, and 68-fold by DNA pol-eta, respectively. Experiments with DNA pol-gamma (174763)-null cell extracts suggested an important role for DNA pol-lambda. On the other hand, DNA pol-iota (605252) together with DNA pol-alpha (312040), -delta (174761), and -beta (174760), showed a much lower correct bypass efficiency. Maga et al. (2007) concluded that their findings showed the existence of an accurate mechanism to reduce the deleterious consequences of oxidative damage and, in addition, pointed to an important role for PCNA and RPA in determining a functional hierarchy among different DNA pols in lesion bypass. </p><p>Gupta et al. (2007) found that FANCJ (BRIP1; 605882) immunoprecipitated with RPA. FANCJ and RPA colocalized in nuclear foci after DNA damage or replication stress. FANCJ and RPA bound with high affinity via the RPA70 subunit. Although FANCJ showed limited ability to unwind even a 47-bp forked duplex, the presence of RPA enabled FANCJ to act as a much more processive helicase. </p><p>Haring et al. (2008) stated that the N-terminal DBD-F domain of RPA1 is involved in protein interactions, the central DBD-A and DBD-B domains bind ssDNA, and the C-terminal DBD-C domain mediates interaction with RPA2 and RPA3. They found that knockdown of RPA1 in HeLa cells caused accumulation of cells in S and G2/M phases, followed by cell death. RPA1 was not required for stability of RPA2 or RPA3. Expression of various mutant RPA1 proteins in RPA1-depleted HeLa cells revealed that amino acids in DBD-A involved in polar interactions with ssDNA mediated DNA binding. However, only RPA1 with mutations at all 6 polar-interacting residues in DBD-A was defective in replication, foci formation at sites of DNA damage, and G2/M checkpoint. RPA1 with mutations at aromatic residues in DBD-A and DBD-B involved in nonpolar ssDNA interactions exhibited weak DNA binding, and its expression caused arrest of cells in G2/M. Expression of RPA1 with mutations in the N-terminal DBD-F domain or deletion of the DBD-F domain and adjacent linker region completely restored replication in RPA1-depleted cells, but these mutant RPA1 proteins exhibited defective responses to DNA damage. Deletion of the C-terminal DBD-C domain produced monomeric RPA1 mutants that bound DNA but were defective in replication. </p><p>Maintenance of telomeres requires both DNA replication and telomere capping by shelterin. These 2 processes use 2 ssDNA-binding proteins, RPA and protection of telomeres-1 (POT1; 606478). POT1 ablation leads to activation of the ATR checkpoint kinase at telomeres, suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. Unexpectedly, Flynn et al. (2011) found that purified POT1 and its functional partner TPP1 (609377) are unable to prevent RPA binding to telomeric ssDNA efficiently. In cell extracts, they identified a novel activity that specifically displaces RPA, but not POT1, from telomeric ssDNA. Using purified protein, Flynn et al. (2011) showed that the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1; 164017) recapitulates the RPA displacing activity. The RPA displacing activity is inhibited by the telomeric repeat-containing RNA (TERRA) in early S phase, but is then unleashed in late S phase when TERRA levels decline at telomeres. Interestingly, TERRA also promotes POT1 binding to telomeric ssDNA by removing hnRNPA1, suggesting that the reaccumulation of TERRA after S phase helps to complete the RPA-to-POT1 switch on telomeric ssDNA. Flynn et al. (2011) concluded that hnRNPA1, TERRA, and POT1 act in concert to displace RPA from telomeric ssDNA after DNA replication, and promote telomere capping to preserve genomic integrity. </p><p>Using small interfering RNA-mediated knockdown studies in human osteosarcoma cells, Hu et al. (2013) showed that ZNF668 (617103) promoted RPA activation at ultraviolet-induced DNA damage sites. </p><p>Flynn et al. (2015) showed that loss of ATRX (300032) compromises cell-cycle regulation of the telomeric noncoding RNA TERRA and leads to persistent association of RPA with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of the protein kinase ATR, a critical regulator of recombination recruited by RPA, disrupts alternative lengthening of telomeres (ALT) and triggers chromosome fragmentation and apoptosis in ALT cells. The cell death induced by ATR inhibitors is highly selective for cancer cells that rely on ALT, suggesting that such inhibitors may be useful for treatment of ALT-positive cancers. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Role in mRNA Secondary Structure</em></strong></p><p>
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The folding of mRNA influences a diverse range of biologic events, such as mRNA splicing and processing and translational control and regulation. Because the structure of mRNA is determined by its nucleotide sequence and its environment, Shen et al. (1999) examined whether the folding of mRNA could be influenced by the presence of single-nucleotide polymorphisms (SNPs). They reported marked differences in mRNA secondary structure associated with SNPs in the coding regions of 2 human mRNAs: alanyl-tRNA synthetase (601065) and RPA70. Enzymatic probing of SNP-containing fragments of the mRNAs revealed pronounced allelic differences in cleavage pattern at sites 14 or 18 nucleotides away from the SNP, suggesting that a single-nucleotide variation can give rise to different mRNA folds. By using oligodeoxyribonucleotides complementary to the region of different allelic structures in the RPA70 mRNA, but not extending to the SNP itself, they found that the SNP exerted an allele-specific effect on the accessibility of its flanking site in the endogenous human RPA70 mRNA. The results demonstrated the contribution of common genetic variation through structural diversity of mRNA and suggested a broader role than previously thought for the effects of SNPs on mRNA structure and, ultimately, biologic function. </p><p><strong><em>Telomere-Related Pulmonary Fibrosis And/Or Bone Marrow Failure Syndrome 6</em></strong></p><p>
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In 4 unrelated probands with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6; 619767), Sharma et al. (2022) identified heterozygous missense mutations in the RPA1 gene affecting residues in the DNA-binding domain-A (DBD-A) (E240K, 179835.0001; V227A, 179835.0002, and T270A, 179835.0003). The mutations, which were found by exome sequencing, were either absent from the gnomAD database or present at a very low frequency. Two mutations occurred de novo and 1 was inherited from an unaffected parent; familial segregation studies for patient 3 could not be determined. In vitro functional expression studies showed that the E240K and V227A variants had increased binding to ssDNA and telomeric DNA compared to controls, consistent with a gain-of-function effect. In contrast, T270A had binding properties similar to wildtype, but was postulated to have other detrimental effects. Expression of the E240K mutation into iPSC-derived hematopoietic cells resulted in shortened telomeres and impaired differentiation of hematopoietic progenitor cells, particularly of the erythroid and myeloid lineages, but also affecting CD34+ cells. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Wang et al. (2005) demonstrated that mice heterozygous for a missense mutation in one of the DNA-binding domains of Rpa1 develop lymphoid tumors and that their homozygous littermates succumb to early embryonic lethality. Array comparative genomic hybridization of the tumors identified large-scale chromosomal changes as well as segmental gains and losses. The Rpa1 mutation resulted in defects in DNA double-strand break repair and precipitated chromosomal breaks as well as aneuploidy in primary heterozygous mutant mouse embryonic fibroblasts. The equivalent mutation in yeast is hypomorphic and semidominant and enhanced the formation of gross chromosomal rearrangements in multiple genetic backgrounds. Wang et al. (2005) concluded that Rpa1 functions in DNA metabolism are essential for the maintenance of chromosomal stability and tumor suppression. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>3 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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<h4>
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<span class="mim-font">
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<strong>.0001 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 6</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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RPA1, GLU240LYS
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<br />
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SNP: rs916648829,
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ClinVar: RCV001843384
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a 28-year-old woman (P1) with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6; 619767), Sharma et al. (2022) identified a de novo heterozygous c.718G-A transition (c.718G-A, NM_002945.5) in exon 9 of the RPA1 gene, resulting in a glu240-to-lys (E240K) substitution in the DNA-binding domain-A (DBD-A). In vitro functional expression studies showed that the E240K variant had increased binding to ssDNA and telomeric DNA compared to controls. These findings suggested a gain-of-function effect. Expression of the E240K mutation into iPSC-derived hematopoietic cells resulted in shortened telomeres and impaired differentiation of hematopoietic progenitor cells, particularly of the erythroid and myeloid lineages, but also affecting CD34+ cells. These findings were consistent with the pancytopenia observed in the patient. She presented at 10 years of age with pancytopenia and hypoplastic bone marrow. Laboratory studies showed shortened telomeres. However, her clinical course was atypical due to stabilization of blood counts and mucocutaneous features without intervention over 18 years. Patient bone marrow analysis at age 13 showed reduced expression of the mutant E240K variant (27%) compared to fibroblasts (50%). Two somatic events were identified in the bone marrow that interfered with expression and proliferation of the mutant E240K allele: an RPA1 truncating (K579X) mutation at 10% allelic frequency and in cis with E240K, causing degradation of germline mutant RNA, and uniparental isodisomy of chromosome 17p, resulting in replacement of the germline variant with a wildtype allele. These allelic patterns were maintained over time and likely caused a rescue effect that coincided with the lack of progressive symptoms in the patient. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 6</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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RPA1, VAL227ALA
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<br />
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SNP: rs570041689,
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gnomAD: rs570041689,
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ClinVar: RCV001843385
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</span>
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<span class="mim-text-font">
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<p>In 2 unrelated patients (P2 and P3) with heterogeneous manifestations of telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6; 619767), Sharma et al. (2022) identified a heterozygous c.680T-C transition (c.680T-C, NM_002945.5) in exon 8 of the RPA1 gene, resulting in a val227-to-ala (V227A) substitution at a highly conserved residue in the DNA-binding domain-A (DBD-A). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in 1 of 152,156 alleles in the gnomAD database and in 2 of 264,690 alleles in the TOPMed database. The RPA1 V227A mutation was also present in the unaffected father and sister of P2, suggesting incomplete penetrance. P3 had 2 deceased sisters with a similar phenotype, but DNA was not available from any family members to confirm segregation. In vitro functional expression studies showed that the V227A variant had increased binding to ssDNA and telomeric DNA compared to controls. These findings suggested a gain-of-function effect. Patient 2 presented at age 13 years with myelodysplastic syndrome (MDS) with excess blasts and a somatic NRAS mutation (G12D; 164790.0007) at 37% allelic frequency. She also had facial dysmorphism and mildly reduced restricted pulmonary function. She died of multiorgan failure after undergoing hematopoietic stem cell transplant. Patient 3 had early hair graying and onset of progressive pulmonary fibrosis at age 58 years. Telomere length was reduced in the blood cells of both patients. </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 PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 6</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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RPA1, THR270ALA
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<br />
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SNP: rs2151286956,
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ClinVar: RCV001787404, RCV001843378
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3-year-old girl (patient 4) with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6; 619767), Sharma et al. (2022) identified a de novo heterozygous c.808A-G transition (c.808A-G, NM_002945.5) in exon 10 of the RPA1 gene, resulting in a thr270-to-ala (T270A) substitution at a conserved residue in the DNA-binding domain-A (DBD-A). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. In vitro functional expression studies showed that the T270A variant bound ssDNA with high affinity, although this binding and binding to telomeric DNA was similar to that of wildtype RPA1. The authors suggested that the variant may have other effects, including altering the interaction of RPA1 with other proteins. P4 was a 3-year-old girl who presented at birth with prematurity, failure to thrive, lymphopenia, and hypogammaglobulinemia. At age 3, she was stable on IgG replacement therapy. Telomere length was decreased in patient blood 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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Chaudhuri, J., Khuong, C., Alt, F. W.
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<strong>Replication protein A interacts with AID to promote deamination of somatic hypermutation targets.</strong>
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Nature 430: 992-998, 2004.
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[PubMed: 15273694]
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[Full Text: https://doi.org/10.1038/nature02821]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Erdile, L. F., Heyer, W.-D., Kolodner, R., Kelly, T. J.
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<strong>Characterization of a cDNA encoding the 70-kDa single-stranded DNA-binding subunit of human replication protein A and the role of the protein in DNA replication.</strong>
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J. Biol. Chem. 266: 12090-12098, 1991. Note: Erratum: J. Biol. Chem. 268: 2268 only, 1993.
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[PubMed: 2050703]
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<li>
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<p class="mim-text-font">
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Flynn, R. L., Centore, R. C., O'Sullivan, R. J., Rai, R., Tse, A., Songyang, Z., Chang, S., Karlseder, J., Zou, L.
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<strong>TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA.</strong>
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Nature 471: 532-536, 2011.
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[PubMed: 21399625]
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[Full Text: https://doi.org/10.1038/nature09772]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Flynn, R. L., Cox, K. E., Jeitany, M., Wakimoto, H., Bryll, A. R., Ganem, N. J., Bersani, F., Pineda, J. R., Suva, M. L., Benes, C. H., Haber, D. A., Boussin, F. D., Zou, L.
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|
<strong>Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.</strong>
|
|
Science 347: 273-277, 2015.
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[PubMed: 25593184]
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[Full Text: https://doi.org/10.1126/science.1257216]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gomes, X. V., Wold, M. S.
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<strong>Functional domains of the 70-kilodalton subunit of human replication protein A.</strong>
|
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Biochemistry 35: 10558-10568, 1996.
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[PubMed: 8756712]
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[Full Text: https://doi.org/10.1021/bi9607517]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gupta, R., Sharma, S., Sommers, J. A., Kenny, M. K., Cantor, S. B., Brosh, R. M., Jr.
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<strong>FANCJ (BACH1) helicase forms DNA damage inducible foci with replication protein A and interacts physically and functionally with the single-stranded DNA-binding protein.</strong>
|
|
Blood 110: 2390-2398, 2007.
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[PubMed: 17596542]
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[Full Text: https://doi.org/10.1182/blood-2006-11-057273]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Haring, S. J., Mason, A. C., Binz, S. K., Wold, M. S.
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<strong>Cellular functions of human RPA1: multiple roles of domains in replication, repair, and checkpoints.</strong>
|
|
J. Biol. Chem. 283: 19095-19111, 2008.
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[PubMed: 18469000]
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[Full Text: https://doi.org/10.1074/jbc.M800881200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Hu, R., Wang, E., Peng, G., Dai, H., Lin, S.-Y.
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<strong>Zinc finger protein 668 interacts with Tip60 to promote H2AX acetylation after DNA damage.</strong>
|
|
Cell Cycle 12: 2033-2041, 2013.
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[PubMed: 23777805]
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[Full Text: https://doi.org/10.4161/cc.25064]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Maga, G., Villani, G., Crespan, E., Wimmer, U., Ferrari, E., Bertocci, B., Hubscher, U.
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<strong>8-oxo-guanine bypass by human DNA polymerases in the presence of auxiliary proteins.</strong>
|
|
Nature 447: 606-608, 2007.
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[PubMed: 17507928]
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[Full Text: https://doi.org/10.1038/nature05843]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Miyamoto, Y., Saito, Y., Nakayama, M., Shimasaki, Y., Yoshimura, T., Yoshimura, M., Harada, M., Kajiyama, N., Kishimoto, I., Kuwahara, K., Hino, J., Ogawa, E., Hamanaka, I., Kamitani, S., Takahashi, N., Kawakami, R., Kangawa, K., Yasue, H., Nakao, K.
|
|
<strong>Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786T-C mutation associated with coronary spastic angina.</strong>
|
|
Hum. Molec. Genet. 9: 2629-2637, 2000.
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[PubMed: 11063722]
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[Full Text: https://doi.org/10.1093/hmg/9.18.2629]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Nakayama, M., Yasue, H., Yoshimura, M., Shimasaki, Y., Kugiyama, K., Ogawa, H., Motoyama, T., Saito, Y., Ogawa, Y., Miyamoto, Y., Nakao, K.
|
|
<strong>T(-786)-C mutation in the 5-prime-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm.</strong>
|
|
Circulation 99: 2864-2870, 1999.
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[PubMed: 10359729]
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[Full Text: https://doi.org/10.1161/01.cir.99.22.2864]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Sharma, R., Sahoo, S. S., Honda, M., Granger, S. L., Goodings, C., Sanchez, L., Kunstner, A., Busch, H., Beier, F., Pruett-Miller, S. M., Valentine, M. B., Fernandez, A., and 21 others.
|
|
<strong>Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.</strong>
|
|
Blood 139: 1039-1051, 2022.
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[PubMed: 34767620]
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[Full Text: https://doi.org/10.1182/blood.2021011980]
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</p>
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<li>
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<p class="mim-text-font">
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Shen, L. X., Basilion, J. P., Stanton, V. P., Jr.
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<strong>Single-nucleotide polymorphisms can cause different structural folds of mRNA.</strong>
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Proc. Nat. Acad. Sci. 96: 7871-7876, 1999.
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[PubMed: 10393914]
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[Full Text: https://doi.org/10.1073/pnas.96.14.7871]
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</p>
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<p class="mim-text-font">
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Umbricht, C. B., Erdile, L. F., Jabs, E. W., Kelly, T. J.
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<strong>Cloning, overexpression, and genomic mapping of the 14-kDa subunit of human replication protein A.</strong>
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J. Biol. Chem. 268: 6131-6138, 1993.
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[PubMed: 8454588]
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<p class="mim-text-font">
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Umbricht, C. B., Griffin, C. A., Hawkins, A. L., Grzeschik, K. H., O'Connell, P., Leach, R., Green, E. D., Kelly, T. J.
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<strong>High-resolution genomic mapping of the three human replication protein A genes (RPA1, RPA2, and RPA3).</strong>
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Genomics 20: 249-257, 1994.
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[PubMed: 8020972]
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<p class="mim-text-font">
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Wang, Y., Putnam, C. D., Kane, M. F., Zhang, W., Edelmann, L., Russell, R., Carrion, D. V., Chin, L., Kucherlapati, R., Kolodner, R. D., Edelmann, W.
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<strong>Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice.</strong>
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Nature Genet. 37: 750-755, 2005.
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[PubMed: 15965476]
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<li>
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<p class="mim-text-font">
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Zou, L., Elledge, S. J.
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<strong>Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.</strong>
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Science 300: 1542-1548, 2003.
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[PubMed: 12791985]
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[Full Text: https://doi.org/10.1126/science.1083430]
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 02/25/2022<br>Paul J. Converse - updated : 08/30/2016<br>Ada Hamosh - updated : 02/01/2016<br>Matthew B. Gross - updated : 3/13/2012<br>Patricia A. Hartz - updated : 1/26/2012<br>Ada Hamosh - updated : 5/9/2011<br>Patricia A. Hartz - updated : 6/19/2008<br>Ada Hamosh - updated : 6/15/2007<br>Victor A. McKusick - updated : 8/19/2005<br>Ada Hamosh - updated : 8/26/2004<br>Ada Hamosh - updated : 6/17/2003<br>George E. Tiller - updated : 1/25/2001<br>Lori M. Kelman - updated : 11/13/1996
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 9/4/1991
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Edit History:
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alopez : 05/10/2023<br>ckniffin : 05/08/2023<br>alopez : 03/03/2022<br>ckniffin : 02/25/2022<br>mgross : 08/30/2016<br>alopez : 02/01/2016<br>terry : 7/3/2012<br>mgross : 3/13/2012<br>mgross : 3/13/2012<br>mgross : 3/13/2012<br>terry : 1/26/2012<br>alopez : 5/12/2011<br>terry : 5/9/2011<br>carol : 3/17/2009<br>mgross : 6/19/2008<br>alopez : 6/21/2007<br>terry : 6/15/2007<br>wwang : 9/1/2005<br>wwang : 8/25/2005<br>terry : 8/19/2005<br>tkritzer : 8/27/2004<br>tkritzer : 8/27/2004<br>terry : 8/26/2004<br>alopez : 6/19/2003<br>terry : 6/17/2003<br>mcapotos : 2/1/2001<br>mcapotos : 1/25/2001<br>alopez : 8/23/1999<br>alopez : 8/23/1999<br>mark : 11/27/1996<br>jamie : 11/13/1996<br>mark : 10/21/1996<br>carol : 4/4/1994<br>carol : 9/24/1993<br>carol : 5/14/1993<br>supermim : 3/16/1992<br>carol : 10/7/1991<br>carol : 9/4/1991
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