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Entry
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- *602667 - NIBRIN; NBN
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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">*602667</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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<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="#geneStructure">Gene Structure</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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<a href="#molecularGenetics">Molecular Genetics</a>
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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/602667">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<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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</ul>
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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=ENSG00000104320;t=ENST00000265433" 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=4683" 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=602667" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000104320;t=ENST00000265433" 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_001024688,NM_002485,XM_011517045,XM_011517046,XM_024447163,XM_047421795,XM_047421796" 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_002485" 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=602667" 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=04050&isoform_id=04050_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/NBN" 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/3098675,3126795,3169125,3687830,33356172,45359959,52545912,57976241,62898073,67189945,74762960,80476693,118142843,119612066,119612067,148922298,158260719,187951541,189065484,223459706,365940883,545910235,545910237,545910239,545910241,545910243,545910245,545910247,767953017,767953020,1370512396,2217372053,2217372055,2462619477,2462619479,2462619481,2462619484" 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/O60934" 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=4683" 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=ENSG00000104320;t=ENST00000265433" 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=NBN" 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=NBN" 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+4683" 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/NBN" 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:4683" 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/4683" 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=chr8&hgg_gene=ENST00000265433.8&hgg_start=89933331&hgg_end=89984667&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:7652" 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:7652" 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://medlineplus.gov/genetics/gene/nbn" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=602667[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
|
|
</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=602667[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000104320" 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=NBN" 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=NBN" 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=NBN" 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.LOVD.nl/NBN" 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=NBN&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/PA31457" 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:7652" 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/FBgn0261530.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:1351625" 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/NBN#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:1351625" 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/4683/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=4683" 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-041008-35" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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<div style="display: table-cell;">Cell Lines</div>
|
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</div>
|
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</a>
|
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</span>
|
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:602667" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
|
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</span>
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</span>
|
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</div>
|
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4683" 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=NBN&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 234638009, 304132006, 306058006<br />
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<strong>ICD10CM:</strong> D61.9<br />
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<strong>ICD9CM:</strong> 284.9<br />
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">ICD+</a>
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</div>
|
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
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602667
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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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NIBRIN; NBN
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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">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
p95 PROTEIN OF THE MRE11/RAD50 COMPLEX<br />
|
|
NBS1
|
|
</span>
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=NBN" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NBN</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/8/392?start=-3&limit=10&highlight=392">8q21.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr8:89933331-89984667&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'})">8:89,933,331-89,984,667</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=609135,613065,251260" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/8/392?start=-3&limit=10&highlight=392">
|
|
8q21.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Aplastic anemia
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p><a href="#35" class="mim-tip-reference" title="Varon, R., Vissinga, C., Platzer, M., Cerosaletti, K. M., Chrzanowska, K. H., Saar, K., Beckmann, G., Seemanova, E., Cooper, P. R., Nowak, N. J., Stumm, M., Weemaes, C. M. R., Gatti, R. A., Wilson, R. K., Digweed, M., Rosenthal, A., Sperling, K., Concannon, P., Reis, A. <strong>Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.</strong> Cell 93: 467-476, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590180</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81174-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590180">Varon et al. (1998)</a> described the positional cloning of a gene encoding a novel protein, termed nibrin, that mapped within a 300-kb critical region for Nijmegen breakage syndrome (NBS; <a href="/entry/251260">251260</a>) on chromosome 8q21. Northern blot analysis revealed mRNA transcripts of 2.4 and 4.4 kb in all tissues examined. The predicted 754-amino acid protein contains 2 domains found in cell cycle checkpoint proteins, a forkhead-associated domain and an adjacent breast cancer carboxy-terminal domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590180" 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="#2" class="mim-tip-reference" title="Carney, J. P., Maser, R. S., Olivares, H., Davis, E. M., Le Beau, M., Yates, J. R., III, Hays, L., Morgan, W. F., Petrini, J. H. J. <strong>The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response.</strong> Cell 93: 477-486, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590181</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81175-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590181">Carney et al. (1998)</a> independently isolated the gene for NBS. They characterized the gene encoding p95, a member of the MRE11/RAD50 double-strand break (DSB) repair complex. Comparison of the p95 cDNA to the NBS1 cDNA of <a href="#35" class="mim-tip-reference" title="Varon, R., Vissinga, C., Platzer, M., Cerosaletti, K. M., Chrzanowska, K. H., Saar, K., Beckmann, G., Seemanova, E., Cooper, P. R., Nowak, N. J., Stumm, M., Weemaes, C. M. R., Gatti, R. A., Wilson, R. K., Digweed, M., Rosenthal, A., Sperling, K., Concannon, P., Reis, A. <strong>Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.</strong> Cell 93: 467-476, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590180</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81174-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590180">Varon et al. (1998)</a> indicated that the p95 and NBS1 genes are identical. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9590181+9590180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Matsuura, S., Tauchi, H., Nakamura, A., Kondo, N., Sakamoto, S., Endo, S., Smeets, D., Solder, B., Belohradsky, B. H., Der Kaloustian, V. M., Oshimura, M., Isomura, M., Nakamura, Y., Komatsu, K. <strong>Positional cloning of the gene for Nijmegen breakage syndrome.</strong> Nature Genet. 19: 179-181, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620777</a>] [<a href="https://doi.org/10.1038/549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620777">Matsuura et al. (1998)</a> reported the positional cloning of the gene responsible for the Nijmegen breakage syndrome, NBS1, from an 800-kb candidate region. They found that the gene is expressed at high levels in testis, suggesting that it may be involved in meiotic recombination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9620777" 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 MRE11/RAD50 DSB repair complex consists of 5 proteins: p95 (NBS1), p200, p400, MRE11, and RAD50 (<a href="/entry/604040">604040</a>). <a href="#2" class="mim-tip-reference" title="Carney, J. P., Maser, R. S., Olivares, H., Davis, E. M., Le Beau, M., Yates, J. R., III, Hays, L., Morgan, W. F., Petrini, J. H. J. <strong>The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response.</strong> Cell 93: 477-486, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590181</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81175-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590181">Carney et al. (1998)</a> found that p95 was absent from NBS cells established from NBS patients and that p95 deficiency in these cells completely abrogated the formation of MRE11/RAD50 ionizing radiation-induced foci. The implication of the MRE11/RAD50/p95 protein complex in NBS reveals a direct molecular link between DSB repair and cell cycle checkpoint functions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590181" 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="#42" class="mim-tip-reference" title="Zhong, Q., Chen, C.-F., Li, S., Chen, Y., Wang, C.-C., Xiao, J., Chen, P.-L., Sharp, Z. D., Lee, W.-H. <strong>Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response.</strong> Science 285: 747-750, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10426999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10426999</a>] [<a href="https://doi.org/10.1126/science.285.5428.747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10426999">Zhong et al. (1999)</a> demonstrated association of BRCA1 (<a href="/entry/113705">113705</a>) with the RAD50/MRE11/p95 complex. Upon irradiation, BRCA1 was detected in the nucleus, in discrete foci which colocalize with RAD50. Formation of irradiation-induced foci positive for BRCA1, RAD50, MRE11, or p95 was dramatically reduced in HCC/1937 breast cancer cells carrying a homozygous mutation in BRCA1 but was restored by transfection of wildtype BRCA1. Ectopic expression of wildtype, but not mutated, BRCA1 in these cells rendered them less sensitive to the DNA damage agent methyl methanesulfonate. These data suggested to the authors that BRCA1 is important for the cellular responses to DNA damage that are mediated by the RAD50-MRE11-p95 complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10426999" 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="#36" class="mim-tip-reference" title="Wang, Y., Cortez, D., Yazdi, P., Neff, N., Elledge, S. J., Qin, J. <strong>BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.</strong> Genes Dev. 14: 927-939, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10783165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10783165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10783165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10783165">Wang et al. (2000)</a> used immunoprecipitation and mass spectrometry analyses to identify BRCA1-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM (<a href="/entry/607585">607585</a>), BLM (<a href="/entry/604610">604610</a>), MSH2 (<a href="/entry/609309">609309</a>), MSH6 (<a href="/entry/600678">600678</a>), MLH1 (<a href="/entry/120436">120436</a>), the RAD50-MRE11-NBS1 complex, and the RFC1 (<a href="/entry/102579">102579</a>)-RFC2 (<a href="/entry/600404">600404</a>)-RFC4 (<a href="/entry/102577">102577</a>) complex. Confocal microscopy demonstrated that BRCA1, BLM, and the RAD50-MRE11-NBS1 complex colocalize to large nuclear foci. <a href="#36" class="mim-tip-reference" title="Wang, Y., Cortez, D., Yazdi, P., Neff, N., Elledge, S. J., Qin, J. <strong>BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.</strong> Genes Dev. 14: 927-939, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10783165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10783165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10783165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10783165">Wang et al. (2000)</a> suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10783165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Because of the similarities between ataxia-telangiectasia (AT; <a href="/entry/208900">208900</a>) and Nijmegen breakage syndrome, <a href="#11" class="mim-tip-reference" title="Lim, D.-S., Kim, S.-T., Xu, B., Maser, R. S., Lin, J., Petrini, J. H. J., Kastan, M. B. <strong>ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway.</strong> Nature 404: 613-617, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10766245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10766245</a>] [<a href="https://doi.org/10.1038/35007091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10766245">Lim et al. (2000)</a> evaluated the functional interactions between the ataxia-telangiectasia mutated (ATM; <a href="/entry/607585">607585</a>) and NBS1 genes. Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that NBS1 may not be required for signaling to ATM after ionizing radiation. However, NBS1 was phosphorylated on serine-343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation. An NBS1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells. These observations linked ATM and NBS1 in a common signaling pathway and provided an explanation for the phenotypic similarities between the 2 disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10766245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Gatei, M., Young, D., Cerosaletti, K. M., Desai-Mehta, A., Spring, K., Kozlov, S., Lavin, M. F., Gatti, R. A., Concannon, P., Khanna, K. <strong>ATM-dependent phosphorylation of nibrin in response to radiation exposure.</strong> Nature Genet. 25: 115-119, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802669</a>] [<a href="https://doi.org/10.1038/75508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802669">Gatei et al. (2000)</a> demonstrated that nibrin is phosphorylated within 1 hour of treatment of cells with ionizing radiation. This response was abrogated in AT cells that either do not express ATM protein or express near full-length mutant protein. <a href="#9" class="mim-tip-reference" title="Gatei, M., Young, D., Cerosaletti, K. M., Desai-Mehta, A., Spring, K., Kozlov, S., Lavin, M. F., Gatti, R. A., Concannon, P., Khanna, K. <strong>ATM-dependent phosphorylation of nibrin in response to radiation exposure.</strong> Nature Genet. 25: 115-119, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802669</a>] [<a href="https://doi.org/10.1038/75508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802669">Gatei et al. (2000)</a> also showed that ATM physically interacts with and phosphorylates nibrin on serine-343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (S343A) does not completely complement radiosensitivity in NBS cells. ATM phosphorylation of nibrin does not affect nibrin-MRE11-RAD50 association, as revealed by radiation-induced foci formation. <a href="#9" class="mim-tip-reference" title="Gatei, M., Young, D., Cerosaletti, K. M., Desai-Mehta, A., Spring, K., Kozlov, S., Lavin, M. F., Gatti, R. A., Concannon, P., Khanna, K. <strong>ATM-dependent phosphorylation of nibrin in response to radiation exposure.</strong> Nature Genet. 25: 115-119, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802669</a>] [<a href="https://doi.org/10.1038/75508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802669">Gatei et al. (2000)</a> concluded that their data provide a biochemical explanation for the similarity in phenotype between AT and NBS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10802669" 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="#40" class="mim-tip-reference" title="Zhao, S., Weng, Y.-C., Yuan, S.-S. F., Lin, Y.-T., Hsu, H.-C., Lin, S.-C. J., Gerbino, E., Song, M., Zdzienicka, M. Z., Gatti, R. A., Shay, J. W., Ziv, Y., Shiloh, Y., Lee, E. Y.-H. P. <strong>Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products.</strong> Nature 405: 473-477, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839544</a>] [<a href="https://doi.org/10.1038/35013083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839544">Zhao et al. (2000)</a> demonstrated that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. <a href="#40" class="mim-tip-reference" title="Zhao, S., Weng, Y.-C., Yuan, S.-S. F., Lin, Y.-T., Hsu, H.-C., Lin, S.-C. J., Gerbino, E., Song, M., Zdzienicka, M. Z., Gatti, R. A., Shay, J. W., Ziv, Y., Shiloh, Y., Lee, E. Y.-H. P. <strong>Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products.</strong> Nature 405: 473-477, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839544</a>] [<a href="https://doi.org/10.1038/35013083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839544">Zhao et al. (2000)</a> identified 2 residues of NBS1, serine-278 and serine-343, that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mre11/Rad50 nuclear foci, and rescue of hypersensitivity to ionizing radiation. <a href="#40" class="mim-tip-reference" title="Zhao, S., Weng, Y.-C., Yuan, S.-S. F., Lin, Y.-T., Hsu, H.-C., Lin, S.-C. J., Gerbino, E., Song, M., Zdzienicka, M. Z., Gatti, R. A., Shay, J. W., Ziv, Y., Shiloh, Y., Lee, E. Y.-H. P. <strong>Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products.</strong> Nature 405: 473-477, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839544</a>] [<a href="https://doi.org/10.1038/35013083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839544">Zhao et al. (2000)</a> concluded that together, these results demonstrated a biochemical link between cell cycle checkpoints activated by DNA damage and DNA repair in 2 genetic diseases with overlapping phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10839544" 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="#44" class="mim-tip-reference" title="Zhu, X.-D., Kuster, B., Mann, M., Petrini, J. H. J., de Lange, T. <strong>Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres.</strong> Nature Genet. 25: 347-352, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888888</a>] [<a href="https://doi.org/10.1038/77139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10888888">Zhu et al. (2000)</a> showed by coimmunoprecipitation that a small fraction of RAD50, MRE11, and NBS1 is associated with the telomeric repeat-binding factor TRF2 (<a href="/entry/602027">602027</a>). Indirect immunofluorescence demonstrated the presence of RAD50 and MRE11 at interphase telomeres. NBS1 was associated with TRF2 and telomeres in S phase, but not in G1 or G2. Although the MRE11 complex accumulated in irradiation-induced foci (IRIFs) in response to gamma-irradiation, TRF2 did not relocate to IRIFs and irradiation did not affect the association of TRF2 with the MRE11 complex, arguing against a role for TRF2 in double-strand break repair. <a href="#44" class="mim-tip-reference" title="Zhu, X.-D., Kuster, B., Mann, M., Petrini, J. H. J., de Lange, T. <strong>Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres.</strong> Nature Genet. 25: 347-352, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888888</a>] [<a href="https://doi.org/10.1038/77139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10888888">Zhu et al. (2000)</a> proposed that the MRE11 complex functions at telomeres, possibly by modulating t-loop formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10888888" 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="#12" class="mim-tip-reference" title="Lombard, D. B., Guarente, L. <strong>Nijmegen breakage syndrome disease protein and MRE11 at PML nuclear bodies and meiotic telomeres.</strong> Cancer Res. 60: 2331-2334, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10811102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10811102</a>]" pmid="10811102">Lombard and Guarente (2000)</a> showed that p95 and MRE11 are specifically present on telomeres during meiosis. They suggested that p95 and MRE11 may have a role in telomere maintenance in mammals, analogous to the role their homologs play in yeast. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10811102" 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="#38" class="mim-tip-reference" title="Wu, X., Ranganathan, V., Weisman, D. S., Heine, W. F., Ciccone, D. N., O'Neill, T. B., Crick, K. E., Pierce, K. A., Lane, W. S., Rathbun, G., Livingston, D. M., Weaver, D. T. <strong>ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response.</strong> Nature 405: 477-482, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839545</a>] [<a href="https://doi.org/10.1038/35013089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839545">Wu et al. (2000)</a> reported that NBS is specifically phosphorylated in response to gamma-radiation, ultraviolet light, and exposure to hydroxyurea. Phosphorylation of NBS mediated by gamma-radiation, but not that induced by hydroxyurea or ultraviolet light, was markedly reduced in ATM cells. In vivo, NBS was phosphorylated on many serine residues, of which serine-343, serine-397, and serine-615 were phosphorylated by ATM in vitro. At least 2 of these sites were underphosphorylated in ATM cells. Inactivation of these serines by mutation partially abrogated ATM-dependent phosphorylation. Reconstituting NBS cells with a mutant form of NBS that cannot be phosphorylated at selected ATM-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation. <a href="#38" class="mim-tip-reference" title="Wu, X., Ranganathan, V., Weisman, D. S., Heine, W. F., Ciccone, D. N., O'Neill, T. B., Crick, K. E., Pierce, K. A., Lane, W. S., Rathbun, G., Livingston, D. M., Weaver, D. T. <strong>ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response.</strong> Nature 405: 477-482, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839545</a>] [<a href="https://doi.org/10.1038/35013089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839545">Wu et al. (2000)</a> concluded that phosphorylation of NBS by ATM is critical for certain responses of human cells to DNA damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10839545" 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="#37" class="mim-tip-reference" title="Wilda, M., Demuth, I., Concannon, P., Sperling, K., Hameister, H. <strong>Expression pattern of the Nijmegen breakage syndrome gene, Nbs1, during murine development.</strong> Hum. Molec. Genet. 9: 1739-1744, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10915761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10915761</a>] [<a href="https://doi.org/10.1093/hmg/9.12.1739" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10915761">Wilda et al. (2000)</a> studied the expression of Nbs1 in mouse embryos at different developmental stages as well as in adult mice. Although a low level of expression was observed in all tissues, highly specific expression was observed in organs with physiologic DNA double-strand breakage (DSB), such as testis, thymus, and spleen. Enhanced expression was also found at sites of high proliferative activity: the subventricular layer of the telencephalon and diencephalon, the liver, lung, kidney, and gut, as well as striated and smooth muscle cells in various organs. In the adult cerebellum, the postmitotic Purkinje cells were marked specifically. The authors hypothesized that in addition to the role of the Nbs1 gene product as part of a DNA DSB repair complex, the Nbs1 gene product may serve further functions during development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10915761" 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="Chen, H. T., Bhandoola, A., Difilippantonio, M. J., Zhu, J., Brown, M. J., Tai, X., Rogakou, E. P., Brotz, T. M., Bonner, W. M., Ried, T., Nussenzweig, A. <strong>Response to RAG-mediated V(D)J cleavage by NBS1 and gamma-H2AX.</strong> Science 290: 1962-1964, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110662</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11110662[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.290.5498.1962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11110662">Chen et al. (2000)</a> reported that the NBS1 protein and histone gamma-H2AX (<a href="/entry/601772">601772</a>), which associate with irradiation-induced DNA DSBs, are also found at sites of V(D)J (variable, diversity, joining) recombination-induced DSBs. In developing thymocytes, NBS1 and gamma-H2AX form nuclear foci that colocalize with the T-cell receptor-alpha (TCRA; see <a href="/entry/186880">186880</a>) locus in response to recombination-activating gene-1 (RAG1; <a href="/entry/179615">179615</a>) protein-mediated V(D)J cleavage. <a href="#3" class="mim-tip-reference" title="Chen, H. T., Bhandoola, A., Difilippantonio, M. J., Zhu, J., Brown, M. J., Tai, X., Rogakou, E. P., Brotz, T. M., Bonner, W. M., Ried, T., Nussenzweig, A. <strong>Response to RAG-mediated V(D)J cleavage by NBS1 and gamma-H2AX.</strong> Science 290: 1962-1964, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110662</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11110662[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.290.5498.1962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11110662">Chen et al. (2000)</a> concluded that their results suggest that surveillance of T-cell receptor recombination intermediates by NBS1 and gamma-H2AX may be important for preventing oncogenic translocations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11110662" 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>Class switch recombination (CSR) is a region-specific DNA recombination reaction that replaces one immunoglobulin heavy-chain constant region gene with another. This enables a single variable region gene to be used in conjunction with different downstream heavy-chain genes, each having a unique biologic activity. Activation-induced cytidine deaminase (AID; <a href="/entry/605257">605257</a>), a putative RNA editing enzyme, is required for this action. <a href="#18" class="mim-tip-reference" title="Petersen, S., Casellas, R., Reina-San-Martin, B., Chen, H. T., Difilippantonio, M. J., Wilson, P. C., Hanitsch, L., Celeste, A., Muramatsu, M., Pilch, D. R., Redon, C., Ried, T., Bonner, W. M., Honjo, T., Nussenzweig, M. C., Nussenzweig, A. <strong>AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching.</strong> Nature 414: 660-665, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11740565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11740565</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11740565[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/414660a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11740565">Petersen et al. (2001)</a> reported that the Nijmegen breakage syndrome protein and gamma-H2AX, which facilitate DNA double-strand break repair, form nuclear foci at the heavy-chain constant region in the G1 phase of the cell cycle in cells undergoing class switch recombination. Class switch recombination is impaired in H2AX -/- mice. Localization of NBS1 and gamma-H2AX to the immunoglobulin heavy-chain locus during class switch recombination is dependent on AID. In addition, AID is required for induction of switch region-specific DNA lesions that precede class switch recombination. <a href="#18" class="mim-tip-reference" title="Petersen, S., Casellas, R., Reina-San-Martin, B., Chen, H. T., Difilippantonio, M. J., Wilson, P. C., Hanitsch, L., Celeste, A., Muramatsu, M., Pilch, D. R., Redon, C., Ried, T., Bonner, W. M., Honjo, T., Nussenzweig, M. C., Nussenzweig, A. <strong>AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching.</strong> Nature 414: 660-665, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11740565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11740565</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11740565[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/414660a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11740565">Petersen et al. (2001)</a> concluded that AID functions upstream of the DNA modifications that initiate class switch recombination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11740565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Falck, J., Petrini, J. H. J., Williams, B. R., Lukas, J., Bartek, J. <strong>The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways.</strong> Nature Genet. 30: 290-294, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11850621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11850621</a>] [<a href="https://doi.org/10.1038/ng845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11850621">Falck et al. (2002)</a> demonstrated that experimental blockade of either the NBS1-MRE11 function or the CHK2 (<a href="/entry/604373">604373</a>)-triggered events leads to a partial radioresistant DNA synthesis phenotype in human cells. In contrast, concomitant interference with NBS1-MRE11 and the CHK2-CDC25A (<a href="/entry/116947">116947</a>)-CDK2 (<a href="/entry/116953">116953</a>) pathways entirely abolishes inhibition of DNA synthesis induced by ionizing radiation, resulting in complete radioresistant DNA synthesis analogous to that caused by defective ATM. In addition, CDK2-dependent loading of CDC45 (<a href="/entry/603465">603465</a>) onto replication origins, a prerequisite for recruitment of DNA polymerase, was prevented upon irradiation of normal or NBS1/MRE11-defective cells but not cells with defective ATM. <a href="#6" class="mim-tip-reference" title="Falck, J., Petrini, J. H. J., Williams, B. R., Lukas, J., Bartek, J. <strong>The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways.</strong> Nature Genet. 30: 290-294, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11850621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11850621</a>] [<a href="https://doi.org/10.1038/ng845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11850621">Falck et al. (2002)</a> concluded that in response to ionizing radiation, phosphorylation of NBS1 and CHK2 by ATM triggers 2 parallel branches of the DNA damage-dependent S-phase checkpoint that cooperate by inhibiting distinct steps of DNA replication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11850621" 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 mammalian cells, a conserved multiprotein complex of MRE11, RAD50, and NBS1 (MRN) is important for double-strand break repair, meiotic recombination, and telomere maintenance. In the absence of the early region E4, the double-stranded genome of adenoviruses is joined into concatemers too large to be packaged. <a href="#26" class="mim-tip-reference" title="Stracker, T. H., Carson, C. T., Weitzman, M. D. <strong>Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex.</strong> Nature 418: 348-352, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12124628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12124628</a>] [<a href="https://doi.org/10.1038/nature00863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12124628">Stracker et al. (2002)</a> investigated the cellular proteins involved in the concatamer formation and how they are inactivated by E4 products during a wildtype infection. They demonstrated that concatamerization requires functional MRE11 and NBS1, and that these proteins are found at foci adjacent to viral replication centers. Infection with wildtype virus results in both reorganization and degradation of members of the MRN complex. These activities are mediated by 3 viral oncoproteins that prevent concatamerization. This targeting of cellular proteins involved in the genomic stability suggested a mechanism for 'hit-and-run' transformation observed for these viral oncoproteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12124628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Franchitto, A., Pichierri, P. <strong>Protecting genomic integrity during DNA replication: correlation between Werner's and Bloom's syndrome gene products and the MRE11 complex.</strong> Hum. Molec. Genet. 11: 2447-2453, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12351580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12351580</a>] [<a href="https://doi.org/10.1093/hmg/11.20.2447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12351580">Franchitto and Pichierri (2002)</a> reviewed the roles of RECQL2 (<a href="/entry/604611">604611</a>) and RECQL3 (<a href="/entry/604610">604610</a>) in resolution of a stall in DNA replication, as well as their possible interaction with the MRN complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12351580" 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="#29" class="mim-tip-reference" title="Tauchi, H., Kobayashi, J., Morishima, K., van Gent, D. C., Shiraishi, T., Verkaik, N. S., vanHeems, D., Ito, E., Nakamura, A., Sonoda, E., Takata, M., Takeda, S., Matsuura, S., Komatsu, K. <strong>Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells.</strong> Nature 420: 93-98, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12422221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12422221</a>] [<a href="https://doi.org/10.1038/nature01125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12422221">Tauchi et al. (2002)</a> established an Nbs1 knockout cell line by using the hyperrecombinogenic chick B-cell line DT40. Exon 4 of the 3 Nbs1 alleles in DT40 cells was targeted. The Nbs1 -/-/- cells were still viable, although they exhibited slow growth owing to a prolonged cell cycle time. The disruption of Nbs1 reduced gene conversion and sister chromatid exchanges, similar to other homologous recombination-deficient mutants. In fact, a site-specific double-strand break repair assay showed a notable reduction of homologous recombination events following generation of such breaks in Nbs1-disrupted cells. The rare recombinations observed in the Nbs1-disrupted cells were frequently found to have aberrant structures, which possibly arose from unusual crossover events, suggesting that the NBS1 complex might be required to process recombination intermediates. Thus, <a href="#29" class="mim-tip-reference" title="Tauchi, H., Kobayashi, J., Morishima, K., van Gent, D. C., Shiraishi, T., Verkaik, N. S., vanHeems, D., Ito, E., Nakamura, A., Sonoda, E., Takata, M., Takeda, S., Matsuura, S., Komatsu, K. <strong>Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells.</strong> Nature 420: 93-98, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12422221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12422221</a>] [<a href="https://doi.org/10.1038/nature01125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12422221">Tauchi et al. (2002)</a> demonstrated that NBS1 is essential for homologous recombination-mediated repair in higher vertebrate cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12422221" 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="#41" class="mim-tip-reference" title="Zhong, H., Bryson, A., Eckersdorff, M., Ferguson, D. O. <strong>Rad50 depletion impacts upon ATR-dependent DNA damage responses.</strong> Hum. Molec. Genet. 14: 2685-2693, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16087684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16087684</a>] [<a href="https://doi.org/10.1093/hmg/ddi302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16087684">Zhong et al. (2005)</a> tested whether the MRN complex has a global controlling role over ATR (<a href="/entry/601215">601215</a>) through the study of MRN deficiencies generated by RNA interference. The MRN complex was required for ATR-dependent phosphorylation of SMC1A (<a href="/entry/300040">300040</a>), which acts within chromatin to ensure sister chromatid cohesion and to effect several DNA damage responses. Novel phenotypes caused by MRN deficiency that support a functional link between this complex, ATR, and SMC1A, included hypersensitivity to UV exposure, a defective UV responsive intra-S phase checkpoint, and a specific pattern of genomic instability. <a href="#41" class="mim-tip-reference" title="Zhong, H., Bryson, A., Eckersdorff, M., Ferguson, D. O. <strong>Rad50 depletion impacts upon ATR-dependent DNA damage responses.</strong> Hum. Molec. Genet. 14: 2685-2693, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16087684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16087684</a>] [<a href="https://doi.org/10.1093/hmg/ddi302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16087684">Zhong et al. (2005)</a> concluded that there is a controlling role for the MRN complex over the ATR kinase, and that downstream events under this control are broad, including both chromatin-associated and diffuse signaling factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16087684" 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="#39" class="mim-tip-reference" title="Yuan, Z., Zhang, X., Sengupta, N., Lane, W. S., Seto, E. <strong>SIRT1 regulates the function of the Nijmegen breakage syndrome protein.</strong> Molec. Cell 27: 149-162, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17612497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17612497</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17612497[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.05.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17612497">Yuan et al. (2007)</a> found that NBS1, the regulatory subunit of MRN, was acetylated, and that its acetylation level was tightly regulated by SIRT1 (<a href="/entry/604479">604479</a>). SIRT1 associated with the MRN complex in human cells via binding to NBS1, and SIRT1 maintained NBS1 in a hypoacetylated state, a requirement for ionizing radiation-induced phosphorylation of NBS1 on ser343. <a href="#39" class="mim-tip-reference" title="Yuan, Z., Zhang, X., Sengupta, N., Lane, W. S., Seto, E. <strong>SIRT1 regulates the function of the Nijmegen breakage syndrome protein.</strong> Molec. Cell 27: 149-162, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17612497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17612497</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17612497[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.05.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17612497">Yuan et al. (2007)</a> concluded that deacetylation of NBS1 by SIRT1 plays a key role in regulation of the DNA damage response and maintenance of genomic stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17612497" 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="#25" class="mim-tip-reference" title="Staples, C. J., Barone, G., Myers, K. N., Ganesh, A., Gibbs-Seymour, I., Patil, A. A., Beveridge, R. D., Daye, C., Beniston, R., Maslen, S., Ahel, I., Skehel, J. M., Collis, S. J. <strong>MRNIP/C5orf45 interacts with the MRN complex and contributes to the DNA damage response.</strong> Cell Rep. 16: 2565-2575, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27568553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27568553</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27568553[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.celrep.2016.07.087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27568553">Staples et al. (2016)</a> found that human cells depleted of MRNIP (<a href="/entry/617154">617154</a>) showed increased DNA damage. Immunoprecipitation analysis revealed interaction of MRNIP with the MRN complex, as well as with other substrates of ATM. Cells lacking MRNIP had reduced MRN function and defective ATM-dependent DNA damage signaling, as well as impaired responses to DNA breaks. <a href="#25" class="mim-tip-reference" title="Staples, C. J., Barone, G., Myers, K. N., Ganesh, A., Gibbs-Seymour, I., Patil, A. A., Beveridge, R. D., Daye, C., Beniston, R., Maslen, S., Ahel, I., Skehel, J. M., Collis, S. J. <strong>MRNIP/C5orf45 interacts with the MRN complex and contributes to the DNA damage response.</strong> Cell Rep. 16: 2565-2575, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27568553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27568553</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27568553[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.celrep.2016.07.087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27568553">Staples et al. (2016)</a> concluded that MRNIP, through its interaction with the MRN complex, is required for robust cellular responses to DNA breaks by promoting chromatin association of the MRN complex and subsequent activation of the ATM-signaling cascade. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27568553" 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 human RAD50/MRE11/NBS1 complex (R/M/N) has a dynamic molecular architecture consisting of a globular DNA binding domain from which two 50-nanometer coiled coils protrude. The coiled coils are flexible and their apices can self-associate. The flexibility of the coiled coils allows their apices to adopt an orientation favorable for interaction. However, this also allows interaction between the tips of the 2 coiled coils within the same complex, which competes with and frustrates the intercomplex interaction required for DNA tethering. <a href="#16" class="mim-tip-reference" title="Moreno-Herrero, F., de Jager, M., Dekker, N. H., Kanaar, R., Wyman, C., Dekker, C. <strong>Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA.</strong> Nature 437: 440-443, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16163361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16163361</a>] [<a href="https://doi.org/10.1038/nature03927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16163361">Moreno-Herrero et al. (2005)</a> showed that the dynamic architecture of the R/M/N complex is markedly affected by DNA binding. DNA binding by the R/M/N globular domain leads to parallel orientation of the coiled coils; this prevents intracomplex interactions and favors intercomplex associations needed for DNA tethering. The R/M/N complex thus is an example of a biologic nanomachine in which binding to its ligand, in this case DNA, affects the functional conformation of a domain located 50 nanometers distant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16163361" 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="#35" class="mim-tip-reference" title="Varon, R., Vissinga, C., Platzer, M., Cerosaletti, K. M., Chrzanowska, K. H., Saar, K., Beckmann, G., Seemanova, E., Cooper, P. R., Nowak, N. J., Stumm, M., Weemaes, C. M. R., Gatti, R. A., Wilson, R. K., Digweed, M., Rosenthal, A., Sperling, K., Concannon, P., Reis, A. <strong>Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.</strong> Cell 93: 467-476, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590180</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81174-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590180">Varon et al. (1998)</a> determined that the NBS1 gene spans more than 50 kb and contains 16 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590180" 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="#35" class="mim-tip-reference" title="Varon, R., Vissinga, C., Platzer, M., Cerosaletti, K. M., Chrzanowska, K. H., Saar, K., Beckmann, G., Seemanova, E., Cooper, P. R., Nowak, N. J., Stumm, M., Weemaes, C. M. R., Gatti, R. A., Wilson, R. K., Digweed, M., Rosenthal, A., Sperling, K., Concannon, P., Reis, A. <strong>Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.</strong> Cell 93: 467-476, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590180</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81174-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590180">Varon et al. (1998)</a> mapped the NBS1 gene to chromosome 8q21. <a href="#2" class="mim-tip-reference" title="Carney, J. P., Maser, R. S., Olivares, H., Davis, E. M., Le Beau, M., Yates, J. R., III, Hays, L., Morgan, W. F., Petrini, J. H. J. <strong>The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response.</strong> Cell 93: 477-486, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590181</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81175-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590181">Carney et al. (1998)</a> mapped the gene to chromosome 8q21.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9590181+9590180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By computer-assisted analysis of 5 BAC clones and an EST sequence, <a href="#30" class="mim-tip-reference" title="Tauchi, H., Matsuura, S., Isomura, M., Kinjo, T., Nakamura, A., Sakamoto, S., Kondo, N., Endo, S., Komatsu, K., Nakamura, Y. <strong>Sequence analysis of an 800-kb genomic DNA region on chromosome 8q21 that contains the Nijmegen breakage syndrome gene, NBS1.</strong> Genomics 55: 242-247, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9933573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9933573</a>] [<a href="https://doi.org/10.1006/geno.1998.5657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9933573">Tauchi et al. (1999)</a> defined the genomic organization of an 800-kb region on chromosome 8q21 as 5-prime C8ORF1 (<a href="/entry/604598">604598</a>), 3-prime NBS1, 5-prime DECR1 (<a href="/entry/222745">222745</a>), and 3-prime CALB1 (<a href="/entry/114050">114050</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9933573" 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="#35" class="mim-tip-reference" title="Varon, R., Vissinga, C., Platzer, M., Cerosaletti, K. M., Chrzanowska, K. H., Saar, K., Beckmann, G., Seemanova, E., Cooper, P. R., Nowak, N. J., Stumm, M., Weemaes, C. M. R., Gatti, R. A., Wilson, R. K., Digweed, M., Rosenthal, A., Sperling, K., Concannon, P., Reis, A. <strong>Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.</strong> Cell 93: 467-476, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590180</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81174-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590180">Varon et al. (1998)</a> identified a truncating 5-bp deletion (<a href="#0001">602667.0001</a>) in the NBS1 gene in the majority of NBS patients studied, all of whom carried a conserved marker haplotype. Five additional truncating mutations were identified in patients with other distinct haplotypes. The domains found in nibrin and the NBS phenotype suggest that this disorder is caused by defective responses to DNA double-strand breaks (DSB). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Matsuura, S., Tauchi, H., Nakamura, A., Kondo, N., Sakamoto, S., Endo, S., Smeets, D., Solder, B., Belohradsky, B. H., Der Kaloustian, V. M., Oshimura, M., Isomura, M., Nakamura, Y., Komatsu, K. <strong>Positional cloning of the gene for Nijmegen breakage syndrome.</strong> Nature Genet. 19: 179-181, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620777</a>] [<a href="https://doi.org/10.1038/549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620777">Matsuura et al. (1998)</a> detected the 5-bp deletion (<a href="#0001">602667.0001</a>) in NBS1 in 13 individuals of Slavic or German origin and concluded that it is likely to be a founder mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9620777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The findings that the ataxia-telangiectasia gene is involved in the pathogenesis of T-cell prolymphocytic leukemia and other forms of leukemia, that there is a high predisposition of NBS patients to lymphoid malignancy, and the fact that NBS and ATM are indistinguishable at the cellular level, prompted <a href="#34" class="mim-tip-reference" title="Varon, R., Reis, A., Henze, G., Einsiedel, H. G., Sperling, K., Seeger, K. <strong>Mutations in the Nijmegen breakage syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL).</strong> Cancer Res. 61: 3570-3572, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11325820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11325820</a>]" pmid="11325820">Varon et al. (2001)</a> to investigate whether the NBS1 gene is involved in the pathogenesis of acute lymphoblastic leukemia (ALL) and whether it influences the course of the disease and so has its place among the tumor suppressor genes. They analyzed samples from 47 children with first relapse of ALL for mutations in all 16 exons of the NBS1 gene and identified 4 novel amino acid substitutions in 7 children. Germline origin of an I171V (<a href="#0007">602667.0007</a>) mutation was confirmed in 3 patients, whereas another change, D95N, was present only in leukemic cells. No additional mutations were found on the second allele in any of these 7 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11325820" 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="#28" class="mim-tip-reference" title="Tanzarella, C., Antoccia, A., Spadoni, E., di Masi, A., Pecile, V., Demori, E., Varon, R., Marseglia, G. L., Tiepolo, L., Maraschio, P. <strong>Chromosome instability and nibrin protein variants in NBS heterozygotes.</strong> Europ. J. Hum. Genet. 11: 297-303, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12708449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12708449</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12708449">Tanzarella et al. (2003)</a> found that heterozygous individuals from 3 unrelated NBS families with distinct gene deletion mutations had spontaneous chromosome instability (chromatid and chromosomal breaks as well as rearrangements) in blood lymphocytes, but their lymphoblastoid cell lines were not different from controls in x-ray G2 sensitivity. Immunoprecipitation of nibrin detected the normal and variant proteins in carriers from all 3 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12708449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Nakanishi, K., Taniguchi, T., Ranganathan, V., New, H. V., Moreau, L. A., Stotsky, M., Mathew, C. G., Kastan, M. B., Weaver, D. T., D'Andrea, A. D. <strong>Interaction of FANCD2 and NBS1 in the DNA damage response.</strong> Nature Cell Biol. 4: 913-920, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447395</a>] [<a href="https://doi.org/10.1038/ncb879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447395">Nakanishi et al. (2002)</a> reported a patient diagnosed with Fanconi anemia (FA; <a href="/entry/227650">227650</a>) on the basis of chromosome breakage induced by mitomycin C. The individual showed atypical FA features, including features of NBS. The clinical syndrome was severe, and the child died at 3 years of age, similar to an affected cousin. Immunoblot analysis of primary lymphocytes indicated expression of both unubiquitinated and monoubiquitinated isoforms of FANCD2 (<a href="/entry/227646">227646</a>); however, no NBS1 protein was expressed. Sequence analysis indicated that the patient cells contained a tyr363-to-ter mutation in NBS1 (<a href="#0008">602667.0008</a>), which resulted in a truncated protein. Genomic sequence analysis showed that the mutation was homozygous. By coimmunoprecipitation, <a href="#17" class="mim-tip-reference" title="Nakanishi, K., Taniguchi, T., Ranganathan, V., New, H. V., Moreau, L. A., Stotsky, M., Mathew, C. G., Kastan, M. B., Weaver, D. T., D'Andrea, A. D. <strong>Interaction of FANCD2 and NBS1 in the DNA damage response.</strong> Nature Cell Biol. 4: 913-920, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447395</a>] [<a href="https://doi.org/10.1038/ncb879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447395">Nakanishi et al. (2002)</a> found constitutive interaction between FANCD2 and NBS1, and they presented evidence that these proteins interact in 2 distinct assemblies to mediate S-phase checkpoint and resistance to mitomycin C-induced chromosome damage. NBS1, ATM, and MRE11 were required for FANCD2 phosphorylation in response to radiation-induced S-phase checkpoint. The assembly of NBS1, MRE11, RAD50, and FANCD2 within nuclear foci was required for mitomycin C resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12447395" 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="#19" class="mim-tip-reference" title="Plisiecka-Halasa, J., Dansonka-Mieszkowska, A., Rembiszewska, A., Bidzinski, M., Steffen, J., Kupryjanczyk, J. <strong>Nijmegen breakage syndrome gene (NBS1) alterations and its protein (nibrin) expression in human ovarian tumours.</strong> Ann. Hum. Genet. 66: 353-359, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12485469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12485469</a>] [<a href="https://doi.org/10.1017/S0003480002001227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12485469">Plisiecka-Halasa et al. (2002)</a> looked for NBS1 gene alterations and changes in nibrin expression in 162 human gynecologic tumors, mostly ovarian. They identified the so-called Slavic mutation, 657del5 (<a href="#0001">602667.0001</a>), in 2 of 117 carcinomas studied (1.7%). In both cases it was present in the germline, and in 1 of these tumors there was loss of heterozygosity (LOH) for the 657del5 mutation and loss of nibrin expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12485469" 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 monozygotic twin brothers with a severe form of NBS, <a href="#23" class="mim-tip-reference" title="Seemanova, E., Sperling, K., Neitzel, H., Varon, R., Hadac, J., Butova, O., Schrock, E., Seeman, P., Digweed, M. <strong>Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability.</strong> J. Med. Genet. 43: 218-224, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16033915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16033915</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16033915[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/10.1136/jmg.2005.035287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16033915">Seemanova et al. (2006)</a> identified compound heterozygosity for the 657del5 mutation and a missense mutation (<a href="#0009">602667.0009</a>) in the NBS1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16033915" 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="#43" class="mim-tip-reference" title="Zhu, J., Petersen, S., Tessarollo, L., Nussenzweig, A. <strong>Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice.</strong> Curr. Biol. 11: 105-109, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11231126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11231126</a>] [<a href="https://doi.org/10.1016/s0960-9822(01)00019-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11231126">Zhu et al. (2001)</a> generated mice deficient in NBS1 by targeted disruption. Nbs1 -/- mice suffered early embryonic lethality and had poorly developed embryonic and extraembryonic tissues. Blastocysts showed greatly diminished expansion of the inner cell mass in culture, suggesting that NBS1 mediates essential functions during proliferation in the absence of externally induced damage. <a href="#43" class="mim-tip-reference" title="Zhu, J., Petersen, S., Tessarollo, L., Nussenzweig, A. <strong>Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice.</strong> Curr. Biol. 11: 105-109, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11231126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11231126</a>] [<a href="https://doi.org/10.1016/s0960-9822(01)00019-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11231126">Zhu et al. (2001)</a> concluded that the complex phenotypes observed in NBS patients and cell lines may not result from a complete inactivation of NBS1 but may instead result from hypomorphic truncation mutations compatible with cell viability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11231126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Demuth, I., Frappart, P.-O., Hildebrand, G., Melchers, A., Lobitz, S., Stockl, L., Varon, R., Herceg, Z., Sperling, K., Wang, Z.-Q., Digweed, M. <strong>An inducible null mutant murine model of Nijmegen breakage syndrome proves the essential function of NBS1 in chromosomal stability and cell viability.</strong> Hum. Molec. Genet. 13: 2385-2397, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15333589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15333589</a>] [<a href="https://doi.org/10.1093/hmg/ddh278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15333589">Demuth et al. (2004)</a> used the Cre/loxP system to generate mice with an inducible Nbs1-null mutation, allowing examination of DNA repair and cell cycle checkpoints in the complete absence of nibrin. Induction of the null mutation led to loss of the G2/M checkpoint, increased chromosome damage, radiomimetic sensitivity, and cell death. In vivo, lymphatic tissues, bone marrow, thymus, and spleen showed a dramatic decrease in cell survival, whereas liver, kidney, and muscle showed no effect on cell survival. In vitro, Nbs1-null murine fibroblasts could be rescued from cell death by transfer of human NBS1 cDNA and, more significantly, by a cDNA carrying the 5-bp deletion. <a href="#4" class="mim-tip-reference" title="Demuth, I., Frappart, P.-O., Hildebrand, G., Melchers, A., Lobitz, S., Stockl, L., Varon, R., Herceg, Z., Sperling, K., Wang, Z.-Q., Digweed, M. <strong>An inducible null mutant murine model of Nijmegen breakage syndrome proves the essential function of NBS1 in chromosomal stability and cell viability.</strong> Hum. Molec. Genet. 13: 2385-2397, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15333589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15333589</a>] [<a href="https://doi.org/10.1093/hmg/ddh278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15333589">Demuth et al. (2004)</a> concluded that the common human 5-bp deletion is hypomorphic and that expression of a truncated protein may be sufficient to restore nibrin's vital cellular functions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15333589" 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="#8" class="mim-tip-reference" title="Frappart, P.-O., Tong, W.-M., Demuth, I., Radovanovic, I., Herceg, Z., Aguzzi, A., Digweed, M., Wang, Z.-Q. <strong>An essential function for NBS1 in the prevention of ataxia and cerebellar defects.</strong> Nature Med. 11: 538-544, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15821748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15821748</a>] [<a href="https://doi.org/10.1038/nm1228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15821748">Frappart et al. (2005)</a> developed mice with Nbs1 inactivation targeted to the central nervous system. Nbs1-deleted mice were viable and appeared normal at birth, but growth retardation was evident by postnatal day 7, and mutants were half the weight of control mice at weaning. All Nbs1-deleted mice showed balance disorders, tremors, altered gait, repetitive movements, and akinesis after postnatal day 7. Macroscopic examination of brains from mutant mice showed reduced cerebella lacking foliation. Histologic analysis indicated that Nbs1 loss caused proliferation arrest of granule cell progenitors and apoptosis of postmitotic cerebellar neurons. Nbs1-deficient neuroprogenitors showed proliferation defects in culture, but no increase in apoptosis. They also contained more chromosomal breaks, which were accompanied by Atm (<a href="/entry/607585">607585</a>)-mediated p53 (TP53; <a href="/entry/191170">191170</a>) activation. Depletion of p53 substantially rescued the neurologic defects of Nbs1 mutant mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15821748" 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="#27" class="mim-tip-reference" title="Stracker, T. H., Morales, M., Couto, S. S., Hussein, H., Petrini, J. H. J. <strong>The carboxy terminus of NBS1 is required for induction of apoptosis by the MRE11 complex.</strong> Nature 447: 218-221, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17429352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17429352</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17429352[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature05740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17429352">Stracker et al. (2007)</a> derived Nbs1 delta-C/delta-C mice in which the C-terminal ATM interaction domain was deleted. Nbs1 delta-C/delta-C cells exhibited intra-S-phase checkpoint defects, but were otherwise indistinguishable from wildtype cells with respect to other checkpoint functions, ionizing radiation sensitivity, and chromosome stability. However, multiple tissues of Nbs1 delta-C/delta-C mice showed a severe apoptotic defect, comparable to that of Atm- or Chk2 (<a href="/entry/604373">604373</a>)-deficient animals. Analysis of p53 transcriptional targets and Atm substrates showed that, in contrast to the phenotype of Chk2 -/- mice, Nbs1-deltaC does not impair the induction of proapoptotic genes. <a href="#27" class="mim-tip-reference" title="Stracker, T. H., Morales, M., Couto, S. S., Hussein, H., Petrini, J. H. J. <strong>The carboxy terminus of NBS1 is required for induction of apoptosis by the MRE11 complex.</strong> Nature 447: 218-221, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17429352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17429352</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17429352[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature05740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17429352">Stracker et al. (2007)</a> concluded that instead, the defects observed in Nbs1 delta-C/delta-C mice resulted from impaired phosphorylation at ATM targets including SMC1 (see <a href="/entry/300040">300040</a>) and the proapoptotic factor BID (<a href="/entry/601997">601997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17429352" 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="#22" class="mim-tip-reference" title="Saidi, A., Li, T., Weih, F., Concannon, P., Wang, Z.-Q. <strong>Dual functions of Nbs1 in the repair of DNA breaks and proliferation ensure proper V(D)J recombination and T-cell development.</strong> Molec. Cell. Biol. 30: 5572-5581, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20921278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20921278</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20921278[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.00917-10" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20921278">Saidi et al. (2010)</a> found that deletion of Nbs1 in T-cell precursors in mice resulted in severe lymphopenia and hindered the transition of double-negative-3 (DN3) thymocytes to DN4 due to abnormal Tcrb (see <a href="/entry/186930">186930</a>) coding and signal joints, as well as the functions of Nbs1 in T-cell expansion. Chromatin immunoprecipitation analysis of TCR loci revealed that Nbs1 depletion compromised the loading of Mre11/Rad50 to V(D)J-generated DNA DSBs and thereby affected resection of DNA termini and chromatin conformation of the postcleavage complex. The DN3-to-DN4 transition in the mutant mice, but not T-cell loss, could be relieved by p53 deficiency. Ectopic Tcra/Tcrb expression also failed to rescue T-cell lymphopenia in the mutant mice. <a href="#22" class="mim-tip-reference" title="Saidi, A., Li, T., Weih, F., Concannon, P., Wang, Z.-Q. <strong>Dual functions of Nbs1 in the repair of DNA breaks and proliferation ensure proper V(D)J recombination and T-cell development.</strong> Molec. Cell. Biol. 30: 5572-5581, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20921278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20921278</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20921278[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.00917-10" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20921278">Saidi et al. (2010)</a> concluded that NBS1 functions in both repair of V(D)J-generated DSBs and in proliferation and that both functions are essential for T-cell development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20921278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In patients of Slavic origin with Nijmegen breakage syndrome (NBS; <a href="/entry/251260">251260</a>), <a href="#35" class="mim-tip-reference" title="Varon, R., Vissinga, C., Platzer, M., Cerosaletti, K. M., Chrzanowska, K. H., Saar, K., Beckmann, G., Seemanova, E., Cooper, P. R., Nowak, N. J., Stumm, M., Weemaes, C. M. R., Gatti, R. A., Wilson, R. K., Digweed, M., Rosenthal, A., Sperling, K., Concannon, P., Reis, A. <strong>Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.</strong> Cell 93: 467-476, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590180</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81174-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590180">Varon et al. (1998)</a> identified a common deletion of 5 nucleotides in exon 6 of the NBS1 gene (657del5), resulting in a frameshift and a truncated protein. A total of 46 patients homozygous for this mutation were identified. The mutation was found exclusively on a specific 'Slavic' haplotype of linked polymorphic markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Matsuura, S., Tauchi, H., Nakamura, A., Kondo, N., Sakamoto, S., Endo, S., Smeets, D., Solder, B., Belohradsky, B. H., Der Kaloustian, V. M., Oshimura, M., Isomura, M., Nakamura, Y., Komatsu, K. <strong>Positional cloning of the gene for Nijmegen breakage syndrome.</strong> Nature Genet. 19: 179-181, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620777</a>] [<a href="https://doi.org/10.1038/549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620777">Matsuura et al. (1998)</a> found the same 5-bp deletion in the NBS1 gene in 13 NBS patients of Slavic or German origin. Twelve patients were homozygous for the deletion and 1 was heterozygous. The deletion introduced a premature termination signal at codon 218, which was predicted to result in a severely truncated polypeptide. <a href="#15" class="mim-tip-reference" title="Matsuura, S., Tauchi, H., Nakamura, A., Kondo, N., Sakamoto, S., Endo, S., Smeets, D., Solder, B., Belohradsky, B. H., Der Kaloustian, V. M., Oshimura, M., Isomura, M., Nakamura, Y., Komatsu, K. <strong>Positional cloning of the gene for Nijmegen breakage syndrome.</strong> Nature Genet. 19: 179-181, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620777</a>] [<a href="https://doi.org/10.1038/549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620777">Matsuura et al. (1998)</a> concluded that they had identified the gene involved in NBS because complementation was effected by a YAC that contained the gene and because no (or extremely reduced) expression of the gene was found in a patient without the deletion but with the NBS phenotype. The presence of a founder mutation in 13 of 14 cases, with no demonstration of the deletion in 50 normal individuals of the same ethnic origin or in 7 normal chromosomes from NBS parents, supported this conclusion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9620777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The truncating 657del5 had been identified in 90% of NBS patients. NBS shares a number of features with ataxia-telangiectasia (<a href="/entry/208900">208900</a>), the most notable being high sensitivity to ionizing radiation and predisposition to cancer. Patients who are heterozygous for the ATM mutation are predisposed to breast cancer. Since the NBS phenotype at the cellular level is very similar to that of ataxia-telangiectasia, <a href="#1" class="mim-tip-reference" title="Carlomagno, F., Chang-Claude, J., Dunning, A. M., Ponder, B. A. J. <strong>Determination of the frequency of the common 675del5 Nijmegen breakage syndrome mutation in the German population: no association with risk of breast cancer.</strong> Genes Chromosomes Cancer 25: 393-395, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10398434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10398434</a>] [<a href="https://doi.org/10.1002/(sici)1098-2264(199908)25:4<393::aid-gcc12>3.0.co;2-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10398434">Carlomagno et al. (1999)</a> screened 477 German breast cancer patients, aged under 51 years, and 866 matched controls for the common NBS mutation. They identified 1 carrier among the cases and 1 among the controls, indicating that the population frequency of this NBS mutation is 1 in 866 persons (95% CI = 1 in 34,376 to 1 in 156) and the estimated prevalence of NBS is thus 1 in 3 million persons. The proportion of breast cancer attributable to this mutation is less than 1%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10398434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Kleier, S., Herrmann, M., Wittwer, B., Varon, R., Reis, A., Horst, J. <strong>Clinical presentation and mutation identification in the NBS1 gene in a boy with Nijmegen breakage syndrome.</strong> Clin. Genet. 57: 384-387, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852373</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2000.570509.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10852373">Kleier et al. (2000)</a> reported a 5-year-old Bosnian boy with severe microcephaly. Because of multiple structural aberrations involving chromosomes 7 and 14 typical for ataxia-telangiectasia, that disorder was diagnosed. However, the diagnosis of NBS was suggested by the boy's remarkable microcephaly, his facial appearance, and the absence of ataxia and telangiectasia. DNA analysis demonstrated homozygosity for the major mutation in the NBS1 gene, 657del5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10852373" 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="#14" class="mim-tip-reference" title="Maser, R. S., Zinkel, R., Petrini, J. H. J. <strong>An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele.</strong> Nature Genet. 27: 417-421, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11279524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11279524</a>] [<a href="https://doi.org/10.1038/86920" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11279524">Maser et al. (2001)</a> tested the hypothesis that the NBS1 657del5 mutation is a hypomorphic defect. They showed that NBS cells harboring the 657del5 mutation contained a predicted 26-kD N-terminal protein, NBS1(p26), and a 70-kD NBS1 protein, NBS1(p70), lacking the native N terminus. The 26-kD protein is not physically associated with the MRE11 complex (<a href="/entry/600814">600814</a>), whereas the 70-kD species is physically associated with it. NBS1(p70) is produced by internal translation initiation within the NBS mRNA using an open reading frame generated by the 657del5 frameshift. <a href="#14" class="mim-tip-reference" title="Maser, R. S., Zinkel, R., Petrini, J. H. J. <strong>An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele.</strong> Nature Genet. 27: 417-421, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11279524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11279524</a>] [<a href="https://doi.org/10.1038/86920" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11279524">Maser et al. (2001)</a> proposed that the common NBS1 allele encodes a partially functional protein that diminishes the severity of the NBS phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11279524" 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="#31" class="mim-tip-reference" title="Tekin, M., Dogu, F., Tacyildiz, N., Akar, E., Ikinciogullari, A., Ogur, G., Yavuz, G., Babacan, E., Akar, N. <strong>657del5 mutation in the NBS1 gene is associated with Nijmegen breakage syndrome in a Turkish family.</strong> Clin. Genet. 62: 84-88, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12123493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12123493</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.620112.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12123493">Tekin et al. (2002)</a> reported a consanguineous Turkish family whose first son died of anal atresia and whose second son, the proband, presented with severe pre- and postnatal growth retardation as well as striking microcephaly, immunodeficiency, congenital heart disease, chromosome instability, and rhabdomyosarcoma in the anal region. The patient was homozygous for the 657del5 mutation in the NBS1 gene, which is responsible for NBS in most Slavic populations. The family was the first diagnosed with NBS in the Turkish population and was one of the most severely affected examples of the syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12123493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Drabek, J., Hajduch, M., Gojova, L., Weigl, E., Mihal, V. <strong>Frequency of 657del(5) mutation of the NBS1 gene in the Czech population by polymerase chain reaction with sequence specific primers.</strong> Cancer Genet. Cytogenet. 138: 157-159, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12505263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12505263</a>] [<a href="https://doi.org/10.1016/s0165-4608(02)00594-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12505263">Drabek et al. (2002)</a> presented PCR with sequence specific primers as a method for detection of the 657del5 mutation. They confirmed a high carrier frequency in the Czech population (1 in 106 persons; 95% CI = 1 in 331 to 1 in 46). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12505263" 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 Russian children, <a href="#21" class="mim-tip-reference" title="Resnick, I. B., Kondratenko, I., Pashanov, E., Maschan, A. A., Karachunsky, A., Togoev, O., Timakov, A., Polyakov, A., Tverskaya, S., Evgrafov, O., Roumiantsev, A. G. <strong>657del5 mutation in the gene for Nijmegen breakage syndrome (NBS1) in a cohort of Russian children with lymphoid tissue malignancies and controls.</strong> Am. J. Med. Genet. 120A: 174-179, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12833396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12833396</a>] [<a href="https://doi.org/10.1002/ajmg.a.20188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12833396">Resnick et al. (2003)</a> screened for the 657del5 NBS1 mutation in 548 controls and 68 patients with lymphoid malignancies. No carrier of the mutation was found in the control group. The mutation was found in heterozygous form in 2 of the 68 patients from the group of lymphoid malignancies, 1 with acute lymphoblastic leukemia (see <a href="/entry/159555">159555</a>) and 1 with non-Hodgkin lymphoma (<a href="/entry/605027">605027</a>). Several relatives of the patient with non-Hodgkin lymphoma who carried the same mutation had cancer (acute lymphoblastic leukemia, breast cancer, gastrointestinal cancers), suggesting that heterozygosity may predispose to malignant disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12833396" 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 monozygotic twin brothers with a severe form of NBS without chromosomal instability, <a href="#23" class="mim-tip-reference" title="Seemanova, E., Sperling, K., Neitzel, H., Varon, R., Hadac, J., Butova, O., Schrock, E., Seeman, P., Digweed, M. <strong>Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability.</strong> J. Med. Genet. 43: 218-224, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16033915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16033915</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16033915[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/10.1136/jmg.2005.035287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16033915">Seemanova et al. (2006)</a> identified compound heterozygosity for the 657del5 mutation and a 643C-T transition in exon 6 of the NBS1 gene, resulting in an arg215-to-trp (R215W) substitution (<a href="#0009">602667.0009</a>). Both infants showed reduced expression of full-length nibrin, and radiation response processes were strongly reduced in their cells. Their mother and father were heterozygous for the 657del5 mutation and the R215W mutation, respectively, as were their respective grandfathers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16033915" 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 3-month-old boy with NBS, <a href="#33" class="mim-tip-reference" title="Varon, R., Muer, A., Wagner, K., Zierler, H., Sodia, S., Rauter, L., Petek, E., Tonnies, H., Neitzel, H., Sperling, K., Kroisel, P. M. <strong>Nijmegen breakage syndrome (NBS) due to maternal isodisomy of chromosome 8. (Letter)</strong> Am. J. Med. Genet. 143A: 92-94, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17103455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17103455</a>] [<a href="https://doi.org/10.1002/ajmg.a.31540" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17103455">Varon et al. (2007)</a> identified homozygosity for the 657del5 mutation; the patient's mother carried the mutation, whereas his father was homozygous for the wildtype allele. Analysis of 27 microsatellite markers covering all of chromosome 8 revealed that the patient had a homozygous haplotype for all of the markers, whereas the mother carried the same haplotype in heterozygous state. The authors stated that this was the first patient with NBS due to maternal isodisomy of chromosome 8. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17103455" 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="#20" class="mim-tip-reference" title="Porhanova, N. V., Sokolenko, A. P., Sherina, N. Y., Ponomariova, D. N., Tkachenko, N. N., Matsko, D. E., Imyanitov, E. N. <strong>Ovarian cancer patient with germline mutations in both BRCA1 and NBN genes. (Letter)</strong> Cancer Genet. Cytogenet. 186: 122-124, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18940477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18940477</a>] [<a href="https://doi.org/10.1016/j.cancergencyto.2008.06.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18940477">Porhanova et al. (2008)</a> reported a 52-year-old Russian woman with ovarian cancer (see <a href="/entry/604370">604370</a>) who was found to be compound heterozygous for a mutation in the BRCA1 gene (<a href="/entry/113705#0018">113705.0018</a>) and the common Slavic 657del5 mutation in the NBN gene. Investigation of the ovarian cancer tissue showed somatic loss of heterozygosity for NBN, but retention of heterozygosity for BRCA1. The patient did not have a particularly severe cancer-prone phenotype, and her parents did not have cancer, although 3 sibs developed cancer as adults. <a href="#20" class="mim-tip-reference" title="Porhanova, N. V., Sokolenko, A. P., Sherina, N. Y., Ponomariova, D. N., Tkachenko, N. N., Matsko, D. E., Imyanitov, E. N. <strong>Ovarian cancer patient with germline mutations in both BRCA1 and NBN genes. (Letter)</strong> Cancer Genet. Cytogenet. 186: 122-124, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18940477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18940477</a>] [<a href="https://doi.org/10.1016/j.cancergencyto.2008.06.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18940477">Porhanova et al. (2008)</a> commented that haploinsufficiency of the BRCA1 gene may contribute to cancer progression without somatic changes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18940477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient of English origin with Nijmegen breakage syndrome (NBS; <a href="/entry/251260">251260</a>), <a href="#35" class="mim-tip-reference" title="Varon, R., Vissinga, C., Platzer, M., Cerosaletti, K. M., Chrzanowska, K. H., Saar, K., Beckmann, G., Seemanova, E., Cooper, P. R., Nowak, N. J., Stumm, M., Weemaes, C. M. R., Gatti, R. A., Wilson, R. K., Digweed, M., Rosenthal, A., Sperling, K., Concannon, P., Reis, A. <strong>Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.</strong> Cell 93: 467-476, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590180</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81174-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590180">Varon et al. (1998)</a> identified a deletion of 4 nucleotides in exon 6 of the NBS1 gene, resulting in a frameshift and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient of Italian origin with Nijmegen breakage syndrome (NBS; <a href="/entry/251260">251260</a>), <a href="#35" class="mim-tip-reference" title="Varon, R., Vissinga, C., Platzer, M., Cerosaletti, K. M., Chrzanowska, K. H., Saar, K., Beckmann, G., Seemanova, E., Cooper, P. R., Nowak, N. J., Stumm, M., Weemaes, C. M. R., Gatti, R. A., Wilson, R. K., Digweed, M., Rosenthal, A., Sperling, K., Concannon, P., Reis, A. <strong>Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.</strong> Cell 93: 467-476, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590180</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81174-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590180">Varon et al. (1998)</a> identified a deletion of 4 nucleotides in exon 7 of the NBS1 gene, resulting in a frameshift and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient of Mexican origin with Nijmegen breakage syndrome (NBS; <a href="/entry/251260">251260</a>), <a href="#35" class="mim-tip-reference" title="Varon, R., Vissinga, C., Platzer, M., Cerosaletti, K. M., Chrzanowska, K. H., Saar, K., Beckmann, G., Seemanova, E., Cooper, P. R., Nowak, N. J., Stumm, M., Weemaes, C. M. R., Gatti, R. A., Wilson, R. K., Digweed, M., Rosenthal, A., Sperling, K., Concannon, P., Reis, A. <strong>Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.</strong> Cell 93: 467-476, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590180</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81174-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590180">Varon et al. (1998)</a> identified an insertion of 1 nucleotide in exon 7 of the NBS1 gene, resulting in a frameshift and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590180" 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> rs587781969 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587781969;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/rs587781969?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=rs587781969" 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=rs587781969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient of Canadian origin with Nijmegen breakage syndrome (NBS; <a href="/entry/251260">251260</a>), <a href="#35" class="mim-tip-reference" title="Varon, R., Vissinga, C., Platzer, M., Cerosaletti, K. M., Chrzanowska, K. H., Saar, K., Beckmann, G., Seemanova, E., Cooper, P. R., Nowak, N. J., Stumm, M., Weemaes, C. M. R., Gatti, R. A., Wilson, R. K., Digweed, M., Rosenthal, A., Sperling, K., Concannon, P., Reis, A. <strong>Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.</strong> Cell 93: 467-476, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590180</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81174-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590180">Varon et al. (1998)</a> identified a deletion of 1 nucleotide in exon 10 of the NBS1 gene, resulting in a frameshift and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590180" 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">rs121908973 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908973;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=rs121908973" 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=rs121908973" 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=RCV000007359 OR RCV000166946" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007359, RCV000166946" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007359...</a>
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<p>In a patient of Dutch origin with Nijmegen breakage syndrome (NBS; <a href="/entry/251260">251260</a>), <a href="#35" class="mim-tip-reference" title="Varon, R., Vissinga, C., Platzer, M., Cerosaletti, K. M., Chrzanowska, K. H., Saar, K., Beckmann, G., Seemanova, E., Cooper, P. R., Nowak, N. J., Stumm, M., Weemaes, C. M. R., Gatti, R. A., Wilson, R. K., Digweed, M., Rosenthal, A., Sperling, K., Concannon, P., Reis, A. <strong>Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.</strong> Cell 93: 467-476, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590180</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81174-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590180">Varon et al. (1998)</a> identified a nonsense mutation, gln326 to ter, in exon 10 of the NBS1 gene, resulting in a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590180" 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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LYMPHOBLASTIC LEUKEMIA, ACUTE, SUSCEPTIBILITY TO, INCLUDED
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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> rs61754966 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61754966;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/rs61754966?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=rs61754966" 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=rs61754966" 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=RCV000007360 OR RCV000007361 OR RCV000115797 OR RCV000121618 OR RCV000197512 OR RCV000490266 OR RCV000589577 OR RCV001030566 OR RCV001262350 OR RCV001358233 OR RCV003492288 OR RCV003891430 OR RCV004776268 OR RCV004776269" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007360, RCV000007361, RCV000115797, RCV000121618, RCV000197512, RCV000490266, RCV000589577, RCV001030566, RCV001262350, RCV001358233, RCV003492288, RCV003891430, RCV004776268, RCV004776269" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007360...</a>
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<p>In 3 patients with acute lymphoblastic leukemia (see <a href="/entry/613065">613065</a>), <a href="#34" class="mim-tip-reference" title="Varon, R., Reis, A., Henze, G., Einsiedel, H. G., Sperling, K., Seeger, K. <strong>Mutations in the Nijmegen breakage syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL).</strong> Cancer Res. 61: 3570-3572, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11325820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11325820</a>]" pmid="11325820">Varon et al. (2001)</a> found germline heterozygosity for an A-to-G change at nucleotide 511, resulting in an ile171-to-val (I171V) mutation occurring in a domain of nibrin that is probably involved in protein-protein interactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11325820" 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 an 11-year-old Japanese girl with aplastic anemia (<a href="/entry/609135">609135</a>) and no features of Nijmegen breakage syndrome, <a href="#24" class="mim-tip-reference" title="Shimada, H., Shimizu, K, Mimaki, S., Sakiyama, T., Mori, T., Shimasaki, N., Yokota, J., Nakachi, K., Ohta, T., Ohki, M. <strong>First case of aplastic anemia in a Japanese child with a homozygous missense mutation in the NBS1 gene (I171V) associated with genomic instability.</strong> Hum. Genet. 115: 372-376, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15338273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15338273</a>] [<a href="https://doi.org/10.1007/s00439-004-1155-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15338273">Shimada et al. (2004)</a> identified homozygosity for the I171V mutation in the NBS1 gene. Genetic analysis of the patient and her healthy parents indicated that she inherited the germline I171V mutation from her father and the wildtype allele from her mother, and that the second I171V hit occurred on the wildtype allele early in embryonic development. Cytogenetic analysis of lymphoblastic cell lines from the patient showed a marked increase in numerical and structural chromosomal aberrations in the absence of clastogens, suggesting genomic instability. <a href="#24" class="mim-tip-reference" title="Shimada, H., Shimizu, K, Mimaki, S., Sakiyama, T., Mori, T., Shimasaki, N., Yokota, J., Nakachi, K., Ohta, T., Ohki, M. <strong>First case of aplastic anemia in a Japanese child with a homozygous missense mutation in the NBS1 gene (I171V) associated with genomic instability.</strong> Hum. Genet. 115: 372-376, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15338273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15338273</a>] [<a href="https://doi.org/10.1007/s00439-004-1155-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15338273">Shimada et al. (2004)</a> also screened 413 normal controls and found heterozygosity for I171V in 5 individuals, corresponding to 1.2% of the Japanese population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15338273" 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> rs121908974 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908974;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/rs121908974?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=rs121908974" 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=rs121908974" 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=RCV000007362 OR RCV003329227 OR RCV003472997" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007362, RCV003329227, RCV003472997" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007362...</a>
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<p><a href="#17" class="mim-tip-reference" title="Nakanishi, K., Taniguchi, T., Ranganathan, V., New, H. V., Moreau, L. A., Stotsky, M., Mathew, C. G., Kastan, M. B., Weaver, D. T., D'Andrea, A. D. <strong>Interaction of FANCD2 and NBS1 in the DNA damage response.</strong> Nature Cell Biol. 4: 913-920, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447395</a>] [<a href="https://doi.org/10.1038/ncb879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447395">Nakanishi et al. (2002)</a> reported a patient diagnosed with Fanconi anemia (FA; <a href="/entry/227650">227650</a>) on the basis of chromosome breakage induced by mitomycin C. The individual showed atypical FA features, including features of Nijmegen breakage syndrome (NBS; <a href="/entry/251260">251260</a>). The clinical syndrome was severe, and the child died at 3 years of age, similar to an affected cousin. In this patient, <a href="#17" class="mim-tip-reference" title="Nakanishi, K., Taniguchi, T., Ranganathan, V., New, H. V., Moreau, L. A., Stotsky, M., Mathew, C. G., Kastan, M. B., Weaver, D. T., D'Andrea, A. D. <strong>Interaction of FANCD2 and NBS1 in the DNA damage response.</strong> Nature Cell Biol. 4: 913-920, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447395</a>] [<a href="https://doi.org/10.1038/ncb879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447395">Nakanishi et al. (2002)</a> identified a homozygous C-to-A mutation at nucleotide 1089 of the NBS1 gene, resulting in a tyr363-to-ter mutation and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12447395" 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> rs34767364 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34767364;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/rs34767364?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=rs34767364" 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=rs34767364" 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=RCV000007363 OR RCV000115802 OR RCV000121621 OR RCV000487932 OR RCV003891431" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007363, RCV000115802, RCV000121621, RCV000487932, RCV003891431" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007363...</a>
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<p>For discussion of the arg215-to-trp (R215W) mutation in the NBN gene that was found in compound heterozygous state in monozygotic twin brothers with Nijmegen breakage syndrome (NBS; <a href="/entry/251260">251260</a>) by <a href="#23" class="mim-tip-reference" title="Seemanova, E., Sperling, K., Neitzel, H., Varon, R., Hadac, J., Butova, O., Schrock, E., Seeman, P., Digweed, M. <strong>Nijmegen breakage syndrome (NBS) with neurological abnormalities and without chromosomal instability.</strong> J. Med. Genet. 43: 218-224, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16033915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16033915</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16033915[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/10.1136/jmg.2005.035287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16033915">Seemanova et al. (2006)</a>, see <a href="#0001">602667.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16033915" 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>.0010 NIJMEGEN BREAKAGE SYNDROME</strong>
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NBN, 2-BP INS, 742GG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864309670 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864309670;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=rs864309670" 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=rs864309670" 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=RCV000007364 OR RCV000657237 OR RCV001525344" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007364, RCV000657237, RCV001525344" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007364...</a>
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<p>In a 53-year-old woman with a mild form of Nijmegen breakage syndrome (NBS; <a href="/entry/251260">251260</a>), who was originally reported by <a href="#13" class="mim-tip-reference" title="Maraschio, P., Peretti, D., Lambiase, S., Lo Curto, F., Caufin, D., Gargantini, L., Minoli, L., Zuffardi, O. <strong>A new chromosome instability disorder.</strong> Clin. Genet. 30: 353-365, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3802554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3802554</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1986.tb01892.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3802554">Maraschio et al. (1986)</a>, <a href="#32" class="mim-tip-reference" title="Varon, R., Dutrannoy, V., Weikert, G., Tanzarella, C., Antoccia, A., Stockl, L., Spadoni, E., Kruger, L.-A., di Masi, A., Sperling, K., Digweed, M., Maraschio, P. <strong>Mild Nijmegen breakage syndrome phenotype due to alternative splicing.</strong> Hum. Molec. Genet. 15: 679-689, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415040</a>] [<a href="https://doi.org/10.1093/hmg/ddi482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415040">Varon et al. (2006)</a> identified a homozygous 2-bp insertion (742insGG) in exon 7 of the NBN gene, predicted to result in premature termination. RT-PCR analysis identified 2 transcripts in both the patient and her parents: the expected transcript carrying the 2-bp insertion and a second transcript with in-frame deletion of exons 6 and 7. The skipping of exons 6 and 7 results in a 650-amino acid protein with a molecular mass of 73 kD; it also eliminates the 742insGG mutation in exon 7. The 73-kD (del6-del7) transcript was observed at levels 100-fold lower in controls than in the patient and her parents, and the del6-del7 transcript was detected as minor product in RNA from patients with the 657del5 mutation (<a href="#0001">602667.0001</a>). The open reading frame of the del6-del7 transcript predicts a partially functional protein, which was confirmed by studies in mouse cells. ESE prediction analysis suggested that 742insGG may affect an ESE sequence, possibly resulting in decreased splicing enhancer activity. Because the NBN transcript can only remain in-frame if both exons 6 and 7 are deleted, the authors hypothesized that the presence of the del6-del7 transcript results from an active mechanism in which reestablishment of the reading frame requires elimination of the 2 exons. The patient had no immunodeficiency and had not had frequent infections. <a href="#32" class="mim-tip-reference" title="Varon, R., Dutrannoy, V., Weikert, G., Tanzarella, C., Antoccia, A., Stockl, L., Spadoni, E., Kruger, L.-A., di Masi, A., Sperling, K., Digweed, M., Maraschio, P. <strong>Mild Nijmegen breakage syndrome phenotype due to alternative splicing.</strong> Hum. Molec. Genet. 15: 679-689, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16415040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16415040</a>] [<a href="https://doi.org/10.1093/hmg/ddi482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16415040">Varon et al. (2006)</a> concluded that the unusually mild phenotype in this patient resulted from residual nibrin activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16415040+3802554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Carney1998" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1016/s0092-8674(00)81175-7" target="_blank">Full Text</a>]
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<a id="Chen2000" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110662</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11110662[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=11110662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.290.5498.1962" target="_blank">Full Text</a>]
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<a id="Demuth2004" class="mim-anchor"></a>
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Demuth, I., Frappart, P.-O., Hildebrand, G., Melchers, A., Lobitz, S., Stockl, L., Varon, R., Herceg, Z., Sperling, K., Wang, Z.-Q., Digweed, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15333589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15333589</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15333589" 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/ddh278" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0165-4608(02)00594-0" target="_blank">Full Text</a>]
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Frappart, P.-O., Tong, W.-M., Demuth, I., Radovanovic, I., Herceg, Z., Aguzzi, A., Digweed, M., Wang, Z.-Q.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15821748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15821748</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15821748" 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/nm1228" target="_blank">Full Text</a>]
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Gatei, M., Young, D., Cerosaletti, K. M., Desai-Mehta, A., Spring, K., Kozlov, S., Lavin, M. F., Gatti, R. A., Concannon, P., Khanna, K.
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[<a href="https://doi.org/10.1038/75508" target="_blank">Full Text</a>]
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<a id="Kleier2000" class="mim-anchor"></a>
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Kleier, S., Herrmann, M., Wittwer, B., Varon, R., Reis, A., Horst, J.
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<strong>Clinical presentation and mutation identification in the NBS1 gene in a boy with Nijmegen breakage syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852373</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10852373" 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/10.1034/j.1399-0004.2000.570509.x" target="_blank">Full Text</a>]
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<a id="Lim2000" class="mim-anchor"></a>
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Lim, D.-S., Kim, S.-T., Xu, B., Maser, R. S., Lin, J., Petrini, J. H. J., Kastan, M. B.
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<strong>ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway.</strong>
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Nature 404: 613-617, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10766245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10766245</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10766245" 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/10.1038/35007091" target="_blank">Full Text</a>]
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Lombard, D. B., Guarente, L.
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<strong>Nijmegen breakage syndrome disease protein and MRE11 at PML nuclear bodies and meiotic telomeres.</strong>
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Cancer Res. 60: 2331-2334, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888888</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10888888" 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/10.1038/77139" target="_blank">Full Text</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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Paul J. Converse - updated : 10/11/2016
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<div class="row collapse" id="mimCollapseContributors">
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Paul J. Converse - updated : 9/27/2011<br>Cassandra L. Kniffin - updated : 11/2/2009<br>Cassandra L. Kniffin - updated : 6/5/2009<br>George E. Tiller - updated : 12/10/2008<br>Patricia A. Hartz - updated : 8/6/2007<br>George E. Tiller - updated : 6/21/2007<br>Ada Hamosh - updated : 6/21/2007<br>Marla J. F. O'Neill - updated : 4/19/2006<br>Ada Hamosh - updated : 11/3/2005<br>Patricia A. Hartz - updated : 5/16/2005<br>Marla J. F. O'Neill - updated : 4/25/2005<br>Victor A. McKusick - updated : 1/12/2005<br>Natalie E. Krasikov - updated : 6/1/2004<br>George E. Tiller - updated : 12/4/2003<br>Victor A. McKusick - updated : 3/12/2003<br>Patricia A. Hartz - updated : 3/10/2003<br>Victor A. McKusick - updated : 3/3/2003<br>Ada Hamosh - updated : 11/13/2002<br>Victor A. McKusick - updated : 8/21/2002<br>Ada Hamosh - updated : 7/24/2002<br>Ada Hamosh - updated : 3/28/2002<br>Ada Hamosh - updated : 1/2/2002<br>Victor A. McKusick - updated : 6/21/2001<br>Ada Hamosh - updated : 3/29/2001<br>Ada Hamosh - updated : 12/18/2000<br>Paul J. Converse - updated : 11/16/2000<br>George E. Tiller - updated : 9/21/2000<br>Victor A. McKusick -updated : 8/31/2000<br>Victor A. McKusick - updated : 6/27/2000<br>Victor A. McKusick - updated : 6/2/2000<br>Ada Hamosh - updated : 5/24/2000<br>Ada Hamosh - updated : 4/27/2000<br>Ada Hamosh - updated : 4/18/2000<br>Paul J. Converse - updated : 2/24/2000<br>Victor A. McKusick - updated : 9/24/1999<br>Ada Hamosh - updated : 7/30/1999<br>Victor A. McKusick - updated : 6/1/1998
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Creation Date:
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<span class="mim-text-font">
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Stylianos E. Antonarakis : 5/28/1998
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carol : 09/29/2023
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mgross : 10/11/2016<br>joanna : 06/24/2016<br>carol : 1/7/2016<br>carol : 12/6/2013<br>mgross : 10/7/2013<br>mgross : 10/4/2013<br>carol : 9/16/2013<br>carol : 10/8/2012<br>mgross : 10/5/2011<br>terry : 9/27/2011<br>wwang : 10/13/2010<br>wwang : 11/5/2009<br>ckniffin : 11/2/2009<br>ckniffin : 10/29/2009<br>wwang : 6/25/2009<br>wwang : 6/23/2009<br>ckniffin : 6/5/2009<br>wwang : 12/10/2008<br>mgross : 8/10/2007<br>terry : 8/6/2007<br>wwang : 6/26/2007<br>wwang : 6/26/2007<br>wwang : 6/22/2007<br>terry : 6/21/2007<br>alopez : 6/21/2007<br>carol : 8/31/2006<br>terry : 8/30/2006<br>wwang : 4/20/2006<br>terry : 4/19/2006<br>alopez : 11/7/2005<br>terry : 11/3/2005<br>mgross : 5/17/2005<br>terry : 5/16/2005<br>wwang : 4/29/2005<br>wwang : 4/27/2005<br>terry : 4/25/2005<br>mgross : 4/14/2005<br>wwang : 1/19/2005<br>wwang : 1/13/2005<br>terry : 1/12/2005<br>carol : 6/1/2004<br>mgross : 12/4/2003<br>cwells : 11/10/2003<br>carol : 10/27/2003<br>carol : 5/15/2003<br>carol : 5/15/2003<br>ckniffin : 3/13/2003<br>mgross : 3/12/2003<br>terry : 3/12/2003<br>terry : 3/10/2003<br>carol : 3/10/2003<br>tkritzer : 3/7/2003<br>terry : 3/3/2003<br>alopez : 11/14/2002<br>terry : 11/13/2002<br>tkritzer : 8/27/2002<br>tkritzer : 8/26/2002<br>terry : 8/21/2002<br>terry : 8/21/2002<br>cwells : 7/26/2002<br>terry : 7/24/2002<br>cwells : 3/29/2002<br>terry : 3/28/2002<br>alopez : 1/9/2002<br>terry : 1/2/2002<br>mcapotos : 7/5/2001<br>mcapotos : 6/27/2001<br>terry : 6/21/2001<br>alopez : 3/29/2001<br>terry : 3/29/2001<br>carol : 3/28/2001<br>joanna : 1/17/2001<br>mgross : 12/18/2000<br>mgross : 12/18/2000<br>mgross : 11/16/2000<br>alopez : 9/21/2000<br>mcapotos : 9/5/2000<br>mcapotos : 8/31/2000<br>alopez : 6/27/2000<br>mcapotos : 6/14/2000<br>terry : 6/2/2000<br>alopez : 5/24/2000<br>alopez : 4/29/2000<br>terry : 4/27/2000<br>alopez : 4/18/2000<br>carol : 2/24/2000<br>alopez : 10/26/1999<br>terry : 9/24/1999<br>alopez : 7/30/1999<br>alopez : 7/28/1999<br>alopez : 7/28/1999<br>terry : 7/16/1999<br>carol : 8/24/1998<br>carol : 6/10/1998<br>carol : 6/1/1998<br>carol : 5/29/1998
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<span class="mim-font">
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<strong>*</strong> 602667
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<h3>
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<span class="mim-font">
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NIBRIN; NBN
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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p95 PROTEIN OF THE MRE11/RAD50 COMPLEX<br />
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NBS1
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NBN</em></strong>
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<strong>SNOMEDCT:</strong> 234638009, 304132006, 306058006;
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<strong>ICD10CM:</strong> D61.9;
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<strong>ICD9CM:</strong> 284.9;
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<strong>
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<em>
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Cytogenetic location: 8q21.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 8:89,933,331-89,984,667 </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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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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8q21.3
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Aplastic anemia
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<span class="mim-font">
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609135
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</td>
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<td>
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<span class="mim-font">
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<span class="mim-font">
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3
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</td>
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Leukemia, acute lymphoblastic
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<span class="mim-font">
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613065
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<span class="mim-font">
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<span class="mim-font">
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3
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<span class="mim-font">
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Nijmegen breakage syndrome
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</td>
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<span class="mim-font">
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251260
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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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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</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>Cloning and Expression</strong>
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<span class="mim-text-font">
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<p>Varon et al. (1998) described the positional cloning of a gene encoding a novel protein, termed nibrin, that mapped within a 300-kb critical region for Nijmegen breakage syndrome (NBS; 251260) on chromosome 8q21. Northern blot analysis revealed mRNA transcripts of 2.4 and 4.4 kb in all tissues examined. The predicted 754-amino acid protein contains 2 domains found in cell cycle checkpoint proteins, a forkhead-associated domain and an adjacent breast cancer carboxy-terminal domain. </p><p>Carney et al. (1998) independently isolated the gene for NBS. They characterized the gene encoding p95, a member of the MRE11/RAD50 double-strand break (DSB) repair complex. Comparison of the p95 cDNA to the NBS1 cDNA of Varon et al. (1998) indicated that the p95 and NBS1 genes are identical. </p><p>Matsuura et al. (1998) reported the positional cloning of the gene responsible for the Nijmegen breakage syndrome, NBS1, from an 800-kb candidate region. They found that the gene is expressed at high levels in testis, suggesting that it may be involved in meiotic recombination. </p>
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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 class="mim-text-font">
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<p>The MRE11/RAD50 DSB repair complex consists of 5 proteins: p95 (NBS1), p200, p400, MRE11, and RAD50 (604040). Carney et al. (1998) found that p95 was absent from NBS cells established from NBS patients and that p95 deficiency in these cells completely abrogated the formation of MRE11/RAD50 ionizing radiation-induced foci. The implication of the MRE11/RAD50/p95 protein complex in NBS reveals a direct molecular link between DSB repair and cell cycle checkpoint functions. </p><p>Zhong et al. (1999) demonstrated association of BRCA1 (113705) with the RAD50/MRE11/p95 complex. Upon irradiation, BRCA1 was detected in the nucleus, in discrete foci which colocalize with RAD50. Formation of irradiation-induced foci positive for BRCA1, RAD50, MRE11, or p95 was dramatically reduced in HCC/1937 breast cancer cells carrying a homozygous mutation in BRCA1 but was restored by transfection of wildtype BRCA1. Ectopic expression of wildtype, but not mutated, BRCA1 in these cells rendered them less sensitive to the DNA damage agent methyl methanesulfonate. These data suggested to the authors that BRCA1 is important for the cellular responses to DNA damage that are mediated by the RAD50-MRE11-p95 complex. </p><p>Wang et al. (2000) used immunoprecipitation and mass spectrometry analyses to identify BRCA1-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM (607585), BLM (604610), MSH2 (609309), MSH6 (600678), MLH1 (120436), the RAD50-MRE11-NBS1 complex, and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Confocal microscopy demonstrated that BRCA1, BLM, and the RAD50-MRE11-NBS1 complex colocalize to large nuclear foci. Wang et al. (2000) suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. </p><p>Because of the similarities between ataxia-telangiectasia (AT; 208900) and Nijmegen breakage syndrome, Lim et al. (2000) evaluated the functional interactions between the ataxia-telangiectasia mutated (ATM; 607585) and NBS1 genes. Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that NBS1 may not be required for signaling to ATM after ionizing radiation. However, NBS1 was phosphorylated on serine-343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation. An NBS1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells. These observations linked ATM and NBS1 in a common signaling pathway and provided an explanation for the phenotypic similarities between the 2 disorders. </p><p>Gatei et al. (2000) demonstrated that nibrin is phosphorylated within 1 hour of treatment of cells with ionizing radiation. This response was abrogated in AT cells that either do not express ATM protein or express near full-length mutant protein. Gatei et al. (2000) also showed that ATM physically interacts with and phosphorylates nibrin on serine-343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (S343A) does not completely complement radiosensitivity in NBS cells. ATM phosphorylation of nibrin does not affect nibrin-MRE11-RAD50 association, as revealed by radiation-induced foci formation. Gatei et al. (2000) concluded that their data provide a biochemical explanation for the similarity in phenotype between AT and NBS. </p><p>Zhao et al. (2000) demonstrated that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. Zhao et al. (2000) identified 2 residues of NBS1, serine-278 and serine-343, that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mre11/Rad50 nuclear foci, and rescue of hypersensitivity to ionizing radiation. Zhao et al. (2000) concluded that together, these results demonstrated a biochemical link between cell cycle checkpoints activated by DNA damage and DNA repair in 2 genetic diseases with overlapping phenotypes. </p><p>Zhu et al. (2000) showed by coimmunoprecipitation that a small fraction of RAD50, MRE11, and NBS1 is associated with the telomeric repeat-binding factor TRF2 (602027). Indirect immunofluorescence demonstrated the presence of RAD50 and MRE11 at interphase telomeres. NBS1 was associated with TRF2 and telomeres in S phase, but not in G1 or G2. Although the MRE11 complex accumulated in irradiation-induced foci (IRIFs) in response to gamma-irradiation, TRF2 did not relocate to IRIFs and irradiation did not affect the association of TRF2 with the MRE11 complex, arguing against a role for TRF2 in double-strand break repair. Zhu et al. (2000) proposed that the MRE11 complex functions at telomeres, possibly by modulating t-loop formation. </p><p>Lombard and Guarente (2000) showed that p95 and MRE11 are specifically present on telomeres during meiosis. They suggested that p95 and MRE11 may have a role in telomere maintenance in mammals, analogous to the role their homologs play in yeast. </p><p>Wu et al. (2000) reported that NBS is specifically phosphorylated in response to gamma-radiation, ultraviolet light, and exposure to hydroxyurea. Phosphorylation of NBS mediated by gamma-radiation, but not that induced by hydroxyurea or ultraviolet light, was markedly reduced in ATM cells. In vivo, NBS was phosphorylated on many serine residues, of which serine-343, serine-397, and serine-615 were phosphorylated by ATM in vitro. At least 2 of these sites were underphosphorylated in ATM cells. Inactivation of these serines by mutation partially abrogated ATM-dependent phosphorylation. Reconstituting NBS cells with a mutant form of NBS that cannot be phosphorylated at selected ATM-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation. Wu et al. (2000) concluded that phosphorylation of NBS by ATM is critical for certain responses of human cells to DNA damage. </p><p>Wilda et al. (2000) studied the expression of Nbs1 in mouse embryos at different developmental stages as well as in adult mice. Although a low level of expression was observed in all tissues, highly specific expression was observed in organs with physiologic DNA double-strand breakage (DSB), such as testis, thymus, and spleen. Enhanced expression was also found at sites of high proliferative activity: the subventricular layer of the telencephalon and diencephalon, the liver, lung, kidney, and gut, as well as striated and smooth muscle cells in various organs. In the adult cerebellum, the postmitotic Purkinje cells were marked specifically. The authors hypothesized that in addition to the role of the Nbs1 gene product as part of a DNA DSB repair complex, the Nbs1 gene product may serve further functions during development. </p><p>Chen et al. (2000) reported that the NBS1 protein and histone gamma-H2AX (601772), which associate with irradiation-induced DNA DSBs, are also found at sites of V(D)J (variable, diversity, joining) recombination-induced DSBs. In developing thymocytes, NBS1 and gamma-H2AX form nuclear foci that colocalize with the T-cell receptor-alpha (TCRA; see 186880) locus in response to recombination-activating gene-1 (RAG1; 179615) protein-mediated V(D)J cleavage. Chen et al. (2000) concluded that their results suggest that surveillance of T-cell receptor recombination intermediates by NBS1 and gamma-H2AX may be important for preventing oncogenic translocations. </p><p>Class switch recombination (CSR) is a region-specific DNA recombination reaction that replaces one immunoglobulin heavy-chain constant region gene with another. This enables a single variable region gene to be used in conjunction with different downstream heavy-chain genes, each having a unique biologic activity. Activation-induced cytidine deaminase (AID; 605257), a putative RNA editing enzyme, is required for this action. Petersen et al. (2001) reported that the Nijmegen breakage syndrome protein and gamma-H2AX, which facilitate DNA double-strand break repair, form nuclear foci at the heavy-chain constant region in the G1 phase of the cell cycle in cells undergoing class switch recombination. Class switch recombination is impaired in H2AX -/- mice. Localization of NBS1 and gamma-H2AX to the immunoglobulin heavy-chain locus during class switch recombination is dependent on AID. In addition, AID is required for induction of switch region-specific DNA lesions that precede class switch recombination. Petersen et al. (2001) concluded that AID functions upstream of the DNA modifications that initiate class switch recombination. </p><p>Falck et al. (2002) demonstrated that experimental blockade of either the NBS1-MRE11 function or the CHK2 (604373)-triggered events leads to a partial radioresistant DNA synthesis phenotype in human cells. In contrast, concomitant interference with NBS1-MRE11 and the CHK2-CDC25A (116947)-CDK2 (116953) pathways entirely abolishes inhibition of DNA synthesis induced by ionizing radiation, resulting in complete radioresistant DNA synthesis analogous to that caused by defective ATM. In addition, CDK2-dependent loading of CDC45 (603465) onto replication origins, a prerequisite for recruitment of DNA polymerase, was prevented upon irradiation of normal or NBS1/MRE11-defective cells but not cells with defective ATM. Falck et al. (2002) concluded that in response to ionizing radiation, phosphorylation of NBS1 and CHK2 by ATM triggers 2 parallel branches of the DNA damage-dependent S-phase checkpoint that cooperate by inhibiting distinct steps of DNA replication. </p><p>In mammalian cells, a conserved multiprotein complex of MRE11, RAD50, and NBS1 (MRN) is important for double-strand break repair, meiotic recombination, and telomere maintenance. In the absence of the early region E4, the double-stranded genome of adenoviruses is joined into concatemers too large to be packaged. Stracker et al. (2002) investigated the cellular proteins involved in the concatamer formation and how they are inactivated by E4 products during a wildtype infection. They demonstrated that concatamerization requires functional MRE11 and NBS1, and that these proteins are found at foci adjacent to viral replication centers. Infection with wildtype virus results in both reorganization and degradation of members of the MRN complex. These activities are mediated by 3 viral oncoproteins that prevent concatamerization. This targeting of cellular proteins involved in the genomic stability suggested a mechanism for 'hit-and-run' transformation observed for these viral oncoproteins. </p><p>Franchitto and Pichierri (2002) reviewed the roles of RECQL2 (604611) and RECQL3 (604610) in resolution of a stall in DNA replication, as well as their possible interaction with the MRN complex. </p><p>Tauchi et al. (2002) established an Nbs1 knockout cell line by using the hyperrecombinogenic chick B-cell line DT40. Exon 4 of the 3 Nbs1 alleles in DT40 cells was targeted. The Nbs1 -/-/- cells were still viable, although they exhibited slow growth owing to a prolonged cell cycle time. The disruption of Nbs1 reduced gene conversion and sister chromatid exchanges, similar to other homologous recombination-deficient mutants. In fact, a site-specific double-strand break repair assay showed a notable reduction of homologous recombination events following generation of such breaks in Nbs1-disrupted cells. The rare recombinations observed in the Nbs1-disrupted cells were frequently found to have aberrant structures, which possibly arose from unusual crossover events, suggesting that the NBS1 complex might be required to process recombination intermediates. Thus, Tauchi et al. (2002) demonstrated that NBS1 is essential for homologous recombination-mediated repair in higher vertebrate cells. </p><p>Zhong et al. (2005) tested whether the MRN complex has a global controlling role over ATR (601215) through the study of MRN deficiencies generated by RNA interference. The MRN complex was required for ATR-dependent phosphorylation of SMC1A (300040), which acts within chromatin to ensure sister chromatid cohesion and to effect several DNA damage responses. Novel phenotypes caused by MRN deficiency that support a functional link between this complex, ATR, and SMC1A, included hypersensitivity to UV exposure, a defective UV responsive intra-S phase checkpoint, and a specific pattern of genomic instability. Zhong et al. (2005) concluded that there is a controlling role for the MRN complex over the ATR kinase, and that downstream events under this control are broad, including both chromatin-associated and diffuse signaling factors. </p><p>Yuan et al. (2007) found that NBS1, the regulatory subunit of MRN, was acetylated, and that its acetylation level was tightly regulated by SIRT1 (604479). SIRT1 associated with the MRN complex in human cells via binding to NBS1, and SIRT1 maintained NBS1 in a hypoacetylated state, a requirement for ionizing radiation-induced phosphorylation of NBS1 on ser343. Yuan et al. (2007) concluded that deacetylation of NBS1 by SIRT1 plays a key role in regulation of the DNA damage response and maintenance of genomic stability. </p><p>Staples et al. (2016) found that human cells depleted of MRNIP (617154) showed increased DNA damage. Immunoprecipitation analysis revealed interaction of MRNIP with the MRN complex, as well as with other substrates of ATM. Cells lacking MRNIP had reduced MRN function and defective ATM-dependent DNA damage signaling, as well as impaired responses to DNA breaks. Staples et al. (2016) concluded that MRNIP, through its interaction with the MRN complex, is required for robust cellular responses to DNA breaks by promoting chromatin association of the MRN complex and subsequent activation of the ATM-signaling cascade. </p>
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<strong>Biochemical Features</strong>
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<p>The human RAD50/MRE11/NBS1 complex (R/M/N) has a dynamic molecular architecture consisting of a globular DNA binding domain from which two 50-nanometer coiled coils protrude. The coiled coils are flexible and their apices can self-associate. The flexibility of the coiled coils allows their apices to adopt an orientation favorable for interaction. However, this also allows interaction between the tips of the 2 coiled coils within the same complex, which competes with and frustrates the intercomplex interaction required for DNA tethering. Moreno-Herrero et al. (2005) showed that the dynamic architecture of the R/M/N complex is markedly affected by DNA binding. DNA binding by the R/M/N globular domain leads to parallel orientation of the coiled coils; this prevents intracomplex interactions and favors intercomplex associations needed for DNA tethering. The R/M/N complex thus is an example of a biologic nanomachine in which binding to its ligand, in this case DNA, affects the functional conformation of a domain located 50 nanometers distant. </p>
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<strong>Gene Structure</strong>
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<p>Varon et al. (1998) determined that the NBS1 gene spans more than 50 kb and contains 16 exons. </p>
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<strong>Mapping</strong>
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<p>Varon et al. (1998) mapped the NBS1 gene to chromosome 8q21. Carney et al. (1998) mapped the gene to chromosome 8q21.3. </p><p>By computer-assisted analysis of 5 BAC clones and an EST sequence, Tauchi et al. (1999) defined the genomic organization of an 800-kb region on chromosome 8q21 as 5-prime C8ORF1 (604598), 3-prime NBS1, 5-prime DECR1 (222745), and 3-prime CALB1 (114050). </p>
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<strong>Molecular Genetics</strong>
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<p>Varon et al. (1998) identified a truncating 5-bp deletion (602667.0001) in the NBS1 gene in the majority of NBS patients studied, all of whom carried a conserved marker haplotype. Five additional truncating mutations were identified in patients with other distinct haplotypes. The domains found in nibrin and the NBS phenotype suggest that this disorder is caused by defective responses to DNA double-strand breaks (DSB). </p><p>Matsuura et al. (1998) detected the 5-bp deletion (602667.0001) in NBS1 in 13 individuals of Slavic or German origin and concluded that it is likely to be a founder mutation. </p><p>The findings that the ataxia-telangiectasia gene is involved in the pathogenesis of T-cell prolymphocytic leukemia and other forms of leukemia, that there is a high predisposition of NBS patients to lymphoid malignancy, and the fact that NBS and ATM are indistinguishable at the cellular level, prompted Varon et al. (2001) to investigate whether the NBS1 gene is involved in the pathogenesis of acute lymphoblastic leukemia (ALL) and whether it influences the course of the disease and so has its place among the tumor suppressor genes. They analyzed samples from 47 children with first relapse of ALL for mutations in all 16 exons of the NBS1 gene and identified 4 novel amino acid substitutions in 7 children. Germline origin of an I171V (602667.0007) mutation was confirmed in 3 patients, whereas another change, D95N, was present only in leukemic cells. No additional mutations were found on the second allele in any of these 7 patients. </p><p>Tanzarella et al. (2003) found that heterozygous individuals from 3 unrelated NBS families with distinct gene deletion mutations had spontaneous chromosome instability (chromatid and chromosomal breaks as well as rearrangements) in blood lymphocytes, but their lymphoblastoid cell lines were not different from controls in x-ray G2 sensitivity. Immunoprecipitation of nibrin detected the normal and variant proteins in carriers from all 3 families. </p><p>Nakanishi et al. (2002) reported a patient diagnosed with Fanconi anemia (FA; 227650) on the basis of chromosome breakage induced by mitomycin C. The individual showed atypical FA features, including features of NBS. The clinical syndrome was severe, and the child died at 3 years of age, similar to an affected cousin. Immunoblot analysis of primary lymphocytes indicated expression of both unubiquitinated and monoubiquitinated isoforms of FANCD2 (227646); however, no NBS1 protein was expressed. Sequence analysis indicated that the patient cells contained a tyr363-to-ter mutation in NBS1 (602667.0008), which resulted in a truncated protein. Genomic sequence analysis showed that the mutation was homozygous. By coimmunoprecipitation, Nakanishi et al. (2002) found constitutive interaction between FANCD2 and NBS1, and they presented evidence that these proteins interact in 2 distinct assemblies to mediate S-phase checkpoint and resistance to mitomycin C-induced chromosome damage. NBS1, ATM, and MRE11 were required for FANCD2 phosphorylation in response to radiation-induced S-phase checkpoint. The assembly of NBS1, MRE11, RAD50, and FANCD2 within nuclear foci was required for mitomycin C resistance. </p><p>Plisiecka-Halasa et al. (2002) looked for NBS1 gene alterations and changes in nibrin expression in 162 human gynecologic tumors, mostly ovarian. They identified the so-called Slavic mutation, 657del5 (602667.0001), in 2 of 117 carcinomas studied (1.7%). In both cases it was present in the germline, and in 1 of these tumors there was loss of heterozygosity (LOH) for the 657del5 mutation and loss of nibrin expression. </p><p>In monozygotic twin brothers with a severe form of NBS, Seemanova et al. (2006) identified compound heterozygosity for the 657del5 mutation and a missense mutation (602667.0009) in the NBS1 gene. </p>
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<strong>Animal Model</strong>
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<p>Zhu et al. (2001) generated mice deficient in NBS1 by targeted disruption. Nbs1 -/- mice suffered early embryonic lethality and had poorly developed embryonic and extraembryonic tissues. Blastocysts showed greatly diminished expansion of the inner cell mass in culture, suggesting that NBS1 mediates essential functions during proliferation in the absence of externally induced damage. Zhu et al. (2001) concluded that the complex phenotypes observed in NBS patients and cell lines may not result from a complete inactivation of NBS1 but may instead result from hypomorphic truncation mutations compatible with cell viability. </p><p>Demuth et al. (2004) used the Cre/loxP system to generate mice with an inducible Nbs1-null mutation, allowing examination of DNA repair and cell cycle checkpoints in the complete absence of nibrin. Induction of the null mutation led to loss of the G2/M checkpoint, increased chromosome damage, radiomimetic sensitivity, and cell death. In vivo, lymphatic tissues, bone marrow, thymus, and spleen showed a dramatic decrease in cell survival, whereas liver, kidney, and muscle showed no effect on cell survival. In vitro, Nbs1-null murine fibroblasts could be rescued from cell death by transfer of human NBS1 cDNA and, more significantly, by a cDNA carrying the 5-bp deletion. Demuth et al. (2004) concluded that the common human 5-bp deletion is hypomorphic and that expression of a truncated protein may be sufficient to restore nibrin's vital cellular functions. </p><p>Frappart et al. (2005) developed mice with Nbs1 inactivation targeted to the central nervous system. Nbs1-deleted mice were viable and appeared normal at birth, but growth retardation was evident by postnatal day 7, and mutants were half the weight of control mice at weaning. All Nbs1-deleted mice showed balance disorders, tremors, altered gait, repetitive movements, and akinesis after postnatal day 7. Macroscopic examination of brains from mutant mice showed reduced cerebella lacking foliation. Histologic analysis indicated that Nbs1 loss caused proliferation arrest of granule cell progenitors and apoptosis of postmitotic cerebellar neurons. Nbs1-deficient neuroprogenitors showed proliferation defects in culture, but no increase in apoptosis. They also contained more chromosomal breaks, which were accompanied by Atm (607585)-mediated p53 (TP53; 191170) activation. Depletion of p53 substantially rescued the neurologic defects of Nbs1 mutant mice. </p><p>Stracker et al. (2007) derived Nbs1 delta-C/delta-C mice in which the C-terminal ATM interaction domain was deleted. Nbs1 delta-C/delta-C cells exhibited intra-S-phase checkpoint defects, but were otherwise indistinguishable from wildtype cells with respect to other checkpoint functions, ionizing radiation sensitivity, and chromosome stability. However, multiple tissues of Nbs1 delta-C/delta-C mice showed a severe apoptotic defect, comparable to that of Atm- or Chk2 (604373)-deficient animals. Analysis of p53 transcriptional targets and Atm substrates showed that, in contrast to the phenotype of Chk2 -/- mice, Nbs1-deltaC does not impair the induction of proapoptotic genes. Stracker et al. (2007) concluded that instead, the defects observed in Nbs1 delta-C/delta-C mice resulted from impaired phosphorylation at ATM targets including SMC1 (see 300040) and the proapoptotic factor BID (601997). </p><p>Saidi et al. (2010) found that deletion of Nbs1 in T-cell precursors in mice resulted in severe lymphopenia and hindered the transition of double-negative-3 (DN3) thymocytes to DN4 due to abnormal Tcrb (see 186930) coding and signal joints, as well as the functions of Nbs1 in T-cell expansion. Chromatin immunoprecipitation analysis of TCR loci revealed that Nbs1 depletion compromised the loading of Mre11/Rad50 to V(D)J-generated DNA DSBs and thereby affected resection of DNA termini and chromatin conformation of the postcleavage complex. The DN3-to-DN4 transition in the mutant mice, but not T-cell loss, could be relieved by p53 deficiency. Ectopic Tcra/Tcrb expression also failed to rescue T-cell lymphopenia in the mutant mice. Saidi et al. (2010) concluded that NBS1 functions in both repair of V(D)J-generated DSBs and in proliferation and that both functions are essential for T-cell development. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>10 Selected Examples):</strong>
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<strong>.0001 NIJMEGEN BREAKAGE SYNDROME</strong>
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OVARIAN CANCER, SUSCEPTIBILITY TO, INCLUDED
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NBN, 5-BP DEL, NT657
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SNP: rs587776650,
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gnomAD: rs587776650,
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ClinVar: RCV000007353, RCV000007354, RCV000133576, RCV000212733, RCV000415248, RCV001270991, RCV001357671, RCV001391203, RCV001535498, RCV001574072, RCV002280859, RCV003389666, RCV003460432, RCV005041999, RCV005055345
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<p>In patients of Slavic origin with Nijmegen breakage syndrome (NBS; 251260), Varon et al. (1998) identified a common deletion of 5 nucleotides in exon 6 of the NBS1 gene (657del5), resulting in a frameshift and a truncated protein. A total of 46 patients homozygous for this mutation were identified. The mutation was found exclusively on a specific 'Slavic' haplotype of linked polymorphic markers. </p><p>Matsuura et al. (1998) found the same 5-bp deletion in the NBS1 gene in 13 NBS patients of Slavic or German origin. Twelve patients were homozygous for the deletion and 1 was heterozygous. The deletion introduced a premature termination signal at codon 218, which was predicted to result in a severely truncated polypeptide. Matsuura et al. (1998) concluded that they had identified the gene involved in NBS because complementation was effected by a YAC that contained the gene and because no (or extremely reduced) expression of the gene was found in a patient without the deletion but with the NBS phenotype. The presence of a founder mutation in 13 of 14 cases, with no demonstration of the deletion in 50 normal individuals of the same ethnic origin or in 7 normal chromosomes from NBS parents, supported this conclusion. </p><p>The truncating 657del5 had been identified in 90% of NBS patients. NBS shares a number of features with ataxia-telangiectasia (208900), the most notable being high sensitivity to ionizing radiation and predisposition to cancer. Patients who are heterozygous for the ATM mutation are predisposed to breast cancer. Since the NBS phenotype at the cellular level is very similar to that of ataxia-telangiectasia, Carlomagno et al. (1999) screened 477 German breast cancer patients, aged under 51 years, and 866 matched controls for the common NBS mutation. They identified 1 carrier among the cases and 1 among the controls, indicating that the population frequency of this NBS mutation is 1 in 866 persons (95% CI = 1 in 34,376 to 1 in 156) and the estimated prevalence of NBS is thus 1 in 3 million persons. The proportion of breast cancer attributable to this mutation is less than 1%. </p><p>Kleier et al. (2000) reported a 5-year-old Bosnian boy with severe microcephaly. Because of multiple structural aberrations involving chromosomes 7 and 14 typical for ataxia-telangiectasia, that disorder was diagnosed. However, the diagnosis of NBS was suggested by the boy's remarkable microcephaly, his facial appearance, and the absence of ataxia and telangiectasia. DNA analysis demonstrated homozygosity for the major mutation in the NBS1 gene, 657del5. </p><p>Maser et al. (2001) tested the hypothesis that the NBS1 657del5 mutation is a hypomorphic defect. They showed that NBS cells harboring the 657del5 mutation contained a predicted 26-kD N-terminal protein, NBS1(p26), and a 70-kD NBS1 protein, NBS1(p70), lacking the native N terminus. The 26-kD protein is not physically associated with the MRE11 complex (600814), whereas the 70-kD species is physically associated with it. NBS1(p70) is produced by internal translation initiation within the NBS mRNA using an open reading frame generated by the 657del5 frameshift. Maser et al. (2001) proposed that the common NBS1 allele encodes a partially functional protein that diminishes the severity of the NBS phenotype. </p><p>Tekin et al. (2002) reported a consanguineous Turkish family whose first son died of anal atresia and whose second son, the proband, presented with severe pre- and postnatal growth retardation as well as striking microcephaly, immunodeficiency, congenital heart disease, chromosome instability, and rhabdomyosarcoma in the anal region. The patient was homozygous for the 657del5 mutation in the NBS1 gene, which is responsible for NBS in most Slavic populations. The family was the first diagnosed with NBS in the Turkish population and was one of the most severely affected examples of the syndrome. </p><p>Drabek et al. (2002) presented PCR with sequence specific primers as a method for detection of the 657del5 mutation. They confirmed a high carrier frequency in the Czech population (1 in 106 persons; 95% CI = 1 in 331 to 1 in 46). </p><p>In Russian children, Resnick et al. (2003) screened for the 657del5 NBS1 mutation in 548 controls and 68 patients with lymphoid malignancies. No carrier of the mutation was found in the control group. The mutation was found in heterozygous form in 2 of the 68 patients from the group of lymphoid malignancies, 1 with acute lymphoblastic leukemia (see 159555) and 1 with non-Hodgkin lymphoma (605027). Several relatives of the patient with non-Hodgkin lymphoma who carried the same mutation had cancer (acute lymphoblastic leukemia, breast cancer, gastrointestinal cancers), suggesting that heterozygosity may predispose to malignant disorders. </p><p>In monozygotic twin brothers with a severe form of NBS without chromosomal instability, Seemanova et al. (2006) identified compound heterozygosity for the 657del5 mutation and a 643C-T transition in exon 6 of the NBS1 gene, resulting in an arg215-to-trp (R215W) substitution (602667.0009). Both infants showed reduced expression of full-length nibrin, and radiation response processes were strongly reduced in their cells. Their mother and father were heterozygous for the 657del5 mutation and the R215W mutation, respectively, as were their respective grandfathers. </p><p>In a 3-month-old boy with NBS, Varon et al. (2007) identified homozygosity for the 657del5 mutation; the patient's mother carried the mutation, whereas his father was homozygous for the wildtype allele. Analysis of 27 microsatellite markers covering all of chromosome 8 revealed that the patient had a homozygous haplotype for all of the markers, whereas the mother carried the same haplotype in heterozygous state. The authors stated that this was the first patient with NBS due to maternal isodisomy of chromosome 8. </p><p>Porhanova et al. (2008) reported a 52-year-old Russian woman with ovarian cancer (see 604370) who was found to be compound heterozygous for a mutation in the BRCA1 gene (113705.0018) and the common Slavic 657del5 mutation in the NBN gene. Investigation of the ovarian cancer tissue showed somatic loss of heterozygosity for NBN, but retention of heterozygosity for BRCA1. The patient did not have a particularly severe cancer-prone phenotype, and her parents did not have cancer, although 3 sibs developed cancer as adults. Porhanova et al. (2008) commented that haploinsufficiency of the BRCA1 gene may contribute to cancer progression without somatic changes. </p>
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<strong>.0002 NIJMEGEN BREAKAGE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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NBN, 4-BP DEL, NT698
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|
<br />
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SNP: rs587780100,
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|
|
gnomAD: rs587780100,
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|
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|
|
ClinVar: RCV000115804, RCV000193543, RCV000212735, RCV001354502, RCV002498497, RCV003467062, RCV004745189
|
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|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
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<span class="mim-text-font">
|
|
<p>In a patient of English origin with Nijmegen breakage syndrome (NBS; 251260), Varon et al. (1998) identified a deletion of 4 nucleotides in exon 6 of the NBS1 gene, resulting in a frameshift and a truncated protein. </p>
|
|
</span>
|
|
</div>
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|
<div>
|
|
<br />
|
|
</div>
|
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</div>
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|
<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 NIJMEGEN BREAKAGE SYNDROME</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
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NBN, 4-BP DEL, NT835
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<br />
|
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|
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SNP: rs864309668,
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|
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ClinVar: RCV000007356, RCV004566687
|
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|
|
</span>
|
|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient of Italian origin with Nijmegen breakage syndrome (NBS; 251260), Varon et al. (1998) identified a deletion of 4 nucleotides in exon 7 of the NBS1 gene, resulting in a frameshift and a truncated protein. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
|
<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 NIJMEGEN BREAKAGE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
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|
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NBN, 1-BP INS
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<br />
|
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|
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SNP: rs864309669,
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|
|
ClinVar: RCV000007357, RCV003343598
|
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|
|
</span>
|
|
</div>
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient of Mexican origin with Nijmegen breakage syndrome (NBS; 251260), Varon et al. (1998) identified an insertion of 1 nucleotide in exon 7 of the NBS1 gene, resulting in a frameshift and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 NIJMEGEN BREAKAGE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NBN, 1-BP DEL, 1142C
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs587781969,
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|
|
gnomAD: rs587781969,
|
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|
|
ClinVar: RCV000007358, RCV000130355, RCV000220768, RCV003467143, RCV004745208, RCV005042256
|
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|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient of Canadian origin with Nijmegen breakage syndrome (NBS; 251260), Varon et al. (1998) identified a deletion of 1 nucleotide in exon 10 of the NBS1 gene, resulting in a frameshift and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 NIJMEGEN BREAKAGE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NBN, GLN326TER
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs121908973,
|
|
|
|
|
|
|
|
ClinVar: RCV000007359, RCV000166946
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient of Dutch origin with Nijmegen breakage syndrome (NBS; 251260), Varon et al. (1998) identified a nonsense mutation, gln326 to ter, in exon 10 of the NBS1 gene, resulting in a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 APLASTIC ANEMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
LYMPHOBLASTIC LEUKEMIA, ACUTE, SUSCEPTIBILITY TO, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NBN, ILE171VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs61754966,
|
|
|
|
|
|
gnomAD: rs61754966,
|
|
|
|
|
|
ClinVar: RCV000007360, RCV000007361, RCV000115797, RCV000121618, RCV000197512, RCV000490266, RCV000589577, RCV001030566, RCV001262350, RCV001358233, RCV003492288, RCV003891430, RCV004776268, RCV004776269
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 patients with acute lymphoblastic leukemia (see 613065), Varon et al. (2001) found germline heterozygosity for an A-to-G change at nucleotide 511, resulting in an ile171-to-val (I171V) mutation occurring in a domain of nibrin that is probably involved in protein-protein interactions. </p><p>In an 11-year-old Japanese girl with aplastic anemia (609135) and no features of Nijmegen breakage syndrome, Shimada et al. (2004) identified homozygosity for the I171V mutation in the NBS1 gene. Genetic analysis of the patient and her healthy parents indicated that she inherited the germline I171V mutation from her father and the wildtype allele from her mother, and that the second I171V hit occurred on the wildtype allele early in embryonic development. Cytogenetic analysis of lymphoblastic cell lines from the patient showed a marked increase in numerical and structural chromosomal aberrations in the absence of clastogens, suggesting genomic instability. Shimada et al. (2004) also screened 413 normal controls and found heterozygosity for I171V in 5 individuals, corresponding to 1.2% of the Japanese population. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 NIJMEGEN BREAKAGE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NBN, TYR363TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908974,
|
|
|
|
|
|
gnomAD: rs121908974,
|
|
|
|
|
|
ClinVar: RCV000007362, RCV003329227, RCV003472997
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Nakanishi et al. (2002) reported a patient diagnosed with Fanconi anemia (FA; 227650) on the basis of chromosome breakage induced by mitomycin C. The individual showed atypical FA features, including features of Nijmegen breakage syndrome (NBS; 251260). The clinical syndrome was severe, and the child died at 3 years of age, similar to an affected cousin. In this patient, Nakanishi et al. (2002) identified a homozygous C-to-A mutation at nucleotide 1089 of the NBS1 gene, resulting in a tyr363-to-ter mutation and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 NIJMEGEN BREAKAGE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NBN, ARG215TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs34767364,
|
|
|
|
|
|
gnomAD: rs34767364,
|
|
|
|
|
|
ClinVar: RCV000007363, RCV000115802, RCV000121621, RCV000487932, RCV003891431
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the arg215-to-trp (R215W) mutation in the NBN gene that was found in compound heterozygous state in monozygotic twin brothers with Nijmegen breakage syndrome (NBS; 251260) by Seemanova et al. (2006), see 602667.0001. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 NIJMEGEN BREAKAGE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NBN, 2-BP INS, 742GG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs864309670,
|
|
|
|
|
|
|
|
ClinVar: RCV000007364, RCV000657237, RCV001525344
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 53-year-old woman with a mild form of Nijmegen breakage syndrome (NBS; 251260), who was originally reported by Maraschio et al. (1986), Varon et al. (2006) identified a homozygous 2-bp insertion (742insGG) in exon 7 of the NBN gene, predicted to result in premature termination. RT-PCR analysis identified 2 transcripts in both the patient and her parents: the expected transcript carrying the 2-bp insertion and a second transcript with in-frame deletion of exons 6 and 7. The skipping of exons 6 and 7 results in a 650-amino acid protein with a molecular mass of 73 kD; it also eliminates the 742insGG mutation in exon 7. The 73-kD (del6-del7) transcript was observed at levels 100-fold lower in controls than in the patient and her parents, and the del6-del7 transcript was detected as minor product in RNA from patients with the 657del5 mutation (602667.0001). The open reading frame of the del6-del7 transcript predicts a partially functional protein, which was confirmed by studies in mouse cells. ESE prediction analysis suggested that 742insGG may affect an ESE sequence, possibly resulting in decreased splicing enhancer activity. Because the NBN transcript can only remain in-frame if both exons 6 and 7 are deleted, the authors hypothesized that the presence of the del6-del7 transcript results from an active mechanism in which reestablishment of the reading frame requires elimination of the 2 exons. The patient had no immunodeficiency and had not had frequent infections. Varon et al. (2006) concluded that the unusually mild phenotype in this patient resulted from residual nibrin activity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Carlomagno, F., Chang-Claude, J., Dunning, A. M., Ponder, B. A. J.
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|
<strong>Determination of the frequency of the common 675del5 Nijmegen breakage syndrome mutation in the German population: no association with risk of breast cancer.</strong>
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|
Genes Chromosomes Cancer 25: 393-395, 1999.
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[PubMed: 10398434]
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[Full Text: https://doi.org/10.1002/(sici)1098-2264(199908)25:4<393::aid-gcc12>3.0.co;2-8]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Carney, J. P., Maser, R. S., Olivares, H., Davis, E. M., Le Beau, M., Yates, J. R., III, Hays, L., Morgan, W. F., Petrini, J. H. J.
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<strong>The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response.</strong>
|
|
Cell 93: 477-486, 1998.
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|
[PubMed: 9590181]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)81175-7]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Chen, H. T., Bhandoola, A., Difilippantonio, M. J., Zhu, J., Brown, M. J., Tai, X., Rogakou, E. P., Brotz, T. M., Bonner, W. M., Ried, T., Nussenzweig, A.
|
|
<strong>Response to RAG-mediated V(D)J cleavage by NBS1 and gamma-H2AX.</strong>
|
|
Science 290: 1962-1964, 2000.
|
|
|
|
|
|
[PubMed: 11110662]
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[Full Text: https://doi.org/10.1126/science.290.5498.1962]
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</p>
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|
</li>
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<li>
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|
<p class="mim-text-font">
|
|
Demuth, I., Frappart, P.-O., Hildebrand, G., Melchers, A., Lobitz, S., Stockl, L., Varon, R., Herceg, Z., Sperling, K., Wang, Z.-Q., Digweed, M.
|
|
<strong>An inducible null mutant murine model of Nijmegen breakage syndrome proves the essential function of NBS1 in chromosomal stability and cell viability.</strong>
|
|
Hum. Molec. Genet. 13: 2385-2397, 2004.
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|
|
[PubMed: 15333589]
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[Full Text: https://doi.org/10.1093/hmg/ddh278]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Drabek, J., Hajduch, M., Gojova, L., Weigl, E., Mihal, V.
|
|
<strong>Frequency of 657del(5) mutation of the NBS1 gene in the Czech population by polymerase chain reaction with sequence specific primers.</strong>
|
|
Cancer Genet. Cytogenet. 138: 157-159, 2002.
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|
|
[PubMed: 12505263]
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[Full Text: https://doi.org/10.1016/s0165-4608(02)00594-0]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Falck, J., Petrini, J. H. J., Williams, B. R., Lukas, J., Bartek, J.
|
|
<strong>The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways.</strong>
|
|
Nature Genet. 30: 290-294, 2002.
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|
|
|
|
[PubMed: 11850621]
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|
|
[Full Text: https://doi.org/10.1038/ng845]
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Franchitto, A., Pichierri, P.
|
|
<strong>Protecting genomic integrity during DNA replication: correlation between Werner's and Bloom's syndrome gene products and the MRE11 complex.</strong>
|
|
Hum. Molec. Genet. 11: 2447-2453, 2002.
|
|
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|
|
|
[PubMed: 12351580]
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|
|
[Full Text: https://doi.org/10.1093/hmg/11.20.2447]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Frappart, P.-O., Tong, W.-M., Demuth, I., Radovanovic, I., Herceg, Z., Aguzzi, A., Digweed, M., Wang, Z.-Q.
|
|
<strong>An essential function for NBS1 in the prevention of ataxia and cerebellar defects.</strong>
|
|
Nature Med. 11: 538-544, 2005.
|
|
|
|
|
|
[PubMed: 15821748]
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|
|
[Full Text: https://doi.org/10.1038/nm1228]
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Gatei, M., Young, D., Cerosaletti, K. M., Desai-Mehta, A., Spring, K., Kozlov, S., Lavin, M. F., Gatti, R. A., Concannon, P., Khanna, K.
|
|
<strong>ATM-dependent phosphorylation of nibrin in response to radiation exposure.</strong>
|
|
Nature Genet. 25: 115-119, 2000.
|
|
|
|
|
|
[PubMed: 10802669]
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|
|
[Full Text: https://doi.org/10.1038/75508]
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</p>
|
|
</li>
|
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|
<li>
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Zhong, Q., Chen, C.-F., Li, S., Chen, Y., Wang, C.-C., Xiao, J., Chen, P.-L., Sharp, Z. D., Lee, W.-H.
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<strong>Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response.</strong>
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[Full Text: https://doi.org/10.1126/science.285.5428.747]
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Zhu, J., Petersen, S., Tessarollo, L., Nussenzweig, A.
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<strong>Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice.</strong>
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Zhu, X.-D., Kuster, B., Mann, M., Petrini, J. H. J., de Lange, T.
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<strong>Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres.</strong>
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Paul J. Converse - updated : 10/11/2016<br>Paul J. Converse - updated : 9/27/2011<br>Cassandra L. Kniffin - updated : 11/2/2009<br>Cassandra L. Kniffin - updated : 6/5/2009<br>George E. Tiller - updated : 12/10/2008<br>Patricia A. Hartz - updated : 8/6/2007<br>George E. Tiller - updated : 6/21/2007<br>Ada Hamosh - updated : 6/21/2007<br>Marla J. F. O'Neill - updated : 4/19/2006<br>Ada Hamosh - updated : 11/3/2005<br>Patricia A. Hartz - updated : 5/16/2005<br>Marla J. F. O'Neill - updated : 4/25/2005<br>Victor A. McKusick - updated : 1/12/2005<br>Natalie E. Krasikov - updated : 6/1/2004<br>George E. Tiller - updated : 12/4/2003<br>Victor A. McKusick - updated : 3/12/2003<br>Patricia A. Hartz - updated : 3/10/2003<br>Victor A. McKusick - updated : 3/3/2003<br>Ada Hamosh - updated : 11/13/2002<br>Victor A. McKusick - updated : 8/21/2002<br>Ada Hamosh - updated : 7/24/2002<br>Ada Hamosh - updated : 3/28/2002<br>Ada Hamosh - updated : 1/2/2002<br>Victor A. McKusick - updated : 6/21/2001<br>Ada Hamosh - updated : 3/29/2001<br>Ada Hamosh - updated : 12/18/2000<br>Paul J. Converse - updated : 11/16/2000<br>George E. Tiller - updated : 9/21/2000<br>Victor A. McKusick -updated : 8/31/2000<br>Victor A. McKusick - updated : 6/27/2000<br>Victor A. McKusick - updated : 6/2/2000<br>Ada Hamosh - updated : 5/24/2000<br>Ada Hamosh - updated : 4/27/2000<br>Ada Hamosh - updated : 4/18/2000<br>Paul J. Converse - updated : 2/24/2000<br>Victor A. McKusick - updated : 9/24/1999<br>Ada Hamosh - updated : 7/30/1999<br>Victor A. McKusick - updated : 6/1/1998
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Stylianos E. Antonarakis : 5/28/1998
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