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- *102579 - REPLICATION FACTOR C, SUBUNIT 1; RFC1
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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">*102579</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/102579">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000035928;t=ENST00000349703" 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=5981" 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=102579" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000035928;t=ENST00000349703" 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_001204747,NM_001363495,NM_001363496,NM_002913,XM_011513731,XM_047416054,XR_007057951" 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_002913" 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=102579" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
|
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=00024&isoform_id=00024_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/RFC1" 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/410218,1335208,2827257,30353858,30354564,31442145,32528306,46430941,52632416,56757608,119613328,119613329,119613330,158256656,325296984,767930418,1390249137,1390249180,2217351734,2462598564,2462598566,2462598568" 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/P35251" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
|
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</div>
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=5981" 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=ENSG00000035928;t=ENST00000349703" 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=RFC1" 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=RFC1" 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+5981" 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/RFC1" 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:5981" 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/5981" 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=chr4&hgg_gene=ENST00000349703.7&hgg_start=39287456&hgg_end=39366362&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:9969" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=102579[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=102579[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/ENSG00000035928" 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=RFC1" 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=RFC1" 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=RFC1" 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=RFC1&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/PA34338" 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:9969" 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/FBgn0004913.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:97891" 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/RFC1#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:97891" 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/5981/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=5981" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00004337;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-070410-99" 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:5981" 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=RFC1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1236804009<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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102579
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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 FACTOR C, SUBUNIT 1; RFC1
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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>
|
|
<span class="mim-font">
|
|
ACTIVATOR 1, 140-KD SUBUNIT<br />
|
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REPLICATION FACTOR C, 140-KD SUBUNIT; RFC140<br />
|
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RFC
|
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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=RFC1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">RFC1</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/4/158?start=-3&limit=10&highlight=158">4p14</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr4:39287456-39366362&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'})">4:39,287,456-39,366,362</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>
|
|
<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">
|
|
<a href="/geneMap/4/158?start=-3&limit=10&highlight=158">
|
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4p14
|
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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">
|
|
Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/614575"> 614575 </a>
|
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|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/102579" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/102579" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
|
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<p />
|
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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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<a id="text" class="mim-anchor"></a>
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<h4>
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<p>The RFC1 gene encodes the large subunit of replication factor C, a 5-subunit DNA polymerase accessory protein required for the coordinated synthesis of both DNA strands during replication or after DNA damage (summary by <a href="#6" class="mim-tip-reference" title="Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., and 18 others. <strong>Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.</strong> Nature Genet. 51: 649-658, 2019. Note: Erratum: Nature Genet. 51: 920 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30926972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30926972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30926972[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/s41588-019-0372-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30926972">Cortese et al., 2019</a>). It is a DNA-dependent ATPase that binds in a structure-specific manner to the 3-prime end of a primer hybridized to a template DNA, an activity thought intrinsic to the 140-kD component of this multisubunit complex (<a href="#4" class="mim-tip-reference" title="Bunz, F., Kobayashi, R., Stillman, B. <strong>cDNAs encoding the large subunit of human replication factor C.</strong> Proc. Nat. Acad. Sci. 90: 11014-11018, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8248204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8248204</a>] [<a href="https://doi.org/10.1073/pnas.90.23.11014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8248204">Bunz et al., 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8248204+30926972" 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="#4" class="mim-tip-reference" title="Bunz, F., Kobayashi, R., Stillman, B. <strong>cDNAs encoding the large subunit of human replication factor C.</strong> Proc. Nat. Acad. Sci. 90: 11014-11018, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8248204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8248204</a>] [<a href="https://doi.org/10.1073/pnas.90.23.11014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8248204">Bunz et al. (1993)</a> isolated and analyzed cDNAs encoding the 140-kD subunit. An open reading frame of 3.4 kb was predicted to encode a 1,148-amino acid protein with a predicted molecular mass of 130 kD. A putative ATP-binding motif was observed that is similar to a motif in several of the smaller subunits of RFC and in functionally homologous replication factors of bacterial and viral origin. The predicted protein showed similarities to other DNA-binding proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8248204" 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="#10" class="mim-tip-reference" title="Luckow, B., Bunz, F., Stillman, B., Lichter, P., Schutz, G. <strong>Cloning, expression, and chromosomal localization of the 140-kilodalton subunit of replication factor C from mice and humans.</strong> Molec. Cell. Biol. 14: 1626-1634, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8114700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8114700</a>] [<a href="https://doi.org/10.1128/mcb.14.3.1626-1634.1994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8114700">Luckow et al. (1994)</a> isolated a full-length mouse cDNA encoding a protein that binds in a sequence-unspecific manner to DNA, is localized exclusively in the nucleus, and represents, they concluded, the 140-kD subunit of mouse replication factor C. They found that it showed 83% identity to the human protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8114700" 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>Human replication factor C (RFC), also called activator-1, is a multimeric primer-recognition protein consisting of 5 distinct subunits of 145, 40, 38, 37, and 36.5 kD. Human RFC was purified from extracts of HeLa cells as a host factor essential for the in vitro replication of simian virus 40 (SV40) DNA (<a href="#12" class="mim-tip-reference" title="Okumura, K., Nogami, M., Taguchi, H., Dean, F. B., Chen, M., Pan, Z.-Q., Hurwitz, J., Shiratori, A., Murakami, Y., Ozawa, K., Eki, T. <strong>Assignment of the 36.5-kDa (RFC5), 37-kDa (RFC4), 38-kDa (RFC3), and 40-kDa (RFC2) subunit genes of human replication factor C to chromosome bands 12q24.2-q24.3, 3q27, 13q12.3-q13, and 7q11.23.</strong> Genomics 25: 274-278, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7774928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7774928</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80135-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7774928">Okumura et al., 1995</a>). RFC, in the presence of ATP, assembles proliferating-cell nuclear antigen (PCNA; <a href="/entry/176740">176740</a>) and DNA polymerase-delta (<a href="/entry/174761">174761</a>) or polymerase-epsilon (<a href="/entry/174762">174762</a>) on primed DNA templates. The complex of primed DNA-RFC-PCNA-DNA polymerase, when supplemented with dNTPs, results in the efficient elongation of DNA in the presence of human single-stranded DNA binding protein. Studies with the complete 5-subunit holoenzyme indicated that the large subunit binds to DNA and the 40-kD subunit binds ATP. The other subunits may play discrete roles in the elongation process catalyzed by polymerase. The subunit genes are numbered in sequence of decreasing molecular weight: RFC1, RFC2 (<a href="/entry/600404">600404</a>), RFC3 (<a href="/entry/600405">600405</a>), RFC4 (<a href="/entry/102577">102577</a>), and RFC5 (<a href="/entry/600407">600407</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7774928" 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 interaction cloning, <a href="#16" class="mim-tip-reference" title="Uchiumi, F., Ohta, T., Tanuma, S. <strong>Replication factor C recognizes 5-prime-phosphate ends of telomeres.</strong> Biochem. Biophys. Res. Commun. 229: 310-315, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8954124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8954124</a>] [<a href="https://doi.org/10.1006/bbrc.1996.1798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8954124">Uchiumi et al. (1996)</a> found that the large subunit of RFC interacts with the DNA sequence repeats of telomeres. They found that RFC recognizes the 5-prime-phosphate termini of double-stranded telomeric repeats. The authors suggested that RFC may be involved in telomere stability or turnover. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8954124" 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="#17" class="mim-tip-reference" title="Wang, Y., Cortez, D., Yazdi, P., Neff, N., Elledge, S. J., Qin, J. <strong>BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.</strong> Genes Dev. 14: 927-939, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10783165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10783165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10783165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10783165">Wang et al. (2000)</a> used immunoprecipitation and mass spectrometry analyses to identify BRCA1 (<a href="/entry/113705">113705</a>)-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM (<a href="/entry/607585">607585</a>), BLM (<a href="/entry/604610">604610</a>), MSH2 (<a href="/entry/609309">609309</a>), MSH6 (<a href="/entry/600678">600678</a>), MLH1 (<a href="/entry/120436">120436</a>), the RAD50 (<a href="/entry/604040">604040</a>)-MRE11 (<a href="/entry/600814">600814</a>)-NBS1 (<a href="/entry/602667">602667</a>) complex, and the RFC1-RFC2 (<a href="/entry/600404">600404</a>)-RFC4 (<a href="/entry/102577">102577</a>) complex. <a href="#17" class="mim-tip-reference" title="Wang, Y., Cortez, D., Yazdi, P., Neff, N., Elledge, S. J., Qin, J. <strong>BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.</strong> Genes Dev. 14: 927-939, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10783165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10783165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10783165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10783165">Wang et al. (2000)</a> suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10783165" 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 RB1 protein (<a href="/entry/614041">614041</a>) promotes cell survival after DNA damage. <a href="#13" class="mim-tip-reference" title="Pennaneach, V., Salles-Passador, I., Munshi, A., Brickner, H., Regazzoni, K., Dick, F., Dyson, N., Chen, T.-T., Wang, J. Y. J., Fotedar, R., Fotedar, A. <strong>The large subunit of replication factor C promotes cell survival after DNA damage in an LxCxE motif- and Rb-dependent manner.</strong> Molec. Cell 7: 715-727, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11336696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11336696</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00217-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11336696">Pennaneach et al. (2001)</a> showed that the LxCxE-binding site in RB1 mediates both cell survival and cell cycle arrest after DNA damage. RFC complex plays an important role in DNA replication. <a href="#13" class="mim-tip-reference" title="Pennaneach, V., Salles-Passador, I., Munshi, A., Brickner, H., Regazzoni, K., Dick, F., Dyson, N., Chen, T.-T., Wang, J. Y. J., Fotedar, R., Fotedar, A. <strong>The large subunit of replication factor C promotes cell survival after DNA damage in an LxCxE motif- and Rb-dependent manner.</strong> Molec. Cell 7: 715-727, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11336696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11336696</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00217-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11336696">Pennaneach et al. (2001)</a> described a function of RFC1 in promoting cell survival after DNA damage. RFC1 contains an LxCxE motif, and mutation of this motif abolished the protective effect of RFC1. The inability of wildtype RFC1 to promote cell survival in RB1 null cells was rescued by RB1 but not by RB1 mutants defective in binding LxCxE proteins. RFC thus enhances cell survival after DNA damage in an RB1-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11336696" 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="Dilley, R. L., Verma, P., Cho, N. W., Winters, H. D., Wondisford, A. R., Greenberg, R. A. <strong>Break-induced telomere synthesis underlies alternative telomere maintenance.</strong> Nature 539: 54-58, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27760120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27760120</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27760120[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/nature20099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27760120">Dilley et al. (2016)</a> defined break-induced telomere synthesis and showed that it utilizes a specialized replisome, which underlies alternate lengthening of telomeres (ALT) maintenance. DNA double-strand breaks enact nascent telomere synthesis by long-tract unidirectional replication. PCNA loading by RFC acts as the initial sensor of telomere damage to establish predominance of DNA polymerase delta through its POLD3 (<a href="/entry/611415">611415</a>) subunit. Break-induced telomere synthesis requires the RFC-PCNA-Pol-delta axis, but is independent of other canonical replisome components, ATM and ATR (<a href="/entry/601215">601215</a>), or the homologous recombination protein RAD51 (<a href="/entry/179617">179617</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27760120" 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="Cannavo, E., Sanchez, A., Anand, R., Ranjha, L., Hugener, J., Adam, C., Acharya, A., Weyland, N., Aran-Guiu, X., Charbonnier, J.-B., Hoffmann, E. R., Borde, V., Matos, J., Cejka, P. <strong>Regulation of the MLH1-MLH3 endonuclease in meiosis.</strong> Nature 586: 618-622, 2020. Note: Erratum: Nature 590: E29, 2021. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32814904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32814904</a>] [<a href="https://doi.org/10.1038/s41586-020-2592-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32814904">Cannavo et al. (2020)</a> showed that human MutS-gamma, a complex of MSH4 (<a href="/entry/602105">602105</a>) and MSH5 (<a href="/entry/603382">603382</a>) that supports crossing over, bound branched recombination intermediates and associated with MutL-gamma, a complex of MLH1 and MLH3 (<a href="/entry/604395">604395</a>), stabilizing the ensemble at joint molecule structures and adjacent double-stranded DNA. MutS-gamma directly stimulated DNA cleavage by the MutL-gamma endonuclease. MutL-gamma activity was further stimulated by exonuclease-1 (EXO1; <a href="/entry/606063">606063</a>), but only when MutS-gamma was present. RFC and PCNA were additional components of the nuclease ensemble, thereby triggering crossing over. S. cerevisiae strains in which MutL-gamma could not interact with Pcna presented defects in forming crossovers. The MutL-gamma-MutS-gamma-EXO1-RFC-PCNA nuclease ensemble preferentially cleaved DNA with Holliday junctions, but it showed no canonical resolvase activity. Instead, the data suggested that the nuclease ensemble processed meiotic recombination intermediates by nicking double-stranded DNA adjacent to the junction points. The authors proposed that, since DNA nicking by MutL-gamma depends on its cofactors, the asymmetric distribution of MutS-gamma and RFC-PCNA on meiotic recombination intermediates may drive biased DNA cleavage. They suggested that this mode of MutL-gamma nuclease activation may explain crossover-specific processing of Holliday junctions or their precursors in meiotic chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32814904" 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>Independently, <a href="#8" class="mim-tip-reference" title="Kulkarni, D. S., Owens, S. N., Honda, M., Ito, M., Yang, Y., Corrigan, M. W., Chen, L., Quan, A. L., Hunter, N. <strong>PCNA activates the MutL-gamma endonuclease to promote meiotic crossing over.</strong> Nature 586: 623-627, 2020. Note: Erratum: Nature 590: E30, 2021. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32814343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32814343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32814343[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/s41586-020-2645-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32814343">Kulkarni et al. (2020)</a> showed that PCNA was important for crossover-biased resolution. In vitro assays with human enzymes showed that PCNA and RFC were sufficient to activate the MutL-gamma endonuclease. MutL-gamma was further stimulated by the codependent activity of the pro-crossover factors EXO1 and MutS-gamma, the latter of which binds Holliday junctions. The authors found that MutL-gamma also bound various branched DNAs, including Holliday junctions, but it did not show canonical resolvase activity, suggesting that the endonuclease incises adjacent to junction branch points to achieve resolution. In vivo, Rfc facilitated MutL-gamma-dependent crossing over in budding yeast. Moreover, Pcna localized to prospective crossover sites along synapsed chromosomes. <a href="#8" class="mim-tip-reference" title="Kulkarni, D. S., Owens, S. N., Honda, M., Ito, M., Yang, Y., Corrigan, M. W., Chen, L., Quan, A. L., Hunter, N. <strong>PCNA activates the MutL-gamma endonuclease to promote meiotic crossing over.</strong> Nature 586: 623-627, 2020. Note: Erratum: Nature 590: E30, 2021. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32814343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32814343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32814343[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/s41586-020-2645-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32814343">Kulkarni et al. (2020)</a> concluded that their data highlight similarities between crossover resolution and the initiation steps of DNA mismatch repair and evoke a novel model for crossover-specific resolution of double Holliday junctions during meiosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32814343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#3" class="mim-tip-reference" title="Bowman, G. D., O'Donnell, M., Kuriyan, J. <strong>Structural analysis of a eukaryotic sliding DNA clamp-clamp loader complex.</strong> Nature 429: 724-730, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15201901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15201901</a>] [<a href="https://doi.org/10.1038/nature02585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15201901">Bowman et al. (2004)</a> reported the crystal structure of the 5-protein clamp loader complex (replication factor-C, RFC) of the yeast S. cerevisiae, bound to the sliding clamp (proliferating cell nuclear antigen, or PCNA). Tight interfacial coordination of the ATP analog ATP-gamma-S by RFC resulted in a spiral arrangement of the ATPase domains of the clamp loader above the PCNA ring. Placement of a model for primed DNA within the central hole of PCNA revealed a striking correspondence between the RFC spiral and the grooves of the DNA double helix. <a href="#3" class="mim-tip-reference" title="Bowman, G. D., O'Donnell, M., Kuriyan, J. <strong>Structural analysis of a eukaryotic sliding DNA clamp-clamp loader complex.</strong> Nature 429: 724-730, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15201901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15201901</a>] [<a href="https://doi.org/10.1038/nature02585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15201901">Bowman et al. (2004)</a> concluded that this model, in which the clamp loader complex locks into primed DNA in a screwcap-like arrangement, provides a simple explanation for the process by which the engagement of primer-template junctions by the RFC:PCNA complex results in ATP hydrolysis and release of the sliding clamp on DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15201901" 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="#10" class="mim-tip-reference" title="Luckow, B., Bunz, F., Stillman, B., Lichter, P., Schutz, G. <strong>Cloning, expression, and chromosomal localization of the 140-kilodalton subunit of replication factor C from mice and humans.</strong> Molec. Cell. Biol. 14: 1626-1634, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8114700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8114700</a>] [<a href="https://doi.org/10.1128/mcb.14.3.1626-1634.1994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8114700">Luckow et al. (1994)</a> assigned RFC1, the gene for the largest subunit of replication factor C, to 4p14-p13 by fluorescence in situ hybridization. They mapped the homolog in the mouse to chromosome 5. <a href="#9" class="mim-tip-reference" title="Lossie, A. C., Haugen, B. R., Wood, W. M., Camper, S. A., Gordon, D. F. <strong>Chromosomal localization of the large subunit of mouse replication factor C in the mouse and human.</strong> Mammalian Genome 6: 58-59, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719032</a>] [<a href="https://doi.org/10.1007/BF00350900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719032">Lossie et al. (1995)</a> likewise mapped this gene, which they symbolized Recc1, to human chromosome 4 by human/rodent somatic cell hybrid analysis and to mouse chromosome 5 by haplotype analysis of an interspecific backcross. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7719032+8114700" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 25 affected individuals from 11 unrelated families with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; <a href="/entry/614575">614575</a>), <a href="#6" class="mim-tip-reference" title="Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., and 18 others. <strong>Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.</strong> Nature Genet. 51: 649-658, 2019. Note: Erratum: Nature Genet. 51: 920 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30926972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30926972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30926972[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/s41588-019-0372-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30926972">Cortese et al. (2019)</a> identified a homozygous expanded 5-bp intronic repeat, (AAGGG)n, in the RFC1 gene. The variant, which was found by a combination of linkage analysis and whole-genome and whole-exome sequencing, was confirmed by Sanger sequencing. Screening of an additional cohort of 150 patients with sporadic late-onset ataxia identified the homozygous (AAGGG)n expansion in 33 cases (22%). Haplotype analysis showed that all affected individuals from the 11 families and 32 of the sporadic cases shared the same haplotype. The reference allele, a simple tandem pentanucleotide AAAAG repeat of 11 (AAAAG)11, was replaced by a variable number of expanded pentanucleotide AAGGG repeated units. The expansion size varied across different families, ranging from about 400 to 2,000 repeats, but the majority of cases had about 1,000 repeats. Repeat size was relatively stable in sibs, and there was no association between age at onset and repeat size. There were no instances of vertical transmission; all families studied consisted of affected sibs or first cousins in the same generation. Patient cells showed normal expression levels of RFC1 mRNA and protein, and postmortem brain tissue from 1 CANVAS patient had normal levels of RFC1 and FXN (<a href="/entry/606829">606829</a>) compared to controls. However, patient cells showed some evidence of altered pre-mRNA processing with an increase in the retention of intron 2 compared to controls. Patient fibroblasts did not show increased susceptibility to DNA damage. <a href="#6" class="mim-tip-reference" title="Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., and 18 others. <strong>Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.</strong> Nature Genet. 51: 649-658, 2019. Note: Erratum: Nature Genet. 51: 920 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30926972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30926972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30926972[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/s41588-019-0372-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30926972">Cortese et al. (2019)</a> noted that their studies did not show evidence of a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30926972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Beecroft, S. J., Cortese, A. Sullivan, R., Yau, W. Y., Dyer, Z., Wu, T. Y., Mulroy, E., Pelosi, L., Rodrigues, M., Taylor, R., Mossman, S., Leadbetter, R., Cleland, J., Anderson, T., Ravenscroft, G., Laing, N. G., Houlden, H., Reilly, M. M., Roxburgh, R. H. <strong>A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele.</strong> Brain 143: 2673-2680, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32851396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32851396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32851396[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awaa203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32851396">Beecroft et al. (2020)</a> identified a biallelic (AAAGG)10-25(AAGGG)n intronic repeat expansion of the RFC1 gene (<a href="#0002">102579.0002</a>) in 13 patients with CANVAS: 2 from a Cook Island Maori family, 6 from a New Zealand Maori family, and 5 from unrelated New Zealand Maori families. Two of the affected individuals also had an additional repeat sequence, (AAAGG)4-6, at the distal end of the repeat sequence. A common haplotype was identified in these patients, suggesting a founder effect, with the most recent common ancestor estimated to date to 1369-1499 CE. There were no apparent phenotypic differences between this patient cohort and patients with the (AAGGG)n repeat expansion (<a href="#0001">102579.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32851396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 patients from 2 unrelated families in the Asian Pacific (consanguineous family Indo1 of Chinese descent and patient N1 from the island of Niue) with CANVAS, <a href="#14" class="mim-tip-reference" title="Scriba, C. K., Beecroft, S. J., Clayton, J. S., Cortese, A., Sullivan, R., Yau, W. Y., Dominik, N., Rodrigues, M., Walker, E., Dyer, Z., Wu, T. Y., Davis, M. R., Chandler, D. C., Weisburd, B., Houlden, H., Reilly, M. M., Laing, N. G., Lamont, P. J., Roxburgh, R. H., Ravenscroft, G. <strong>A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families.</strong> Brain 143: 2904-2910, 2020. Note: Erratum: Brain 144: e51, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33103729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33103729</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33103729[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awaa263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33103729">Scriba et al. (2020)</a> identified a homozygous expanded 5-bp repeat, (ACAGG)n, in intron 2 of the RFC1 gene (<a href="#0007">102579.0007</a>). The variant, which was found by PCR analysis and confirmed by Sanger sequencing, segregated with the disorder in family Indo1. Southern blot analysis in family Indo1 showed that the pathogenic allele was about 10,000 kb (the control allele being about 5,000 kb) and contained about 1,015 repeated units. Haplotype analysis showed that the ACAGG and AAGGG motifs share the same core haplotype, suggesting a single ancient origin of the disease. The RFC1 (ACAGG) motif was present in 7 of 26,745 samples in gnomAD (v.3), including individuals of African, South Asian, and East Asian origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33103729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 72-year-old Japanese man with sporadic CANVAS, <a href="#15" class="mim-tip-reference" title="Tsuchiya, M., Nan, H., Koh, K., Ichinose, Y., Gao, L., Shimozono, K., Hata, T., Kim, Y.-J., Ohtsuka, T., Cortese, A., Takiyama, Y. <strong>RFC1 repeat expansion in Japanese patients with late-onset cerebellar ataxia.</strong> J. Hum. Genet. 65: 1143-1147, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32694621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32694621</a>] [<a href="https://doi.org/10.1038/s10038-020-0807-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32694621">Tsuchiya et al. (2020)</a> identified a homozygous (ACAGG)n repeat expansion in the RFC1 gene. The patient was part of a cohort of 37 Japanese patients with late-onset cerebellar ataxia who underwent genetic studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32694621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with CANVAS, <a href="#2" class="mim-tip-reference" title="Benkirane, M., Da Cunha, D., Marelli, C., Larrieu, L., Renaud, M., Varilh, J., Pointaux, M., Baux, D., Ardouin, O., Vangoethem, C., Taulan, M., Daumas Duport, B., Bergougnoux, A., Corbille, A. G., Cossee, M., Juntas Morales, R., Tuffery-Giraud, S., Koenig, M., Isidor, B., Vincent, M. C. <strong>RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.</strong> Brain 145: 3770-3775, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35883251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35883251</a>] [<a href="https://doi.org/10.1093/brain/awac280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35883251">Benkirane et al. (2022)</a> identified compound heterozygous mutations in the RFC1 gene, an AAGGG repeat expansion on one allele in both patients and a nonsense mutation (R388X; <a href="#0003">102579.0003</a>) in patient 1 and a frameshift mutation (c.575delA; <a href="#0004">102579.0004</a>) in patient 2 on the other allele. In both patients, RFC1 expression was reduced from the allele with the truncating mutation. <a href="#2" class="mim-tip-reference" title="Benkirane, M., Da Cunha, D., Marelli, C., Larrieu, L., Renaud, M., Varilh, J., Pointaux, M., Baux, D., Ardouin, O., Vangoethem, C., Taulan, M., Daumas Duport, B., Bergougnoux, A., Corbille, A. G., Cossee, M., Juntas Morales, R., Tuffery-Giraud, S., Koenig, M., Isidor, B., Vincent, M. C. <strong>RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.</strong> Brain 145: 3770-3775, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35883251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35883251</a>] [<a href="https://doi.org/10.1093/brain/awac280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35883251">Benkirane et al. (2022)</a> concluded that CANVAS likely results from a loss of function of RFC1. Clinical features in these 2 patients did not differ from what had been reported in patients with homozygosity for repeat expansion mutations in RFC1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35883251" 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>Among 16 Japanese patients from 11 unrelated families with CANVAS, <a href="#11" class="mim-tip-reference" title="Miyatake, S., Yoshida, K., Koshimizu, E., Doi, H., Yamada, M., Miyaji, Y., Ueda, N., Tsuyuzaki, J., Kodaira, M., Onoue, H., Taguri, M., Imamura, S., and 24 others. <strong>Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.</strong> Brain 145: 1139-1150, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35355059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35355059</a>] [<a href="https://doi.org/10.1093/brain/awab363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35355059">Miyatake et al. (2022)</a> found heterogeneity for RFC1 repeat expansions. Seven patients had homozygous ACAGG(n) expansions (<a href="#0007">102579.0007</a>), 7 had homozygous AAGGG(n) expansions (<a href="#0001">102579.0001</a>), and 2 were compound heterozygous for ACAGG(n) and AAGGG(n) expansions. There were no interrupting sequences. Of note, of 6 affected sibs in consanguineous family A, 5 (P2-P6) were homozygous for ACAGG, whereas 1 (P1) was compound heterozygous for ACAGG and AAGGG. The number of repeats varied between 310 and 1,615. The authors found some evidence for a genotype/phenotype correlation: patients homozygous for the AAGGG repeat expansion tended to have a higher frequency of chronic cough, hearing impairment, vestibular dysfunction, autonomic dysfunction, and mild cognitive impairment compared to those with a homozygous ACAGG repeat expansion. Compound heterozygosity for these expansions was associated with a slightly later age at onset and slower disease progression, although the authors noted that this observation was difficult to explain from a functional point of view. Functional studies and studies of patient cells were not performed. In the Japanese population, the carrier frequency of the AAGGG expanded allele was 7.8%, and that of the ACAGG expanded allele was 0%; however, the authors noted that gnomAD had reported a carrier frequency of 0.26% for ACAGG in the South Asian population. The overall detection rate of RFC1 repeat expansions in the cohort studied was 5.2% (11 of 212 families). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35355059" 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="#18" class="mim-tip-reference" title="Weber, S., Coarelli, G., Heinzmann, A., Monin, M. L., Richard, N., Gerard, M., Durr, A., Huin, V. <strong>Two RFC1 splicing variants in CANVAS.</strong> Brain 146: e14-e16, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36478048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36478048</a>] [<a href="https://doi.org/10.1093/brain/awac466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36478048">Weber et al. (2023)</a> identified compound heterozygous mutations in the RFC1 gene in 2 unrelated patients with CANVAS; both patients had an AAGGG repeat expansion on one allele with a different mutation on the other allele, c.2535+2T-C (<a href="#0005">102579.0005</a>) or c.2690+1G-A (<a href="#0006">102579.0006</a>). Both patients had an earlier onset of disease than that reported for classical CANVAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36478048" 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 CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME</strong>
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<p>In 25 affected individuals from 11 unrelated families with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; <a href="/entry/614575">614575</a>), <a href="#6" class="mim-tip-reference" title="Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., and 18 others. <strong>Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.</strong> Nature Genet. 51: 649-658, 2019. Note: Erratum: Nature Genet. 51: 920 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30926972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30926972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30926972[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/s41588-019-0372-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30926972">Cortese et al. (2019)</a> identified a homozygous expanded 5-bp intronic repeat, (AAGGG)n, in the RFC1 gene. The variant, which was found by a combination of linkage analysis and whole-genome and whole-exome sequencing, was confirmed by Sanger sequencing. Screening of an additional cohort of 150 patients with sporadic late-onset ataxia identified the homozygous (AAGGG)n expansion in 33 patients (22%). The reference allele, a simple tandem pentanucleotide AAAAG repeat of 11 (AAAAG)11, was replaced by a variable number of expanded pentanucleotide AAGGG repeated units. The expansion size varied across different families, ranging from about 400 to 2,000 repeats, but the majority of cases had about 1,000 repeats. Repeat size was relatively stable in sibs, and there was no association between age at onset and repeat size. There were no instances of vertical transmission; all families studied consisted of affected sibs or first cousins in the same generation. The expansion resides at the 3-prime end of a deep intronic AluSx3 element and increases the size of the poly(A) tail. Haplotype analysis showed that all affected individuals from the 11 families and 32 of the sporadic cases shared the same haplotype, which had had a carrier frequency of 18% in the 1000 Genomes Project database. Biallelic AAGGG repeat expansions were not found in 304 controls, although 0.7% carried an AAGGG expansion in heterozygous state. The region where the expansions occurred was highly polymorphic and often showed interruptions and nucleotide changes in the expanded sequence. Patient cells showed normal expression levels of RFC1 mRNA and protein, and postmortem brain tissue from 1 CANVAS patient had normal levels of RFC1 and FXN (<a href="/entry/606829">606829</a>) compared to controls. However, patient cells showed some evidence of altered pre-mRNA processing with an increase in the retention of intron 2 compared to controls. Patient fibroblasts did not show increased susceptibility to DNA damage. <a href="#6" class="mim-tip-reference" title="Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., and 18 others. <strong>Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.</strong> Nature Genet. 51: 649-658, 2019. Note: Erratum: Nature Genet. 51: 920 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30926972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30926972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30926972[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/s41588-019-0372-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30926972">Cortese et al. (2019)</a> noted that their studies did not show evidence of a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30926972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with CANVAS, <a href="#2" class="mim-tip-reference" title="Benkirane, M., Da Cunha, D., Marelli, C., Larrieu, L., Renaud, M., Varilh, J., Pointaux, M., Baux, D., Ardouin, O., Vangoethem, C., Taulan, M., Daumas Duport, B., Bergougnoux, A., Corbille, A. G., Cossee, M., Juntas Morales, R., Tuffery-Giraud, S., Koenig, M., Isidor, B., Vincent, M. C. <strong>RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.</strong> Brain 145: 3770-3775, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35883251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35883251</a>] [<a href="https://doi.org/10.1093/brain/awac280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35883251">Benkirane et al. (2022)</a> identified compound heterozygosity for mutations in the RFC1 gene. Both patients had the AAGGG repeat expansion on one allele; patient 1 also carried a c.1162C-T transition, resulting in an arg388-to-ter (R388X; <a href="#0003">102579.0003</a>) substitution, and patient 2 carried a 1-bp deletion (c.575delA; <a href="#0004">102579.0004</a>), resulting in a frameshift and premature termination (Asn192IlefsTer7). The mutations were identified by whole-exome sequencing and repeat primer PCR. In patient 1, the repeat expansion was inherited from the mother, and although the father was not available for testing, SNP analysis determined that the R388X mutation presumably occurred de novo on the paternal allele. In patient 2, the repeat expansion was inherited from the father, and the c.575delA mutation was inherited from the mother. RFC1 expression analysis in patient blood demonstrated that both the R388X and c.575delA mutations resulted in decreased gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35883251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 7 unrelated Japanese patients (P10-P16) with CANVAS, <a href="#11" class="mim-tip-reference" title="Miyatake, S., Yoshida, K., Koshimizu, E., Doi, H., Yamada, M., Miyaji, Y., Ueda, N., Tsuyuzaki, J., Kodaira, M., Onoue, H., Taguri, M., Imamura, S., and 24 others. <strong>Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.</strong> Brain 145: 1139-1150, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35355059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35355059</a>] [<a href="https://doi.org/10.1093/brain/awab363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35355059">Miyatake et al. (2022)</a> identified homozygosity for the AAGGG repeat expansion in the RFC1 gene. There were no interrupting sequences. Two additional unrelated patients (P1 and P9) were compound heterozygous for AAGGG(n) and an ACAGG(n) repeat expansion (<a href="#0007">102579.0007</a>). Functional studies and studies of patient cells were not performed. In the Japanese population, the carrier frequency of the AAGGG expanded allele was 7.8%, and that of the ACAGG expanded allele was 0%; however, the authors noted that gnomAD has reported a carrier frequency of 0.26% for ACAGG in the South Asian population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35355059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with CANVAS, <a href="#18" class="mim-tip-reference" title="Weber, S., Coarelli, G., Heinzmann, A., Monin, M. L., Richard, N., Gerard, M., Durr, A., Huin, V. <strong>Two RFC1 splicing variants in CANVAS.</strong> Brain 146: e14-e16, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36478048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36478048</a>] [<a href="https://doi.org/10.1093/brain/awac466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36478048">Weber et al. (2023)</a> identified compound heterozygosity for mutations in the RFC1 gene. Both patients carried the AAGGG repeat expansion on one allele. Case 1 also carried a c.2535+2T-C transition (<a href="#0005">102579.0005</a>) at the splice acceptor site of exon 19, predicted to cause a splicing abnormality. Case 2 carried a c.2690+1G-A transition (<a href="#0006">102579.0006</a>) at the splice acceptor site of exon 20, predicted to cause a splicing abnormality. The mutations were identified by whole-exome sequencing, repeat primer PCR, or RFC1 gene screening. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36478048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 patients from a Cook Island Maori family, 6 patients from a New Zealand Maori family, and 5 unrelated New Zealand Maori patients with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; <a href="/entry/614575">614575</a>), <a href="#1" class="mim-tip-reference" title="Beecroft, S. J., Cortese, A. Sullivan, R., Yau, W. Y., Dyer, Z., Wu, T. Y., Mulroy, E., Pelosi, L., Rodrigues, M., Taylor, R., Mossman, S., Leadbetter, R., Cleland, J., Anderson, T., Ravenscroft, G., Laing, N. G., Houlden, H., Reilly, M. M., Roxburgh, R. H. <strong>A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele.</strong> Brain 143: 2673-2680, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32851396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32851396</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32851396[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awaa203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32851396">Beecroft et al. (2020)</a> identified a biallelic (AAAGG)10-25(AAGGG)n intronic repeat expansion of the RFC1 gene. Two of the affected individuals also had an additional repeat, (AAAGG)4-6, at the distal end of the repeat sequence. The mutations were identified by whole-genome sequencing, whole-exome sequencing, or direct gene analysis. The repeat expansions were characterized by repeat-primed PCR. One unaffected individual from each family was found to be a carrier for the repeat expansion. A common haplotype was identified in these patients, suggesting a founder effect with the most recent common ancestor estimated to date to 1369-1499 CE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32851396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>For discussion of the c.1162C-T transition (c.1162C-T, NM_002913.5) in the RFC1 gene, resulting in an arg388-to-ter (R388X) substitution, that was identified in compound heterozygous state in a patient (patient 1) with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; <a href="/entry/614575">614575</a>) by <a href="#2" class="mim-tip-reference" title="Benkirane, M., Da Cunha, D., Marelli, C., Larrieu, L., Renaud, M., Varilh, J., Pointaux, M., Baux, D., Ardouin, O., Vangoethem, C., Taulan, M., Daumas Duport, B., Bergougnoux, A., Corbille, A. G., Cossee, M., Juntas Morales, R., Tuffery-Giraud, S., Koenig, M., Isidor, B., Vincent, M. C. <strong>RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.</strong> Brain 145: 3770-3775, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35883251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35883251</a>] [<a href="https://doi.org/10.1093/brain/awac280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35883251">Benkirane et al. (2022)</a>, see <a href="#0001">102579.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35883251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>For discussion of the 1-bp deletion (c.575delA, NM_002913.5) in the RFC1 gene, resulting in a frameshift and premature termination (Asn192IlefsTer7), that was identified in compound heterozygous state in a patient (patient 2) with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; <a href="/entry/614575">614575</a>) by <a href="#2" class="mim-tip-reference" title="Benkirane, M., Da Cunha, D., Marelli, C., Larrieu, L., Renaud, M., Varilh, J., Pointaux, M., Baux, D., Ardouin, O., Vangoethem, C., Taulan, M., Daumas Duport, B., Bergougnoux, A., Corbille, A. G., Cossee, M., Juntas Morales, R., Tuffery-Giraud, S., Koenig, M., Isidor, B., Vincent, M. C. <strong>RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.</strong> Brain 145: 3770-3775, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35883251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35883251</a>] [<a href="https://doi.org/10.1093/brain/awac280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35883251">Benkirane et al. (2022)</a>, see <a href="#0001">102579.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35883251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003324874" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003324874" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003324874</a>
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<p>For discussion of the c.2535+2T-C transition (c.2535+2T-C, NM_002913.5) in the RFC1 gene, predicted to cause a splicing abnormality, that was identified in compound heterozygous state in a patient (case 1) with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; <a href="/entry/614575">614575</a>) by <a href="#18" class="mim-tip-reference" title="Weber, S., Coarelli, G., Heinzmann, A., Monin, M. L., Richard, N., Gerard, M., Durr, A., Huin, V. <strong>Two RFC1 splicing variants in CANVAS.</strong> Brain 146: e14-e16, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36478048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36478048</a>] [<a href="https://doi.org/10.1093/brain/awac466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36478048">Weber et al. (2023)</a>, see <a href="#0001">102579.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36478048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME</strong>
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RFC1, IVS20, G-A, +1
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003324875" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003324875" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003324875</a>
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<p>For discussion of the c.2690+1G-A transition (c.2690+1G-A, NM_002913.5) in the RFC1 gene, predicted to cause a splicing abnormality, that was identified in compound heterozygous state in a patient (case 2) with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; <a href="/entry/614575">614575</a>) by <a href="#18" class="mim-tip-reference" title="Weber, S., Coarelli, G., Heinzmann, A., Monin, M. L., Richard, N., Gerard, M., Durr, A., Huin, V. <strong>Two RFC1 splicing variants in CANVAS.</strong> Brain 146: e14-e16, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36478048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36478048</a>] [<a href="https://doi.org/10.1093/brain/awac466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36478048">Weber et al. (2023)</a>, see <a href="#0001">102579.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36478048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME</strong>
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RFC1, (ACAGG)n REPEAT EXPANSION
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV004780759" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004780759" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004780759</a>
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<p>In 3 patients from 2 unrelated families in the Asian Pacific (consanguineous family Indo1 of Chinese descent and patient N1 from the island of Niue) with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; <a href="/entry/614575">614575</a>), <a href="#14" class="mim-tip-reference" title="Scriba, C. K., Beecroft, S. J., Clayton, J. S., Cortese, A., Sullivan, R., Yau, W. Y., Dominik, N., Rodrigues, M., Walker, E., Dyer, Z., Wu, T. Y., Davis, M. R., Chandler, D. C., Weisburd, B., Houlden, H., Reilly, M. M., Laing, N. G., Lamont, P. J., Roxburgh, R. H., Ravenscroft, G. <strong>A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families.</strong> Brain 143: 2904-2910, 2020. Note: Erratum: Brain 144: e51, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33103729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33103729</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33103729[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awaa263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33103729">Scriba et al. (2020)</a> identified a homozygous expanded 5-bp repeat, (ACAGG)n, in intron 2 of the RFC1 gene. The variant, which was found by PCR analysis and confirmed by Sanger sequencing, segregated with the disorder in family Indo1. Southern blot analysis in family Indo1 showed that the pathogenic allele was about 10,000 kb (the control allele being about 5,000 kb) and contained about 1,015 repeated units. Haplotype analysis showed that the ACAGG and AAGGG (<a href="#0001">102579.0001</a>) motifs share the same core haplotype, suggesting a single ancient origin of the disease. The RFC1 (ACAGG) motif was present in 7 of 26,745 samples in gnomAD (v.3), including individuals of African, South Asian, and East Asian origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33103729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 72-year-old Japanese man with sporadic CANVAS, <a href="#15" class="mim-tip-reference" title="Tsuchiya, M., Nan, H., Koh, K., Ichinose, Y., Gao, L., Shimozono, K., Hata, T., Kim, Y.-J., Ohtsuka, T., Cortese, A., Takiyama, Y. <strong>RFC1 repeat expansion in Japanese patients with late-onset cerebellar ataxia.</strong> J. Hum. Genet. 65: 1143-1147, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32694621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32694621</a>] [<a href="https://doi.org/10.1038/s10038-020-0807-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32694621">Tsuchiya et al. (2020)</a> identified a homozygous (ACAGG)n repeat expansion in the RFC1 gene. The patient was part of a cohort of 37 Japanese patients with late-onset cerebellar ataxia who underwent genetic studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32694621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 7 patients from 3 unrelated Japanese families with CANVAS (P2-P8), <a href="#11" class="mim-tip-reference" title="Miyatake, S., Yoshida, K., Koshimizu, E., Doi, H., Yamada, M., Miyaji, Y., Ueda, N., Tsuyuzaki, J., Kodaira, M., Onoue, H., Taguri, M., Imamura, S., and 24 others. <strong>Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.</strong> Brain 145: 1139-1150, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35355059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35355059</a>] [<a href="https://doi.org/10.1093/brain/awab363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35355059">Miyatake et al. (2022)</a> identified a homozygous ACAGG(n) repeat expansion in the RFC1 gene. There were no interrupting sequences. Of note, of 6 affected sibs in consanguineous family A, 5 (P2-P6) were homozygous for ACAGG, whereas 1 (P1) was compound heterozygous for ACAGG and AAGGG (<a href="#0001">102579.0001</a>). Another unrelated patient (P9) was also compound heterozygous for these expansions. In the Japanese population, the carrier frequency of the AAGGG expanded allele was 7.8%, and that of the ACAGG expanded allele was 0%; however, the authors noted that gnomAD had reported a carrier frequency of 0.26% for ACAGG in the South Asian population. Functional studies and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35355059" 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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Beecroft, S. J., Cortese, A. Sullivan, R., Yau, W. Y., Dyer, Z., Wu, T. Y., Mulroy, E., Pelosi, L., Rodrigues, M., Taylor, R., Mossman, S., Leadbetter, R., Cleland, J., Anderson, T., Ravenscroft, G., Laing, N. G., Houlden, H., Reilly, M. M., Roxburgh, R. H.
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[<a href="https://doi.org/10.1093/brain/awaa203" target="_blank">Full Text</a>]
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Benkirane, M., Da Cunha, D., Marelli, C., Larrieu, L., Renaud, M., Varilh, J., Pointaux, M., Baux, D., Ardouin, O., Vangoethem, C., Taulan, M., Daumas Duport, B., Bergougnoux, A., Corbille, A. G., Cossee, M., Juntas Morales, R., Tuffery-Giraud, S., Koenig, M., Isidor, B., Vincent, M. C.
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Bowman, G. D., O'Donnell, M., Kuriyan, J.
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Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., and 18 others.
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Dilley, R. L., Verma, P., Cho, N. W., Winters, H. D., Wondisford, A. R., Greenberg, R. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27760120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27760120</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27760120[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=27760120" 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/nature20099" target="_blank">Full Text</a>]
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<a id="Kulkarni2020" class="mim-anchor"></a>
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<div class="">
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Kulkarni, D. S., Owens, S. N., Honda, M., Ito, M., Yang, Y., Corrigan, M. W., Chen, L., Quan, A. L., Hunter, N.
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[<a href="https://doi.org/10.1038/s41586-020-2645-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00350900" target="_blank">Full Text</a>]
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<strong>Cloning, expression, and chromosomal localization of the 140-kilodalton subunit of replication factor C from mice and humans.</strong>
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[<a href="https://doi.org/10.1128/mcb.14.3.1626-1634.1994" target="_blank">Full Text</a>]
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<a id="Miyatake2022" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Miyatake, S., Yoshida, K., Koshimizu, E., Doi, H., Yamada, M., Miyaji, Y., Ueda, N., Tsuyuzaki, J., Kodaira, M., Onoue, H., Taguri, M., Imamura, S., and 24 others.
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<strong>Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35355059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35355059</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35355059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awab363" target="_blank">Full Text</a>]
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<a id="Okumura1995" class="mim-anchor"></a>
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<div class="">
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Okumura, K., Nogami, M., Taguchi, H., Dean, F. B., Chen, M., Pan, Z.-Q., Hurwitz, J., Shiratori, A., Murakami, Y., Ozawa, K., Eki, T.
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<strong>Assignment of the 36.5-kDa (RFC5), 37-kDa (RFC4), 38-kDa (RFC3), and 40-kDa (RFC2) subunit genes of human replication factor C to chromosome bands 12q24.2-q24.3, 3q27, 13q12.3-q13, and 7q11.23.</strong>
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Genomics 25: 274-278, 1995.
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[<a href="https://doi.org/10.1016/0888-7543(95)80135-9" target="_blank">Full Text</a>]
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Pennaneach, V., Salles-Passador, I., Munshi, A., Brickner, H., Regazzoni, K., Dick, F., Dyson, N., Chen, T.-T., Wang, J. Y. J., Fotedar, R., Fotedar, A.
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<strong>The large subunit of replication factor C promotes cell survival after DNA damage in an LxCxE motif- and Rb-dependent manner.</strong>
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Molec. Cell 7: 715-727, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11336696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11336696</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11336696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s1097-2765(01)00217-9" target="_blank">Full Text</a>]
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<a id="Scriba2020" class="mim-anchor"></a>
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Scriba, C. K., Beecroft, S. J., Clayton, J. S., Cortese, A., Sullivan, R., Yau, W. Y., Dominik, N., Rodrigues, M., Walker, E., Dyer, Z., Wu, T. Y., Davis, M. R., Chandler, D. C., Weisburd, B., Houlden, H., Reilly, M. M., Laing, N. G., Lamont, P. J., Roxburgh, R. H., Ravenscroft, G.
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<strong>A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33103729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33103729</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33103729[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=33103729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awaa263" target="_blank">Full Text</a>]
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Tsuchiya, M., Nan, H., Koh, K., Ichinose, Y., Gao, L., Shimozono, K., Hata, T., Kim, Y.-J., Ohtsuka, T., Cortese, A., Takiyama, Y.
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[<a href="https://doi.org/10.1038/s10038-020-0807-x" target="_blank">Full Text</a>]
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Uchiumi, F., Ohta, T., Tanuma, S.
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<strong>Replication factor C recognizes 5-prime-phosphate ends of telomeres.</strong>
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Biochem. Biophys. Res. Commun. 229: 310-315, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8954124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8954124</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8954124" 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/bbrc.1996.1798" target="_blank">Full Text</a>]
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Wang, Y., Cortez, D., Yazdi, P., Neff, N., Elledge, S. J., Qin, J.
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<strong>BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10783165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10783165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10783165[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=10783165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Weber2023" class="mim-anchor"></a>
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Weber, S., Coarelli, G., Heinzmann, A., Monin, M. L., Richard, N., Gerard, M., Durr, A., Huin, V.
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<strong>Two RFC1 splicing variants in CANVAS.</strong>
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Brain 146: e14-e16, 2023.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36478048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36478048</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36478048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awac466" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 10/31/2024
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Hilary J. Vernon - updated : 08/28/2023<br>Ada Hamosh - updated : 01/20/2021<br>Hilary J. Vernon - updated : 11/18/2020<br>Ada Hamosh - updated : 08/30/2019<br>Cassandra L. Kniffin -updated : 04/17/2019<br>Patricia A. Hartz - updated : 1/12/2010<br>Ada Hamosh - updated : 6/22/2004<br>Stylianos E. Antonarakis - updated : 8/6/2001<br>Paul J. Converse - updated : 11/16/2000<br>Jennifer P. Macke - updated : 8/27/1997
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Victor A. McKusick : 12/14/1993
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alopez : 11/04/2024<br>ckniffin : 10/31/2024<br>carol : 08/29/2023<br>carol : 08/28/2023<br>alopez : 04/06/2021<br>alopez : 03/31/2021<br>mgross : 01/21/2021<br>mgross : 01/20/2021<br>carol : 11/19/2020<br>carol : 11/18/2020<br>alopez : 10/31/2019<br>alopez : 08/30/2019<br>alopez : 05/23/2019<br>carol : 04/18/2019<br>carol : 04/17/2019<br>ckniffin : 04/17/2019<br>carol : 06/17/2011<br>wwang : 1/12/2010<br>mgross : 4/14/2005<br>alopez : 6/22/2004<br>alopez : 6/22/2004<br>terry : 6/22/2004<br>ckniffin : 3/11/2003<br>terry : 11/15/2001<br>mgross : 8/6/2001<br>joanna : 1/17/2001<br>mgross : 11/16/2000<br>alopez : 9/4/1998<br>alopez : 10/6/1997<br>alopez : 10/6/1997<br>alopez : 7/9/1997<br>alopez : 6/3/1997<br>terry : 4/18/1995<br>carol : 2/20/1995<br>carol : 12/14/1993
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<div>
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<h3>
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<span class="mim-font">
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REPLICATION FACTOR C, SUBUNIT 1; RFC1
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</h3>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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<h4>
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<span class="mim-font">
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ACTIVATOR 1, 140-KD SUBUNIT<br />
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REPLICATION FACTOR C, 140-KD SUBUNIT; RFC140<br />
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RFC
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</span>
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: RFC1</em></strong>
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</span>
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</p>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1236804009;
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</span>
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</p>
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<strong>
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<em>
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Cytogenetic location: 4p14
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Genomic coordinates <span class="small">(GRCh38)</span> : 4:39,287,456-39,366,362 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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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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4p14
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<td>
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<span class="mim-font">
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Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome
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</td>
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<td>
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<span class="mim-font">
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614575
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<td>
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<span class="mim-font">
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Autosomal recessive
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</tr>
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</tbody>
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</table>
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<h4>
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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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</h4>
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</div>
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<span class="mim-text-font">
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<p>The RFC1 gene encodes the large subunit of replication factor C, a 5-subunit DNA polymerase accessory protein required for the coordinated synthesis of both DNA strands during replication or after DNA damage (summary by Cortese et al., 2019). It is a DNA-dependent ATPase that binds in a structure-specific manner to the 3-prime end of a primer hybridized to a template DNA, an activity thought intrinsic to the 140-kD component of this multisubunit complex (Bunz et al., 1993). </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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</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>Bunz et al. (1993) isolated and analyzed cDNAs encoding the 140-kD subunit. An open reading frame of 3.4 kb was predicted to encode a 1,148-amino acid protein with a predicted molecular mass of 130 kD. A putative ATP-binding motif was observed that is similar to a motif in several of the smaller subunits of RFC and in functionally homologous replication factors of bacterial and viral origin. The predicted protein showed similarities to other DNA-binding proteins. </p><p>Luckow et al. (1994) isolated a full-length mouse cDNA encoding a protein that binds in a sequence-unspecific manner to DNA, is localized exclusively in the nucleus, and represents, they concluded, the 140-kD subunit of mouse replication factor C. They found that it showed 83% identity to the human protein. </p><p>Human replication factor C (RFC), also called activator-1, is a multimeric primer-recognition protein consisting of 5 distinct subunits of 145, 40, 38, 37, and 36.5 kD. Human RFC was purified from extracts of HeLa cells as a host factor essential for the in vitro replication of simian virus 40 (SV40) DNA (Okumura et al., 1995). RFC, in the presence of ATP, assembles proliferating-cell nuclear antigen (PCNA; 176740) and DNA polymerase-delta (174761) or polymerase-epsilon (174762) on primed DNA templates. The complex of primed DNA-RFC-PCNA-DNA polymerase, when supplemented with dNTPs, results in the efficient elongation of DNA in the presence of human single-stranded DNA binding protein. Studies with the complete 5-subunit holoenzyme indicated that the large subunit binds to DNA and the 40-kD subunit binds ATP. The other subunits may play discrete roles in the elongation process catalyzed by polymerase. The subunit genes are numbered in sequence of decreasing molecular weight: RFC1, RFC2 (600404), RFC3 (600405), RFC4 (102577), and RFC5 (600407). </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using interaction cloning, Uchiumi et al. (1996) found that the large subunit of RFC interacts with the DNA sequence repeats of telomeres. They found that RFC recognizes the 5-prime-phosphate termini of double-stranded telomeric repeats. The authors suggested that RFC may be involved in telomere stability or turnover. </p><p>Wang et al. (2000) used immunoprecipitation and mass spectrometry analyses to identify BRCA1 (113705)-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM (607585), BLM (604610), MSH2 (609309), MSH6 (600678), MLH1 (120436), the RAD50 (604040)-MRE11 (600814)-NBS1 (602667) complex, and the RFC1-RFC2 (600404)-RFC4 (102577) complex. Wang et al. (2000) suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. </p><p>The RB1 protein (614041) promotes cell survival after DNA damage. Pennaneach et al. (2001) showed that the LxCxE-binding site in RB1 mediates both cell survival and cell cycle arrest after DNA damage. RFC complex plays an important role in DNA replication. Pennaneach et al. (2001) described a function of RFC1 in promoting cell survival after DNA damage. RFC1 contains an LxCxE motif, and mutation of this motif abolished the protective effect of RFC1. The inability of wildtype RFC1 to promote cell survival in RB1 null cells was rescued by RB1 but not by RB1 mutants defective in binding LxCxE proteins. RFC thus enhances cell survival after DNA damage in an RB1-dependent manner. </p><p>Dilley et al. (2016) defined break-induced telomere synthesis and showed that it utilizes a specialized replisome, which underlies alternate lengthening of telomeres (ALT) maintenance. DNA double-strand breaks enact nascent telomere synthesis by long-tract unidirectional replication. PCNA loading by RFC acts as the initial sensor of telomere damage to establish predominance of DNA polymerase delta through its POLD3 (611415) subunit. Break-induced telomere synthesis requires the RFC-PCNA-Pol-delta axis, but is independent of other canonical replisome components, ATM and ATR (601215), or the homologous recombination protein RAD51 (179617). </p><p>Cannavo et al. (2020) showed that human MutS-gamma, a complex of MSH4 (602105) and MSH5 (603382) that supports crossing over, bound branched recombination intermediates and associated with MutL-gamma, a complex of MLH1 and MLH3 (604395), stabilizing the ensemble at joint molecule structures and adjacent double-stranded DNA. MutS-gamma directly stimulated DNA cleavage by the MutL-gamma endonuclease. MutL-gamma activity was further stimulated by exonuclease-1 (EXO1; 606063), but only when MutS-gamma was present. RFC and PCNA were additional components of the nuclease ensemble, thereby triggering crossing over. S. cerevisiae strains in which MutL-gamma could not interact with Pcna presented defects in forming crossovers. The MutL-gamma-MutS-gamma-EXO1-RFC-PCNA nuclease ensemble preferentially cleaved DNA with Holliday junctions, but it showed no canonical resolvase activity. Instead, the data suggested that the nuclease ensemble processed meiotic recombination intermediates by nicking double-stranded DNA adjacent to the junction points. The authors proposed that, since DNA nicking by MutL-gamma depends on its cofactors, the asymmetric distribution of MutS-gamma and RFC-PCNA on meiotic recombination intermediates may drive biased DNA cleavage. They suggested that this mode of MutL-gamma nuclease activation may explain crossover-specific processing of Holliday junctions or their precursors in meiotic chromosomes. </p><p>Independently, Kulkarni et al. (2020) showed that PCNA was important for crossover-biased resolution. In vitro assays with human enzymes showed that PCNA and RFC were sufficient to activate the MutL-gamma endonuclease. MutL-gamma was further stimulated by the codependent activity of the pro-crossover factors EXO1 and MutS-gamma, the latter of which binds Holliday junctions. The authors found that MutL-gamma also bound various branched DNAs, including Holliday junctions, but it did not show canonical resolvase activity, suggesting that the endonuclease incises adjacent to junction branch points to achieve resolution. In vivo, Rfc facilitated MutL-gamma-dependent crossing over in budding yeast. Moreover, Pcna localized to prospective crossover sites along synapsed chromosomes. Kulkarni et al. (2020) concluded that their data highlight similarities between crossover resolution and the initiation steps of DNA mismatch repair and evoke a novel model for crossover-specific resolution of double Holliday junctions during meiosis. </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>Biochemical Features</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>Crystal Structure</em></strong></p><p>
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Bowman et al. (2004) reported the crystal structure of the 5-protein clamp loader complex (replication factor-C, RFC) of the yeast S. cerevisiae, bound to the sliding clamp (proliferating cell nuclear antigen, or PCNA). Tight interfacial coordination of the ATP analog ATP-gamma-S by RFC resulted in a spiral arrangement of the ATPase domains of the clamp loader above the PCNA ring. Placement of a model for primed DNA within the central hole of PCNA revealed a striking correspondence between the RFC spiral and the grooves of the DNA double helix. Bowman et al. (2004) concluded that this model, in which the clamp loader complex locks into primed DNA in a screwcap-like arrangement, provides a simple explanation for the process by which the engagement of primer-template junctions by the RFC:PCNA complex results in ATP hydrolysis and release of the sliding clamp on DNA. </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Luckow et al. (1994) assigned RFC1, the gene for the largest subunit of replication factor C, to 4p14-p13 by fluorescence in situ hybridization. They mapped the homolog in the mouse to chromosome 5. Lossie et al. (1995) likewise mapped this gene, which they symbolized Recc1, to human chromosome 4 by human/rodent somatic cell hybrid analysis and to mouse chromosome 5 by haplotype analysis of an interspecific backcross. </p>
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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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<p>In 25 affected individuals from 11 unrelated families with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; 614575), Cortese et al. (2019) identified a homozygous expanded 5-bp intronic repeat, (AAGGG)n, in the RFC1 gene. The variant, which was found by a combination of linkage analysis and whole-genome and whole-exome sequencing, was confirmed by Sanger sequencing. Screening of an additional cohort of 150 patients with sporadic late-onset ataxia identified the homozygous (AAGGG)n expansion in 33 cases (22%). Haplotype analysis showed that all affected individuals from the 11 families and 32 of the sporadic cases shared the same haplotype. The reference allele, a simple tandem pentanucleotide AAAAG repeat of 11 (AAAAG)11, was replaced by a variable number of expanded pentanucleotide AAGGG repeated units. The expansion size varied across different families, ranging from about 400 to 2,000 repeats, but the majority of cases had about 1,000 repeats. Repeat size was relatively stable in sibs, and there was no association between age at onset and repeat size. There were no instances of vertical transmission; all families studied consisted of affected sibs or first cousins in the same generation. Patient cells showed normal expression levels of RFC1 mRNA and protein, and postmortem brain tissue from 1 CANVAS patient had normal levels of RFC1 and FXN (606829) compared to controls. However, patient cells showed some evidence of altered pre-mRNA processing with an increase in the retention of intron 2 compared to controls. Patient fibroblasts did not show increased susceptibility to DNA damage. Cortese et al. (2019) noted that their studies did not show evidence of a loss-of-function effect. </p><p>Beecroft et al. (2020) identified a biallelic (AAAGG)10-25(AAGGG)n intronic repeat expansion of the RFC1 gene (102579.0002) in 13 patients with CANVAS: 2 from a Cook Island Maori family, 6 from a New Zealand Maori family, and 5 from unrelated New Zealand Maori families. Two of the affected individuals also had an additional repeat sequence, (AAAGG)4-6, at the distal end of the repeat sequence. A common haplotype was identified in these patients, suggesting a founder effect, with the most recent common ancestor estimated to date to 1369-1499 CE. There were no apparent phenotypic differences between this patient cohort and patients with the (AAGGG)n repeat expansion (102579.0001). </p><p>In 3 patients from 2 unrelated families in the Asian Pacific (consanguineous family Indo1 of Chinese descent and patient N1 from the island of Niue) with CANVAS, Scriba et al. (2020) identified a homozygous expanded 5-bp repeat, (ACAGG)n, in intron 2 of the RFC1 gene (102579.0007). The variant, which was found by PCR analysis and confirmed by Sanger sequencing, segregated with the disorder in family Indo1. Southern blot analysis in family Indo1 showed that the pathogenic allele was about 10,000 kb (the control allele being about 5,000 kb) and contained about 1,015 repeated units. Haplotype analysis showed that the ACAGG and AAGGG motifs share the same core haplotype, suggesting a single ancient origin of the disease. The RFC1 (ACAGG) motif was present in 7 of 26,745 samples in gnomAD (v.3), including individuals of African, South Asian, and East Asian origin. </p><p>In a 72-year-old Japanese man with sporadic CANVAS, Tsuchiya et al. (2020) identified a homozygous (ACAGG)n repeat expansion in the RFC1 gene. The patient was part of a cohort of 37 Japanese patients with late-onset cerebellar ataxia who underwent genetic studies. </p><p>In 2 patients with CANVAS, Benkirane et al. (2022) identified compound heterozygous mutations in the RFC1 gene, an AAGGG repeat expansion on one allele in both patients and a nonsense mutation (R388X; 102579.0003) in patient 1 and a frameshift mutation (c.575delA; 102579.0004) in patient 2 on the other allele. In both patients, RFC1 expression was reduced from the allele with the truncating mutation. Benkirane et al. (2022) concluded that CANVAS likely results from a loss of function of RFC1. Clinical features in these 2 patients did not differ from what had been reported in patients with homozygosity for repeat expansion mutations in RFC1. </p><p>Among 16 Japanese patients from 11 unrelated families with CANVAS, Miyatake et al. (2022) found heterogeneity for RFC1 repeat expansions. Seven patients had homozygous ACAGG(n) expansions (102579.0007), 7 had homozygous AAGGG(n) expansions (102579.0001), and 2 were compound heterozygous for ACAGG(n) and AAGGG(n) expansions. There were no interrupting sequences. Of note, of 6 affected sibs in consanguineous family A, 5 (P2-P6) were homozygous for ACAGG, whereas 1 (P1) was compound heterozygous for ACAGG and AAGGG. The number of repeats varied between 310 and 1,615. The authors found some evidence for a genotype/phenotype correlation: patients homozygous for the AAGGG repeat expansion tended to have a higher frequency of chronic cough, hearing impairment, vestibular dysfunction, autonomic dysfunction, and mild cognitive impairment compared to those with a homozygous ACAGG repeat expansion. Compound heterozygosity for these expansions was associated with a slightly later age at onset and slower disease progression, although the authors noted that this observation was difficult to explain from a functional point of view. Functional studies and studies of patient cells were not performed. In the Japanese population, the carrier frequency of the AAGGG expanded allele was 7.8%, and that of the ACAGG expanded allele was 0%; however, the authors noted that gnomAD had reported a carrier frequency of 0.26% for ACAGG in the South Asian population. The overall detection rate of RFC1 repeat expansions in the cohort studied was 5.2% (11 of 212 families). </p><p>Weber et al. (2023) identified compound heterozygous mutations in the RFC1 gene in 2 unrelated patients with CANVAS; both patients had an AAGGG repeat expansion on one allele with a different mutation on the other allele, c.2535+2T-C (102579.0005) or c.2690+1G-A (102579.0006). Both patients had an earlier onset of disease than that reported for classical CANVAS. </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>7 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME</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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RFC1, (AAGGG)n REPEAT EXPANSION
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<br />
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ClinVar: RCV000767848
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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 25 affected individuals from 11 unrelated families with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; 614575), Cortese et al. (2019) identified a homozygous expanded 5-bp intronic repeat, (AAGGG)n, in the RFC1 gene. The variant, which was found by a combination of linkage analysis and whole-genome and whole-exome sequencing, was confirmed by Sanger sequencing. Screening of an additional cohort of 150 patients with sporadic late-onset ataxia identified the homozygous (AAGGG)n expansion in 33 patients (22%). The reference allele, a simple tandem pentanucleotide AAAAG repeat of 11 (AAAAG)11, was replaced by a variable number of expanded pentanucleotide AAGGG repeated units. The expansion size varied across different families, ranging from about 400 to 2,000 repeats, but the majority of cases had about 1,000 repeats. Repeat size was relatively stable in sibs, and there was no association between age at onset and repeat size. There were no instances of vertical transmission; all families studied consisted of affected sibs or first cousins in the same generation. The expansion resides at the 3-prime end of a deep intronic AluSx3 element and increases the size of the poly(A) tail. Haplotype analysis showed that all affected individuals from the 11 families and 32 of the sporadic cases shared the same haplotype, which had had a carrier frequency of 18% in the 1000 Genomes Project database. Biallelic AAGGG repeat expansions were not found in 304 controls, although 0.7% carried an AAGGG expansion in heterozygous state. The region where the expansions occurred was highly polymorphic and often showed interruptions and nucleotide changes in the expanded sequence. Patient cells showed normal expression levels of RFC1 mRNA and protein, and postmortem brain tissue from 1 CANVAS patient had normal levels of RFC1 and FXN (606829) compared to controls. However, patient cells showed some evidence of altered pre-mRNA processing with an increase in the retention of intron 2 compared to controls. Patient fibroblasts did not show increased susceptibility to DNA damage. Cortese et al. (2019) noted that their studies did not show evidence of a loss-of-function effect. </p><p>In 2 patients with CANVAS, Benkirane et al. (2022) identified compound heterozygosity for mutations in the RFC1 gene. Both patients had the AAGGG repeat expansion on one allele; patient 1 also carried a c.1162C-T transition, resulting in an arg388-to-ter (R388X; 102579.0003) substitution, and patient 2 carried a 1-bp deletion (c.575delA; 102579.0004), resulting in a frameshift and premature termination (Asn192IlefsTer7). The mutations were identified by whole-exome sequencing and repeat primer PCR. In patient 1, the repeat expansion was inherited from the mother, and although the father was not available for testing, SNP analysis determined that the R388X mutation presumably occurred de novo on the paternal allele. In patient 2, the repeat expansion was inherited from the father, and the c.575delA mutation was inherited from the mother. RFC1 expression analysis in patient blood demonstrated that both the R388X and c.575delA mutations resulted in decreased gene expression. </p><p>In 7 unrelated Japanese patients (P10-P16) with CANVAS, Miyatake et al. (2022) identified homozygosity for the AAGGG repeat expansion in the RFC1 gene. There were no interrupting sequences. Two additional unrelated patients (P1 and P9) were compound heterozygous for AAGGG(n) and an ACAGG(n) repeat expansion (102579.0007). Functional studies and studies of patient cells were not performed. In the Japanese population, the carrier frequency of the AAGGG expanded allele was 7.8%, and that of the ACAGG expanded allele was 0%; however, the authors noted that gnomAD has reported a carrier frequency of 0.26% for ACAGG in the South Asian population. </p><p>In 2 patients with CANVAS, Weber et al. (2023) identified compound heterozygosity for mutations in the RFC1 gene. Both patients carried the AAGGG repeat expansion on one allele. Case 1 also carried a c.2535+2T-C transition (102579.0005) at the splice acceptor site of exon 19, predicted to cause a splicing abnormality. Case 2 carried a c.2690+1G-A transition (102579.0006) at the splice acceptor site of exon 20, predicted to cause a splicing abnormality. The mutations were identified by whole-exome sequencing, repeat primer PCR, or RFC1 gene screening. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME</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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RFC1, (AAAGG)10-25(AAGGG)n REPEAT EXPANSION
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<br />
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ClinVar: RCV001267634
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</div>
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<span class="mim-text-font">
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<p>In 2 patients from a Cook Island Maori family, 6 patients from a New Zealand Maori family, and 5 unrelated New Zealand Maori patients with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; 614575), Beecroft et al. (2020) identified a biallelic (AAAGG)10-25(AAGGG)n intronic repeat expansion of the RFC1 gene. Two of the affected individuals also had an additional repeat, (AAAGG)4-6, at the distal end of the repeat sequence. The mutations were identified by whole-genome sequencing, whole-exome sequencing, or direct gene analysis. The repeat expansions were characterized by repeat-primed PCR. One unaffected individual from each family was found to be a carrier for the repeat expansion. A common haplotype was identified in these patients, suggesting a founder effect with the most recent common ancestor estimated to date to 1369-1499 CE. </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>.0003 CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME</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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RFC1, ARG388TER
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<br />
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ClinVar: RCV003324872
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.1162C-T transition (c.1162C-T, NM_002913.5) in the RFC1 gene, resulting in an arg388-to-ter (R388X) substitution, that was identified in compound heterozygous state in a patient (patient 1) with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; 614575) by Benkirane et al. (2022), see 102579.0001. </p>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME</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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RFC1, 1-BP DEL, 575A
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<br />
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ClinVar: RCV003324873
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the 1-bp deletion (c.575delA, NM_002913.5) in the RFC1 gene, resulting in a frameshift and premature termination (Asn192IlefsTer7), that was identified in compound heterozygous state in a patient (patient 2) with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; 614575) by Benkirane et al. (2022), see 102579.0001. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME</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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RFC1, IVS19, T-C, +2
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<br />
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ClinVar: RCV003324874
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.2535+2T-C transition (c.2535+2T-C, NM_002913.5) in the RFC1 gene, predicted to cause a splicing abnormality, that was identified in compound heterozygous state in a patient (case 1) with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; 614575) by Weber et al. (2023), see 102579.0001. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME</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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RFC1, IVS20, G-A, +1
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<br />
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ClinVar: RCV003324875
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.2690+1G-A transition (c.2690+1G-A, NM_002913.5) in the RFC1 gene, predicted to cause a splicing abnormality, that was identified in compound heterozygous state in a patient (case 2) with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; 614575) by Weber et al. (2023), see 102579.0001. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0007 CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME</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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|
RFC1, (ACAGG)n REPEAT EXPANSION
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<br />
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ClinVar: RCV004780759
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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 patients from 2 unrelated families in the Asian Pacific (consanguineous family Indo1 of Chinese descent and patient N1 from the island of Niue) with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS; 614575), Scriba et al. (2020) identified a homozygous expanded 5-bp repeat, (ACAGG)n, in intron 2 of the RFC1 gene. The variant, which was found by PCR analysis and confirmed by Sanger sequencing, segregated with the disorder in family Indo1. Southern blot analysis in family Indo1 showed that the pathogenic allele was about 10,000 kb (the control allele being about 5,000 kb) and contained about 1,015 repeated units. Haplotype analysis showed that the ACAGG and AAGGG (102579.0001) motifs share the same core haplotype, suggesting a single ancient origin of the disease. The RFC1 (ACAGG) motif was present in 7 of 26,745 samples in gnomAD (v.3), including individuals of African, South Asian, and East Asian origin. </p><p>In a 72-year-old Japanese man with sporadic CANVAS, Tsuchiya et al. (2020) identified a homozygous (ACAGG)n repeat expansion in the RFC1 gene. The patient was part of a cohort of 37 Japanese patients with late-onset cerebellar ataxia who underwent genetic studies. </p><p>In 7 patients from 3 unrelated Japanese families with CANVAS (P2-P8), Miyatake et al. (2022) identified a homozygous ACAGG(n) repeat expansion in the RFC1 gene. There were no interrupting sequences. Of note, of 6 affected sibs in consanguineous family A, 5 (P2-P6) were homozygous for ACAGG, whereas 1 (P1) was compound heterozygous for ACAGG and AAGGG (102579.0001). Another unrelated patient (P9) was also compound heterozygous for these expansions. In the Japanese population, the carrier frequency of the AAGGG expanded allele was 7.8%, and that of the ACAGG expanded allele was 0%; however, the authors noted that gnomAD had reported a carrier frequency of 0.26% for ACAGG in the South Asian population. Functional studies and studies of patient cells were not performed. </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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Beecroft, S. J., Cortese, A. Sullivan, R., Yau, W. Y., Dyer, Z., Wu, T. Y., Mulroy, E., Pelosi, L., Rodrigues, M., Taylor, R., Mossman, S., Leadbetter, R., Cleland, J., Anderson, T., Ravenscroft, G., Laing, N. G., Houlden, H., Reilly, M. M., Roxburgh, R. H.
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<strong>A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele.</strong>
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Brain 143: 2673-2680, 2020.
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Benkirane, M., Da Cunha, D., Marelli, C., Larrieu, L., Renaud, M., Varilh, J., Pointaux, M., Baux, D., Ardouin, O., Vangoethem, C., Taulan, M., Daumas Duport, B., Bergougnoux, A., Corbille, A. G., Cossee, M., Juntas Morales, R., Tuffery-Giraud, S., Koenig, M., Isidor, B., Vincent, M. C.
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Brain 145: 3770-3775, 2022.
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Bowman, G. D., O'Donnell, M., Kuriyan, J.
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<strong>Structural analysis of a eukaryotic sliding DNA clamp-clamp loader complex.</strong>
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Bunz, F., Kobayashi, R., Stillman, B.
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Cannavo, E., Sanchez, A., Anand, R., Ranjha, L., Hugener, J., Adam, C., Acharya, A., Weyland, N., Aran-Guiu, X., Charbonnier, J.-B., Hoffmann, E. R., Borde, V., Matos, J., Cejka, P.
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<strong>Regulation of the MLH1-MLH3 endonuclease in meiosis.</strong>
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Cortese, A., Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., and 18 others.
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<strong>Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.</strong>
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Nature Genet. 51: 649-658, 2019. Note: Erratum: Nature Genet. 51: 920 only, 2019.
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Dilley, R. L., Verma, P., Cho, N. W., Winters, H. D., Wondisford, A. R., Greenberg, R. A.
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Kulkarni, D. S., Owens, S. N., Honda, M., Ito, M., Yang, Y., Corrigan, M. W., Chen, L., Quan, A. L., Hunter, N.
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Lossie, A. C., Haugen, B. R., Wood, W. M., Camper, S. A., Gordon, D. F.
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Luckow, B., Bunz, F., Stillman, B., Lichter, P., Schutz, G.
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<strong>Cloning, expression, and chromosomal localization of the 140-kilodalton subunit of replication factor C from mice and humans.</strong>
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[PubMed: 8114700]
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[Full Text: https://doi.org/10.1128/mcb.14.3.1626-1634.1994]
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<li>
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<p class="mim-text-font">
|
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Miyatake, S., Yoshida, K., Koshimizu, E., Doi, H., Yamada, M., Miyaji, Y., Ueda, N., Tsuyuzaki, J., Kodaira, M., Onoue, H., Taguri, M., Imamura, S., and 24 others.
|
|
<strong>Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.</strong>
|
|
Brain 145: 1139-1150, 2022.
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[PubMed: 35355059]
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[Full Text: https://doi.org/10.1093/brain/awab363]
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</p>
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</li>
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Okumura, K., Nogami, M., Taguchi, H., Dean, F. B., Chen, M., Pan, Z.-Q., Hurwitz, J., Shiratori, A., Murakami, Y., Ozawa, K., Eki, T.
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<strong>Assignment of the 36.5-kDa (RFC5), 37-kDa (RFC4), 38-kDa (RFC3), and 40-kDa (RFC2) subunit genes of human replication factor C to chromosome bands 12q24.2-q24.3, 3q27, 13q12.3-q13, and 7q11.23.</strong>
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Pennaneach, V., Salles-Passador, I., Munshi, A., Brickner, H., Regazzoni, K., Dick, F., Dyson, N., Chen, T.-T., Wang, J. Y. J., Fotedar, R., Fotedar, A.
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Cassandra L. Kniffin - updated : 10/31/2024<br>Hilary J. Vernon - updated : 08/28/2023<br>Ada Hamosh - updated : 01/20/2021<br>Hilary J. Vernon - updated : 11/18/2020<br>Ada Hamosh - updated : 08/30/2019<br>Cassandra L. Kniffin -updated : 04/17/2019<br>Patricia A. Hartz - updated : 1/12/2010<br>Ada Hamosh - updated : 6/22/2004<br>Stylianos E. Antonarakis - updated : 8/6/2001<br>Paul J. Converse - updated : 11/16/2000<br>Jennifer P. Macke - updated : 8/27/1997
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