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Entry
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- *613534 - FANCD2/FANCI-ASSOCIATED NUCLEASE 1; FAN1
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- OMIM
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<p>
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<span class="h4">*613534</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="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/613534">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<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=ENSG00000198690;t=ENST00000362065" 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=22909" 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=613534" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000198690;t=ENST00000362065" 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_001146094,NM_001146095,NM_001146096,NM_014967,XM_011521370,XM_011521372,XM_017022013,XM_024449874,XM_047432250" 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_014967" 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=613534" 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=17205&isoform_id=17205_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/FAN1" 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/28839601,119581661,158255410,160410012,226246523,226246525,226246527,226246529,300390584,608785551,608785553,608785698,767983643,767983647,929654321,1034590046,1370466342,2217300457,2462492717,2462492719,2462492721,2462492723,2462492725,2462498212,2462498214,2462498216,2462498218,2462498220,2462543239,2462543241,2462543243,2462543245,2462543247" 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/Q9Y2M0" 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=22909" 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=ENSG00000198690;t=ENST00000362065" 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=FAN1" 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=FAN1" 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+22909" 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/FAN1" 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:22909" 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/22909" 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=chr15&hgg_gene=ENST00000362065.9&hgg_start=30903852&hgg_end=30943108&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:29170" 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:29170" 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=613534[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=613534[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/ENSG00000198690" 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=FAN1" 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=FAN1" 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=FAN1" 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=FAN1&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/PA165478601" 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:29170" 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://www.mousephenotype.org/data/genes/MGI:3045266" 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/FAN1#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:3045266" 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/22909/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://omia.org/OMIA002683/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=22909" 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=WBGene00015310;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-030131-6225" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:22909" 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=FAN1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 782738008<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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613534
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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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FANCD2/FANCI-ASSOCIATED NUCLEASE 1; FAN1
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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">
|
|
MYOTUBULARIN-RELATED PROTEIN 15; MTMR15<br />
|
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KIAA1018
|
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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=FAN1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FAN1</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/15/53?start=-3&limit=10&highlight=53">15q13.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:30903852-30943108&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'})">15:30,903,852-30,943,108</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>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
|
Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
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|
<tr>
|
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<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/15/53?start=-3&limit=10&highlight=53">
|
|
15q13.3
|
|
</a>
|
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</span>
|
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</td>
|
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|
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<td>
|
|
<span class="mim-font">
|
|
Interstitial nephritis, karyomegalic
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/614817"> 614817 </a>
|
|
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/613534" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/613534" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<p>FAN1 is a DNA endo- and exonuclease involved in the repair of DNA damage caused by crosslinking agents. FAN1 is recruited to sites of interstrand crosslink damage by interacting with the FANCI (<a href="/entry/611360">611360</a>)-FANCD2 (<a href="/entry/227646">227646</a>) complex (<a href="#8" class="mim-tip-reference" title="MacKay, C., Declais, A.-C., Lundin, C., Agostinho, A., Deans, A. J., MacArtney, T. J., Hofmann, K., Gartner, A., West, S. C., Helleday, T., Lilley, D. M. J., Rouse, J. <strong>Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2.</strong> Cell 142: 65-76, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603015[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.cell.2010.06.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603015">MacKay et al., 2010</a>; <a href="#5" class="mim-tip-reference" title="Kratz, K., Schopf, B., Kaden, S., Sendoel, A., Eberhard, R., Lademann, C., Cannavo, E., Sartori, A. A., Hengartner, M. O., Jiricny, J. <strong>Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents.</strong> Cell 142: 77-88, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603016</a>] [<a href="https://doi.org/10.1016/j.cell.2010.06.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603016">Kratz et al., 2010</a>; <a href="#11" class="mim-tip-reference" title="Smogorzewska, A., Desetty, R., Saito, T. T., Schlabach, M., Lach, F. P., Sowa, M. E., Clark, A. B., Kunkel, T. A., Harper, J. W., Colaiacovo, M. P., Elledge, S. J. <strong>A genetic screen identifies FAN1, a Fanconi-anemia-associated nuclease necessary for DNA interstrand crosslink repair.</strong> Molec. Cell 39: 36-47, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603073</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603073[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.molcel.2010.06.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603073">Smogorzewska et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20603073+20603016+20603015" 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 sequencing clones obtained from a size-fractionated brain cDNA library, <a href="#9" class="mim-tip-reference" title="Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong> DNA Res. 6: 63-70, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10231032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10231032</a>] [<a href="https://doi.org/10.1093/dnares/6.1.63" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10231032">Nagase et al. (1999)</a> cloned FAN1, which they designated KIAA1018. The deduced protein contains 1,017 amino acids. RT-PCR analysis detected relatively uniform FAN1 expression in all adult and fetal tissues and specific adult brain regions examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10231032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Kratz, K., Schopf, B., Kaden, S., Sendoel, A., Eberhard, R., Lademann, C., Cannavo, E., Sartori, A. A., Hengartner, M. O., Jiricny, J. <strong>Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents.</strong> Cell 142: 77-88, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603016</a>] [<a href="https://doi.org/10.1016/j.cell.2010.06.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603016">Kratz et al. (2010)</a> stated that the FAN1 protein contains a predicted N-terminal RAD18 (<a href="/entry/605256">605256</a>)-like ubiquitin (<a href="/entry/191339">191339</a>)-binding zinc finger domain and a C-terminal nuclease domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20603016" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., and 32 others. <strong>FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.</strong> Nature Genet. 44: 910-915, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22772369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22772369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22772369[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22772369">Zhou et al. (2012)</a> found expression of the FAN1 gene in multiple parenchymatous human tissues, including the kidney, liver, neuronal tissue, and female reproductive organs. The expression pattern differed from that of FANCD2, which was found primarily in lymphatic and bone marrow-derived sources, as well as in skin and testes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22772369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using tandem affinity purification and large-scale immunoprecipitation analysis, followed by mass spectroscopy, <a href="#2" class="mim-tip-reference" title="Cannavo, E., Gerrits, B., Marra, G., Schlapbach, R., Jiricny, J. <strong>Characterization of the interactome of the human MutL homologues MLH1, PMS1, and PMS2.</strong> J. Biol. Chem. 282: 2976-2986, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17148452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17148452</a>] [<a href="https://doi.org/10.1074/jbc.M609989200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17148452">Cannavo et al. (2007)</a> identified FAN1 as a protein that interacted with the mismatch repair proteins MLH1 (<a href="/entry/120436">120436</a>), PMS1 (<a href="/entry/600258">600258</a>), and PMS2 (<a href="/entry/600259">600259</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17148452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Independently, <a href="#8" class="mim-tip-reference" title="MacKay, C., Declais, A.-C., Lundin, C., Agostinho, A., Deans, A. J., MacArtney, T. J., Hofmann, K., Gartner, A., West, S. C., Helleday, T., Lilley, D. M. J., Rouse, J. <strong>Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2.</strong> Cell 142: 65-76, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603015[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.cell.2010.06.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603015">MacKay et al. (2010)</a> and <a href="#5" class="mim-tip-reference" title="Kratz, K., Schopf, B., Kaden, S., Sendoel, A., Eberhard, R., Lademann, C., Cannavo, E., Sartori, A. A., Hengartner, M. O., Jiricny, J. <strong>Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents.</strong> Cell 142: 77-88, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603016</a>] [<a href="https://doi.org/10.1016/j.cell.2010.06.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603016">Kratz et al. (2010)</a> found that recombinant human FAN1 exhibited DNA endonuclease activity toward 5-prime flaps and had 5-prime exonuclease activity mediated by its C-terminal nuclease domain. Only DNA damage caused by interstrand crosslinking agents resulted in recruitment of FAN1 to sites of DNA damage, and this recruitment required interaction of FAN1 with monoubiquitinated FANCD2. Depletion of FAN1 sensitized human cell lines to interstrand crosslinking agents and caused chromosomal instability. <a href="#11" class="mim-tip-reference" title="Smogorzewska, A., Desetty, R., Saito, T. T., Schlabach, M., Lach, F. P., Sowa, M. E., Clark, A. B., Kunkel, T. A., Harper, J. W., Colaiacovo, M. P., Elledge, S. J. <strong>A genetic screen identifies FAN1, a Fanconi-anemia-associated nuclease necessary for DNA interstrand crosslink repair.</strong> Molec. Cell 39: 36-47, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603073</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603073[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.molcel.2010.06.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603073">Smogorzewska et al. (2010)</a> reported similar findings and showed that FAN1 required both FANCI and FANCD2 (<a href="/entry/613984">613984</a>) for localization at sites of DNA damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20603073+20603016+20603015" 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 central event in the Fanconi pathway is monoubiquitylation of the FANCI-FANCD2 protein complex. <a href="#7" class="mim-tip-reference" title="Liu, T., Ghosal, G., Yuan, J., Chen, J., Huang, J. <strong>FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair.</strong> Science 329: 693-696, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20671156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20671156</a>] [<a href="https://doi.org/10.1126/science.1192656" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20671156">Liu et al. (2010)</a> characterized FAN1, which promotes interstrand crosslink repair in a manner strictly dependent on its ability to accumulate at or near sites of DNA damage and that relies on monoubiquitylation of the FANCI-FANCD2 complex. <a href="#7" class="mim-tip-reference" title="Liu, T., Ghosal, G., Yuan, J., Chen, J., Huang, J. <strong>FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair.</strong> Science 329: 693-696, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20671156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20671156</a>] [<a href="https://doi.org/10.1126/science.1192656" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20671156">Liu et al. (2010)</a> concluded that the monoubiquitylated complex recruits the downstream repair protein FAN1 and facilitates repair of DNA interstrand crosslinks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20671156" 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="#16" class="mim-tip-reference" title="Yoshikiyo, K., Kratz, K., Hirota, K., Nishihara, K., Takata, M., Kurumizaka, H., Horimoto, S., Takeda, S., Jiricny, J. <strong>KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents.</strong> Proc. Nat. Acad. Sci. 107: 21553-21557, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21115814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21115814</a>] [<a href="https://doi.org/10.1073/pnas.1011081107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21115814">Yoshikiyo et al. (2010)</a> found that recombinant chicken Fan1 functioned as an endonuclease that mostly shared substrate specificity with its human ortholog. Fan1 also had a 5-prime-to-3-prime exonuclease activity that preferred double-stranded DNA ends. Knockout of Fan1 in chicken DT40 cells did not affect growth, but the cells became more sensitive to interstrand crosslink-inducing agents. Loss of Fan1 resulted in chromosomal instability quantitatively comparable to that seen in Fanconi anemia (FA) cells. Fan1 was not involved in processing of spontaneous DNA damage with FA proteins, as FA and Fan1 deficiencies were additive rather than epistatic. Unlike FA cells, Fan1 deficiency in DT40 cells did not affect ubiquitylation of Fancd2. Fan1 and Fancd2 colocalized and were targeted to the same foci, and this targeting depended on a functional FA complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21115814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a series of mutant Fan1 and Fancd2 constructs with wildtype and mutant mouse embryonic fibroblasts, <a href="#6" class="mim-tip-reference" title="Lachaud, C., Moreno, A., Marchesi, F., Toth, R., Blow, J. J., Rouse, J. <strong>Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability.</strong> Science 351: 846-849, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26797144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26797144</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26797144[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aad5634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26797144">Lachaud et al. (2016)</a> found that the nuclease activity of Fan1, but not its interaction with ubiquitinated Fancd2, was required for Fan1-dependent repair of DNA interstrand crosslinks. However, both its nuclease activity and its interaction with ubiquitinated Fancd2 were required for Fan1 to restrain stalled forks in DNA and prevent subsequent chromosome abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26797144" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a transcriptomewide association study, <a href="#4" class="mim-tip-reference" title="Goold, R., Flower, M., Moss, D. H., Medway, C., Wood-Kaczmar, A., Andre, R., Farshim, P., Bates, G. P., Holmans, P., Jones, L., Tabrizi, S. J. <strong>FAN1 modifies Huntington's disease progression by stabilizing the expanded HTT CAG repeat.</strong> Hum. Molec. Genet. 28: 650-661, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30358836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30358836</a>] [<a href="https://doi.org/10.1093/hmg/ddy375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30358836">Goold et al. (2019)</a> found that FAN1 expression was associated with slower Huntington disease (HD; <a href="/entry/143100">143100</a>) progression and delayed age at onset. Expression of FAN1 in FAN1 -/- U2OS osteosarcoma cells increased the length-dependent stability of the CAG repeat in the huntingtin (HTT; <a href="/entry/613004">613004</a>) gene. The nuclease domain of FAN1 was not required to stabilize the HTT CAG repeat in U2OS cells. FAN1 protected against expansion of the endogenous HTT CAG repeat, as knockout of FAN1 increased the expansion rate. FAN1 bound to the HTT CAG repeat, and the binding was not length specific. Moreover, CAG repeat binding by FAN1 was not specific to the HTT gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30358836" 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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Using FAN1 DNA crystal structures and biochemical data, <a href="#15" class="mim-tip-reference" title="Wang, R., Persky, N. S., Yoo, B., Ouerfelli, O., Smogorzewska, A., Elledge, S. J., Pavletich, N. P. <strong>Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1.</strong> Science 346: 1127-1130, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25430771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25430771</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25430771[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1258973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25430771">Wang et al. (2014)</a> found that human FAN1 cleaves DNA successively at every third nucleotide in a DNA interstrand crosslink. In vitro, this exonuclease mechanism allows FAN1 to excise an interstrand crosslink from 1 strand through flanking incisions. DNA access requires a 5-prime terminal phosphate anchor at a nick or a 1- or 2-nucleotide flap and is augmented by a 3-prime flap, suggesting that FAN1 action is coupled to DNA synthesis or recombination. <a href="#15" class="mim-tip-reference" title="Wang, R., Persky, N. S., Yoo, B., Ouerfelli, O., Smogorzewska, A., Elledge, S. J., Pavletich, N. P. <strong>Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1.</strong> Science 346: 1127-1130, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25430771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25430771</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25430771[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1258973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25430771">Wang et al. (2014)</a> suggested that FAN1's mechanism of interstrand crosslink excision is well suited for processing other localized DNA adducts as well. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25430771" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using radiation hybrid analysis, <a href="#9" class="mim-tip-reference" title="Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong> DNA Res. 6: 63-70, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10231032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10231032</a>] [<a href="https://doi.org/10.1093/dnares/6.1.63" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10231032">Nagase et al. (1999)</a> mapped the FAN1 gene to chromosome 15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10231032" 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="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 07/14/2021."None>Stumpf (2021)</a> mapped the FAN1 gene to chromosome 15q13.3 based on an alignment of the FAN1 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC047882" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC047882</a>) with the genomic sequence (GRCh38).</p>
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<p>In affected members of 9 unrelated families with karyomegalic interstitial nephritis (KMIN; <a href="/entry/614817">614817</a>), <a href="#17" class="mim-tip-reference" title="Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., and 32 others. <strong>FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.</strong> Nature Genet. 44: 910-915, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22772369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22772369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22772369[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22772369">Zhou et al. (2012)</a> identified 12 different homozygous or compound heterozygous mutations in the FAN1 gene (see, e.g., <a href="#0001">613534.0001</a>-<a href="#0008">613534.0008</a>). Eight of the 12 mutations resulted in a truncated protein. The first mutation was identified by homozygosity mapping and exome sequencing in 1 affected family. Upon exposure to mitomycin C, FAN1 mutant cells showed genomic instability, as manifest by increased chromatid breaks and radial chromosomes on metaphase spreads. Although the results of the test for Fanconi anemia (see, e.g., <a href="/entry/227650">227650</a>), diepoxybutane-induced breakage, were negative in FAN1-mutant cells lines, these cells still showed decreased survival in response to either inducer of interstrand crosslink repair (ICL) compared to controls. Thus, there were subtle differences in cell reaction between FANCA (<a href="/entry/607139">607139</a>)-mutant and FAN1-mutant cells, suggesting that these proteins act in somewhat distinct manners. None of the FAN1 mutant proteins was able to correct mitomycin C-induced decreased survival in cells lacking FAN1 nuclease activity. Morpholino knockdown of Fan1 in zebrafish embryos resulted in a nephronophthisis (NPHP; <a href="/entry/256100">256100</a>)-like phenotype, with shortened and curved body axis, as well as a Fanconi anemia-like phenotype, with microcephaly, microphthalmia, and massive apoptosis. There was evidence of activation of the DNA damage repair pathway, as demonstrated by increased signaling for gamma-H2AX (H2AFX; <a href="/entry/601772">601772</a>). Knockdown of born Fan1 and p53 (<a href="/entry/191170">191170</a>) in zebrafish caused renal cysts, reminiscent of a ciliopathy. In the fawn-hooded hypertensive rat, an animal model of chronic kidney disease, as well as in kidney samples from humans with genetically heterogeneous forms of chronic kidney disease, <a href="#17" class="mim-tip-reference" title="Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., and 32 others. <strong>FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.</strong> Nature Genet. 44: 910-915, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22772369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22772369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22772369[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22772369">Zhou et al. (2012)</a> found increased nuclear staining for gamma-H2AX, indicating activation of the DNA damage response pathway. These findings supported the hypothesis that DNA lesions and DNA damage response pathways may partially drive renal damage in NPHP-related ciliopathies and in chronic kidney disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22772369" 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>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation in the FAN1 gene and colorectal cancer, see <a href="/entry/114500">114500</a>.</p>
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<p><a href="#6" class="mim-tip-reference" title="Lachaud, C., Moreno, A., Marchesi, F., Toth, R., Blow, J. J., Rouse, J. <strong>Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability.</strong> Science 351: 846-849, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26797144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26797144</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26797144[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aad5634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26797144">Lachaud et al. (2016)</a> found that homozygous transgenic mice expressing a nuclease-dead (nd) Fan1, but not wildtype controls, developed tumors by 20 month of age. The majority of tumors in Fan1(nd/nd) mice were pulmonary carcinomas or hepatic lymphomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26797144" 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> rs953653119 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs953653119;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/rs953653119?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=rs953653119" 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=rs953653119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 brothers of Maori descent with karyomegalic interstitial nephritis (KMIN; <a href="/entry/614817">614817</a>) (<a href="#10" class="mim-tip-reference" title="Palmer, D., Lallu, S., Matheson, P., Bethwaite, P., Tompson, K. <strong>Karyomegalic interstitial nephritis: a pitfall in urine cytology.</strong> Diagn. Cytopathol. 35: 179-182, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17304531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17304531</a>] [<a href="https://doi.org/10.1002/dc.20603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17304531">Palmer et al., 2007</a>), <a href="#17" class="mim-tip-reference" title="Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., and 32 others. <strong>FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.</strong> Nature Genet. 44: 910-915, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22772369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22772369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22772369[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22772369">Zhou et al. (2012)</a> identified a homozygous 2120G-A transition in exon 8 of the FAN1 gene, resulting in a trp707-to-ter (W707X) substitution. The mutation was found by homozygosity mapping and exome sequencing of the candidate region. The mutation was not found in 96 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22772369+17304531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of 2 French families with karyomegalic interstitial nephritis (KMIN; <a href="/entry/614817">614817</a>), <a href="#17" class="mim-tip-reference" title="Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., and 32 others. <strong>FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.</strong> Nature Genet. 44: 910-915, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22772369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22772369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22772369[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22772369">Zhou et al. (2012)</a> identified compound heterozygosity for 2 mutations in the FAN1 gene. Both families carried a T-to-A transition in intron 2 (1234+2T-A), resulting in a splice site mutation on 1 allele. One family (<a href="#3" class="mim-tip-reference" title="Godin, M., Francois, A., Le Roy, F., Morin, J.-P., Creppy, E., Hemet, J., Fillastre, J.-P. <strong>Karyomegalic interstitial nephritis. (Letter)</strong> Am. J. Kidney Dis. 27: 166 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8546134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8546134</a>] [<a href="https://doi.org/10.1016/s0272-6386(96)90047-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8546134">Godin et al., 1996</a>) carried a 2-bp deletion in exon 7 (2036_2037delGA; <a href="#0003">613534.0003</a>) on the second allele, and the other family carried a 2245C-T transition in exon 9, resulting in an arg749-to-ter (R749X; <a href="#0004">613534.0004</a>) substitution on the second allele. None of the mutations were found in 96 controls, and haplotype analysis suggested a founder effect for the splice site mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8546134+22772369" 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">rs1566921085 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1566921085;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=rs1566921085" 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=rs1566921085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the 2-bp deletion in the FAN1 gene (2036_2037delGA) that was found in compound heterozygous state in affected members of a family with karyomegalic interstitial nephritis (KMIN; <a href="/entry/614817">614817</a>) by <a href="#17" class="mim-tip-reference" title="Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., and 32 others. <strong>FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.</strong> Nature Genet. 44: 910-915, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22772369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22772369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22772369[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22772369">Zhou et al. (2012)</a>, see <a href="#0002">613534.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22772369" 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> rs387907279 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907279;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/rs387907279?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=rs387907279" 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=rs387907279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the arg749-to-ter mutation (R749X) in the FAN1 gene that was found in compound heterozygous state in affected members of a family with karyomegalic interstitial nephritis (KMIN; <a href="/entry/614817">614817</a>) by <a href="#17" class="mim-tip-reference" title="Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., and 32 others. <strong>FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.</strong> Nature Genet. 44: 910-915, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22772369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22772369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22772369[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22772369">Zhou et al. (2012)</a>, see <a href="#0002">613534.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22772369" 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> rs750056424 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs750056424;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/rs750056424?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=rs750056424" 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=rs750056424" 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=RCV000501496 OR RCV001857188" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000501496, RCV001857188" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000501496...</a>
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<p>In a woman of Spanish descent with karyomegalic interstitial nephritis (KMIN; <a href="/entry/614817">614817</a>) originally reported by <a href="#12" class="mim-tip-reference" title="Spoendlin, M., Moch, H., Brunner, F., Brunner, W., Burger, H.-R., Kiss, D., Wegmann, W., Dalquen, P., Oberholzer, M., Thiel, G., Mihatsch, M. J. <strong>Karyomegalic interstitial nephritis: further support for a distinct entity and evidence for a genetic defect.</strong> Am. J. Kidney Dis. 25: 242-252, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7847351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7847351</a>] [<a href="https://doi.org/10.1016/0272-6386(95)90005-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7847351">Spoendlin et al. (1995)</a>, <a href="#17" class="mim-tip-reference" title="Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., and 32 others. <strong>FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.</strong> Nature Genet. 44: 910-915, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22772369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22772369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22772369[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22772369">Zhou et al. (2012)</a> identified a homozygous 1-bp deletion (2616delA) in exon 12 of the FAN1 gene, resulting in a frameshift and premature termination (Asp873ThrfsTer17). An unrelated woman of French descent (<a href="#14" class="mim-tip-reference" title="Verine, J., Reade, R., Janin, A., Droz, D. <strong>Nephrite interstitielle caryomegalique: un nouveau cas francais.</strong> Ann. Path. 30: 240-242, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20621605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20621605</a>] [<a href="https://doi.org/10.1016/j.annpat.2010.03.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20621605">Verine et al., 2010</a>) was compound heterozygous for 2616delA and a G-to-A transition in intron 3 (1375+1G-A), resulting in a splice site mutation (<a href="#0006">613534.0006</a>). Neither mutation was found in 96 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20621605+7847351+22772369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>For discussion of the splice site mutation in the FAN1 gene (1375+1G-A) that was found in compound heterozygous state in a patient with karyomegalic interstitial nephritis (KMIN; <a href="/entry/614817">614817</a>) by <a href="#17" class="mim-tip-reference" title="Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., and 32 others. <strong>FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.</strong> Nature Genet. 44: 910-915, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22772369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22772369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22772369[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22772369">Zhou et al. (2012)</a>, see <a href="#0005">613534.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22772369" 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> rs765970053 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs765970053;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/rs765970053?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=rs765970053" 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=rs765970053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with karyomegalic interstitial nephritis (KMIN; <a href="/entry/614817">614817</a>) originally reported by <a href="#1" class="mim-tip-reference" title="Baba, F., Nanovic, L., Jaffery, J. B., Friedl, A. <strong>Karyomegalic tubulointerstitial nephritis--a case report.</strong> Path. Res. Pract. 202: 555-559, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16678356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16678356</a>] [<a href="https://doi.org/10.1016/j.prp.2006.02.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16678356">Baba et al. (2006)</a>, <a href="#17" class="mim-tip-reference" title="Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., and 32 others. <strong>FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.</strong> Nature Genet. 44: 910-915, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22772369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22772369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22772369[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22772369">Zhou et al. (2012)</a> identified compound heterozygosity for 2 mutations in the FAN1 gene: a 2-bp deletion (2774_2775delTT) in exon 12, resulting in a frameshift and premature termination (Leu925ProfsTer25), and a 2810G-A transition in exon 13, resulting in a gly937-to-asp (G937D; <a href="#0008">613534.0008</a>) substitution at a highly conserved residue. Neither mutation was found in 96 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16678356+22772369" 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 INTERSTITIAL NEPHRITIS, KARYOMEGALIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387907280 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907280;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/rs387907280?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=rs387907280" 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=rs387907280" 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=RCV000030748" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030748" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030748</a>
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<p>For discussion of the gly937-to-asp (G937D) mutation in the FAN1 gene that was found in compound heterozygous state in a patient with karyomegalic interstitial nephritis (KMIN; <a href="#0007">613534.0007</a>) by <a href="#17" class="mim-tip-reference" title="Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., and 32 others. <strong>FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.</strong> Nature Genet. 44: 910-915, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22772369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22772369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22772369[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22772369">Zhou et al. (2012)</a>, see <a href="#0007">613534.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22772369" 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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Baba, F., Nanovic, L., Jaffery, J. B., Friedl, A.
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<strong>Karyomegalic tubulointerstitial nephritis--a case report.</strong>
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Path. Res. Pract. 202: 555-559, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16678356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16678356</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16678356" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Characterization of the interactome of the human MutL homologues MLH1, PMS1, and PMS2.</strong>
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Godin, M., Francois, A., Le Roy, F., Morin, J.-P., Creppy, E., Hemet, J., Fillastre, J.-P.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8546134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8546134</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8546134" 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/s0272-6386(96)90047-5" target="_blank">Full Text</a>]
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Goold, R., Flower, M., Moss, D. H., Medway, C., Wood-Kaczmar, A., Andre, R., Farshim, P., Bates, G. P., Holmans, P., Jones, L., Tabrizi, S. J.
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<strong>FAN1 modifies Huntington's disease progression by stabilizing the expanded HTT CAG repeat.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30358836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30358836</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30358836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddy375" target="_blank">Full Text</a>]
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Kratz, K., Schopf, B., Kaden, S., Sendoel, A., Eberhard, R., Lademann, C., Cannavo, E., Sartori, A. A., Hengartner, M. O., Jiricny, J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603016</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20603016" 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.cell.2010.06.022" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.aad5634" target="_blank">Full Text</a>]
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Liu, T., Ghosal, G., Yuan, J., Chen, J., Huang, J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20671156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20671156</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20671156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10231032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10231032</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10231032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Palmer2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Palmer, D., Lallu, S., Matheson, P., Bethwaite, P., Tompson, K.
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|
<strong>Karyomegalic interstitial nephritis: a pitfall in urine cytology.</strong>
|
|
Diagn. Cytopathol. 35: 179-182, 2007.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17304531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17304531</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17304531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/dc.20603" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Smogorzewska2010" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
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Smogorzewska, A., Desetty, R., Saito, T. T., Schlabach, M., Lach, F. P., Sowa, M. E., Clark, A. B., Kunkel, T. A., Harper, J. W., Colaiacovo, M. P., Elledge, S. J.
|
|
<strong>A genetic screen identifies FAN1, a Fanconi-anemia-associated nuclease necessary for DNA interstrand crosslink repair.</strong>
|
|
Molec. Cell 39: 36-47, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603073</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603073[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=20603073" 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.molcel.2010.06.023" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Spoendlin1995" class="mim-anchor"></a>
|
|
<div class="">
|
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<p class="mim-text-font">
|
|
Spoendlin, M., Moch, H., Brunner, F., Brunner, W., Burger, H.-R., Kiss, D., Wegmann, W., Dalquen, P., Oberholzer, M., Thiel, G., Mihatsch, M. J.
|
|
<strong>Karyomegalic interstitial nephritis: further support for a distinct entity and evidence for a genetic defect.</strong>
|
|
Am. J. Kidney Dis. 25: 242-252, 1995.
|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7847351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7847351</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7847351" 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/10.1016/0272-6386(95)90005-5" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Stumpf2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
|
Stumpf, A. M.
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|
<strong>Personal Communication.</strong>
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|
Baltimore, Md. 07/14/2021.
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Verine2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Verine, J., Reade, R., Janin, A., Droz, D.
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<strong>Nephrite interstitielle caryomegalique: un nouveau cas francais.</strong>
|
|
Ann. Path. 30: 240-242, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20621605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20621605</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20621605" 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.annpat.2010.03.001" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Wang2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, R., Persky, N. S., Yoo, B., Ouerfelli, O., Smogorzewska, A., Elledge, S. J., Pavletich, N. P.
|
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<strong>Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1.</strong>
|
|
Science 346: 1127-1130, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25430771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25430771</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25430771[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=25430771" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1258973" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Yoshikiyo2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yoshikiyo, K., Kratz, K., Hirota, K., Nishihara, K., Takata, M., Kurumizaka, H., Horimoto, S., Takeda, S., Jiricny, J.
|
|
<strong>KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents.</strong>
|
|
Proc. Nat. Acad. Sci. 107: 21553-21557, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21115814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21115814</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21115814" 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/10.1073/pnas.1011081107" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Zhou2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, W., Otto, E. A., Cluckey, A., Airik, R., Hurd, T. W., Chaki, M., Diaz, K., Lach, F. P., Bennett, G. R., Gee, H. Y., Ghosh, A. K., Natarajan, S., and 32 others.
|
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<strong>FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.</strong>
|
|
Nature Genet. 44: 910-915, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22772369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22772369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22772369[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=22772369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.2347" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 07/14/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 03/28/2019<br>Patricia A. Hartz - updated : 08/10/2016<br>Ada Hamosh - updated : 1/14/2015<br>Cassandra L. Kniffin - updated : 5/20/2013<br>Cassandra L. Kniffin - updated : 9/13/2012<br>Ada Hamosh - updated : 9/1/2010
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz : 8/20/2010
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/15/2021
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</span>
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</div>
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</div>
|
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<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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|
alopez : 07/14/2021<br>alopez : 07/14/2021<br>carol : 05/23/2019<br>mgross : 03/29/2019<br>mgross : 03/28/2019<br>alopez : 08/10/2016<br>alopez : 08/11/2015<br>mcolton : 7/31/2015<br>alopez : 1/14/2015<br>alopez : 1/14/2015<br>carol : 8/29/2013<br>ckniffin : 5/20/2013<br>carol : 9/13/2012<br>ckniffin : 9/13/2012<br>alopez : 9/2/2010<br>terry : 9/1/2010<br>mgross : 8/20/2010
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</span>
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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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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
|
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<strong>*</strong> 613534
|
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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FANCD2/FANCI-ASSOCIATED NUCLEASE 1; FAN1
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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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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
MYOTUBULARIN-RELATED PROTEIN 15; MTMR15<br />
|
|
KIAA1018
|
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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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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: FAN1</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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<p>
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<span class="mim-text-font">
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|
<strong>SNOMEDCT:</strong> 782738008;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: 15q13.3
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 15:30,903,852-30,943,108 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
|
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</p>
|
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</div>
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<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">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
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</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
15q13.3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Interstitial nephritis, karyomegalic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614817
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>FAN1 is a DNA endo- and exonuclease involved in the repair of DNA damage caused by crosslinking agents. FAN1 is recruited to sites of interstrand crosslink damage by interacting with the FANCI (611360)-FANCD2 (227646) complex (MacKay et al., 2010; Kratz et al., 2010; Smogorzewska et al., 2010). </p>
|
|
</span>
|
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<div>
|
|
<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</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 sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1999) cloned FAN1, which they designated KIAA1018. The deduced protein contains 1,017 amino acids. RT-PCR analysis detected relatively uniform FAN1 expression in all adult and fetal tissues and specific adult brain regions examined. </p><p>Kratz et al. (2010) stated that the FAN1 protein contains a predicted N-terminal RAD18 (605256)-like ubiquitin (191339)-binding zinc finger domain and a C-terminal nuclease domain. </p><p>Zhou et al. (2012) found expression of the FAN1 gene in multiple parenchymatous human tissues, including the kidney, liver, neuronal tissue, and female reproductive organs. The expression pattern differed from that of FANCD2, which was found primarily in lymphatic and bone marrow-derived sources, as well as in skin and testes. </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>Using tandem affinity purification and large-scale immunoprecipitation analysis, followed by mass spectroscopy, Cannavo et al. (2007) identified FAN1 as a protein that interacted with the mismatch repair proteins MLH1 (120436), PMS1 (600258), and PMS2 (600259). </p><p>Independently, MacKay et al. (2010) and Kratz et al. (2010) found that recombinant human FAN1 exhibited DNA endonuclease activity toward 5-prime flaps and had 5-prime exonuclease activity mediated by its C-terminal nuclease domain. Only DNA damage caused by interstrand crosslinking agents resulted in recruitment of FAN1 to sites of DNA damage, and this recruitment required interaction of FAN1 with monoubiquitinated FANCD2. Depletion of FAN1 sensitized human cell lines to interstrand crosslinking agents and caused chromosomal instability. Smogorzewska et al. (2010) reported similar findings and showed that FAN1 required both FANCI and FANCD2 (613984) for localization at sites of DNA damage. </p><p>A central event in the Fanconi pathway is monoubiquitylation of the FANCI-FANCD2 protein complex. Liu et al. (2010) characterized FAN1, which promotes interstrand crosslink repair in a manner strictly dependent on its ability to accumulate at or near sites of DNA damage and that relies on monoubiquitylation of the FANCI-FANCD2 complex. Liu et al. (2010) concluded that the monoubiquitylated complex recruits the downstream repair protein FAN1 and facilitates repair of DNA interstrand crosslinks. </p><p>Yoshikiyo et al. (2010) found that recombinant chicken Fan1 functioned as an endonuclease that mostly shared substrate specificity with its human ortholog. Fan1 also had a 5-prime-to-3-prime exonuclease activity that preferred double-stranded DNA ends. Knockout of Fan1 in chicken DT40 cells did not affect growth, but the cells became more sensitive to interstrand crosslink-inducing agents. Loss of Fan1 resulted in chromosomal instability quantitatively comparable to that seen in Fanconi anemia (FA) cells. Fan1 was not involved in processing of spontaneous DNA damage with FA proteins, as FA and Fan1 deficiencies were additive rather than epistatic. Unlike FA cells, Fan1 deficiency in DT40 cells did not affect ubiquitylation of Fancd2. Fan1 and Fancd2 colocalized and were targeted to the same foci, and this targeting depended on a functional FA complex. </p><p>Using a series of mutant Fan1 and Fancd2 constructs with wildtype and mutant mouse embryonic fibroblasts, Lachaud et al. (2016) found that the nuclease activity of Fan1, but not its interaction with ubiquitinated Fancd2, was required for Fan1-dependent repair of DNA interstrand crosslinks. However, both its nuclease activity and its interaction with ubiquitinated Fancd2 were required for Fan1 to restrain stalled forks in DNA and prevent subsequent chromosome abnormalities. </p><p>In a transcriptomewide association study, Goold et al. (2019) found that FAN1 expression was associated with slower Huntington disease (HD; 143100) progression and delayed age at onset. Expression of FAN1 in FAN1 -/- U2OS osteosarcoma cells increased the length-dependent stability of the CAG repeat in the huntingtin (HTT; 613004) gene. The nuclease domain of FAN1 was not required to stabilize the HTT CAG repeat in U2OS cells. FAN1 protected against expansion of the endogenous HTT CAG repeat, as knockout of FAN1 increased the expansion rate. FAN1 bound to the HTT CAG repeat, and the binding was not length specific. Moreover, CAG repeat binding by FAN1 was not specific to the HTT gene. </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>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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|
Using FAN1 DNA crystal structures and biochemical data, Wang et al. (2014) found that human FAN1 cleaves DNA successively at every third nucleotide in a DNA interstrand crosslink. In vitro, this exonuclease mechanism allows FAN1 to excise an interstrand crosslink from 1 strand through flanking incisions. DNA access requires a 5-prime terminal phosphate anchor at a nick or a 1- or 2-nucleotide flap and is augmented by a 3-prime flap, suggesting that FAN1 action is coupled to DNA synthesis or recombination. Wang et al. (2014) suggested that FAN1's mechanism of interstrand crosslink excision is well suited for processing other localized DNA adducts as well. </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>Using radiation hybrid analysis, Nagase et al. (1999) mapped the FAN1 gene to chromosome 15. </p><p>Stumpf (2021) mapped the FAN1 gene to chromosome 15q13.3 based on an alignment of the FAN1 sequence (GenBank BC047882) with the genomic sequence (GRCh38).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In affected members of 9 unrelated families with karyomegalic interstitial nephritis (KMIN; 614817), Zhou et al. (2012) identified 12 different homozygous or compound heterozygous mutations in the FAN1 gene (see, e.g., 613534.0001-613534.0008). Eight of the 12 mutations resulted in a truncated protein. The first mutation was identified by homozygosity mapping and exome sequencing in 1 affected family. Upon exposure to mitomycin C, FAN1 mutant cells showed genomic instability, as manifest by increased chromatid breaks and radial chromosomes on metaphase spreads. Although the results of the test for Fanconi anemia (see, e.g., 227650), diepoxybutane-induced breakage, were negative in FAN1-mutant cells lines, these cells still showed decreased survival in response to either inducer of interstrand crosslink repair (ICL) compared to controls. Thus, there were subtle differences in cell reaction between FANCA (607139)-mutant and FAN1-mutant cells, suggesting that these proteins act in somewhat distinct manners. None of the FAN1 mutant proteins was able to correct mitomycin C-induced decreased survival in cells lacking FAN1 nuclease activity. Morpholino knockdown of Fan1 in zebrafish embryos resulted in a nephronophthisis (NPHP; 256100)-like phenotype, with shortened and curved body axis, as well as a Fanconi anemia-like phenotype, with microcephaly, microphthalmia, and massive apoptosis. There was evidence of activation of the DNA damage repair pathway, as demonstrated by increased signaling for gamma-H2AX (H2AFX; 601772). Knockdown of born Fan1 and p53 (191170) in zebrafish caused renal cysts, reminiscent of a ciliopathy. In the fawn-hooded hypertensive rat, an animal model of chronic kidney disease, as well as in kidney samples from humans with genetically heterogeneous forms of chronic kidney disease, Zhou et al. (2012) found increased nuclear staining for gamma-H2AX, indicating activation of the DNA damage response pathway. These findings supported the hypothesis that DNA lesions and DNA damage response pathways may partially drive renal damage in NPHP-related ciliopathies and in chronic kidney disease. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
|
|
For discussion of a possible association between variation in the FAN1 gene and colorectal cancer, see 114500.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lachaud et al. (2016) found that homozygous transgenic mice expressing a nuclease-dead (nd) Fan1, but not wildtype controls, developed tumors by 20 month of age. The majority of tumors in Fan1(nd/nd) mice were pulmonary carcinomas or hepatic lymphomas. </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">
|
|
<strong>ALLELIC VARIANTS</strong>
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</span>
|
|
<strong>8 Selected Examples):</strong>
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</span>
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</h4>
|
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<div>
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<p />
|
|
</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>.0001 INTERSTITIAL NEPHRITIS, KARYOMEGALIC</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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FAN1, TRP707TER
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<br />
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SNP: rs953653119,
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gnomAD: rs953653119,
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ClinVar: RCV000030741
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 brothers of Maori descent with karyomegalic interstitial nephritis (KMIN; 614817) (Palmer et al., 2007), Zhou et al. (2012) identified a homozygous 2120G-A transition in exon 8 of the FAN1 gene, resulting in a trp707-to-ter (W707X) substitution. The mutation was found by homozygosity mapping and exome sequencing of the candidate region. The mutation was not found in 96 controls. </p>
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</span>
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</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 INTERSTITIAL NEPHRITIS, KARYOMEGALIC</strong>
|
|
</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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|
|
FAN1, IVS2DS, T-A, +2
|
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<br />
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|
|
SNP: rs767435461,
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|
|
|
|
|
gnomAD: rs767435461,
|
|
|
|
|
|
ClinVar: RCV000030742
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 French families with karyomegalic interstitial nephritis (KMIN; 614817), Zhou et al. (2012) identified compound heterozygosity for 2 mutations in the FAN1 gene. Both families carried a T-to-A transition in intron 2 (1234+2T-A), resulting in a splice site mutation on 1 allele. One family (Godin et al., 1996) carried a 2-bp deletion in exon 7 (2036_2037delGA; 613534.0003) on the second allele, and the other family carried a 2245C-T transition in exon 9, resulting in an arg749-to-ter (R749X; 613534.0004) substitution on the second allele. None of the mutations were found in 96 controls, and haplotype analysis suggested a founder effect for the splice site mutation. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 INTERSTITIAL NEPHRITIS, KARYOMEGALIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FAN1, 2-BP DEL, 2036GA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1566921085,
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|
|
|
|
|
|
|
ClinVar: RCV000030743
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 2-bp deletion in the FAN1 gene (2036_2037delGA) that was found in compound heterozygous state in affected members of a family with karyomegalic interstitial nephritis (KMIN; 614817) by Zhou et al. (2012), see 613534.0002. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 INTERSTITIAL NEPHRITIS, KARYOMEGALIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FAN1, ARG749TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387907279,
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|
|
|
|
|
gnomAD: rs387907279,
|
|
|
|
|
|
ClinVar: RCV000030744, RCV001852612, RCV004751230
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the arg749-to-ter mutation (R749X) in the FAN1 gene that was found in compound heterozygous state in affected members of a family with karyomegalic interstitial nephritis (KMIN; 614817) by Zhou et al. (2012), see 613534.0002. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 INTERSTITIAL NEPHRITIS, KARYOMEGALIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FAN1, 1-BP DEL, 2616A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs750056424,
|
|
|
|
|
|
gnomAD: rs750056424,
|
|
|
|
|
|
ClinVar: RCV000501496, RCV001857188
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman of Spanish descent with karyomegalic interstitial nephritis (KMIN; 614817) originally reported by Spoendlin et al. (1995), Zhou et al. (2012) identified a homozygous 1-bp deletion (2616delA) in exon 12 of the FAN1 gene, resulting in a frameshift and premature termination (Asp873ThrfsTer17). An unrelated woman of French descent (Verine et al., 2010) was compound heterozygous for 2616delA and a G-to-A transition in intron 3 (1375+1G-A), resulting in a splice site mutation (613534.0006). Neither mutation was found in 96 controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 INTERSTITIAL NEPHRITIS, KARYOMEGALIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FAN1, IVS3DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1305708707,
|
|
|
|
|
|
|
|
ClinVar: RCV000030746
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the splice site mutation in the FAN1 gene (1375+1G-A) that was found in compound heterozygous state in a patient with karyomegalic interstitial nephritis (KMIN; 614817) by Zhou et al. (2012), see 613534.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 INTERSTITIAL NEPHRITIS, KARYOMEGALIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FAN1, 2-BP DEL, 2774TT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs765970053,
|
|
|
|
|
|
gnomAD: rs765970053,
|
|
|
|
|
|
ClinVar: RCV000030747
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with karyomegalic interstitial nephritis (KMIN; 614817) originally reported by Baba et al. (2006), Zhou et al. (2012) identified compound heterozygosity for 2 mutations in the FAN1 gene: a 2-bp deletion (2774_2775delTT) in exon 12, resulting in a frameshift and premature termination (Leu925ProfsTer25), and a 2810G-A transition in exon 13, resulting in a gly937-to-asp (G937D; 613534.0008) substitution at a highly conserved residue. Neither mutation was found in 96 controls. </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 INTERSTITIAL NEPHRITIS, KARYOMEGALIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FAN1, GLY937ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387907280,
|
|
|
|
|
|
gnomAD: rs387907280,
|
|
|
|
|
|
ClinVar: RCV000030748
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gly937-to-asp (G937D) mutation in the FAN1 gene that was found in compound heterozygous state in a patient with karyomegalic interstitial nephritis (KMIN; 613534.0007) by Zhou et al. (2012), see 613534.0007. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
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|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
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