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Entry
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- *608111 - FANCL GENE; FANCL
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*608111</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/608111">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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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=ENSG00000115392;t=ENST00000233741" 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=55120" 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=608111" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000115392;t=ENST00000233741" 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_001114636,NM_001374615,NM_001410792,NM_018062,NR_156742,NR_164659,XM_005264395,XM_011532939,XM_011532940,XM_011532942,XM_011532944,XM_011532945,XM_017004416,XM_047444852,XM_047444853,XM_047444854,XM_047444855,XM_047444856,XR_007077528" 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_018062" 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=608111" 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=06997&isoform_id=06997_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/FANCL" 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/7022300,32493396,46255698,49472819,62822472,116241360,119620461,119620462,119620463,119620464,119620465,119620466,167860138,194387444,530367763,767914778,767914780,767914784,767914790,767914792,1034614918,1757649832,2217329108,2217329110,2217329112,2217329115,2217329119,2287254602,2462574643,2462574645,2462574647,2462574649,2462574652,2462574654,2462574656,2462574658,2462574660,2462574662,2462574664,2462574666" 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/Q9NW38" 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=55120" 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=ENSG00000115392;t=ENST00000233741" 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=FANCL" 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=FANCL" 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+55120" 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/FANCL" 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:55120" 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/55120" 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=chr2&hgg_gene=ENST00000233741.9&hgg_start=58159243&hgg_end=58241380&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:20748" 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:20748" 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=608111[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=608111[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://www.deciphergenomics.org/gene/FANCL/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000115392" 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=FANCL" 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=FANCL" 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=FANCL" 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="http://www.rockefeller.edu/fanconi/mutate/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FANCL&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/PA134887656" 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:20748" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0037781.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1914280" 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/FANCL#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:1914280" 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/55120/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=55120" 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://zfin.org/ZDB-GENE-040426-1045" 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:55120" 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=FANCL&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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608111
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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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FANCL GENE; FANCL
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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PHD FINGER PROTEIN 9; PHF9<br />
|
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FANCONI ANEMIA-ASSOCIATED POLYPEPTIDE, 43-KD; FAAP43
|
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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=FANCL" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FANCL</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/2/274?start=-3&limit=10&highlight=274">2p16.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:58159243-58241380&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'})">2:58,159,243-58,241,380</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
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Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
|
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<tbody>
|
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<tr>
|
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<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/274?start=-3&limit=10&highlight=274">
|
|
2p16.1
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Fanconi anemia, complementation group L
|
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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/614083"> 614083 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/608111" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/608111" 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>By mass spectrometry, <a href="#6" class="mim-tip-reference" title="Meetei, A. R., de Winter, J. P., Medhurst, A. L., Wallisch, M., Waisfisz, Q., van de Vrugt, H. J., Oostra, A. B., Yan, Z., Ling, C., Bishop, C. E., Hoatlin, M. E., Joenje, H., Wang, W. <strong>A novel ubiquitin ligase is deficient in Fanconi anemia.</strong> Nature Genet. 35: 165-170, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12973351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12973351</a>] [<a href="https://doi.org/10.1038/ng1241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12973351">Meetei et al. (2003)</a> identified a previously isolated 43-kD FA-associated polypeptide (<a href="#7" class="mim-tip-reference" title="Meetei, A. R., Sechi, S., Wallisch, M., Yang, D., Young, M. K., Joenje, H., Hoatlin, M. E., Wang, W. <strong>A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.</strong> Molec. Cell. Biol. 23: 3417-3426, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12724401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12724401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12724401[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/10.1128/MCB.23.10.3417-3426.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12724401">Meetei et al., 2003</a>) as PHD finger protein-9 (PHF9). The deduced 373-amino acid protein, which contains 3 potential WD40 repeats and a PHD-type zinc finger motif, shares 80% sequence identity with its mouse homolog. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12973351+12724401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Meetei, A. R., de Winter, J. P., Medhurst, A. L., Wallisch, M., Waisfisz, Q., van de Vrugt, H. J., Oostra, A. B., Yan, Z., Ling, C., Bishop, C. E., Hoatlin, M. E., Joenje, H., Wang, W. <strong>A novel ubiquitin ligase is deficient in Fanconi anemia.</strong> Nature Genet. 35: 165-170, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12973351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12973351</a>] [<a href="https://doi.org/10.1038/ng1241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12973351">Meetei et al. (2003)</a> presented several pieces of evidence that suggested that PHF9 is a stable component of the FA core complex. They detected PHF9 in both the nuclear and cytoplasmic extracts of wildtype cells; however, in lysates from 2 FANCA (<a href="/entry/607139">607139</a>) cell lines, the level of PHF9 was markedly lower than wildtype in the nuclear extract but was normal in the cytoplasm, suggesting that the nuclear accumulation of PHF9 depends on FANCA. <a href="#6" class="mim-tip-reference" title="Meetei, A. R., de Winter, J. P., Medhurst, A. L., Wallisch, M., Waisfisz, Q., van de Vrugt, H. J., Oostra, A. B., Yan, Z., Ling, C., Bishop, C. E., Hoatlin, M. E., Joenje, H., Wang, W. <strong>A novel ubiquitin ligase is deficient in Fanconi anemia.</strong> Nature Genet. 35: 165-170, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12973351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12973351</a>] [<a href="https://doi.org/10.1038/ng1241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12973351">Meetei et al. (2003)</a> found that PHF9 possessed E3 ubiquitin ligase activity in vitro and was essential for FANCD2 (<a href="/entry/227646">227646</a>) monoubiquitination in vivo. They concluded that PHF9 is crucial in the FA pathway as the catalytic subunit required for monoubiquitination of FANCD2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12973351" 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="#3" class="mim-tip-reference" title="Grompe, M. <strong>FANCL, as in ligase.</strong> Nature Genet. 35: 113-114, 2003."None>Grompe (2003)</a> pointed out that PHF9 was the first Fanconi anemia protein identified by a biochemical approach and the first Fanconi anemia protein with a defined enzymatic activity. In the Fanconi anemia core complex, which senses exogenous DNA damage associated with DNA replication, PHF9 had been designated FAAP43. <a href="#3" class="mim-tip-reference" title="Grompe, M. <strong>FANCL, as in ligase.</strong> Nature Genet. 35: 113-114, 2003."None>Grompe (2003)</a> stated that FAAP90, FAAP100, and FAAP250 probably represent additional Fanconi anemia proteins that hold promise of offering insight into the function of the pathway.</p><p>Using yeast 2-hybrid and coimmunoprecipitation assays, <a href="#10" class="mim-tip-reference" title="Tremblay, C. S., Huang, F. F., Habi, O., Huard, C. C., Godin, C., Levesque, G., Carreau, M. <strong>HES1 is a novel interactor of the Fanconi anemia core complex.</strong> Blood 112: 2062-2070, 2008. Note: Erratum: Blood 114: 3974 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18550849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18550849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18550849[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood-2008-04-152710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18550849">Tremblay et al. (2008)</a> found that HES1 (<a href="/entry/139605">139605</a>), a NOTCH1 (<a href="/entry/190198">190198</a>) pathway component involved in hematopoietic stem cell (HSC) self-renewal, interacted directly with FANCA, FANCF (<a href="/entry/603467">603467</a>), FANCG (XRCC9; <a href="/entry/602956">602956</a>), and FANCL, but not with other FA core complex components. Mutation analysis showed that interactions with individual FA core components required different domains within HES1. HES1 did not interact with FA core components if any of them contained an FA-related mutation, suggesting that a functional FA pathway is required for HES1 interaction. Depletion of HES1 from HeLa cells resulted in failure of normal interactions between individual FA core components, as well as altered protein levels and mislocalization of some FA core components. Depletion of HES1 also increased cell sensitivity to the DNA crosslinking agent mitomycin C (MMC) and reduced MMC-induced monoubiquitination of FANCD2 and localization of FANCD2 to MMC-induced foci. <a href="#10" class="mim-tip-reference" title="Tremblay, C. S., Huang, F. F., Habi, O., Huard, C. C., Godin, C., Levesque, G., Carreau, M. <strong>HES1 is a novel interactor of the Fanconi anemia core complex.</strong> Blood 112: 2062-2070, 2008. Note: Erratum: Blood 114: 3974 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18550849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18550849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18550849[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood-2008-04-152710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18550849">Tremblay et al. (2008)</a> concluded that interaction with HES1 is required for normal FA core complex function in the DNA damage response. They proposed that the HSC defect in FA may result from the inability of HES1 to interact with the defective FA core complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18550849" 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 yeast 2-hybrid analysis, <a href="#12" class="mim-tip-reference" title="Zhang, Y., Zhou, X., Zhao, L., Li, C., Zhu, H., Xu, L., Shan, L., Liao, X., Guo, Z., Huang, P. <strong>UBE2W interacts with FANCL and regulates the monoubiquitination of Fanconi anemia protein FANCD2.</strong> Molec. Cells 31: 113-122, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21229326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21229326</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21229326[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/10.1007/s10059-011-0015-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21229326">Zhang et al. (2011)</a> showed that mouse ubiquitin-conjugating enzyme-2W (UBE2W; <a href="/entry/614277">614277</a>) interacted with Fancl. They confirmed the interaction by protein pull-down and coimmunoprecipitation analyses. Fancl showed a ubiquitous intracellular localization in the absence of Ube2w and a nuclear localization in the presence of Ube2w. Ube2w exhibited ubiquitin-conjugating activity and monoubiquitinated the PHD domain of Fancl in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21229326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#8" class="mim-tip-reference" title="Shakeel, S., Rajendra, E., Alcon, P., O'Reilly, F., Chorev, D. S., Maslen, S., Degliesposti, G., Russo, C. J., He, S., Hill, C. H., Skehel, J. M., Scheres, S. H. W., Patel, K. J., Rappsilber, J., Robinson, C. V., Passmore, L. A. <strong>Structure of the Fanconi anaemia monoubiquitin ligase complex.</strong> Nature 575: 234-237, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31666700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31666700</a>] [<a href="https://doi.org/10.1038/s41586-019-1703-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31666700">Shakeel et al. (2019)</a> reconstituted an active, recombinant Fanconi anemia core complex, and used cryoelectron microscopy and mass spectrometry to determine its structure. The FA core complex comprises 2 central dimers of the FANCB (<a href="/entry/300515">300515</a>) and FA-associated protein of 100 kD (FAAP100; <a href="/entry/611301">611301</a>) subunits, flanked by 2 copies of the RING finger subunit FANCL. These 2 heterotrimers act as a scaffold to assemble the remaining 5 subunits, resulting in an extended asymmetric structure. Destabilization of the scaffold would disrupt the entire complex, resulting in a nonfunctional FA pathway. Thus, the structure provides a mechanistic basis for the low numbers of patients with mutations in FANCB, FANCL, and FAAP100. Despite a lack of sequence homology, FANCB and FAAP100 adopt similar structures. The 2 FANCL subunits are in different conformations at opposite ends of the complex, suggesting that each FANCL has a distinct role. <a href="#8" class="mim-tip-reference" title="Shakeel, S., Rajendra, E., Alcon, P., O'Reilly, F., Chorev, D. S., Maslen, S., Degliesposti, G., Russo, C. J., He, S., Hill, C. H., Skehel, J. M., Scheres, S. H. W., Patel, K. J., Rappsilber, J., Robinson, C. V., Passmore, L. A. <strong>Structure of the Fanconi anaemia monoubiquitin ligase complex.</strong> Nature 575: 234-237, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31666700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31666700</a>] [<a href="https://doi.org/10.1038/s41586-019-1703-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31666700">Shakeel et al. (2019)</a> suggested that this structural and functional asymmetry of dimeric RING finger domains may be a general feature of E3 ligases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31666700" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 12/06/2019."None>Stumpf (2019)</a> mapped the FANCL gene to chromosome 2p16.1 based on an alignment of the FANCL sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC009042.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC009042.1</a>) with the genomic sequence (GRCh38). The mouse homolog maps to chromosome 11 (<a href="#1" class="mim-tip-reference" title="Agoulnik, A. I., Lu, B., Zhu, Q., Truong, C., Ty, M. T., Arango, N., Chada, K. K., Bishop, C. E. <strong>A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd.</strong> Hum. Molec. Genet. 11: 3047-3053, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417526</a>] [<a href="https://doi.org/10.1093/hmg/11.24.3047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12417526">Agoulnik et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12417526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Meetei, A. R., de Winter, J. P., Medhurst, A. L., Wallisch, M., Waisfisz, Q., van de Vrugt, H. J., Oostra, A. B., Yan, Z., Ling, C., Bishop, C. E., Hoatlin, M. E., Joenje, H., Wang, W. <strong>A novel ubiquitin ligase is deficient in Fanconi anemia.</strong> Nature Genet. 35: 165-170, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12973351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12973351</a>] [<a href="https://doi.org/10.1038/ng1241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12973351">Meetei et al. (2003)</a> detected little or no PHF9 protein in a cell line (EUFA868) derived from an individual with Fanconi anemia of an unassigned complementation group. PHF9 cDNA from this cell line was found to lack exon 11, which removed the conserved PHD finger and part of the third WD40 repeat (<a href="#0001">608111.0001</a>). The complementation group was designated FANCL (<a href="/entry/614083">614083</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12973351" 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 male patient with FA of complementation group L, <a href="#2" class="mim-tip-reference" title="Ali, A. M., Kirby, M., Jansen, M., Lach, F. P., Schulte, J., Singh, T. R., Batish, S. D., Auerbach, A. D., Williams, D. A., Meetei, A. R. <strong>Identification and characterization of mutations in FANCL gene: a second case of Fanconi anemia belonging to FA-L complementation group.</strong> Hum. Mutat. 30: E761-E770, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19405097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19405097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19405097[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19405097">Ali et al. (2009)</a> identified compound heterozygous mutations in the FANCL gene (<a href="#0002">608111.0002</a>-<a href="#0003">608111.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19405097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated infants with lethal FANCL, <a href="#11" class="mim-tip-reference" title="Vetro, A., Iascone, M., Limongelli, I., Ameziane, N., Gana, S., Della Mina, E., Giussani, U., Ciccone, R., Forlino, A., Pezzoli, L., Rooimans, M. A., van Essen, A. J., Messa, J., Rizzuti, T., Bianchi, P., Dorsman, J., de Winter, J. P., Lalatta, F., Zuffardi, O. <strong>Loss-of-function FANCL mutations associate with severe Fanconi anemia overlapping the VACTERL association.</strong> Hum. Mutat. 36: 562-568, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25754594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25754594</a>] [<a href="https://doi.org/10.1002/humu.22784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25754594">Vetro et al. (2015)</a> identified 2 different homozygous truncating mutations in the FANCL gene (<a href="#0004">608111.0004</a> and <a href="#0005">608111.0005</a>). The mutation in the first patient was found by whole-exome sequencing and segregated with the disorder in the family. The mutation in the second patient was found by targeted sequencing of known Fanconi anemia genes. Cell lines from both patients showed increased chromosomal breakage and increased sensitivity to MMC, which was rescued after transfection with wildtype FANCL. Both patients had a severe phenotype and multiple congenital anomalies reminiscent of VACTERL (<a href="/entry/192350">192350</a>) or VACTERL-H (<a href="/entry/276950">276950</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25754594" 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>Reviews</em></strong></p><p>
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<a href="#5" class="mim-tip-reference" title="Levitus, M., Rooimans, M. A., Steltenpool, J., Cool, N. F. C., Oostra, A. B., Mathew, C. G., Hoatlin, M. E., Waisfisz, Q., Arwert, F., de Winter, J. P., Joenje, H. <strong>Heterogeneity in Fanconi anemia: evidence for 2 new genetic subtypes.</strong> Blood 103: 2498-2503, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14630800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14630800</a>] [<a href="https://doi.org/10.1182/blood-2003-08-2915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14630800">Levitus et al. (2004)</a> tabulated 11 genetic subtypes of Fanconi anemia, giving the nature of the defects identified in each. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14630800" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The mouse Fancl gene, previously named Pog (for proliferation of germ cells), underlies the germ cell-deficient (gcd) phenotype in mice. Gcd mice, like mice carrying Pog null alleles generated by targeted disruption, are less fertile and have defective proliferation of germ cells (<a href="#1" class="mim-tip-reference" title="Agoulnik, A. I., Lu, B., Zhu, Q., Truong, C., Ty, M. T., Arango, N., Chada, K. K., Bishop, C. E. <strong>A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd.</strong> Hum. Molec. Genet. 11: 3047-3053, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417526</a>] [<a href="https://doi.org/10.1093/hmg/11.24.3047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12417526">Agoulnik et al., 2002</a>), characteristics that are also found in FA knockout mice. Moreover, <a href="#4" class="mim-tip-reference" title="Koomen, M., Cheng, N. C., van de Vrugt, H. J., Godthelp, B. C., van der Valk, M. A., Oostra, A. B., Zdzienicka, M. Z., Joenje, H., Arwert, F. <strong>Reduced fertility and hypersensitivity to mitomycin C characterize Fancg/Xrcc9 null mice.</strong> Hum. Molec. Genet. 11: 273-281, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823446</a>] [<a href="https://doi.org/10.1093/hmg/11.3.273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823446">Koomen et al. (2002)</a> found that bone marrow cells isolated from Pog knockout mice were hypersensitive to mitomycin C. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11823446+12417526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=608111[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p>In a cell line (EUFA868) from an individual with Fanconi anemia of complementation group L (FANCL; <a href="/entry/614083">614083</a>), <a href="#6" class="mim-tip-reference" title="Meetei, A. R., de Winter, J. P., Medhurst, A. L., Wallisch, M., Waisfisz, Q., van de Vrugt, H. J., Oostra, A. B., Yan, Z., Ling, C., Bishop, C. E., Hoatlin, M. E., Joenje, H., Wang, W. <strong>A novel ubiquitin ligase is deficient in Fanconi anemia.</strong> Nature Genet. 35: 165-170, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12973351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12973351</a>] [<a href="https://doi.org/10.1038/ng1241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12973351">Meetei et al. (2003)</a> found little or no PHF9 protein. PHF9 cDNA from this cell line lacked exon 11, thus removing the conserved PHD finger and part of the third WD40 repeat. The genomic DNA from this individual showed a homo- or hemizygous insertion of 177 bp into a pyrimidine-rich sequence at the splice junction between intron 10 and exon 11. As pyrimidine-rich sequences serve as signals for intron-exon junctions, <a href="#6" class="mim-tip-reference" title="Meetei, A. R., de Winter, J. P., Medhurst, A. L., Wallisch, M., Waisfisz, Q., van de Vrugt, H. J., Oostra, A. B., Yan, Z., Ling, C., Bishop, C. E., Hoatlin, M. E., Joenje, H., Wang, W. <strong>A novel ubiquitin ligase is deficient in Fanconi anemia.</strong> Nature Genet. 35: 165-170, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12973351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12973351</a>] [<a href="https://doi.org/10.1038/ng1241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12973351">Meetei et al. (2003)</a> concluded that this insertion disturbs splicing at this particular junction, resulting in the observed deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12973351" 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> rs747253294 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs747253294;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/rs747253294?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=rs747253294" 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=rs747253294" 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 male patient with Fanconi anemia of complementation group L (FANCL; <a href="/entry/614083">614083</a>) who had a mild clinical phenotype, <a href="#2" class="mim-tip-reference" title="Ali, A. M., Kirby, M., Jansen, M., Lach, F. P., Schulte, J., Singh, T. R., Batish, S. D., Auerbach, A. D., Williams, D. A., Meetei, A. R. <strong>Identification and characterization of mutations in FANCL gene: a second case of Fanconi anemia belonging to FA-L complementation group.</strong> Hum. Mutat. 30: E761-E770, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19405097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19405097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19405097[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19405097">Ali et al. (2009)</a> identified compound heterozygosity for 2 mutations in the FANCL gene. One allele carried an in-frame 3-bp deletion (1007_1009delTAT) in exon 12. The deletion was in the PHD/RING finger domain and resulted in the loss of ile366 and the conversion of cys337 to ser. The other allele carried a 4-bp duplication (1095_1098dupAATT) in exon 14 (<a href="#0003">608111.0003</a>). The duplication was just outside the RING finger domain and resulted in a frameshift (Thr367AsnfsTer13). The mother was heterozygous for the deletion and the father was heterozygous for the duplication. Functional analyses indicated that the deletion was a null mutation and the duplication was a hypomorphic mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19405097" 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> rs759217526 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs759217526;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/rs759217526?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=rs759217526" 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=rs759217526" 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=RCV000192919 OR RCV000226300 OR RCV000513086 OR RCV000986760 OR RCV001195069 OR RCV003401051" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000192919, RCV000226300, RCV000513086, RCV000986760, RCV001195069, RCV003401051" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000192919...</a>
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<p>For discussion of the 4-bp duplication in the FANCL gene (1095_1098dupAATT) that was found in compound heterozygous state in a patient with Fanconi anemia of complementation group L (FANCL; <a href="/entry/614083">614083</a>) by <a href="#2" class="mim-tip-reference" title="Ali, A. M., Kirby, M., Jansen, M., Lach, F. P., Schulte, J., Singh, T. R., Batish, S. D., Auerbach, A. D., Williams, D. A., Meetei, A. R. <strong>Identification and characterization of mutations in FANCL gene: a second case of Fanconi anemia belonging to FA-L complementation group.</strong> Hum. Mutat. 30: E761-E770, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19405097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19405097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19405097[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19405097">Ali et al. (2009)</a>, see <a href="#0002">608111.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19405097" 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">rs869320684 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869320684;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=rs869320684" 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=rs869320684" 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=RCV000191022 OR RCV001195063 OR RCV001388973" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000191022, RCV001195063, RCV001388973" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000191022...</a>
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<p>In an infant (case 1b), born of consanguineous Moroccan parents, with Fanconi anemia of complementation group L (FANCL; <a href="/entry/614083">614083</a>), <a href="#11" class="mim-tip-reference" title="Vetro, A., Iascone, M., Limongelli, I., Ameziane, N., Gana, S., Della Mina, E., Giussani, U., Ciccone, R., Forlino, A., Pezzoli, L., Rooimans, M. A., van Essen, A. J., Messa, J., Rizzuti, T., Bianchi, P., Dorsman, J., de Winter, J. P., Lalatta, F., Zuffardi, O. <strong>Loss-of-function FANCL mutations associate with severe Fanconi anemia overlapping the VACTERL association.</strong> Hum. Mutat. 36: 562-568, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25754594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25754594</a>] [<a href="https://doi.org/10.1002/humu.22784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25754594">Vetro et al. (2015)</a> identified a homozygous 1-bp deletion (c.268del, NM_018062.3) in exon 4 of the FANCL gene, resulting in a frameshift and premature termination (Leu90PhefsTer6). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Sequencing Project databases. Patient cells showed decreased mutant transcript, consistent with nonsense-mediated mRNA decay and a complete loss of function. Patient cell lines showed increased chromosomal breakage and increased sensitivity to MMC, which was rescued after after transfection with wildtype FANCL. The patient had a severe phenotype and multiple congenital anomalies reminiscent of VACTERL (<a href="/entry/192350">192350</a>); he died at 2 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25754594" 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">rs869320685 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869320685;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=rs869320685" 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=rs869320685" 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=RCV000191023 OR RCV001195065 OR RCV001530171 OR RCV001857678" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000191023, RCV001195065, RCV001530171, RCV001857678" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000191023...</a>
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<p>In an infant (case 2), born of Dutch parents, with Fanconi anemia of complementation group L (FANCL; <a href="/entry/614083">614083</a>), <a href="#11" class="mim-tip-reference" title="Vetro, A., Iascone, M., Limongelli, I., Ameziane, N., Gana, S., Della Mina, E., Giussani, U., Ciccone, R., Forlino, A., Pezzoli, L., Rooimans, M. A., van Essen, A. J., Messa, J., Rizzuti, T., Bianchi, P., Dorsman, J., de Winter, J. P., Lalatta, F., Zuffardi, O. <strong>Loss-of-function FANCL mutations associate with severe Fanconi anemia overlapping the VACTERL association.</strong> Hum. Mutat. 36: 562-568, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25754594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25754594</a>] [<a href="https://doi.org/10.1002/humu.22784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25754594">Vetro et al. (2015)</a> identified a homozygous 1-bp deletion (c.430del, NM_018062.3) in exon 6 of the FANCL gene, resulting in a frameshift and premature termination (Ser144LeufsTer6). The mutation was found by targeted sequencing of known Fanconi anemia genes and confirmed by Sanger sequencing. DNA from the parents was unavailable for segregation analysis. Patient cell lines showed increased chromosomal breakage and increased sensitivity to MMC, which was rescued after after transfection with wildtype FANCL. The patient had a severe phenotype and multiple congenital anomalies reminiscent of VACTERL-H (<a href="/entry/276950">276950</a>); she died at 2 days of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25754594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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Agoulnik, A. I., Lu, B., Zhu, Q., Truong, C., Ty, M. T., Arango, N., Chada, K. K., Bishop, C. E.
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<strong>A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd.</strong>
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Hum. Molec. Genet. 11: 3047-3053, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417526</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12417526" 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/11.24.3047" target="_blank">Full Text</a>]
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Ali, A. M., Kirby, M., Jansen, M., Lach, F. P., Schulte, J., Singh, T. R., Batish, S. D., Auerbach, A. D., Williams, D. A., Meetei, A. R.
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<strong>Identification and characterization of mutations in FANCL gene: a second case of Fanconi anemia belonging to FA-L complementation group.</strong>
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Hum. Mutat. 30: E761-E770, 2009. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19405097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19405097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19405097[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=19405097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.21032" target="_blank">Full Text</a>]
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<a id="Grompe2003" class="mim-anchor"></a>
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Grompe, M.
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<strong>FANCL, as in ligase.</strong>
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Nature Genet. 35: 113-114, 2003.
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Koomen, M., Cheng, N. C., van de Vrugt, H. J., Godthelp, B. C., van der Valk, M. A., Oostra, A. B., Zdzienicka, M. Z., Joenje, H., Arwert, F.
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<strong>Reduced fertility and hypersensitivity to mitomycin C characterize Fancg/Xrcc9 null mice.</strong>
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Hum. Molec. Genet. 11: 273-281, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823446</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11823446" 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/11.3.273" target="_blank">Full Text</a>]
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Levitus, M., Rooimans, M. A., Steltenpool, J., Cool, N. F. C., Oostra, A. B., Mathew, C. G., Hoatlin, M. E., Waisfisz, Q., Arwert, F., de Winter, J. P., Joenje, H.
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<strong>Heterogeneity in Fanconi anemia: evidence for 2 new genetic subtypes.</strong>
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Blood 103: 2498-2503, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14630800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14630800</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14630800" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1182/blood-2003-08-2915" target="_blank">Full Text</a>]
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Meetei, A. R., de Winter, J. P., Medhurst, A. L., Wallisch, M., Waisfisz, Q., van de Vrugt, H. J., Oostra, A. B., Yan, Z., Ling, C., Bishop, C. E., Hoatlin, M. E., Joenje, H., Wang, W.
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<strong>A novel ubiquitin ligase is deficient in Fanconi anemia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12973351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12973351</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12973351" 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/ng1241" target="_blank">Full Text</a>]
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Meetei, A. R., Sechi, S., Wallisch, M., Yang, D., Young, M. K., Joenje, H., Hoatlin, M. E., Wang, W.
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<strong>A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12724401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12724401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12724401[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=12724401" 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/10.1128/MCB.23.10.3417-3426.2003" target="_blank">Full Text</a>]
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<a id="Shakeel2019" class="mim-anchor"></a>
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Shakeel, S., Rajendra, E., Alcon, P., O'Reilly, F., Chorev, D. S., Maslen, S., Degliesposti, G., Russo, C. J., He, S., Hill, C. H., Skehel, J. M., Scheres, S. H. W., Patel, K. J., Rappsilber, J., Robinson, C. V., Passmore, L. A.
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<strong>Structure of the Fanconi anaemia monoubiquitin ligase complex.</strong>
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Nature 575: 234-237, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31666700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31666700</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31666700" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41586-019-1703-4" target="_blank">Full Text</a>]
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 12/06/2019.
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Tremblay, C. S., Huang, F. F., Habi, O., Huard, C. C., Godin, C., Levesque, G., Carreau, M.
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<strong>HES1 is a novel interactor of the Fanconi anemia core complex.</strong>
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Blood 112: 2062-2070, 2008. Note: Erratum: Blood 114: 3974 only, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18550849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18550849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18550849[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=18550849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1182/blood-2008-04-152710" 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="Vetro2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vetro, A., Iascone, M., Limongelli, I., Ameziane, N., Gana, S., Della Mina, E., Giussani, U., Ciccone, R., Forlino, A., Pezzoli, L., Rooimans, M. A., van Essen, A. J., Messa, J., Rizzuti, T., Bianchi, P., Dorsman, J., de Winter, J. P., Lalatta, F., Zuffardi, O.
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<strong>Loss-of-function FANCL mutations associate with severe Fanconi anemia overlapping the VACTERL association.</strong>
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Hum. Mutat. 36: 562-568, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25754594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25754594</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25754594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.22784" 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="Zhang2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, Y., Zhou, X., Zhao, L., Li, C., Zhu, H., Xu, L., Shan, L., Liao, X., Guo, Z., Huang, P.
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<strong>UBE2W interacts with FANCL and regulates the monoubiquitination of Fanconi anemia protein FANCD2.</strong>
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Molec. Cells 31: 113-122, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21229326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21229326</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21229326[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=21229326" 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/10.1007/s10059-011-0015-9" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<br />
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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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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 12/06/2019
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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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Ada Hamosh - updated : 12/06/2019<br>Cassandra L. Kniffin - updated : 9/17/2015<br>Patricia A. Hartz - updated : 11/2/2011<br>Carol A. Bocchini - updated : 7/13/2011<br>Patricia A. Hartz - updated : 8/28/2009<br>Victor A. McKusick - updated : 11/19/2004<br>Victor A. McKusick - updated : 12/9/2003
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</span>
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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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Victor A. McKusick : 9/23/2003
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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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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alopez : 12/06/2019
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</span>
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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 : 12/06/2019<br>alopez : 09/24/2015<br>alopez : 9/22/2015<br>ckniffin : 9/17/2015<br>mcolton : 8/18/2015<br>terry : 5/29/2012<br>mgross : 11/2/2011<br>carol : 7/13/2011<br>terry : 7/12/2011<br>carol : 7/11/2011<br>mgross : 10/14/2009<br>terry : 8/28/2009<br>alopez : 11/29/2004<br>terry : 11/19/2004<br>carol : 3/17/2004<br>tkritzer : 12/17/2003<br>terry : 12/9/2003<br>alopez : 10/16/2003<br>tkritzer : 9/26/2003<br>tkritzer : 9/25/2003<br>tkritzer : 9/25/2003
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</span>
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<div class="container visible-print-block">
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 608111
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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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FANCL GENE; FANCL
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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PHD FINGER PROTEIN 9; PHF9<br />
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FANCONI ANEMIA-ASSOCIATED POLYPEPTIDE, 43-KD; FAAP43
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: FANCL</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 2p16.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:58,159,243-58,241,380 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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2p16.1
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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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Fanconi anemia, complementation group L
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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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614083
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By mass spectrometry, Meetei et al. (2003) identified a previously isolated 43-kD FA-associated polypeptide (Meetei et al., 2003) as PHD finger protein-9 (PHF9). The deduced 373-amino acid protein, which contains 3 potential WD40 repeats and a PHD-type zinc finger motif, shares 80% sequence identity with its mouse homolog. </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>Meetei et al. (2003) presented several pieces of evidence that suggested that PHF9 is a stable component of the FA core complex. They detected PHF9 in both the nuclear and cytoplasmic extracts of wildtype cells; however, in lysates from 2 FANCA (607139) cell lines, the level of PHF9 was markedly lower than wildtype in the nuclear extract but was normal in the cytoplasm, suggesting that the nuclear accumulation of PHF9 depends on FANCA. Meetei et al. (2003) found that PHF9 possessed E3 ubiquitin ligase activity in vitro and was essential for FANCD2 (227646) monoubiquitination in vivo. They concluded that PHF9 is crucial in the FA pathway as the catalytic subunit required for monoubiquitination of FANCD2. </p><p>Grompe (2003) pointed out that PHF9 was the first Fanconi anemia protein identified by a biochemical approach and the first Fanconi anemia protein with a defined enzymatic activity. In the Fanconi anemia core complex, which senses exogenous DNA damage associated with DNA replication, PHF9 had been designated FAAP43. Grompe (2003) stated that FAAP90, FAAP100, and FAAP250 probably represent additional Fanconi anemia proteins that hold promise of offering insight into the function of the pathway.</p><p>Using yeast 2-hybrid and coimmunoprecipitation assays, Tremblay et al. (2008) found that HES1 (139605), a NOTCH1 (190198) pathway component involved in hematopoietic stem cell (HSC) self-renewal, interacted directly with FANCA, FANCF (603467), FANCG (XRCC9; 602956), and FANCL, but not with other FA core complex components. Mutation analysis showed that interactions with individual FA core components required different domains within HES1. HES1 did not interact with FA core components if any of them contained an FA-related mutation, suggesting that a functional FA pathway is required for HES1 interaction. Depletion of HES1 from HeLa cells resulted in failure of normal interactions between individual FA core components, as well as altered protein levels and mislocalization of some FA core components. Depletion of HES1 also increased cell sensitivity to the DNA crosslinking agent mitomycin C (MMC) and reduced MMC-induced monoubiquitination of FANCD2 and localization of FANCD2 to MMC-induced foci. Tremblay et al. (2008) concluded that interaction with HES1 is required for normal FA core complex function in the DNA damage response. They proposed that the HSC defect in FA may result from the inability of HES1 to interact with the defective FA core complex. </p><p>Using yeast 2-hybrid analysis, Zhang et al. (2011) showed that mouse ubiquitin-conjugating enzyme-2W (UBE2W; 614277) interacted with Fancl. They confirmed the interaction by protein pull-down and coimmunoprecipitation analyses. Fancl showed a ubiquitous intracellular localization in the absence of Ube2w and a nuclear localization in the presence of Ube2w. Ube2w exhibited ubiquitin-conjugating activity and monoubiquitinated the PHD domain of Fancl in vitro. </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>Cryoelectron Microscopy</em></strong></p><p>
|
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Shakeel et al. (2019) reconstituted an active, recombinant Fanconi anemia core complex, and used cryoelectron microscopy and mass spectrometry to determine its structure. The FA core complex comprises 2 central dimers of the FANCB (300515) and FA-associated protein of 100 kD (FAAP100; 611301) subunits, flanked by 2 copies of the RING finger subunit FANCL. These 2 heterotrimers act as a scaffold to assemble the remaining 5 subunits, resulting in an extended asymmetric structure. Destabilization of the scaffold would disrupt the entire complex, resulting in a nonfunctional FA pathway. Thus, the structure provides a mechanistic basis for the low numbers of patients with mutations in FANCB, FANCL, and FAAP100. Despite a lack of sequence homology, FANCB and FAAP100 adopt similar structures. The 2 FANCL subunits are in different conformations at opposite ends of the complex, suggesting that each FANCL has a distinct role. Shakeel et al. (2019) suggested that this structural and functional asymmetry of dimeric RING finger domains may be a general feature of E3 ligases. </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>Stumpf (2019) mapped the FANCL gene to chromosome 2p16.1 based on an alignment of the FANCL sequence (GenBank BC009042.1) with the genomic sequence (GRCh38). The mouse homolog maps to chromosome 11 (Agoulnik et al., 2002). </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>Meetei et al. (2003) detected little or no PHF9 protein in a cell line (EUFA868) derived from an individual with Fanconi anemia of an unassigned complementation group. PHF9 cDNA from this cell line was found to lack exon 11, which removed the conserved PHD finger and part of the third WD40 repeat (608111.0001). The complementation group was designated FANCL (614083). </p><p>In a male patient with FA of complementation group L, Ali et al. (2009) identified compound heterozygous mutations in the FANCL gene (608111.0002-608111.0003). </p><p>In 2 unrelated infants with lethal FANCL, Vetro et al. (2015) identified 2 different homozygous truncating mutations in the FANCL gene (608111.0004 and 608111.0005). The mutation in the first patient was found by whole-exome sequencing and segregated with the disorder in the family. The mutation in the second patient was found by targeted sequencing of known Fanconi anemia genes. Cell lines from both patients showed increased chromosomal breakage and increased sensitivity to MMC, which was rescued after transfection with wildtype FANCL. Both patients had a severe phenotype and multiple congenital anomalies reminiscent of VACTERL (192350) or VACTERL-H (276950). </p><p><strong><em>Reviews</em></strong></p><p>
|
|
Levitus et al. (2004) tabulated 11 genetic subtypes of Fanconi anemia, giving the nature of the defects identified in each. </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>The mouse Fancl gene, previously named Pog (for proliferation of germ cells), underlies the germ cell-deficient (gcd) phenotype in mice. Gcd mice, like mice carrying Pog null alleles generated by targeted disruption, are less fertile and have defective proliferation of germ cells (Agoulnik et al., 2002), characteristics that are also found in FA knockout mice. Moreover, Koomen et al. (2002) found that bone marrow cells isolated from Pog knockout mice were hypersensitive to mitomycin C. </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>5 Selected Examples):</strong>
|
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</span>
|
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</h4>
|
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 FANCONI ANEMIA, COMPLEMENTATION GROUP L</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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FANCL, 177-BP INS, EX11DEL
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<br />
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ClinVar: RCV000002644
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a cell line (EUFA868) from an individual with Fanconi anemia of complementation group L (FANCL; 614083), Meetei et al. (2003) found little or no PHF9 protein. PHF9 cDNA from this cell line lacked exon 11, thus removing the conserved PHD finger and part of the third WD40 repeat. The genomic DNA from this individual showed a homo- or hemizygous insertion of 177 bp into a pyrimidine-rich sequence at the splice junction between intron 10 and exon 11. As pyrimidine-rich sequences serve as signals for intron-exon junctions, Meetei et al. (2003) concluded that this insertion disturbs splicing at this particular junction, resulting in the observed deletion. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 FANCONI ANEMIA, COMPLEMENTATION GROUP L</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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FANCL, 3-BP DEL, 1007TAT
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<br />
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SNP: rs747253294,
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gnomAD: rs747253294,
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ClinVar: RCV000228349, RCV000479284, RCV000500979, RCV000766177, RCV002298549, RCV003955360
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male patient with Fanconi anemia of complementation group L (FANCL; 614083) who had a mild clinical phenotype, Ali et al. (2009) identified compound heterozygosity for 2 mutations in the FANCL gene. One allele carried an in-frame 3-bp deletion (1007_1009delTAT) in exon 12. The deletion was in the PHD/RING finger domain and resulted in the loss of ile366 and the conversion of cys337 to ser. The other allele carried a 4-bp duplication (1095_1098dupAATT) in exon 14 (608111.0003). The duplication was just outside the RING finger domain and resulted in a frameshift (Thr367AsnfsTer13). The mother was heterozygous for the deletion and the father was heterozygous for the duplication. Functional analyses indicated that the deletion was a null mutation and the duplication was a hypomorphic mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 FANCONI ANEMIA, COMPLEMENTATION GROUP L</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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FANCL, 4-BP DUP, 1095AATT
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<br />
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SNP: rs759217526,
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gnomAD: rs759217526,
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ClinVar: RCV000192919, RCV000226300, RCV000513086, RCV000986760, RCV001195069, RCV003401051
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the 4-bp duplication in the FANCL gene (1095_1098dupAATT) that was found in compound heterozygous state in a patient with Fanconi anemia of complementation group L (FANCL; 614083) by Ali et al. (2009), see 608111.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 FANCONI ANEMIA, COMPLEMENTATION GROUP L</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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FANCL, 1-BP DEL, NT268
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<br />
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SNP: rs869320684,
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ClinVar: RCV000191022, RCV001195063, RCV001388973
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an infant (case 1b), born of consanguineous Moroccan parents, with Fanconi anemia of complementation group L (FANCL; 614083), Vetro et al. (2015) identified a homozygous 1-bp deletion (c.268del, NM_018062.3) in exon 4 of the FANCL gene, resulting in a frameshift and premature termination (Leu90PhefsTer6). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Sequencing Project databases. Patient cells showed decreased mutant transcript, consistent with nonsense-mediated mRNA decay and a complete loss of function. Patient cell lines showed increased chromosomal breakage and increased sensitivity to MMC, which was rescued after after transfection with wildtype FANCL. The patient had a severe phenotype and multiple congenital anomalies reminiscent of VACTERL (192350); he died at 2 months of age. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 FANCONI ANEMIA, COMPLEMENTATION GROUP L</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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FANCL, 1-BP DEL, 430T
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<br />
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SNP: rs869320685,
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ClinVar: RCV000191023, RCV001195065, RCV001530171, RCV001857678
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</span>
|
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an infant (case 2), born of Dutch parents, with Fanconi anemia of complementation group L (FANCL; 614083), Vetro et al. (2015) identified a homozygous 1-bp deletion (c.430del, NM_018062.3) in exon 6 of the FANCL gene, resulting in a frameshift and premature termination (Ser144LeufsTer6). The mutation was found by targeted sequencing of known Fanconi anemia genes and confirmed by Sanger sequencing. DNA from the parents was unavailable for segregation analysis. Patient cell lines showed increased chromosomal breakage and increased sensitivity to MMC, which was rescued after after transfection with wildtype FANCL. The patient had a severe phenotype and multiple congenital anomalies reminiscent of VACTERL-H (276950); she died at 2 days of age. </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>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
|
<div>
|
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
|
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<p class="mim-text-font">
|
|
Agoulnik, A. I., Lu, B., Zhu, Q., Truong, C., Ty, M. T., Arango, N., Chada, K. K., Bishop, C. E.
|
|
<strong>A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd.</strong>
|
|
Hum. Molec. Genet. 11: 3047-3053, 2002.
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[PubMed: 12417526]
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[Full Text: https://doi.org/10.1093/hmg/11.24.3047]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ali, A. M., Kirby, M., Jansen, M., Lach, F. P., Schulte, J., Singh, T. R., Batish, S. D., Auerbach, A. D., Williams, D. A., Meetei, A. R.
|
|
<strong>Identification and characterization of mutations in FANCL gene: a second case of Fanconi anemia belonging to FA-L complementation group.</strong>
|
|
Hum. Mutat. 30: E761-E770, 2009. Note: Electronic Article.
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[PubMed: 19405097]
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[Full Text: https://doi.org/10.1002/humu.21032]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Grompe, M.
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|
<strong>FANCL, as in ligase.</strong>
|
|
Nature Genet. 35: 113-114, 2003.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Koomen, M., Cheng, N. C., van de Vrugt, H. J., Godthelp, B. C., van der Valk, M. A., Oostra, A. B., Zdzienicka, M. Z., Joenje, H., Arwert, F.
|
|
<strong>Reduced fertility and hypersensitivity to mitomycin C characterize Fancg/Xrcc9 null mice.</strong>
|
|
Hum. Molec. Genet. 11: 273-281, 2002.
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[PubMed: 11823446]
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[Full Text: https://doi.org/10.1093/hmg/11.3.273]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Levitus, M., Rooimans, M. A., Steltenpool, J., Cool, N. F. C., Oostra, A. B., Mathew, C. G., Hoatlin, M. E., Waisfisz, Q., Arwert, F., de Winter, J. P., Joenje, H.
|
|
<strong>Heterogeneity in Fanconi anemia: evidence for 2 new genetic subtypes.</strong>
|
|
Blood 103: 2498-2503, 2004.
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[PubMed: 14630800]
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[Full Text: https://doi.org/10.1182/blood-2003-08-2915]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Meetei, A. R., de Winter, J. P., Medhurst, A. L., Wallisch, M., Waisfisz, Q., van de Vrugt, H. J., Oostra, A. B., Yan, Z., Ling, C., Bishop, C. E., Hoatlin, M. E., Joenje, H., Wang, W.
|
|
<strong>A novel ubiquitin ligase is deficient in Fanconi anemia.</strong>
|
|
Nature Genet. 35: 165-170, 2003.
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[PubMed: 12973351]
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[Full Text: https://doi.org/10.1038/ng1241]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Meetei, A. R., Sechi, S., Wallisch, M., Yang, D., Young, M. K., Joenje, H., Hoatlin, M. E., Wang, W.
|
|
<strong>A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.</strong>
|
|
Molec. Cell. Biol. 23: 3417-3426, 2003.
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[PubMed: 12724401]
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[Full Text: https://doi.org/10.1128/MCB.23.10.3417-3426.2003]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Shakeel, S., Rajendra, E., Alcon, P., O'Reilly, F., Chorev, D. S., Maslen, S., Degliesposti, G., Russo, C. J., He, S., Hill, C. H., Skehel, J. M., Scheres, S. H. W., Patel, K. J., Rappsilber, J., Robinson, C. V., Passmore, L. A.
|
|
<strong>Structure of the Fanconi anaemia monoubiquitin ligase complex.</strong>
|
|
Nature 575: 234-237, 2019.
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|
[PubMed: 31666700]
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[Full Text: https://doi.org/10.1038/s41586-019-1703-4]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 12/06/2019.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Tremblay, C. S., Huang, F. F., Habi, O., Huard, C. C., Godin, C., Levesque, G., Carreau, M.
|
|
<strong>HES1 is a novel interactor of the Fanconi anemia core complex.</strong>
|
|
Blood 112: 2062-2070, 2008. Note: Erratum: Blood 114: 3974 only, 2009.
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[PubMed: 18550849]
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[Full Text: https://doi.org/10.1182/blood-2008-04-152710]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Vetro, A., Iascone, M., Limongelli, I., Ameziane, N., Gana, S., Della Mina, E., Giussani, U., Ciccone, R., Forlino, A., Pezzoli, L., Rooimans, M. A., van Essen, A. J., Messa, J., Rizzuti, T., Bianchi, P., Dorsman, J., de Winter, J. P., Lalatta, F., Zuffardi, O.
|
|
<strong>Loss-of-function FANCL mutations associate with severe Fanconi anemia overlapping the VACTERL association.</strong>
|
|
Hum. Mutat. 36: 562-568, 2015.
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[PubMed: 25754594]
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[Full Text: https://doi.org/10.1002/humu.22784]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Zhang, Y., Zhou, X., Zhao, L., Li, C., Zhu, H., Xu, L., Shan, L., Liao, X., Guo, Z., Huang, P.
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<strong>UBE2W interacts with FANCL and regulates the monoubiquitination of Fanconi anemia protein FANCD2.</strong>
|
|
Molec. Cells 31: 113-122, 2011.
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[PubMed: 21229326]
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[Full Text: https://doi.org/10.1007/s10059-011-0015-9]
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</p>
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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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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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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 : 12/06/2019<br>Ada Hamosh - updated : 12/06/2019<br>Cassandra L. Kniffin - updated : 9/17/2015<br>Patricia A. Hartz - updated : 11/2/2011<br>Carol A. Bocchini - updated : 7/13/2011<br>Patricia A. Hartz - updated : 8/28/2009<br>Victor A. McKusick - updated : 11/19/2004<br>Victor A. McKusick - updated : 12/9/2003
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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 class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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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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Victor A. McKusick : 9/23/2003
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<span class="text-nowrap mim-text-font">
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Edit History:
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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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alopez : 12/06/2019<br>alopez : 12/06/2019<br>alopez : 09/24/2015<br>alopez : 9/22/2015<br>ckniffin : 9/17/2015<br>mcolton : 8/18/2015<br>terry : 5/29/2012<br>mgross : 11/2/2011<br>carol : 7/13/2011<br>terry : 7/12/2011<br>carol : 7/11/2011<br>mgross : 10/14/2009<br>terry : 8/28/2009<br>alopez : 11/29/2004<br>terry : 11/19/2004<br>carol : 3/17/2004<br>tkritzer : 12/17/2003<br>terry : 12/9/2003<br>alopez : 10/16/2003<br>tkritzer : 9/26/2003<br>tkritzer : 9/25/2003<br>tkritzer : 9/25/2003
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NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
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