4286 lines
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- *133520 - ERCC EXCISION REPAIR 4, ENDONUCLEASE CATALYTIC SUBUNIT; ERCC4
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- OMIM
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<p>
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<span class="h4">*133520</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#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/133520">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<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=ENSG00000175595;t=ENST00000311895" 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=2072" 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=133520" 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=ENSG00000175595;t=ENST00000311895" 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_005236,XM_011522424,XM_011522427,XM_047433774" 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_005236" 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=133520" 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=00594&isoform_id=00594_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/ERCC4" 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/1524411,1905924,4885217,19550957,118142857,119605523,119605524,148745634,158260475,194377974,229463004,767987039,767987046,1172384976,1172384978,1172384980,1172384982,2217305040,2462547954,2462547956,2462547958" 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/Q92889" 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=2072" 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=ENSG00000175595;t=ENST00000311895" 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=ERCC4" 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=ERCC4" 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+2072" 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/ERCC4" 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:2072" 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/2072" 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=chr16&hgg_gene=ENST00000311895.8&hgg_start=13920154&hgg_end=13952348&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3436" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3436" 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=133520[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=133520[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/ENSG00000175595" 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=ERCC4" 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=ERCC4" 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=ERCC4" 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=ERCC4&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/PA27850" 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:3436" 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/FBgn0002707.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:1354163" 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/ERCC4#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:1354163" 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/2072/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=2072" 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=WBGene00008140;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-5533" 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="mimCellLines">
|
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<span class="panel-title">
|
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:133520" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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:2072" 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=ERCC4&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
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133520
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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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ERCC EXCISION REPAIR 4, ENDONUCLEASE CATALYTIC SUBUNIT; ERCC4
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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">
|
|
EXCISION REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 4<br />
|
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XPF GENE
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ERCC4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ERCC4</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>
|
|
Cytogenetic location: <a href="/geneMap/16/205?start=-3&limit=10&highlight=205">16p13.12</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:13920154-13952348&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'})">16:13,920,154-13,952,348</a> </span>
|
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</em>
|
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</strong>
|
|
<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>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=615272,278760,278760,610965" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
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</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/16/205?start=-3&limit=10&highlight=205">
|
|
16p13.12
|
|
</a>
|
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</span>
|
|
</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Fanconi anemia, complementation group Q
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/615272"> 615272 </a>
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<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>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
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<span class="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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<p>Nucleotide excision repair (NER), which is defective in xeroderma pigmentosum (see <a href="/entry/278700">278700</a>), involves incision of a DNA strand on each side of a lesion. There is evidence that the 2 incisions made during NER are catalyzed by separate DNA endonucleases (<a href="#12" class="mim-tip-reference" title="Sijbers, A. M., de Laat, W. L., Ariza, R. R., Biggerstaff, M., Wei, Y.-F., Moggs, J. G., Carter, K. C., Shell, B. K., Evans, E., de Jong, M. C., Rademakers, S., de Rooij, J., Jaspers, N. G. J., Hoeijmakers, J. H. J., Wood, R. D. <strong>Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease.</strong> Cell 86: 811-822, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8797827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8797827</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80155-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8797827">Sijbers et al., 1996</a>). In humans, XPG endonuclease (<a href="/entry/133530">133530</a>) makes the 3-prime incision relative to the lesion. The ERCC4 gene encodes a protein that together with ERCC1 (<a href="/entry/126380">126380</a>) make up the ERCC1-XPF 5-prime endonuclease. The XPF/ERCC1 endonuclease also plays a role in interstrand crosslink (ICL) DNA repair (summary by <a href="#3" class="mim-tip-reference" title="Gregg, S. Q., Robinson, A. R., Niedernhofer, L. J. <strong>Physiological consequences of defects in ERCC1-XPF DNA repair endonuclease.</strong> DNA Repair 10: 781-791, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21612988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21612988</a>] [<a href="https://doi.org/10.1016/j.dnarep.2011.04.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21612988">Gregg et al., 2011</a> and <a href="#1" class="mim-tip-reference" title="Bogliolo, M., Schuster, B., Stoepker, C., Derkunt, B., Su, Y., Raams, A., Trujillo, J. P., Minguillon, J., Ramirez, M. J., Pujol, R,, Casado, J. A., Banos, R., and 10 others. <strong>Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.</strong> Am. J. Hum. Genet. 92: 800-806, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623386">Bogliolo et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21612988+23623386+8797827" 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="#12" class="mim-tip-reference" title="Sijbers, A. M., de Laat, W. L., Ariza, R. R., Biggerstaff, M., Wei, Y.-F., Moggs, J. G., Carter, K. C., Shell, B. K., Evans, E., de Jong, M. C., Rademakers, S., de Rooij, J., Jaspers, N. G. J., Hoeijmakers, J. H. J., Wood, R. D. <strong>Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease.</strong> Cell 86: 811-822, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8797827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8797827</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80155-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8797827">Sijbers et al. (1996)</a> isolated a human gene homologous to yeast Rad1 and found that it corrected the repair defects of xeroderma pigmentosum group F (XPF; <a href="/entry/278760">278760</a>), as well as rodent groups 4 and 11. The gene, ERCC4, encodes a 905-amino acid polypeptide with significant homology to RAD1 (<a href="/entry/603153">603153</a>) and RAD16. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8797827" 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="#12" class="mim-tip-reference" title="Sijbers, A. M., de Laat, W. L., Ariza, R. R., Biggerstaff, M., Wei, Y.-F., Moggs, J. G., Carter, K. C., Shell, B. K., Evans, E., de Jong, M. C., Rademakers, S., de Rooij, J., Jaspers, N. G. J., Hoeijmakers, J. H. J., Wood, R. D. <strong>Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease.</strong> Cell 86: 811-822, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8797827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8797827</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80155-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8797827">Sijbers et al. (1996)</a> purified the ERCC4, or XPF, protein from mammalian cells in a tight complex with ERCC1 (<a href="/entry/126380">126380</a>). This complex is a structure-specific endonuclease responsible for the 5-prime incision during repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8797827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By Northern blot analysis, <a href="#2" class="mim-tip-reference" title="Brookman, K. W., Lamerdin, J. E., Thelen, M. P., Hwang, M., Reardon, J. T., Sancar, A., Zhou, Z.-Q., Walter, C. A., Parris, C. N., Thompson, L. H. <strong>ERCC4 (XPF) encodes a human nucleotide excision repair protein with eukaryotic recombination homologs.</strong> Molec. Cell. Biol. 16: 6553-6562, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8887684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8887684</a>] [<a href="https://doi.org/10.1128/MCB.16.11.6553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8887684">Brookman et al. (1996)</a> detected human ERCC4 expression as approximately 7-kb, 3.8-kb, and 2.4-kb mRNAs. Baboon ERCC4 was expressed ubiquitously. The predicted human ERCC4 protein has 2 leucine zipper domains in the N-terminal region. ERCC4 protein expressed in mammalian cells has a molecular mass of 110-kD by Western blot analysis. In cells of an XPF patient, ERCC4 protein levels were less than 5% of normal. <a href="#2" class="mim-tip-reference" title="Brookman, K. W., Lamerdin, J. E., Thelen, M. P., Hwang, M., Reardon, J. T., Sancar, A., Zhou, Z.-Q., Walter, C. A., Parris, C. N., Thompson, L. H. <strong>ERCC4 (XPF) encodes a human nucleotide excision repair protein with eukaryotic recombination homologs.</strong> Molec. Cell. Biol. 16: 6553-6562, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8887684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8887684</a>] [<a href="https://doi.org/10.1128/MCB.16.11.6553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8887684">Brookman et al. (1996)</a> also identified a prevalent ERCC4 transcript that encodes a truncated protein in HeLa cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8887684" 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>To study the nuclear organization and dynamics of nucleotide excision repair, <a href="#4" class="mim-tip-reference" title="Houtsmuller, A. B., Rademakers, S., Nigg, A. L., Hoogstraten, D., Hoeijmakers, J. H. J., Vermeulen, W. <strong>Action of DNA repair endonuclease ERCC1/XPF in living cells.</strong> Science 284: 958-961, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10320375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10320375</a>] [<a href="https://doi.org/10.1126/science.284.5416.958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10320375">Houtsmuller et al. (1999)</a> tagged the ERCC1 subunit of the ERCC1/XPF endonuclease with green fluorescent protein and monitored its mobility in living Chinese hamster ovary cells. In the absence of DNA damage, the complex moved freely through the nucleus, with a diffusion coefficient (15 +/- 5 square microns per second) consistent with its molecular size. Ultraviolet light-induced DNA damage caused a transient dose-dependent immobilization of ERCC1/XPF, likely due to engagement of the complex in a single repair event. After 4 minutes, the complex regained mobility. These results suggested that nucleotide excision repair operates by assembly of individual nucleotide excision repair factors at sites of DNA damage rather than by preassembly of holocomplexes, and that ERCC1/XPF participates in repair of DNA damage in a distributive fashion rather than by processive scanning of large genome segments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10320375" 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="#15" class="mim-tip-reference" title="Volker, M., Mone, M. J., Karmakar, P., van Hoffen, A., Schul, W., Vermeulen, W., Hoeijmakers, J. H. J., van Driel, R., van Zeeland, A. A., Mullenders, L. H. F. <strong>Sequential assembly of the nucleotide excision repair factors in vivo.</strong> Molec. Cell 8: 213-224, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11511374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11511374</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00281-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11511374">Volker et al. (2001)</a> described the assembly of the NER complex in normal and repair-deficient (xeroderma pigmentosum) human cells by employing a novel technique of local ultraviolet irradiation combined with fluorescent antibody labeling. The damage recognition complex XPC-HR23B (<a href="/entry/613208">613208</a>, <a href="/entry/600062">600062</a>) appeared to be essential for the recruitment of all subsequent NER factors in the preincision complex, including transcription repair factor TFIIH (see <a href="/entry/189972">189972</a>). <a href="#15" class="mim-tip-reference" title="Volker, M., Mone, M. J., Karmakar, P., van Hoffen, A., Schul, W., Vermeulen, W., Hoeijmakers, J. H. J., van Driel, R., van Zeeland, A. A., Mullenders, L. H. F. <strong>Sequential assembly of the nucleotide excision repair factors in vivo.</strong> Molec. Cell 8: 213-224, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11511374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11511374</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00281-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11511374">Volker et al. (2001)</a> found that the XPA gene (<a href="/entry/611153">611153</a>) associates relatively late, is required for anchoring of ERCC1-XPF, and may be essential for activation of the endonuclease activity of XPG. These findings identified XPC as the earliest known NER factor in the reaction mechanism, gave insight into the order of subsequent NER components, provided evidence for a dual role of XPA, and supported a concept of sequential assembly of repair proteins at the site of damage rather than a preassembled repairosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11511374" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Brookman, K. W., Lamerdin, J. E., Thelen, M. P., Hwang, M., Reardon, J. T., Sancar, A., Zhou, Z.-Q., Walter, C. A., Parris, C. N., Thompson, L. H. <strong>ERCC4 (XPF) encodes a human nucleotide excision repair protein with eukaryotic recombination homologs.</strong> Molec. Cell. Biol. 16: 6553-6562, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8887684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8887684</a>] [<a href="https://doi.org/10.1128/MCB.16.11.6553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8887684">Brookman et al. (1996)</a> reported that the ERCC4 gene contains 11 exons and spans 28.2 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8887684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By study of somatic cell hybrids, <a href="#11" class="mim-tip-reference" title="Siciliano, M. J., Bachinski, L., Dolf, G., Carrano, A. V., Thompson, L. H. <strong>Chromosomal assignments of human DNA repair genes that complement Chinese hamster ovary (CHO) cell mutants. (Abstract)</strong> Cytogenet. Cell Genet. 46: 691-692, 1987."None>Siciliano et al. (1987)</a> mapped the ERCC4 gene to chromosome 16. <a href="#6" class="mim-tip-reference" title="Liu, P., Callen, D. F., Reeders, S. T., Sutherland, G. R., Thompson, L., Siciliano, M. J. <strong>Human DNA excision repair gene ERCC4 is located on chromosome 16 short arm 16p13.13-p13.3. (Abstract)</strong> Cytogenet. Cell Genet. 51: 1035 only, 1989."None>Liu et al. (1989)</a> refined the assignment of ERCC4 to 16p13.3-p13.13 based on retention of the phenotype in somatic cell hybrids containing varying fragments of human chromosome 16. <a href="#7" class="mim-tip-reference" title="Liu, P., Siciliano, J., White, B., Legerski, R., Callen, D., Reeders, S., Siciliano, M. J., Thompson, L. H. <strong>Regional mapping of human DNA excision-repair gene ERCC4 to chromosome 16p13.13-p13.2.</strong> Mutagenesis 8: 199-205, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8332082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8332082</a>] [<a href="https://doi.org/10.1093/mutage/8.3.199" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8332082">Liu et al. (1993)</a> further refined the location of the ERCC4 gene to 16p13.2-p13.13. By fluorescence in situ hybridization, <a href="#12" class="mim-tip-reference" title="Sijbers, A. M., de Laat, W. L., Ariza, R. R., Biggerstaff, M., Wei, Y.-F., Moggs, J. G., Carter, K. C., Shell, B. K., Evans, E., de Jong, M. C., Rademakers, S., de Rooij, J., Jaspers, N. G. J., Hoeijmakers, J. H. J., Wood, R. D. <strong>Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease.</strong> Cell 86: 811-822, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8797827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8797827</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80155-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8797827">Sijbers et al. (1996)</a> mapped the ERCC4 gene to 16p13.2-p13.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8797827+8332082" 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>Since ERCC4 had been assigned to chromosome 16 and a cosmid library of this chromosome was available, <a href="#14" class="mim-tip-reference" title="Thompson, L. H., Brookman, K. W., Weber, C. A., Salazar, E. P., Reardon, J. T., Sancar, A., Deng, Z., Siciliano, M. J. <strong>Molecular cloning of the human nucleotide-excision-repair gene ERCC4.</strong> Proc. Nat. Acad. Sci. 91: 6855-6859, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8041709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8041709</a>] [<a href="https://doi.org/10.1073/pnas.91.15.6855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8041709">Thompson et al. (1994)</a> chose a cloning strategy in which the UV41 NER mutant was first corrected by transfection with that library. They succeeded in isolating functional cosmid clones that mapped to the previously assigned chromosomal region of ERCC4 (16p13.2-p13.13) and partially restored UV resistance. The chromosomal localization was performed by means of fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8041709" 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><strong><em>Xeroderma Pigmentosum, Complementation Group F, And Cockayne Syndrome</em></strong></p><p>
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<a href="#12" class="mim-tip-reference" title="Sijbers, A. M., de Laat, W. L., Ariza, R. R., Biggerstaff, M., Wei, Y.-F., Moggs, J. G., Carter, K. C., Shell, B. K., Evans, E., de Jong, M. C., Rademakers, S., de Rooij, J., Jaspers, N. G. J., Hoeijmakers, J. H. J., Wood, R. D. <strong>Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease.</strong> Cell 86: 811-822, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8797827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8797827</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80155-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8797827">Sijbers et al. (1996)</a> identified causative mutations in the ERCC4 gene (see <a href="#0001">133520.0001</a> and <a href="#0002">133520.0002</a>) and strongly reduced levels of encoded protein in patients with group F xeroderma pigmentosum (XPF; <a href="/entry/278760">278760</a>). Genes encoding the XPA (<a href="/entry/611153">611153</a>), XPB (<a href="/entry/133510">133510</a>), XPC (<a href="/entry/613208">613208</a>), XPD (<a href="/entry/278730">278730</a>, <a href="/entry/126340">126340</a>), and XPG (<a href="/entry/278780">278780</a>) proteins had previously been isolated and mutations causing XP identified in each. XPF was the last of the NER-defective XP groups to be characterized. A factor defective in at least some XPE cells (<a href="/entry/278740">278740</a>) had been identified, although it is not required for the core NER system. The work of <a href="#12" class="mim-tip-reference" title="Sijbers, A. M., de Laat, W. L., Ariza, R. R., Biggerstaff, M., Wei, Y.-F., Moggs, J. G., Carter, K. C., Shell, B. K., Evans, E., de Jong, M. C., Rademakers, S., de Rooij, J., Jaspers, N. G. J., Hoeijmakers, J. H. J., Wood, R. D. <strong>Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease.</strong> Cell 86: 811-822, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8797827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8797827</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80155-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8797827">Sijbers et al. (1996)</a> demonstrated that the XPF gene is equivalent to the ERCC4 and ERCC11 genes, which are defective in rodent group 4 and 11 cells, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8797827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated patients with XPF/Cockayne syndrome (see <a href="/entry/278760">278760</a>), <a href="#5" class="mim-tip-reference" title="Kashiyama, K., Nakazawa, Y., Pilz, D. T., Guo, C., Shimada, M., Sasaki, K., Fawcett, H., Wing, J. F., Lewin, S. O., Carr, L., Li, T.-S., Yoshiura, K., and 14 others. <strong>Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.</strong> Am. J. Hum. Genet. 92: 807-819, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623389</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623389[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623389">Kashiyama et al. (2013)</a> identified compound heterozygous mutations in the ERCC4 gene (<a href="#0008">133520.0008</a>-<a href="#0010">133520.0010</a>). One of the patients also had features of Fanconi anemia (FANQ; <a href="/entry/615272">615272</a>). Dermal fibroblasts from both patients showed significantly decreased RNA synthesis activity compared to controls, indicating a deficiency in transcription-coupled NER (TC-NER), as expected for Cockayne syndrome cells, as well as a decrease in unscheduled DNA synthesis, indicating a defect in global genome NER (GG-NER). Complementation studies showed that the 2 patients could be assigned to group XPF. Both cell lines were also sensitive to the crosslinking agent mitomycin-C, indicating a defect in the repair of DNA ICLs. The common mutation carried by both patients (C236R; <a href="#0008">133520.0008</a>) showed reduced endonuclease incision activity against stem-loop DNA structures, indicating protein malfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23623389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>XFE Progeroid Syndrome</em></strong></p><p>
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<a href="#9" class="mim-tip-reference" title="Niedernhofer, L. J., Garinis, G. A., Raams, A., Lalai, A. S., Robinson, A. R., Appeldoorn, E., Odijk, H., Oostendorp, R., Ahmad, A., van Leeuwen, W., Theil, A. F., Vermeulen, W., van der Horst, G. T. J., Meinecke, P., Kleijer, W. J., Vijg, J., Jaspers, N. G. J., Hoeijmakers, J. H. J. <strong>A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.</strong> Nature 444: 1038-1043, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17183314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17183314</a>] [<a href="https://doi.org/10.1038/nature05456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17183314">Niedernhofer et al. (2006)</a> identified a homozygous point mutation in ERCC4 (R153P; <a href="#0003">133520.0003</a>) that resulted in XFE progeroid syndrome (XFEPS; <a href="/entry/610965">610965</a>). XPF-ERCC1 (XFE) fibroblasts from the patient had lower levels of ERCC4 and ERCC1 than did cells from XPF patients. XFE fibroblasts were exquisitely sensitive to ICL damage, confirming a role for XPF-ERCC1 in ICL resistance, distinct from that in nucleotide excision repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17183314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Niedernhofer, L. J., Garinis, G. A., Raams, A., Lalai, A. S., Robinson, A. R., Appeldoorn, E., Odijk, H., Oostendorp, R., Ahmad, A., van Leeuwen, W., Theil, A. F., Vermeulen, W., van der Horst, G. T. J., Meinecke, P., Kleijer, W. J., Vijg, J., Jaspers, N. G. J., Hoeijmakers, J. H. J. <strong>A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.</strong> Nature 444: 1038-1043, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17183314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17183314</a>] [<a href="https://doi.org/10.1038/nature05456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17183314">Niedernhofer et al. (2006)</a> noted a striking correlation between the phenotype of Ercc1-null mice (see <a href="/entry/126380">126380</a>) and that of human XFE progeroid syndrome. They observed that changes in these mice correlated with those seen in aged mice and developed a model connecting DNA damage, the growth hormone axis, and aging. Different mutations in XPF result in distinct clinical outcomes: either cancer, as in xeroderma pigmentosum, or progeroid symptoms, as in XFE syndrome. One explanation is that the R153 XFE mutation, compromising both nucleotide excision repair (NER) and ICL repair, results primarily in cell death and senescence in response to DNA damage. This suppresses carcinogenesis but enhances aging. In contrast, the milder NER defect in classic XPF patients causes less cell death, allowing mutation accumulation and consequently cancer. The specific sensitivity of XPF-ERRC1-deficient cells to crosslink damage makes ICLs a likely candidate for contributing to the unique phenotype of the XPE progeroid syndrome. Intriguingly, IGFBP1 (<a href="/entry/146730">146730</a>), which is extremely elevated in the Ercc1-null mouse liver, is strongly induced in rodents exposed to the crosslinking agent cisplatin, or fed a diet rich in polyunsaturated fatty acids, which promotes lipid peroxidation. <a href="#9" class="mim-tip-reference" title="Niedernhofer, L. J., Garinis, G. A., Raams, A., Lalai, A. S., Robinson, A. R., Appeldoorn, E., Odijk, H., Oostendorp, R., Ahmad, A., van Leeuwen, W., Theil, A. F., Vermeulen, W., van der Horst, G. T. J., Meinecke, P., Kleijer, W. J., Vijg, J., Jaspers, N. G. J., Hoeijmakers, J. H. J. <strong>A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.</strong> Nature 444: 1038-1043, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17183314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17183314</a>] [<a href="https://doi.org/10.1038/nature05456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17183314">Niedernhofer et al. (2006)</a> concluded that accumulation of nuclear DNA damage causes many of the pathophysiologic and metabolic changes associated with aging, probably through increased cell death or senescence, without mutations and telomere loss. This is consistent with the damage accumulation theory of aging and predicts that cytotoxic genotoxins used in adjuvant chemotherapy for cancer may promote aging. The model proposed by <a href="#9" class="mim-tip-reference" title="Niedernhofer, L. J., Garinis, G. A., Raams, A., Lalai, A. S., Robinson, A. R., Appeldoorn, E., Odijk, H., Oostendorp, R., Ahmad, A., van Leeuwen, W., Theil, A. F., Vermeulen, W., van der Horst, G. T. J., Meinecke, P., Kleijer, W. J., Vijg, J., Jaspers, N. G. J., Hoeijmakers, J. H. J. <strong>A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.</strong> Nature 444: 1038-1043, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17183314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17183314</a>] [<a href="https://doi.org/10.1038/nature05456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17183314">Niedernhofer et al. (2006)</a> reconciled 2 apparently disparate hypotheses of aging: that aging is genetically regulated and that aging is a consequence of the accumulation of stochastic damage. In fact, both are correct. Damage drives the functional decline that is associated with aging; however, a highly conserved longevity assurance mechanism, mediated by the IGF1/insulin pathway, influences how rapidly damage accumulates and function is lost. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17183314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By exome sequencing of 18 patients from the International Registry of Werner Syndrome in whom mutations in other genes causing premature aging (WRN, <a href="/entry/604611">604611</a>; LMNA, <a href="/entry/150330">150330</a>; and POLD1, <a href="/entry/174761">174761</a>) had been excluded, <a href="#8" class="mim-tip-reference" title="Mori, T., Yousefzadeh, M. J., Faridounnia, M., Chong, J. X., Hisama, F. M., Hudgins, L., Mercado, G., Wade, E. A., Barghouthy, A. S., Lee, L., Martin, G. M., Nickerson, D. A., Bamshad, M. J., University of Washington Center for Mendelian Genomics, Niedernhofer, L. J., Oshima, J. <strong>ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.</strong> Hum. Mutat. 39: 255-265, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29105242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29105242</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29105242[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.23367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29105242">Mori et al. (2018)</a> identified a patient (MME1010) with 2 mutations in the ERCC4 gene (G496H and A860D), which were found to be in cis. By screening the ERCC4 gene in an additional 24 genetically undiagnosed atypical Werner syndrome patients, <a href="#8" class="mim-tip-reference" title="Mori, T., Yousefzadeh, M. J., Faridounnia, M., Chong, J. X., Hisama, F. M., Hudgins, L., Mercado, G., Wade, E. A., Barghouthy, A. S., Lee, L., Martin, G. M., Nickerson, D. A., Bamshad, M. J., University of Washington Center for Mendelian Genomics, Niedernhofer, L. J., Oshima, J. <strong>ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.</strong> Hum. Mutat. 39: 255-265, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29105242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29105242</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29105242[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.23367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29105242">Mori et al. (2018)</a> identified a patient (CALIF1010) who was compound heterozygous for a missense mutation (R799W; <a href="#0011">133520.0011</a>) and a frameshift mutation (<a href="#0012">133520.0012</a>). Expression of ERCC4 was dramatically reduced to approximately 6% of control in patient CALIF1010, but no difference from control was seen in patient MME1010. Survival of cells in the presence of mitomycin C (a test of the mutation's effect on interstrand crosslink repair) was about 59% of that of control in patient CALIF1010, but was not reduced in patient MME1010. These data suggested that the ERCC4 variants found in compound heterozygosity are responsible for the progeroid features of the patient, but that the ERCC4 variants found in cis in patient MME1010 are unlikely to be pathogenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29105242" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Fanconi Anemia, Complementation Group Q</em></strong></p><p>
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By exome sequencing of a girl with Fanconi anemia, complementation group Q (FANCQ; <a href="/entry/615272">615272</a>), <a href="#1" class="mim-tip-reference" title="Bogliolo, M., Schuster, B., Stoepker, C., Derkunt, B., Su, Y., Raams, A., Trujillo, J. P., Minguillon, J., Ramirez, M. J., Pujol, R,, Casado, J. A., Banos, R., and 10 others. <strong>Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.</strong> Am. J. Hum. Genet. 92: 800-806, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623386">Bogliolo et al. (2013)</a> identified compound heterozygous mutations in the ERCC4 gene (<a href="#0004">133520.0004</a> and <a href="#0005">133520.0005</a>). Direct sequencing of this gene in 18 patients with unclassified Fanconi anemia revealed 1 patient with compound heterozygous mutations (<a href="#0006">133520.0006</a> and <a href="#0007">133520.0007</a>). Each patient carried 1 truncating and 1 missense mutation. Both patients had variable features consistent with Fanconi anemia, including absent thumbs, esophageal atresia, heart defects, and bone marrow failure, but neither had skin lesions suggesting UV sensitivity as seen in XP. Laboratory studies showed that patient cells had increased chromosome breakage in response to certain crosslinking agents, such as mitomycin-C and melphalan, but did not show increased sensitivity to UV light. Transduction of wildtype ERCC4 into patient cells complemented the mitomycin-C sensitivity. Detailed cellular studies showed the Fanconi anemia cells with ERCC4 mutations were completely deficient in interstrand crosslink (ICL) repair, as observed with the XFE R153P mutation (<a href="#0003">133520.0003</a>), but retained significant levels of nucleotide excision repair (NER) activity to prevent skin photosensitivity from UV damage. The Fanconi anemia-associated missense mutations were capable of translocating to the cell nucleus, interacting with ERCC1 and SLX4 (<a href="/entry/613278">613278</a>), and localizing to sites of active NER. In vitro studies showed that the mutant ERCC4 R689S (<a href="#0005">133520.0005</a>) had impaired nuclease incision activity on a stem-loop DNA substrate. The L230P mutation (<a href="#0007">133520.0007</a>) was less stable and may have a tendency to aggregate in the cytoplasm. Both missense mutations restored the incision defect of Ercc4-null mouse cells, but the cells remained sensitive to ICL, suggesting that the ICL sensitivity was not directly linked to the absence of nuclease activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23623386" 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="Bogliolo, M., Schuster, B., Stoepker, C., Derkunt, B., Su, Y., Raams, A., Trujillo, J. P., Minguillon, J., Ramirez, M. J., Pujol, R,, Casado, J. A., Banos, R., and 10 others. <strong>Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.</strong> Am. J. Hum. Genet. 92: 800-806, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623386">Bogliolo et al. (2013)</a> distinguished ERCC4-mutant phenotypes at the biochemical level. Cells from individuals with XP-F, a relatively mild form of XP, have a reduced level of ERCC4 in the nucleus because the mutant ERCC4 has a tendency to aggregate in the cytoplasm. This reduced level of ERCC4 is insufficient to mediate complete NER but still has enough ICL repair-specific functions to prevent clinical manifestations of Fanconi anemia. Mutations resulting in Fanconi anemia allow localization of the protein to the nucleus, where it exerts a certain level of NER activity but is completely deficient in ICL repair. Mutations in ERCC4 that result in the XFE progeroid syndrome result in very low levels of nuclear ERCC4 that are insufficient to support either NER or ICL repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23623386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=133520[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs869025184 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025184;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs869025184?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs869025184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs869025184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In patient XP126LO with XPF (<a href="/entry/278760">278760</a>) (<a href="#10" class="mim-tip-reference" title="Norris, P. G., Hawk, J. L. M., Avery, J. A., Giannelli, F. <strong>Xeroderma pigmentosum complementation group F in a non-Japanese patient.</strong> J. Am. Acad. Derm. 18: 1185-1188, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3372781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3372781</a>] [<a href="https://doi.org/10.1016/s0190-9622(88)70121-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3372781">Norris et al., 1988</a>), <a href="#12" class="mim-tip-reference" title="Sijbers, A. M., de Laat, W. L., Ariza, R. R., Biggerstaff, M., Wei, Y.-F., Moggs, J. G., Carter, K. C., Shell, B. K., Evans, E., de Jong, M. C., Rademakers, S., de Rooij, J., Jaspers, N. G. J., Hoeijmakers, J. H. J., Wood, R. D. <strong>Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease.</strong> Cell 86: 811-822, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8797827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8797827</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80155-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8797827">Sijbers et al. (1996)</a> demonstrated a 4-nucleotide deletion, TCTC, in a repetitive sequence at position 2281 of the XPF gene. The lesion may have been caused by replication slippage and resulted in a frameshift and a truncated protein of 803 amino acids (fs803ter). The other allele carried a C-to-T transition at nucleotide 2377 (<a href="#0002">133520.0002</a>), presumably due to deamination of a methylated cytosine at a CpG site, changing arginine-788 (conserved in S. pombe, Drosophila, and human) into a tryptophan (R788W). This patient, a compound heterozygote, had nonconsanguineous parents and was of non-Japanese ancestry. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3372781+8797827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913049 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913049;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121913049?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018048 OR RCV000120808 OR RCV000415873 OR RCV000467658 OR RCV000766208 OR RCV000768209 OR RCV001034542 OR RCV001262417 OR RCV001391196 OR RCV001787804 OR RCV002257360 OR RCV003924841" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018048, RCV000120808, RCV000415873, RCV000467658, RCV000766208, RCV000768209, RCV001034542, RCV001262417, RCV001391196, RCV001787804, RCV002257360, RCV003924841" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018048...</a>
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<p>For discussion of the arg788-to-trp (R788W) mutation in the ERCC4 gene that was found in compound heterozygous state in a patient with xeroderma pigmentosum type F (XPF; <a href="/entry/278760">278760</a>) by <a href="#12" class="mim-tip-reference" title="Sijbers, A. M., de Laat, W. L., Ariza, R. R., Biggerstaff, M., Wei, Y.-F., Moggs, J. G., Carter, K. C., Shell, B. K., Evans, E., de Jong, M. C., Rademakers, S., de Rooij, J., Jaspers, N. G. J., Hoeijmakers, J. H. J., Wood, R. D. <strong>Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease.</strong> Cell 86: 811-822, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8797827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8797827</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80155-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8797827">Sijbers et al. (1996)</a>, see <a href="#0001">133520.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8797827" 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="#13" class="mim-tip-reference" title="Sijbers, A. M., van Voorst Vader, P. C., Snoek, J. W., Raams, A., Jaspers, N. G. J., Kleijer, W. J. <strong>Homozygous R788W point mutation in the XPF gene of a patient with xeroderma pigmentosum and late-onset neurologic disease.</strong> J. Invest. Derm. 110: 832-836, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9579555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9579555</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1998.00171.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9579555">Sijbers et al. (1998)</a> found the R788W mutation in homozygous state in a second Caucasian patient with XPF. Mild ocular photophobia had been present from childhood, and acute skin reactions occurred upon exposure to sunlight. Basal and squamous cell carcinomas developed after his twenty-seventh year. In his late forties, progressive neurologic symptoms emerged, which included intellectual decline, mild chorea and ataxia, and marked cerebral and cerebellar atrophy. <a href="#13" class="mim-tip-reference" title="Sijbers, A. M., van Voorst Vader, P. C., Snoek, J. W., Raams, A., Jaspers, N. G. J., Kleijer, W. J. <strong>Homozygous R788W point mutation in the XPF gene of a patient with xeroderma pigmentosum and late-onset neurologic disease.</strong> J. Invest. Derm. 110: 832-836, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9579555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9579555</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1998.00171.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9579555">Sijbers et al. (1998)</a> stated that such neurologic abnormalities were unusual in XPF, having been described in only 1 of 17 other XPF individuals. The patient's 5-fold reduced activity of nucleotide excision repair in cultured cells, combined with moderately affected cell survival and DNA replication after UV exposure, was typical of XPF. Biochemical, genetic, and clinical data indicated the presence of considerable residual repair activity, strongly suggesting that the R788W mutation is leaky. The 2 Caucasian patients carrying this mutation were not known to be related. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9579555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913050 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913050;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121913050?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913050" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913050" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018049" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018049" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018049</a>
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<p>In an Afghan male of consanguineous parents with a novel progeroid syndrome (XFEPS; <a href="/entry/610965">610965</a>), <a href="#9" class="mim-tip-reference" title="Niedernhofer, L. J., Garinis, G. A., Raams, A., Lalai, A. S., Robinson, A. R., Appeldoorn, E., Odijk, H., Oostendorp, R., Ahmad, A., van Leeuwen, W., Theil, A. F., Vermeulen, W., van der Horst, G. T. J., Meinecke, P., Kleijer, W. J., Vijg, J., Jaspers, N. G. J., Hoeijmakers, J. H. J. <strong>A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.</strong> Nature 444: 1038-1043, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17183314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17183314</a>] [<a href="https://doi.org/10.1038/nature05456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17183314">Niedernhofer et al. (2006)</a> identified homozygosity for a G-to-C transversion at position 458 of the ERCC4 gene resulting in a nonconservative substitution of a proline for a highly conserved arginine at position 153 to proline (R153P). R153 resides in a domain harboring helicase motifs and a leucine-rich region frequently involved in protein interactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17183314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397509400 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509400;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397509400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397509400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000049244 OR RCV000722038" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049244, RCV000722038" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049244...</a>
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<p>In a Spanish girl with Fanconi anemia complementation group Q (FANCQ; <a href="/entry/615272">615272</a>), <a href="#1" class="mim-tip-reference" title="Bogliolo, M., Schuster, B., Stoepker, C., Derkunt, B., Su, Y., Raams, A., Trujillo, J. P., Minguillon, J., Ramirez, M. J., Pujol, R,, Casado, J. A., Banos, R., and 10 others. <strong>Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.</strong> Am. J. Hum. Genet. 92: 800-806, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623386">Bogliolo et al. (2013)</a> identified compound heterozygous mutations in the ERCC4 gene: a 5-bp deletion in exon 8 (c.1484_1488delCTCAA), predicted to result in a frameshift and premature termination (Thr495AsnfsTer6), and a c.2065C-A transversion in exon 11, resulting in an arg689-to-ser (R689S; <a href="#0005">133520.0005</a>) substitution at a highly conserved residue in the nuclease active site. The mutations, which were identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder. Ectopic expression of R689S in embryonic fibroblasts from Ercc4-null mice did not complement mitomycin-C sensitivity, confirming the pathogenicity of the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23623386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs149364215 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs149364215;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs149364215?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs149364215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs149364215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000049245 OR RCV001067959 OR RCV003144119 OR RCV004700343 OR RCV005016345" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049245, RCV001067959, RCV003144119, RCV004700343, RCV005016345" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049245...</a>
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<p>For discussion of the arg689-to-ser (R689S) mutation in the ERCC4 gene that was found in compound heterozygous state in a patient with Fanconi anemia complementation group Q (FANCQ; <a href="/entry/615272">615272</a>) by <a href="#1" class="mim-tip-reference" title="Bogliolo, M., Schuster, B., Stoepker, C., Derkunt, B., Su, Y., Raams, A., Trujillo, J. P., Minguillon, J., Ramirez, M. J., Pujol, R,, Casado, J. A., Banos, R., and 10 others. <strong>Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.</strong> Am. J. Hum. Genet. 92: 800-806, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623386">Bogliolo et al. (2013)</a>, see <a href="#0004">133520.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23623386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397509401 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509401;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397509401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397509401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000049246 OR RCV001310216" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049246, RCV001310216" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049246...</a>
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<p>In a German patient with Fanconi anemia complementation group Q (FANCQ; <a href="/entry/615272">615272</a>), <a href="#1" class="mim-tip-reference" title="Bogliolo, M., Schuster, B., Stoepker, C., Derkunt, B., Su, Y., Raams, A., Trujillo, J. P., Minguillon, J., Ramirez, M. J., Pujol, R,, Casado, J. A., Banos, R., and 10 others. <strong>Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.</strong> Am. J. Hum. Genet. 92: 800-806, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623386">Bogliolo et al. (2013)</a> identified compound heterozygous mutations in the ERCC4 gene: a 28-bp duplication (c.2371_2398dup28) in exon 11 of the maternal allele, predicted to result in a truncated protein (Ile800ThrfsTer24) that lacks the double helix-hairpin-helix (HhH2) domain involved in heterodimerization with ERCC1 and DNA binding, and a c.689T-C transition on the paternal allele, resulting in a leu230-to-pro (L230P; <a href="#0007">133520.0007</a>) substitution at a highly conserved residue in the helicase-like domain. Ectopic expression of L230P in embryonic fibroblasts from Ercc4-null mice did not complement mitomycin-C sensitivity, confirming the pathogenicity of the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23623386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397509402 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509402;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs397509402?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397509402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397509402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000049247" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049247" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049247</a>
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<p>For discussion of the leu230-to-pro (L230P) mutation in the ERCC4 gene that was found in compound heterozygous state in a patient with Fanconi anemia complementation group Q (FANCQ; <a href="/entry/615272">615272</a>) by <a href="#1" class="mim-tip-reference" title="Bogliolo, M., Schuster, B., Stoepker, C., Derkunt, B., Su, Y., Raams, A., Trujillo, J. P., Minguillon, J., Ramirez, M. J., Pujol, R,, Casado, J. A., Banos, R., and 10 others. <strong>Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.</strong> Am. J. Hum. Genet. 92: 800-806, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623386">Bogliolo et al. (2013)</a>, see <a href="#0006">133520.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23623386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 XERODERMA PIGMENTOSUM, TYPE F/COCKAYNE SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397509403 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509403;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397509403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397509403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000049248 OR RCV001568088 OR RCV004814985" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049248, RCV001568088, RCV004814985" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049248...</a>
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<p>In a 16-year-old boy with XPF/Cockayne syndrome (see <a href="/entry/278760">278760</a>), <a href="#5" class="mim-tip-reference" title="Kashiyama, K., Nakazawa, Y., Pilz, D. T., Guo, C., Shimada, M., Sasaki, K., Fawcett, H., Wing, J. F., Lewin, S. O., Carr, L., Li, T.-S., Yoshiura, K., and 14 others. <strong>Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.</strong> Am. J. Hum. Genet. 92: 807-819, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623389</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623389[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623389">Kashiyama et al. (2013)</a> identified compound heterozygous mutations in the ERCC4 gene: a c.706T-C transition in exon 4, resulting in a cys236-to-arg (C236R) substitution in the N-terminal large SF2 helicase domain, and a 1-bp insertion in exon 8 (c.1730_1731insA; <a href="#0009">133520.0009</a>), resulting in a frameshift and premature termination (Tyr577Ter). The C236R mutation was expressed, whereas the 1-bp insertion was subject to nonsense-mediated mRNA decay. Coimmunoprecipitation studies showed that the C236R mutant protein still interacted with ERCC1, but showed reduced affinity with the p89 subunit of TFIIH (see <a href="/entry/189972">189972</a>). Purified C236R also showed reduced endonuclease incision activity against stem-loop DNA structures, indicating protein malfunction. The patient had plantar warts, unusual freckling and sun sensitivity, poor growth, microcephaly, and contractures. Neurologic involvement included hearing impairment, learning disabilities, attention deficit-hyperactivity disorder, migraines, and feeding difficulties. Brain MRI showed some delayed myelination and basal ganglia shortening. The C236R mutation was also found in compound heterozygosity in a second patient who had some features of Fanconi anemia (see <a href="#0010">133520.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23623389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397509404 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509404;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397509404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397509404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000049249 OR RCV001646986 OR RCV001853034" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049249, RCV001646986, RCV001853034" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049249...</a>
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<p>For discussion of the 1-bp insertion (1730_1731insA) in the ERCC4 gene that was found in compound heterozygous state in a 16-year-old boy with XPF/Cockayne syndrome (see <a href="/entry/278760">278760</a>) by <a href="#5" class="mim-tip-reference" title="Kashiyama, K., Nakazawa, Y., Pilz, D. T., Guo, C., Shimada, M., Sasaki, K., Fawcett, H., Wing, J. F., Lewin, S. O., Carr, L., Li, T.-S., Yoshiura, K., and 14 others. <strong>Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.</strong> Am. J. Hum. Genet. 92: 807-819, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623389</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623389[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623389">Kashiyama et al. (2013)</a>, see <a href="#0008">133520.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23623389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs147105770 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs147105770;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs147105770?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs147105770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs147105770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000049250 OR RCV000700109 OR RCV000762956 OR RCV002222373 OR RCV003415812" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049250, RCV000700109, RCV000762956, RCV002222373, RCV003415812" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049250...</a>
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<p>In a girl with XPF/Cockayne syndrome (see <a href="/entry/278760">278760</a>), as well as bone marrow failure and renal impairment consistent with features of Fanconi anemia (see FANCQ; <a href="/entry/615272">615272</a>), <a href="#5" class="mim-tip-reference" title="Kashiyama, K., Nakazawa, Y., Pilz, D. T., Guo, C., Shimada, M., Sasaki, K., Fawcett, H., Wing, J. F., Lewin, S. O., Carr, L., Li, T.-S., Yoshiura, K., and 14 others. <strong>Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.</strong> Am. J. Hum. Genet. 92: 807-819, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623389</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623389[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23623389">Kashiyama et al. (2013)</a> identified compound heterozygous mutations in the ERCC4 gene: a c.1765C-T transition, resulting in an arg589-to-trp (R589W) substitution in the SF2 domain, and C236R (<a href="#0008">133520.0008</a>). The patient showed intrauterine growth failure and later had short stature and microcephaly. Development was globally delayed. She had sun sensitivity and hearing loss, followed by progressive ataxia, tremor, weakness, nystagmus, bone marrow failure, and renal failure. The R589W mutation, in combination with another pathogenic ERCC4 allele, had been reported in several patients with XPF, including at least 2 patients with neurologic signs (summary by <a href="#3" class="mim-tip-reference" title="Gregg, S. Q., Robinson, A. R., Niedernhofer, L. J. <strong>Physiological consequences of defects in ERCC1-XPF DNA repair endonuclease.</strong> DNA Repair 10: 781-791, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21612988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21612988</a>] [<a href="https://doi.org/10.1016/j.dnarep.2011.04.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21612988">Gregg et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23623389+21612988" 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=RCV000018048 OR RCV000120808 OR RCV000415873 OR RCV000467658 OR RCV000766208 OR RCV000768209 OR RCV001034542 OR RCV001262417 OR RCV001391196 OR RCV001787804 OR RCV002257360 OR RCV003924841" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018048, RCV000120808, RCV000415873, RCV000467658, RCV000766208, RCV000768209, RCV001034542, RCV001262417, RCV001391196, RCV001787804, RCV002257360, RCV003924841" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018048...</a>
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<p>In a 35-year-old woman with XFE progeroid syndrome (XFEPS; <a href="/entry/610965">610965</a>), <a href="#8" class="mim-tip-reference" title="Mori, T., Yousefzadeh, M. J., Faridounnia, M., Chong, J. X., Hisama, F. M., Hudgins, L., Mercado, G., Wade, E. A., Barghouthy, A. S., Lee, L., Martin, G. M., Nickerson, D. A., Bamshad, M. J., University of Washington Center for Mendelian Genomics, Niedernhofer, L. J., Oshima, J. <strong>ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.</strong> Hum. Mutat. 39: 255-265, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29105242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29105242</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29105242[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.23367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29105242">Mori et al. (2018)</a> identified compound heterozygosity for 2 mutations in the ERCC4 gene: a c.2395C-T transition (c.2395C-T, NM_005236.2), resulting in an arg799-to-trp (R799W) substitution, and a 5,656-bp deletion (c.388+1164_792+795del; <a href="#0012">133520.0012</a>), resulting in a frameshift and a premature termination codon (Gly130AspfsTer18). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29105242" 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=RCV000766209 OR RCV001034543 OR RCV001194774" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000766209, RCV001034543, RCV001194774" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000766209...</a>
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<p>For discussion of the 5,656-bp deletion (c.388+1164_792+795del, NM_005236.2) in the ERCC4 gene, resulting in a frameshift and a premature termination codon (Gly130AspfsTer18), that was found in compound heterozygous state in a patient with XFE progeroid syndrome (XFEPS; <a href="/entry/610965">610965</a>) by <a href="#8" class="mim-tip-reference" title="Mori, T., Yousefzadeh, M. J., Faridounnia, M., Chong, J. X., Hisama, F. M., Hudgins, L., Mercado, G., Wade, E. A., Barghouthy, A. S., Lee, L., Martin, G. M., Nickerson, D. A., Bamshad, M. J., University of Washington Center for Mendelian Genomics, Niedernhofer, L. J., Oshima, J. <strong>ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.</strong> Hum. Mutat. 39: 255-265, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29105242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29105242</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29105242[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.23367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29105242">Mori et al. (2018)</a>, see <a href="#0011">133520.0011</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29105242" 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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Bogliolo, M., Schuster, B., Stoepker, C., Derkunt, B., Su, Y., Raams, A., Trujillo, J. P., Minguillon, J., Ramirez, M. J., Pujol, R,, Casado, J. A., Banos, R., and 10 others.
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<strong>Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.</strong>
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Am. J. Hum. Genet. 92: 800-806, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23623386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23623386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23623386[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=23623386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.04.002" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/MCB.16.11.6553" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.dnarep.2011.04.026" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.284.5416.958" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.04.007" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/mutage/8.3.199" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.23367" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature05456" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0190-9622(88)70121-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)80155-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1523-1747.1998.00171.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.91.15.6855" target="_blank">Full Text</a>]
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Volker, M., Mone, M. J., Karmakar, P., van Hoffen, A., Schul, W., Vermeulen, W., Hoeijmakers, J. H. J., van Driel, R., van Zeeland, A. A., Mullenders, L. H. F.
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[<a href="https://doi.org/10.1016/s1097-2765(01)00281-7" target="_blank">Full Text</a>]
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Sonja A. Rasmussen - updated : 04/03/2019
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Cassandra L. Kniffin - updated : 6/20/2013<br>Ada Hamosh - updated : 4/20/2007<br>Stylianos E. Antonarakis - updated : 8/3/2001<br>Ada Hamosh - updated : 5/5/1999<br>Victor A. McKusick - updated : 7/13/1998<br>Rebekah S. Rasooly - updated : 5/8/1998
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Victor A. McKusick : 9/2/1987
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carol : 04/19/2019<br>carol : 04/04/2019<br>carol : 04/03/2019<br>carol : 10/13/2015<br>carol : 10/13/2015<br>mcolton : 6/3/2015<br>carol : 9/18/2013<br>alopez : 7/3/2013<br>alopez : 7/2/2013<br>ckniffin : 6/20/2013<br>terry : 11/15/2012<br>carol : 12/3/2010<br>carol : 1/13/2010<br>carol : 1/12/2010<br>carol : 7/12/2007<br>carol : 5/4/2007<br>carol : 5/4/2007<br>alopez : 4/24/2007<br>alopez : 4/24/2007<br>terry : 4/20/2007<br>alopez : 10/11/2005<br>mgross : 8/3/2001<br>mgross : 8/3/2001<br>alopez : 5/7/1999<br>terry : 5/5/1999<br>alopez : 10/16/1998<br>carol : 7/16/1998<br>terry : 7/13/1998<br>psherman : 5/8/1998<br>mark : 10/26/1996<br>carol : 10/10/1994<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>carol : 6/7/1989
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<h3>
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<span class="mim-font">
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<strong>*</strong> 133520
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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ERCC EXCISION REPAIR 4, ENDONUCLEASE CATALYTIC SUBUNIT; ERCC4
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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EXCISION REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 4<br />
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XPF GENE
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</span>
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</h4>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ERCC4</em></strong>
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</span>
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</p>
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</div>
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<p>
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<strong>
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<em>
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Cytogenetic location: 16p13.12
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:13,920,154-13,952,348 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<th>
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Location
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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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Inheritance
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<th>
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Phenotype <br /> mapping key
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</thead>
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<tbody>
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<td rowspan="4">
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<span class="mim-font">
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16p13.12
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</span>
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<td>
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<span class="mim-font">
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Fanconi anemia, complementation group Q
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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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615272
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</span>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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<tr>
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<td>
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<span class="mim-font">
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Xeroderma pigmentosum, group F
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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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278760
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Xeroderma pigmentosum, type F/Cockayne syndrome
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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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278760
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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XFE progeroid syndrome
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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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610965
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</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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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Nucleotide excision repair (NER), which is defective in xeroderma pigmentosum (see 278700), involves incision of a DNA strand on each side of a lesion. There is evidence that the 2 incisions made during NER are catalyzed by separate DNA endonucleases (Sijbers et al., 1996). In humans, XPG endonuclease (133530) makes the 3-prime incision relative to the lesion. The ERCC4 gene encodes a protein that together with ERCC1 (126380) make up the ERCC1-XPF 5-prime endonuclease. The XPF/ERCC1 endonuclease also plays a role in interstrand crosslink (ICL) DNA repair (summary by Gregg et al., 2011 and Bogliolo et al., 2013). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Sijbers et al. (1996) isolated a human gene homologous to yeast Rad1 and found that it corrected the repair defects of xeroderma pigmentosum group F (XPF; 278760), as well as rodent groups 4 and 11. The gene, ERCC4, encodes a 905-amino acid polypeptide with significant homology to RAD1 (603153) and RAD16. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Sijbers et al. (1996) purified the ERCC4, or XPF, protein from mammalian cells in a tight complex with ERCC1 (126380). This complex is a structure-specific endonuclease responsible for the 5-prime incision during repair. </p><p>By Northern blot analysis, Brookman et al. (1996) detected human ERCC4 expression as approximately 7-kb, 3.8-kb, and 2.4-kb mRNAs. Baboon ERCC4 was expressed ubiquitously. The predicted human ERCC4 protein has 2 leucine zipper domains in the N-terminal region. ERCC4 protein expressed in mammalian cells has a molecular mass of 110-kD by Western blot analysis. In cells of an XPF patient, ERCC4 protein levels were less than 5% of normal. Brookman et al. (1996) also identified a prevalent ERCC4 transcript that encodes a truncated protein in HeLa cells. </p><p>To study the nuclear organization and dynamics of nucleotide excision repair, Houtsmuller et al. (1999) tagged the ERCC1 subunit of the ERCC1/XPF endonuclease with green fluorescent protein and monitored its mobility in living Chinese hamster ovary cells. In the absence of DNA damage, the complex moved freely through the nucleus, with a diffusion coefficient (15 +/- 5 square microns per second) consistent with its molecular size. Ultraviolet light-induced DNA damage caused a transient dose-dependent immobilization of ERCC1/XPF, likely due to engagement of the complex in a single repair event. After 4 minutes, the complex regained mobility. These results suggested that nucleotide excision repair operates by assembly of individual nucleotide excision repair factors at sites of DNA damage rather than by preassembly of holocomplexes, and that ERCC1/XPF participates in repair of DNA damage in a distributive fashion rather than by processive scanning of large genome segments. </p><p>Volker et al. (2001) described the assembly of the NER complex in normal and repair-deficient (xeroderma pigmentosum) human cells by employing a novel technique of local ultraviolet irradiation combined with fluorescent antibody labeling. The damage recognition complex XPC-HR23B (613208, 600062) appeared to be essential for the recruitment of all subsequent NER factors in the preincision complex, including transcription repair factor TFIIH (see 189972). Volker et al. (2001) found that the XPA gene (611153) associates relatively late, is required for anchoring of ERCC1-XPF, and may be essential for activation of the endonuclease activity of XPG. These findings identified XPC as the earliest known NER factor in the reaction mechanism, gave insight into the order of subsequent NER components, provided evidence for a dual role of XPA, and supported a concept of sequential assembly of repair proteins at the site of damage rather than a preassembled repairosome. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Brookman et al. (1996) reported that the ERCC4 gene contains 11 exons and spans 28.2 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By study of somatic cell hybrids, Siciliano et al. (1987) mapped the ERCC4 gene to chromosome 16. Liu et al. (1989) refined the assignment of ERCC4 to 16p13.3-p13.13 based on retention of the phenotype in somatic cell hybrids containing varying fragments of human chromosome 16. Liu et al. (1993) further refined the location of the ERCC4 gene to 16p13.2-p13.13. By fluorescence in situ hybridization, Sijbers et al. (1996) mapped the ERCC4 gene to 16p13.2-p13.1. </p><p>Since ERCC4 had been assigned to chromosome 16 and a cosmid library of this chromosome was available, Thompson et al. (1994) chose a cloning strategy in which the UV41 NER mutant was first corrected by transfection with that library. They succeeded in isolating functional cosmid clones that mapped to the previously assigned chromosomal region of ERCC4 (16p13.2-p13.13) and partially restored UV resistance. The chromosomal localization was performed by means of fluorescence in situ hybridization. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Xeroderma Pigmentosum, Complementation Group F, And Cockayne Syndrome</em></strong></p><p>
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Sijbers et al. (1996) identified causative mutations in the ERCC4 gene (see 133520.0001 and 133520.0002) and strongly reduced levels of encoded protein in patients with group F xeroderma pigmentosum (XPF; 278760). Genes encoding the XPA (611153), XPB (133510), XPC (613208), XPD (278730, 126340), and XPG (278780) proteins had previously been isolated and mutations causing XP identified in each. XPF was the last of the NER-defective XP groups to be characterized. A factor defective in at least some XPE cells (278740) had been identified, although it is not required for the core NER system. The work of Sijbers et al. (1996) demonstrated that the XPF gene is equivalent to the ERCC4 and ERCC11 genes, which are defective in rodent group 4 and 11 cells, respectively. </p><p>In 2 unrelated patients with XPF/Cockayne syndrome (see 278760), Kashiyama et al. (2013) identified compound heterozygous mutations in the ERCC4 gene (133520.0008-133520.0010). One of the patients also had features of Fanconi anemia (FANQ; 615272). Dermal fibroblasts from both patients showed significantly decreased RNA synthesis activity compared to controls, indicating a deficiency in transcription-coupled NER (TC-NER), as expected for Cockayne syndrome cells, as well as a decrease in unscheduled DNA synthesis, indicating a defect in global genome NER (GG-NER). Complementation studies showed that the 2 patients could be assigned to group XPF. Both cell lines were also sensitive to the crosslinking agent mitomycin-C, indicating a defect in the repair of DNA ICLs. The common mutation carried by both patients (C236R; 133520.0008) showed reduced endonuclease incision activity against stem-loop DNA structures, indicating protein malfunction. </p><p><strong><em>XFE Progeroid Syndrome</em></strong></p><p>
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Niedernhofer et al. (2006) identified a homozygous point mutation in ERCC4 (R153P; 133520.0003) that resulted in XFE progeroid syndrome (XFEPS; 610965). XPF-ERCC1 (XFE) fibroblasts from the patient had lower levels of ERCC4 and ERCC1 than did cells from XPF patients. XFE fibroblasts were exquisitely sensitive to ICL damage, confirming a role for XPF-ERCC1 in ICL resistance, distinct from that in nucleotide excision repair. </p><p>Niedernhofer et al. (2006) noted a striking correlation between the phenotype of Ercc1-null mice (see 126380) and that of human XFE progeroid syndrome. They observed that changes in these mice correlated with those seen in aged mice and developed a model connecting DNA damage, the growth hormone axis, and aging. Different mutations in XPF result in distinct clinical outcomes: either cancer, as in xeroderma pigmentosum, or progeroid symptoms, as in XFE syndrome. One explanation is that the R153 XFE mutation, compromising both nucleotide excision repair (NER) and ICL repair, results primarily in cell death and senescence in response to DNA damage. This suppresses carcinogenesis but enhances aging. In contrast, the milder NER defect in classic XPF patients causes less cell death, allowing mutation accumulation and consequently cancer. The specific sensitivity of XPF-ERRC1-deficient cells to crosslink damage makes ICLs a likely candidate for contributing to the unique phenotype of the XPE progeroid syndrome. Intriguingly, IGFBP1 (146730), which is extremely elevated in the Ercc1-null mouse liver, is strongly induced in rodents exposed to the crosslinking agent cisplatin, or fed a diet rich in polyunsaturated fatty acids, which promotes lipid peroxidation. Niedernhofer et al. (2006) concluded that accumulation of nuclear DNA damage causes many of the pathophysiologic and metabolic changes associated with aging, probably through increased cell death or senescence, without mutations and telomere loss. This is consistent with the damage accumulation theory of aging and predicts that cytotoxic genotoxins used in adjuvant chemotherapy for cancer may promote aging. The model proposed by Niedernhofer et al. (2006) reconciled 2 apparently disparate hypotheses of aging: that aging is genetically regulated and that aging is a consequence of the accumulation of stochastic damage. In fact, both are correct. Damage drives the functional decline that is associated with aging; however, a highly conserved longevity assurance mechanism, mediated by the IGF1/insulin pathway, influences how rapidly damage accumulates and function is lost. </p><p>By exome sequencing of 18 patients from the International Registry of Werner Syndrome in whom mutations in other genes causing premature aging (WRN, 604611; LMNA, 150330; and POLD1, 174761) had been excluded, Mori et al. (2018) identified a patient (MME1010) with 2 mutations in the ERCC4 gene (G496H and A860D), which were found to be in cis. By screening the ERCC4 gene in an additional 24 genetically undiagnosed atypical Werner syndrome patients, Mori et al. (2018) identified a patient (CALIF1010) who was compound heterozygous for a missense mutation (R799W; 133520.0011) and a frameshift mutation (133520.0012). Expression of ERCC4 was dramatically reduced to approximately 6% of control in patient CALIF1010, but no difference from control was seen in patient MME1010. Survival of cells in the presence of mitomycin C (a test of the mutation's effect on interstrand crosslink repair) was about 59% of that of control in patient CALIF1010, but was not reduced in patient MME1010. These data suggested that the ERCC4 variants found in compound heterozygosity are responsible for the progeroid features of the patient, but that the ERCC4 variants found in cis in patient MME1010 are unlikely to be pathogenic. </p><p><strong><em>Fanconi Anemia, Complementation Group Q</em></strong></p><p>
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By exome sequencing of a girl with Fanconi anemia, complementation group Q (FANCQ; 615272), Bogliolo et al. (2013) identified compound heterozygous mutations in the ERCC4 gene (133520.0004 and 133520.0005). Direct sequencing of this gene in 18 patients with unclassified Fanconi anemia revealed 1 patient with compound heterozygous mutations (133520.0006 and 133520.0007). Each patient carried 1 truncating and 1 missense mutation. Both patients had variable features consistent with Fanconi anemia, including absent thumbs, esophageal atresia, heart defects, and bone marrow failure, but neither had skin lesions suggesting UV sensitivity as seen in XP. Laboratory studies showed that patient cells had increased chromosome breakage in response to certain crosslinking agents, such as mitomycin-C and melphalan, but did not show increased sensitivity to UV light. Transduction of wildtype ERCC4 into patient cells complemented the mitomycin-C sensitivity. Detailed cellular studies showed the Fanconi anemia cells with ERCC4 mutations were completely deficient in interstrand crosslink (ICL) repair, as observed with the XFE R153P mutation (133520.0003), but retained significant levels of nucleotide excision repair (NER) activity to prevent skin photosensitivity from UV damage. The Fanconi anemia-associated missense mutations were capable of translocating to the cell nucleus, interacting with ERCC1 and SLX4 (613278), and localizing to sites of active NER. In vitro studies showed that the mutant ERCC4 R689S (133520.0005) had impaired nuclease incision activity on a stem-loop DNA substrate. The L230P mutation (133520.0007) was less stable and may have a tendency to aggregate in the cytoplasm. Both missense mutations restored the incision defect of Ercc4-null mouse cells, but the cells remained sensitive to ICL, suggesting that the ICL sensitivity was not directly linked to the absence of nuclease activity. </p><p>Bogliolo et al. (2013) distinguished ERCC4-mutant phenotypes at the biochemical level. Cells from individuals with XP-F, a relatively mild form of XP, have a reduced level of ERCC4 in the nucleus because the mutant ERCC4 has a tendency to aggregate in the cytoplasm. This reduced level of ERCC4 is insufficient to mediate complete NER but still has enough ICL repair-specific functions to prevent clinical manifestations of Fanconi anemia. Mutations resulting in Fanconi anemia allow localization of the protein to the nucleus, where it exerts a certain level of NER activity but is completely deficient in ICL repair. Mutations in ERCC4 that result in the XFE progeroid syndrome result in very low levels of nuclear ERCC4 that are insufficient to support either NER or ICL repair. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>12 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 XERODERMA PIGMENTOSUM, TYPE F</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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ERCC4, 4-BP DEL, 2281TCTC
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|
<br />
|
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SNP: rs869025184,
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|
|
gnomAD: rs869025184,
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|
|
ClinVar: RCV000018047
|
|
|
|
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|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>In patient XP126LO with XPF (278760) (Norris et al., 1988), Sijbers et al. (1996) demonstrated a 4-nucleotide deletion, TCTC, in a repetitive sequence at position 2281 of the XPF gene. The lesion may have been caused by replication slippage and resulted in a frameshift and a truncated protein of 803 amino acids (fs803ter). The other allele carried a C-to-T transition at nucleotide 2377 (133520.0002), presumably due to deamination of a methylated cytosine at a CpG site, changing arginine-788 (conserved in S. pombe, Drosophila, and human) into a tryptophan (R788W). This patient, a compound heterozygote, had nonconsanguineous parents and was of non-Japanese ancestry. </p>
|
|
</span>
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</div>
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<div>
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|
<br />
|
|
</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>.0002 XERODERMA PIGMENTOSUM, TYPE F</strong>
|
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</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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ERCC4, ARG788TRP
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<br />
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SNP: rs121913049,
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gnomAD: rs121913049,
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|
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|
ClinVar: RCV000018048, RCV000120808, RCV000415873, RCV000467658, RCV000766208, RCV000768209, RCV001034542, RCV001262417, RCV001391196, RCV001787804, RCV002257360, RCV003924841
|
|
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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 arg788-to-trp (R788W) mutation in the ERCC4 gene that was found in compound heterozygous state in a patient with xeroderma pigmentosum type F (XPF; 278760) by Sijbers et al. (1996), see 133520.0001. </p><p>Sijbers et al. (1998) found the R788W mutation in homozygous state in a second Caucasian patient with XPF. Mild ocular photophobia had been present from childhood, and acute skin reactions occurred upon exposure to sunlight. Basal and squamous cell carcinomas developed after his twenty-seventh year. In his late forties, progressive neurologic symptoms emerged, which included intellectual decline, mild chorea and ataxia, and marked cerebral and cerebellar atrophy. Sijbers et al. (1998) stated that such neurologic abnormalities were unusual in XPF, having been described in only 1 of 17 other XPF individuals. The patient's 5-fold reduced activity of nucleotide excision repair in cultured cells, combined with moderately affected cell survival and DNA replication after UV exposure, was typical of XPF. Biochemical, genetic, and clinical data indicated the presence of considerable residual repair activity, strongly suggesting that the R788W mutation is leaky. The 2 Caucasian patients carrying this mutation were not known to be related. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
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</div>
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|
<div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 XFE PROGEROID SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
<div>
|
|
<span class="mim-text-font">
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|
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|
ERCC4, ARG153PRO
|
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<br />
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|
|
|
SNP: rs121913050,
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|
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|
|
|
gnomAD: rs121913050,
|
|
|
|
|
|
ClinVar: RCV000018049
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Afghan male of consanguineous parents with a novel progeroid syndrome (XFEPS; 610965), Niedernhofer et al. (2006) identified homozygosity for a G-to-C transversion at position 458 of the ERCC4 gene resulting in a nonconservative substitution of a proline for a highly conserved arginine at position 153 to proline (R153P). R153 resides in a domain harboring helicase motifs and a leucine-rich region frequently involved in protein interactions. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
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|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 FANCONI ANEMIA, COMPLEMENTATION GROUP Q</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ERCC4, 5-BP DEL, 1484CTCAA
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs397509400,
|
|
|
|
|
|
|
|
ClinVar: RCV000049244, RCV000722038
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Spanish girl with Fanconi anemia complementation group Q (FANCQ; 615272), Bogliolo et al. (2013) identified compound heterozygous mutations in the ERCC4 gene: a 5-bp deletion in exon 8 (c.1484_1488delCTCAA), predicted to result in a frameshift and premature termination (Thr495AsnfsTer6), and a c.2065C-A transversion in exon 11, resulting in an arg689-to-ser (R689S; 133520.0005) substitution at a highly conserved residue in the nuclease active site. The mutations, which were identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder. Ectopic expression of R689S in embryonic fibroblasts from Ercc4-null mice did not complement mitomycin-C sensitivity, confirming the pathogenicity of the mutation. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 FANCONI ANEMIA, COMPLEMENTATION GROUP Q</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ERCC4, ARG689SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs149364215,
|
|
|
|
|
|
gnomAD: rs149364215,
|
|
|
|
|
|
ClinVar: RCV000049245, RCV001067959, RCV003144119, RCV004700343, RCV005016345
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the arg689-to-ser (R689S) mutation in the ERCC4 gene that was found in compound heterozygous state in a patient with Fanconi anemia complementation group Q (FANCQ; 615272) by Bogliolo et al. (2013), see 133520.0004. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 FANCONI ANEMIA, COMPLEMENTATION GROUP Q</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ERCC4, 28-BP DUP, NT2371
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397509401,
|
|
|
|
|
|
|
|
ClinVar: RCV000049246, RCV001310216
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a German patient with Fanconi anemia complementation group Q (FANCQ; 615272), Bogliolo et al. (2013) identified compound heterozygous mutations in the ERCC4 gene: a 28-bp duplication (c.2371_2398dup28) in exon 11 of the maternal allele, predicted to result in a truncated protein (Ile800ThrfsTer24) that lacks the double helix-hairpin-helix (HhH2) domain involved in heterodimerization with ERCC1 and DNA binding, and a c.689T-C transition on the paternal allele, resulting in a leu230-to-pro (L230P; 133520.0007) substitution at a highly conserved residue in the helicase-like domain. Ectopic expression of L230P in embryonic fibroblasts from Ercc4-null mice did not complement mitomycin-C sensitivity, confirming the pathogenicity of the mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 FANCONI ANEMIA, COMPLEMENTATION GROUP Q</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ERCC4, LEU230PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397509402,
|
|
|
|
|
|
gnomAD: rs397509402,
|
|
|
|
|
|
ClinVar: RCV000049247
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the leu230-to-pro (L230P) mutation in the ERCC4 gene that was found in compound heterozygous state in a patient with Fanconi anemia complementation group Q (FANCQ; 615272) by Bogliolo et al. (2013), see 133520.0006. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 XERODERMA PIGMENTOSUM, TYPE F/COCKAYNE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ERCC4, CYS236ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397509403,
|
|
|
|
|
|
|
|
ClinVar: RCV000049248, RCV001568088, RCV004814985
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 16-year-old boy with XPF/Cockayne syndrome (see 278760), Kashiyama et al. (2013) identified compound heterozygous mutations in the ERCC4 gene: a c.706T-C transition in exon 4, resulting in a cys236-to-arg (C236R) substitution in the N-terminal large SF2 helicase domain, and a 1-bp insertion in exon 8 (c.1730_1731insA; 133520.0009), resulting in a frameshift and premature termination (Tyr577Ter). The C236R mutation was expressed, whereas the 1-bp insertion was subject to nonsense-mediated mRNA decay. Coimmunoprecipitation studies showed that the C236R mutant protein still interacted with ERCC1, but showed reduced affinity with the p89 subunit of TFIIH (see 189972). Purified C236R also showed reduced endonuclease incision activity against stem-loop DNA structures, indicating protein malfunction. The patient had plantar warts, unusual freckling and sun sensitivity, poor growth, microcephaly, and contractures. Neurologic involvement included hearing impairment, learning disabilities, attention deficit-hyperactivity disorder, migraines, and feeding difficulties. Brain MRI showed some delayed myelination and basal ganglia shortening. The C236R mutation was also found in compound heterozygosity in a second patient who had some features of Fanconi anemia (see 133520.0010). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 XERODERMA PIGMENTOSUM, TYPE F/COCKAYNE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ERCC4, 1-BP INS, 1730A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397509404,
|
|
|
|
|
|
|
|
ClinVar: RCV000049249, RCV001646986, RCV001853034
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp insertion (1730_1731insA) in the ERCC4 gene that was found in compound heterozygous state in a 16-year-old boy with XPF/Cockayne syndrome (see 278760) by Kashiyama et al. (2013), see 133520.0008. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 XERODERMA PIGMENTOSUM, TYPE F/COCKAYNE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ERCC4, ARG589TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs147105770,
|
|
|
|
|
|
gnomAD: rs147105770,
|
|
|
|
|
|
ClinVar: RCV000049250, RCV000700109, RCV000762956, RCV002222373, RCV003415812
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with XPF/Cockayne syndrome (see 278760), as well as bone marrow failure and renal impairment consistent with features of Fanconi anemia (see FANCQ; 615272), Kashiyama et al. (2013) identified compound heterozygous mutations in the ERCC4 gene: a c.1765C-T transition, resulting in an arg589-to-trp (R589W) substitution in the SF2 domain, and C236R (133520.0008). The patient showed intrauterine growth failure and later had short stature and microcephaly. Development was globally delayed. She had sun sensitivity and hearing loss, followed by progressive ataxia, tremor, weakness, nystagmus, bone marrow failure, and renal failure. The R589W mutation, in combination with another pathogenic ERCC4 allele, had been reported in several patients with XPF, including at least 2 patients with neurologic signs (summary by Gregg et al., 2011). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 XFE PROGEROID SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ERCC4, ARG799TRP
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000018048, RCV000120808, RCV000415873, RCV000467658, RCV000766208, RCV000768209, RCV001034542, RCV001262417, RCV001391196, RCV001787804, RCV002257360, RCV003924841
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 35-year-old woman with XFE progeroid syndrome (XFEPS; 610965), Mori et al. (2018) identified compound heterozygosity for 2 mutations in the ERCC4 gene: a c.2395C-T transition (c.2395C-T, NM_005236.2), resulting in an arg799-to-trp (R799W) substitution, and a 5,656-bp deletion (c.388+1164_792+795del; 133520.0012), resulting in a frameshift and a premature termination codon (Gly130AspfsTer18). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 XFE PROGEROID SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ERCC4, 5,656-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000766209, RCV001034543, RCV001194774
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 5,656-bp deletion (c.388+1164_792+795del, NM_005236.2) in the ERCC4 gene, resulting in a frameshift and a premature termination codon (Gly130AspfsTer18), that was found in compound heterozygous state in a patient with XFE progeroid syndrome (XFEPS; 610965) by Mori et al. (2018), see 133520.0011. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bogliolo, M., Schuster, B., Stoepker, C., Derkunt, B., Su, Y., Raams, A., Trujillo, J. P., Minguillon, J., Ramirez, M. J., Pujol, R,, Casado, J. A., Banos, R., and 10 others.
|
|
<strong>Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.</strong>
|
|
Am. J. Hum. Genet. 92: 800-806, 2013.
|
|
|
|
|
|
[PubMed: 23623386]
|
|
|
|
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