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<title>
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Entry
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- *601215 - ATR SERINE/THREONINE KINASE; ATR
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- OMIM
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</ul>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<li role="separator" class="divider"></li>
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<li>
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<a href="/history"> Search History </a>
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</ul>
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Display:
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<label style="font-weight: normal"><input type="checkbox" id="mimToggleChangeBars" checked /> Change Bars </label>
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</form>
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<p />
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</div>
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<div id="mimAlertBanner">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601215</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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</li>
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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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601215">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div 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=ENSG00000175054;t=ENST00000350721" 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=545" 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=601215" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000175054;t=ENST00000350721" 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_001184,NM_001354579,XM_011512924,XM_011512925,XM_047448360,XM_047448361,XM_047448362,XM_047448363,XM_047448364" 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_001184" 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=601215" 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=08369&isoform_id=08369_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/ATR" 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/1235902,1653996,1666240,3715798,13447783,62087274,62286460,119599375,119599376,157266317,767926988,767926992,1237937718,2217344508,2217344510,2217344513,2217344515,2217344517,2462590664,2462590666,2462590668,2462590670,2462590672,2462590674,2462590676" 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/Q13535" 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=545" 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=ENSG00000175054;t=ENST00000350721" 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=ATR" 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=ATR" 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+545" 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/ATR" 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:545" 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/545" 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=chr3&hgg_gene=ENST00000350721.9&hgg_start=142449235&hgg_end=142578733&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:882" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601215[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601215[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/ENSG00000175054" 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=ATR" 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=ATR" 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=ATR" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ATR&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/PA74" 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:882" 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/FBgn0004367.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:108028" 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/ATR#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:108028" 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/545/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=545" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00000226;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-070912-458" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:601215" 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:545" 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=ATR&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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601215
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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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ATR SERINE/THREONINE KINASE; ATR
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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ATR GENE<br />
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ATAXIA-TELANGIECTASIA AND RAD3-RELATED<br />
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FRAP-RELATED PROTEIN 1; FRP1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ATR" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ATR</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/3/744?start=-3&limit=10&highlight=744">3q23</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:142449235-142578733&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'})">3:142,449,235-142,578,733</a> </span>
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</em>
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</strong>
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?Cutaneous telangiectasia and cancer syndrome, familial
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/601215" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/601215" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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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>ATR, an essential regulator of genomic integrity, controls and coordinates DNA-replication origin firing, replication-fork stability, cell cycle checkpoints, and DNA repair (summary by <a href="#33" class="mim-tip-reference" title="Tanaka, A., Weinel, S., Nagy, N., O'Driscoll, M., Lai-Cheong, J. E., Kulp-Shorten, C. L., Knable, A., Carpenter, G., Fisher, S. A., Hiragun, M., Yanase, Y., Hide, M., Callen, J., McGrath, J. A. <strong>Germline mutation in ATR in autosomal-dominant oropharyngeal cancer syndrome.</strong> Am. J. Hum. Genet. 90: 511-517, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22341969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22341969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22341969[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.01.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22341969">Tanaka et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22341969" 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>Members of the phosphatidylinositol kinase-related kinase (PIKK) family are high molecular mass kinases involved in cell cycle progression, DNA recombination, and the detection of DNA damage (<a href="#7" class="mim-tip-reference" title="Cimprich, K. A., Shin, T. B., Keith, C. T., Schreiber, S. L. <strong>cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein.</strong> Proc. Nat. Acad. Sci. 93: 2850-2855, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8610130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8610130</a>] [<a href="https://doi.org/10.1073/pnas.93.7.2850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8610130">Cimprich et al., 1996</a>). The human ATM gene (<a href="/entry/607585">607585</a>), which is defective in cells of patients with ataxia-telangiectasia (<a href="/entry/208900">208900</a>) and is involved in detection and response of cells to damaged DNA (<a href="#9" class="mim-tip-reference" title="Enoch, T., Norbury, C. <strong>Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM.</strong> Trends Biochem. Sci. 20: 426-430, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8533157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8533157</a>] [<a href="https://doi.org/10.1016/s0968-0004(00)89093-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8533157">Enoch and Norbury, 1995</a>), is a member of this family. Another is FRAP (<a href="/entry/601231">601231</a>), which is involved in a rapamycin-sensitive pathway leading to G1 cell cycle progression. <a href="#7" class="mim-tip-reference" title="Cimprich, K. A., Shin, T. B., Keith, C. T., Schreiber, S. L. <strong>cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein.</strong> Proc. Nat. Acad. Sci. 93: 2850-2855, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8610130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8610130</a>] [<a href="https://doi.org/10.1073/pnas.93.7.2850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8610130">Cimprich et al. (1996)</a> cloned a human cDNA encoding a protein with significant homology to members of the PIK-related kinase family. Three overlapping clones isolated from a Jurkat T-cell cDNA library revealed a 7.9-kb open reading frame encoding a protein that they named FRP1 for FRAP-related protein 1. The deduced protein contained 2,644 amino acids and a predicted molecular mass of 301 kD. FRP1 is most closely related to 3 of the family members involved in checkpoint function--Mei-41 (Drosophila), Mec1 (S. cerevisiae), and Rad3 (Schizosaccharomyces)--and as such may be the functional human counterpart of these proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8610130+8533157" 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 RT-PCR of cell lines originating from several human tissues, <a href="#20" class="mim-tip-reference" title="Mannino, J. L., Kim, W.-J., Wernick, M., Nguyen, S. V., Braquet, R., Adamson, A. W., Den, Z., Batzer, M. A., Collins, C. C., Brown, K. D. <strong>Evidence for alternate splicing within the mRNA transcript encoding the DNA damage response kinase ATR.</strong> Gene 272: 35-43, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11470508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11470508</a>] [<a href="https://doi.org/10.1016/s0378-1119(01)00543-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11470508">Mannino et al. (2001)</a> found evidence for 2 ATR transcripts due to alternative splicing within the noncatalytic domain. RT-PCR of a human tissue panel indicated a single transcript in adult heart, testis, and ovary, and 2 or more transcripts in pancreas, placenta, and liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11470508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using fluorescence in situ hybridization and a full-length cDNA FRP1 clone, <a href="#7" class="mim-tip-reference" title="Cimprich, K. A., Shin, T. B., Keith, C. T., Schreiber, S. L. <strong>cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein.</strong> Proc. Nat. Acad. Sci. 93: 2850-2855, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8610130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8610130</a>] [<a href="https://doi.org/10.1073/pnas.93.7.2850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8610130">Cimprich et al. (1996)</a> mapped the FRP1 gene to 3q22-q24. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8610130" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 9/30/2014."None>Gross (2014)</a> mapped the ATR gene to chromosome 3q23 based on an alignment of the ATR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AB208847" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AB208847</a>) with the genomic sequence (GRCh38).</p>
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<p><a href="#32" class="mim-tip-reference" title="Smith, L., Liu, S. J., Goodrich, L., Jacobson, D., Degnin, C., Bentley, N., Carr, A., Flaggs, G., Keegan, K., Hoekstra, M., Thayer, M. J. <strong>Duplication of ATR inhibits MyoD, induces aneuploidy and eliminates radiation-induced G1 arrest.</strong> Nature Genet. 19: 39-46, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590286</a>] [<a href="https://doi.org/10.1038/ng0598-39" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590286">Smith et al. (1998)</a> referred to this gene as ATR, for 'ataxia telangiectasia' and 'rad3-related.' In a genetic screen for loci present in rhabdomyosarcomas, they identified an isochromosome 3q, i(3q), that inhibited muscle differentiation when transferred into myoblasts. Specifically, the i(3q) inhibited the function of myogenic differentiation antigen-1 (MYOD1; <a href="/entry/159970">159970</a>), resulting in a nondifferentiating phenotype. Furthermore, the i(3q) induced a 'cut' ('cell untimely torn') phenotype in which cytokinesis occurred before nuclear division. These results indicated that introduction of the i(3q) into the test cells caused abnormal cell division resulting in aneuploidy. There was also loss of G1 arrest following gamma-irradiation. <a href="#32" class="mim-tip-reference" title="Smith, L., Liu, S. J., Goodrich, L., Jacobson, D., Degnin, C., Bentley, N., Carr, A., Flaggs, G., Keegan, K., Hoekstra, M., Thayer, M. J. <strong>Duplication of ATR inhibits MyoD, induces aneuploidy and eliminates radiation-induced G1 arrest.</strong> Nature Genet. 19: 39-46, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590286</a>] [<a href="https://doi.org/10.1038/ng0598-39" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590286">Smith et al. (1998)</a> showed that forced expression of the ATR gene resulted in a phenocopy of the i(3q). Thus, genetic alteration of ATR leads to loss of differentiation as well as cell cycle abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590286" 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="Bao, S., Tibbetts, R. S., Brumbaugh, K. M., Fang, Y., Richardson, D. A., Ali, A., Chen, S. M., Abraham, R. T., Wang, X.-F. <strong>ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses.</strong> Nature 411: 969-974, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11418864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11418864</a>] [<a href="https://doi.org/10.1038/35082110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11418864">Bao et al. (2001)</a> demonstrated a direct regulatory linkage between RAD17 (<a href="/entry/603139">603139</a>) and the checkpoint kinases ATM and ATR. Treatment of human cells with genotoxic agents induced ATM/ATR-phosphorylation of RAD17 at serine-635 and serine-645. Overexpression of a RAD17 mutant bearing alanine substitutions at both phosphorylation sites abrogated the DNA damage-induced G2 checkpoint and sensitized human fibroblasts to genotoxic stress. In contrast to wildtype RAD17, the RAD17 mutant showed no ionizing radiation-inducible association with RAD1 (<a href="/entry/603153">603153</a>), a component of the RAD1-RAD9 (<a href="/entry/603761">603761</a>)-HUS1 (<a href="/entry/603760">603760</a>) checkpoint complex. These findings demonstrated that ATR/ATM-dependent phosphorylation of RAD17 is a critical early event during checkpoint signaling in DNA-damaged cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11418864" 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="Cortez, D., Guntuku, S., Qin, J., Elledge, S. J. <strong>ATR and ATRIP: partners in checkpoint signaling.</strong> Science 294: 1713-1716, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11721054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11721054</a>] [<a href="https://doi.org/10.1126/science.1065521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11721054">Cortez et al. (2001)</a> identified an ATR-interacting protein that is phosphorylated by ATR, regulates ATR expression, and is an essential component of the DNA damage checkpoint pathway. ATR and ATRIP (<a href="/entry/606605">606605</a>) both localize to intranuclear foci after DNA damage or inhibition of replication. Deletion of ATR mediated by the Cre recombinase caused the loss of ATR and ATRIP expression, loss of DNA damage checkpoint responses, and cell death. Therefore, <a href="#8" class="mim-tip-reference" title="Cortez, D., Guntuku, S., Qin, J., Elledge, S. J. <strong>ATR and ATRIP: partners in checkpoint signaling.</strong> Science 294: 1713-1716, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11721054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11721054</a>] [<a href="https://doi.org/10.1126/science.1065521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11721054">Cortez et al. (2001)</a> concluded that ATR is essential for the viability of human somatic cells. Small interfering RNA directed against ATRIP caused the loss of both ATRIP and ATR expression and the loss of checkpoint responses to DNA damage. Thus, ATRIP and ATR are mutually dependent partners in cell cycle checkpoint signaling pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11721054" 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>S. cerevisiae Mec1, homolog of mammalian ATR, is an essential protein that mediates S-phase checkpoint responses and meiotic recombination. <a href="#6" class="mim-tip-reference" title="Cha, R. S., Kleckner, N. <strong>ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones.</strong> Science 297: 602-606, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12142538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12142538</a>] [<a href="https://doi.org/10.1126/science.1071398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12142538">Cha and Kleckner (2002)</a> found that elimination of Mec1 function leads to genomewide fork stalling followed by chromosome breakage. Breaks do not result from stochastic collapse of stalled forks or other incidental lesions; instead, they occur in specific regions of the genome during a G2 chromosomal transition. <a href="#6" class="mim-tip-reference" title="Cha, R. S., Kleckner, N. <strong>ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones.</strong> Science 297: 602-606, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12142538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12142538</a>] [<a href="https://doi.org/10.1126/science.1071398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12142538">Cha and Kleckner (2002)</a> found break regions to be genetically encoded replication slow zones, a yeast chromosomal determinant. Thus, <a href="#6" class="mim-tip-reference" title="Cha, R. S., Kleckner, N. <strong>ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones.</strong> Science 297: 602-606, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12142538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12142538</a>] [<a href="https://doi.org/10.1126/science.1071398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12142538">Cha and Kleckner (2002)</a> concluded that Mec1 has important functions in normal S phase, and the genome instability of Mec1 (and, analogously, ATR -/-) mutants stems from defects in these basic roles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12142538" 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="Casper, A. M., Nghiem, P., Arlt, M. F., Glover, T. W. <strong>ATR regulates fragile site stability.</strong> Cell 111: 779-789, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12526805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12526805</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)01113-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12526805">Casper et al. (2002)</a> demonstrated that ATR, but not ATM (<a href="/entry/607585">607585</a>), is critical for maintenance of fragile site stability. ATR deficiency resulted in fragile site expression with and without addition of replication inhibitors. The authors proposed that fragile sites are unreplicated chromosomal regions resulting from stalled forks that escape the ATR replication checkpoint. They stated that these findings have important implications for understanding both the mechanism of fragile site instability and the consequences of stalled replication in mammalian cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12526805" 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>Common fragile sites are specific loci that preferentially exhibit gaps and breaks on metaphase chromosomes under conditions that partially inhibit DNA replication (<a href="#13" class="mim-tip-reference" title="Glover, T. W., Berger, C., Coyle, J., Echo, B. <strong>DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes.</strong> Hum. Genet. 67: 136-142, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6430783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6430783</a>] [<a href="https://doi.org/10.1007/BF00272988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6430783">Glover et al., 1984</a>). Although they are normally stable in cultured human cells, under replicative stress, fragile sites are hotspots for sister chromatid exchanges (SCEs), translocations, and deletions (Glover and Stein (<a href="#14" class="mim-tip-reference" title="Glover, T. W., Stein, C. K. <strong>Induction of sister chromatid exchanges at common fragile sites.</strong> Am. J. Hum. Genet. 41: 882-890, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3674017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3674017</a>]" pmid="3674017">1987</a>, <a href="#15" class="mim-tip-reference" title="Glover, T. W., Stein, C. K. <strong>Chromosome breakage and recombination at fragile sites.</strong> Am. J. Hum. Genet. 43: 265-273, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3137811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3137811</a>]" pmid="3137811">1988</a>)), as well as integration of foreign DNA, and they may trigger some gene amplification events via a breakage-fusion-bridge cycle. Numerous studies have shown that fragile sites are unstable in tumors (review by <a href="#17" class="mim-tip-reference" title="Huebner, K., Croce, C. M. <strong>FRA3B and other common fragile sites: the weakest links.</strong> Nature Rev. Cancer 1: 214-221, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11902576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11902576</a>] [<a href="https://doi.org/10.1038/35106058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11902576">Huebner and Croce, 2001</a>). <a href="#4" class="mim-tip-reference" title="Casper, A. M., Durkin, S. G., Arlt, M. F., Glover, T. W. <strong>Chromosomal instability at common fragile sites in Seckel syndrome.</strong> Am. J. Hum. Genet. 75: 654-660, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15309689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15309689</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15309689[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/10.1086/422701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15309689">Casper et al. (2004)</a> pursued further the relationship between ATR and instability at common chromosomal fragile sites by testing whether cells from patients with Seckel syndrome (SCKL1; <a href="/entry/210600">210600</a>) caused by the 2101A-G transition in the ATR gene (<a href="#0001">601215.0001</a>) showed increased chromosome breakage following replication stress. Compared with controls, there was greater chromosomal instability, particularly at fragile sites, in cells from patients with Seckel syndrome after treatment with aphidicolin, an inhibitor of DNA polymerase alpha (<a href="/entry/312040">312040</a>) and other polymerases. The difference in chromosomal instability between control and patient cells increased at higher levels of aphidicolin treatment, suggesting that the low level of ATR present in these patients was not sufficient to respond appropriately to replication stress. <a href="#4" class="mim-tip-reference" title="Casper, A. M., Durkin, S. G., Arlt, M. F., Glover, T. W. <strong>Chromosomal instability at common fragile sites in Seckel syndrome.</strong> Am. J. Hum. Genet. 75: 654-660, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15309689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15309689</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15309689[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/10.1086/422701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15309689">Casper et al. (2004)</a> pointed out that this was the first human genetic syndrome associated with increased chromosome instability at fragile sites following replication stress, and suggested that these findings may be related to the phenotypic findings of patients with Seckel syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3137811+15309689+11902576+3674017+6430783" 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 function of the ATR-ATRIP protein kinase complex is crucial for the cellular response to replication stress and DNA damage. <a href="#35" class="mim-tip-reference" title="Zou, L., Elledge, S. J. <strong>Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.</strong> Science 300: 1542-1548, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12791985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12791985</a>] [<a href="https://doi.org/10.1126/science.1083430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12791985">Zou and Elledge (2003)</a> demonstrated that the replication protein A (RPA) complex (see <a href="/entry/179835">179835</a>), which associates with single-stranded DNA, is required for recruitment of ATR to sites of DNA damage and for ATR-mediated CHK1 (<a href="/entry/603078">603078</a>) activation in human cells. In vitro, RPA stimulates the binding of ATRIP to single-stranded DNA. The binding of ATRIP to RPA-coated single-stranded DNA enables the ATR-ATRIP complex to associate with DNA and stimulates phosphorylation of the RAD17 protein that is bound to DNA. Furthermore, Ddc2, the budding yeast homolog of ATRIP, is specifically recruited to double-stranded DNA breaks in an RPA-dependent manner. A checkpoint-deficient mutant of RPA, rfa1-t11, is defective for recruiting Ddc2 to single-stranded DNA both in vivo and in vitro. <a href="#35" class="mim-tip-reference" title="Zou, L., Elledge, S. J. <strong>Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.</strong> Science 300: 1542-1548, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12791985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12791985</a>] [<a href="https://doi.org/10.1126/science.1083430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12791985">Zou and Elledge (2003)</a> concluded that RPA-coated single-stranded DNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12791985" 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="Giuliano, P., de Cristofaro, T., Affaitati, A., Pizzulo, G. M., Feliciello, A., Criscuolo, C., De Michele, G., Filla, A., Avvedimento, E. V., Varrone, S. <strong>DNA damage induced by polyglutamine-expanded proteins.</strong> Hum. Molec. Genet. 12: 2301-2309, 2003. Note: Erratum: Hum. Molec. Genet. 33: 2177 only, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915485</a>] [<a href="https://doi.org/10.1093/hmg/ddg242" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915485">Giuliano et al. (2003)</a> developed stable cell lines expressing GFP fusion proteins containing polyglutamine repeats of various lengths. The expression of the expanded (43Q) repeat protein resulted in aggregate formation in a time-dependent fashion, but did not induce apoptosis. However, the expression of 43Q expanded protein strongly activated the ATM/ATR-dependent DNA damage response, as shown by selective phosphorylation of ATM substrates. Similarly, <a href="#12" class="mim-tip-reference" title="Giuliano, P., de Cristofaro, T., Affaitati, A., Pizzulo, G. M., Feliciello, A., Criscuolo, C., De Michele, G., Filla, A., Avvedimento, E. V., Varrone, S. <strong>DNA damage induced by polyglutamine-expanded proteins.</strong> Hum. Molec. Genet. 12: 2301-2309, 2003. Note: Erratum: Hum. Molec. Genet. 33: 2177 only, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915485</a>] [<a href="https://doi.org/10.1093/hmg/ddg242" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915485">Giuliano et al. (2003)</a> found phosphorylated ATM substrates in fibroblasts from Huntington disease (<a href="/entry/143100">143100</a>) and SCA2 (<a href="/entry/183090">183090</a>) patients. Oxidative stress increased accumulation of these phosphorylated ATM substrates. The authors concluded that polyglutamine induces ATM/ATR-dependent DNA damage response through accumulation of reactive oxygen species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915485" 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="Falck, J., Coates, J., Jackson, S. P. <strong>Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage.</strong> Nature 434: 605-611, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15758953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15758953</a>] [<a href="https://doi.org/10.1038/nature03442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15758953">Falck et al. (2005)</a> identified related, conserved C-terminal motifs in human NBS1 (<a href="/entry/602667">602667</a>), ATRIP, and Ku80 (<a href="/entry/194364">194364</a>) proteins that are required for their interaction with ATM, ATR, and DNA-PKcs (<a href="/entry/600899">600899</a>), respectively. These EEXXXDDL motifs are essential not only for efficient recruitment of ATM, ATR, and DNA-PKcs to sites of damage, but are also critical for ATM-, ATR-, and DNA-PKcs-mediated signaling events that trigger cell cycle checkpoints and DNA repair. <a href="#10" class="mim-tip-reference" title="Falck, J., Coates, J., Jackson, S. P. <strong>Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage.</strong> Nature 434: 605-611, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15758953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15758953</a>] [<a href="https://doi.org/10.1038/nature03442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15758953">Falck et al. (2005)</a> concluded that recruitment of these PIKKs to DNA lesions occurs by common mechanisms through an evolutionarily conserved motif, and provide direct evidence that PIKK recruitment is required for PIKK-dependent DNA-damage signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15758953" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast mutants, <a href="#30" class="mim-tip-reference" title="Saiardi, A., Resnick, A. C., Snowman, A. M., Wendland, B., Snyder, S. H. <strong>Inositol pyrophosphates regulate cell death and telomere length through phosphoinositide 3-kinase-related protein kinases.</strong> Proc. Nat. Acad. Sci. 102: 1911-1914, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15665079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15665079</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15665079[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/10.1073/pnas.0409322102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15665079">Saiardi et al. (2005)</a> showed that inositol pyrophosphates physiologically antagonized the actions of Tel1 and Mec1, the yeast homologs of ATM (<a href="/entry/607585">607585</a>) and ATR, respectively. Mutants with reduced or elevated levels of inositol pyrophosphates displayed longer and shorter telomeres, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15665079" 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="#21" class="mim-tip-reference" title="Matsuoka, S., Ballif, B. A., Smogorzewska, A., McDonald, E. R., III, Hurov, K. E., Luo, J., Bakalarski, C. E., Zhao, Z., Solimini, N., Lerenthal, Y., Shiloh, Y., Gygi, S. P., Elledge, S. J. <strong>ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.</strong> Science 316: 1160-1166, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17525332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17525332</a>] [<a href="https://doi.org/10.1126/science.1140321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17525332">Matsuoka et al. (2007)</a> performed a large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR and identified more than 900 regulated phosphorylation sites encompassing over 700 proteins. Functional analysis of a subset of this dataset indicated that this list was highly enriched for proteins involved in the DNA damage response. This set of proteins was highly interconnected, and <a href="#21" class="mim-tip-reference" title="Matsuoka, S., Ballif, B. A., Smogorzewska, A., McDonald, E. R., III, Hurov, K. E., Luo, J., Bakalarski, C. E., Zhao, Z., Solimini, N., Lerenthal, Y., Shiloh, Y., Gygi, S. P., Elledge, S. J. <strong>ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.</strong> Science 316: 1160-1166, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17525332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17525332</a>] [<a href="https://doi.org/10.1126/science.1140321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17525332">Matsuoka et al. (2007)</a> identified a large number of protein modules and networks not previously linked to the DNA damage response. <a href="#21" class="mim-tip-reference" title="Matsuoka, S., Ballif, B. A., Smogorzewska, A., McDonald, E. R., III, Hurov, K. E., Luo, J., Bakalarski, C. E., Zhao, Z., Solimini, N., Lerenthal, Y., Shiloh, Y., Gygi, S. P., Elledge, S. J. <strong>ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.</strong> Science 316: 1160-1166, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17525332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17525332</a>] [<a href="https://doi.org/10.1126/science.1140321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17525332">Matsuoka et al. (2007)</a> concluded that their database painted a much broader landscape for the DNA damage response than had been appreciated and opened new avenues of investigation into the responses to DNA damage in mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17525332" 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="Liu, H., Takeda, S., Kumar, R., Westergard, T. D., Brown, E. J., Pandita, T. K., Cheng, E. H.-Y., Hsieh, J. J.-D. <strong>Phosphorylation of MLL by ATR is required for execution of mammalian S-phase checkpoint.</strong> Nature 467: 343-346, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20818375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20818375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20818375[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/nature09350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20818375">Liu et al. (2010)</a> assigned MLL (<a href="/entry/159555">159555</a>) as a novel effector in the mammalian S-phase checkpoint network and identified checkpoint dysfunction as an underlying mechanism of MLL leukemias. MLL is phosphorylated at ser516 by ATR in response to genotoxic stress in the S phase, which disrupts its interaction with, and hence its degradation by, the SCF(Skp2) (<a href="/entry/601436">601436</a>) E3 ligase, leading to its accumulation. Stabilized MLL protein accumulates on chromatin, methylates histone H3 lysine-4 (H3K4) at late replication origins, and inhibits the loading of CDC45 (<a href="/entry/603465">603465</a>) to delay DNA replication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20818375" 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="Robert, T., Vanoli, F., Chiolo, I., Shubassi, G., Bernstein, K. A., Rothstein, R., Botrugno, O. A., Parazzoli, D., Oldani, A., Minucci, S., Foiani, M. <strong>HDACs link the DNA damage response, processing of double-strand breaks and autophagy.</strong> Nature 471: 74-79, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21368826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21368826</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21368826[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/nature09803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21368826">Robert et al. (2011)</a> showed that histone deacetylase (HDAC) inhibition/ablation specifically counteracts yeast Mec1 (ortholog of human ATR) activation, double-strand break processing, and single-strand DNA-RFA nucleofilament formation. Moreover, the recombination protein Sae2 (human CTIP; <a href="/entry/604124">604124</a>) is acetylated and degraded after HDAC inhibition. Two HDACs, Hda1 (see HDAC4, <a href="/entry/605314">605314</a>) and Rpd3 (HDAC1; <a href="/entry/601241">601241</a>) and 1 histone acetyltransferase (HAT), Gcn5 (GCN5L2; <a href="/entry/602301">602301</a>), have key roles in these processes. <a href="#27" class="mim-tip-reference" title="Robert, T., Vanoli, F., Chiolo, I., Shubassi, G., Bernstein, K. A., Rothstein, R., Botrugno, O. A., Parazzoli, D., Oldani, A., Minucci, S., Foiani, M. <strong>HDACs link the DNA damage response, processing of double-strand breaks and autophagy.</strong> Nature 471: 74-79, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21368826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21368826</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21368826[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/nature09803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21368826">Robert et al. (2011)</a> also found that HDAC inhibition triggers Sae2 degradation by promoting autophagy that affects the DNA damage sensitivity of Hda1 and Rpd3 mutants. Rapamycin, which stimulates autophagy by inhibiting Tor (MTOR; <a href="/entry/601231">601231</a>), also causes Sae2 degradation. <a href="#27" class="mim-tip-reference" title="Robert, T., Vanoli, F., Chiolo, I., Shubassi, G., Bernstein, K. A., Rothstein, R., Botrugno, O. A., Parazzoli, D., Oldani, A., Minucci, S., Foiani, M. <strong>HDACs link the DNA damage response, processing of double-strand breaks and autophagy.</strong> Nature 471: 74-79, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21368826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21368826</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21368826[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/nature09803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21368826">Robert et al. (2011)</a> proposed that Rpd3, Hda1, and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand break processing with autophagy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21368826" 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="#11" class="mim-tip-reference" title="Flynn, R. L., Cox, K. E., Jeitany, M., Wakimoto, H., Bryll, A. R., Ganem, N. J., Bersani, F., Pineda, J. R., Suva, M. L., Benes, C. H., Haber, D. A., Boussin, F. D., Zou, L. <strong>Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.</strong> Science 347: 273-277, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25593184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25593184</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25593184[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.1257216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25593184">Flynn et al. (2015)</a> showed that loss of ATRX (<a href="/entry/300032">300032</a>) compromises cell-cycle regulation of the telomeric noncoding RNA TERRA and leads to persistent association of replication protein A (RPA; see <a href="/entry/179835">179835</a>) with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of the protein kinase ATR, a critical regulator of recombination recruited by RPA, disrupts alternative lengthening of telomeres (ALT) and triggers chromosome fragmentation and apoptosis in ALT cells. The cell death induced by ATR inhibitors is highly selective for cancer cells that rely on ALT, suggesting that such inhibitors may be useful for treatment of ALT-positive cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25593184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Kabeche, L., Nguyen, H. D., Buisson, R., Zou, L. <strong>A mitosis-specific and R loop-driven ATR pathway promotes faithful chromosome segregation.</strong> Science 359: 108-114, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29170278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29170278</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29170278[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.aan6490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29170278">Kabeche et al. (2018)</a> described an unexpected role of ATR in mitosis. Acute inhibition or degradation of ATR in mitosis induces whole-chromosome missegregation. The effect of ATR ablation is not due to altered cyclin-dependent kinase-1 (CDK1; <a href="/entry/116940">116940</a>) activity, DNA damage responses, or unscheduled DNA synthesis, but to loss of an ATR function at centromeres. In mitosis, ATR localizes to centromeres through Aurora A (<a href="/entry/603072">603072</a>)-regulated association with centromere protein F (CENPF; <a href="/entry/600236">600236</a>), allowing ATR to engage RPA-coated centromeric R loops. As ATR is activated at centromeres, it stimulates Aurora B (<a href="/entry/604970">604970</a>) through Chk1, preventing formation of lagging chromosomes. Thus, a mitosis-specific and R loop-driven ATR pathway acts at centromeres to promote faithful chromosome segregation, revealing functions of R loops and ATR in suppressing chromosome instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29170278" 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="Saldivar, J. C., Hamperl, S., Bocek, M. J., Chung, M., Bass, T. E., Cisneros-Soberanis, F., Samejima, K., Xie, L., Paulson, J. R., Earnshaw, W. C., Cortez, D., Meyer, T., Cimprich, K. A. <strong>An intrinsic S/G2 checkpoint enforced by ATR.</strong> Science 361: 806-810, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30139873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30139873</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30139873[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.aap9346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30139873">Saldivar et al. (2018)</a> demonstrated that cells transactivate the mitotic gene network as they exit the S phase through a CDK1 (<a href="/entry/116940">116940</a>)-directed FOXM1 (<a href="/entry/602341">602341</a>) phosphorylation switch. During normal DNA replication, the checkpoint kinase ATR is activated by ETAA1 (<a href="/entry/613196">613196</a>) to block this switch until the S phase ends. ATR inhibition prematurely activates FOXM1, deregulating the S/G2 transition and leading to early mitosis, underreplicated DNA, and DNA damage. Thus, ATR couples DNA replication with mitosis and preserves genome integrity by enforcing an S/G2 checkpoint. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30139873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Seckel Syndrome 1</em></strong></p><p>
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Seckel syndrome (see <a href="/entry/210600">210600</a>) is an autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly, and mental retardation. Clinically, Seckel syndrome shares features in common with disorders involving impaired DNA-damage responses, such as Nijmegen breakage syndrome (<a href="/entry/251260">251260</a>) and LIG4 syndrome (<a href="/entry/606593">606593</a>). <a href="#25" class="mim-tip-reference" title="O'Driscoll, M., Ruiz-Perez, V. L., Woods, C. G., Jeggo, P. A., Goodship, J. A. <strong>A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome.</strong> Nature Genet. 33: 497-501, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640452</a>] [<a href="https://doi.org/10.1038/ng1129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640452">O'Driscoll et al. (2003)</a> investigated the ATR gene, which maps to the Seckel syndrome-1 critical region, and found a synonymous (translationally silent) mutation (<a href="#0001">601215.0001</a>) in affected individuals that alters ATR splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12640452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Alderton, G. K., Joenje, H., Varon, R., Borglum, A. D., Jeggo, P. A., O'Driscoll, M. <strong>Seckel syndrome exhibits cellular features demonstrating defects in the ATR-signalling pathway.</strong> Hum. Molec. Genet. 13: 3127-3138, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15496423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15496423</a>] [<a href="https://doi.org/10.1093/hmg/ddh335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15496423">Alderton et al. (2004)</a> reported that ATR-Seckel cells displayed impaired phosphorylation of ATR-dependent substrates, impaired G2/M checkpoint arrest, and elevated micronucleus (MN) formation following exposure to UV and agents that cause replication stalling. Nuclear fragmentation (NF) occurred following replication arrest. ATR-Seckel cells also had an endogenously increased number of centrosomes in mitotic cells, suggesting a role for ATR in regulating centrosome stability. Among 7 unrelated Seckel syndrome cell lines, impaired phosphorylation of ATR-dependent substrates was a common but not invariant feature. In contrast, all cell lines displayed defective G2/M arrest, increased levels of NF and MN formation following exposure to agents that cause replication stalling, and increased endogenous centrosome numbers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15496423" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated English patients with Seckel syndrome-1, <a href="#26" class="mim-tip-reference" title="Ogi, T., Walker, S., Stiff, T., Hobson, E., Limsirichaikul, S., Carpenter, G., Prescott, K., Suri, M., Byrd, P. J., Matsuse, M., Mitsutake, N., Nakazawa, Y., Vasudevan, P., Barrow, M., Stewart, G. S., Taylor, A. M. R., O'Driscoll, M., Jeggo, P. A. <strong>Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel syndrome.</strong> PLoS Genet. 8: e1002945, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23144622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23144622</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23144622[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/10.1371/journal.pgen.1002945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23144622">Ogi et al. (2012)</a> identified the same compound heterozygous mutations in the ATR gene (<a href="#0004">601215.0004</a> and <a href="#0005">601215.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23144622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Familial Cutaneous Telangiectasia and Cancer Syndrome</em></strong></p><p>
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In a large 4-generation family with a syndrome involving early-onset cutaneous telangiectases, mild developmental anomalies of hair, teeth, and nails, and a predisposition to cancer mapping to chromosome 3q22-q24 (FCTCS; <a href="/entry/614564">614564</a>), <a href="#33" class="mim-tip-reference" title="Tanaka, A., Weinel, S., Nagy, N., O'Driscoll, M., Lai-Cheong, J. E., Kulp-Shorten, C. L., Knable, A., Carpenter, G., Fisher, S. A., Hiragun, M., Yanase, Y., Hide, M., Callen, J., McGrath, J. A. <strong>Germline mutation in ATR in autosomal-dominant oropharyngeal cancer syndrome.</strong> Am. J. Hum. Genet. 90: 511-517, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22341969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22341969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22341969[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.01.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22341969">Tanaka et al. (2012)</a> analyzed 42 candidate genes and identified a heterozygous missense mutation in the ATR gene (Q2144R; <a href="#0002">601215.0002</a>) that segregated with the disorder and was not found in 220 ethnically matched control chromosomes. Analysis of DNA from an affected family member's oropharyngeal cancer lesion showed loss of heterozygosity for the wildtype ATR allele, implicating ATR in the pathophysiology of oropharyngeal cancer and indicating a tumor-suppressing role for ATR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22341969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Impaired ATR Signaling in Other Disorders</em></strong></p><p>
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In addition to ATR-Seckel syndrome, impaired ATR signaling is also observed in cell lines from other disorders characterized by microcephaly and growth delay, including non-ATR Seckel syndrome (<a href="/entry/606744">606744</a>), Nijmegen breakage syndrome, and primary autosomal recessive microcephaly (MCPH1; <a href="/entry/251200">251200</a>). <a href="#24" class="mim-tip-reference" title="O'Driscoll, M., Dobyns, W. B., van Hagen, J. M., Jeggo, P. A. <strong>Cellular and clinical impact of haploinsufficiency for genes involved in ATR signaling.</strong> Am. J. Hum. Genet. 81: 77-86, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17564965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17564965</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17564965[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/10.1086/518696" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17564965">O'Driscoll et al. (2007)</a> examined ATR pathway function in cell lines from 3 haploinsufficient contiguous gene deletion disorders: a subset of blepharophimosis-ptosis-epicanthus inversus syndrome (BPES; <a href="/entry/110100">110100</a>), Miller-Dieker lissencephaly syndrome (<a href="/entry/247200">247200</a>), and Williams-Beuren syndrome (<a href="/entry/194050">194050</a>). In these 3 syndromes the deleted region encompasses ATR, RPA1 (<a href="/entry/179835">179835</a>), and RFC2 (<a href="/entry/600404">600404</a>), respectively. These 3 genes function in ATR signaling. Cell lines from these disorders displayed an impaired ATR-dependent DNA damage response. Thus, <a href="#24" class="mim-tip-reference" title="O'Driscoll, M., Dobyns, W. B., van Hagen, J. M., Jeggo, P. A. <strong>Cellular and clinical impact of haploinsufficiency for genes involved in ATR signaling.</strong> Am. J. Hum. Genet. 81: 77-86, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17564965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17564965</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17564965[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/10.1086/518696" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17564965">O'Driscoll et al. (2007)</a> described ATR signaling as a pathway unusually sensitive to haploinsufficiency and identified 3 further human disorders displaying a defective ATR-dependent DNA damage response. The striking correlation of ATR pathway dysfunction with the presence of microcephaly and growth delay strongly suggested a causal relationship. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17564965" 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 9.5-year-old French girl with Seckel syndrome, <a href="#22" class="mim-tip-reference" title="Mokrani-Benhelli, H., Gaillard, L., Biasutto, P., Le Guen, T., Touzot, F., Vasquez, N., Komatsu, J., Conseiller, E., Picard, C., Gluckman, E., Francannet, C., Fischer, A., Durandy, A., Soulier, J., de Villartay, J.-P., Cavazzana-Calvo, M. <strong>Primary microcephaly, impaired DNA replication, and genomic instability caused by compound heterozygous ATR mutations.</strong> Hum. Mutat. 34: 374-384, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23111928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23111928</a>] [<a href="https://doi.org/10.1002/humu.22245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23111928">Mokrani-Benhelli et al. (2013)</a> identified compound heterozygosity for a missense mutation in the ATR gene (D1879Y; <a href="#0003">601215.0003</a>) and a 540-kb deletion on chromosome 3 encompassing ATR as well as 3 other genes, XRN1 (<a href="/entry/607994">607994</a>), PLS1 (<a href="/entry/602734">602734</a>), and TRPC1 (<a href="/entry/602343">602343</a>). DNA combing technology revealed a profound spontaneous alteration of several DNA replication parameters in patient cells, and FISH analysis demonstrated the genomic instability caused by ATR deficiency. <a href="#22" class="mim-tip-reference" title="Mokrani-Benhelli, H., Gaillard, L., Biasutto, P., Le Guen, T., Touzot, F., Vasquez, N., Komatsu, J., Conseiller, E., Picard, C., Gluckman, E., Francannet, C., Fischer, A., Durandy, A., Soulier, J., de Villartay, J.-P., Cavazzana-Calvo, M. <strong>Primary microcephaly, impaired DNA replication, and genomic instability caused by compound heterozygous ATR mutations.</strong> Hum. Mutat. 34: 374-384, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23111928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23111928</a>] [<a href="https://doi.org/10.1002/humu.22245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23111928">Mokrani-Benhelli et al. (2013)</a> stated that these results emphasized the crucial role for ATR in the control of DNA replication, and reinforced the complementary and nonredundant contributions of ATM and ATR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23111928" 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="#3" class="mim-tip-reference" title="Brown, E. J., Baltimore, D. <strong>ATR disruption leads to chromosomal fragmentation and early embryonic lethality.</strong> Genes Dev. 14: 397-402, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10691732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10691732</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10691732[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10691732">Brown and Baltimore (2000)</a> noted that ATM and ATR belong to a conserved family of high molecular weight kinases. They generated mice with a targeted disruption of the Atr gene by deleting 3 exons encoding the initiating met and the following 90 amino acids. Atr +/- mice survived nearly as long as ATR +/+ mice but had an increase in tumor incidence. In contrast, and unlike Atm -/- or p53 (<a href="/entry/191170">191170</a>) -/- mice, Atr -/- embryos survived to the blastocyst stage at day 3.5 postcoitum but not to day 7.5. In culture, wildtype and heterozygous blastocysts were initially indistinguishable from the Atr -/- cells, but the Atr -/- cells then died, suffering from chromosomal fragmentation. TUNEL analysis revealed widespread apoptosis after 3 days of culture, and the apoptosis could be blocked by inhibition of Casp3 (<a href="/entry/600636">600636</a>). The authors speculated that ATR may be particularly essential in the early embryo to sense incomplete DNA replication and prevent mitotic catastrophe. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10691732" 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="Ruzankina, Y., Pinzon-Guzman, C., Asare, A., Ong, T., Pontano, L., Cotsarelis, G., Zediak, V. P., Velez, M., Bhandoola, A., Brown, E. J. <strong>Deletion of developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss.</strong> Cell Stem Cell 1: 113-126, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18371340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18371340</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18371340[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.stem.2007.03.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18371340">Ruzankina et al. (2007)</a> found that deletion of Atr in adult mice led to defects in tissue homeostasis and rapid appearance of age-related phenotypes. Histologic and genetic analysis indicated that Atr deletion caused acute cellular loss in tissues that require continuous cell proliferation for maintenance. Thymic involution, alopecia, and hair graying in Atr-knockout mice were associated with dramatic reductions in tissue-specific stem and progenitor cells and exhaustion of tissue renewal and homeostatic capacity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18371340" 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="Ruzankina, Y., Schoppy, D. W., Asare, A., Clark, C. E., Vonderheide, R. H., Brown, E. J. <strong>Tissue regenerative delays and synthetic lethality in adult mice after combined deletion of Atr and Trp53.</strong> Nature Genet. 41: 1144-1149, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19718024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19718024</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19718024[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19718024">Ruzankina et al. (2009)</a> reported that p53 deficiency severely exacerbates tissue degeneration caused by mosaic deletion of the essential genome maintenance regulator Atr. Combined loss of Atr and p53 led to severe defects in hair follicle regeneration, localized inflammation (Mac1+Gr1+ infiltrates), accelerated deterioration of the intestinal epithelium, and synthetic lethality in adult mice. Tissue degeneration in double-null mice was characterized by the accumulation of cells maintaining high levels of DNA damage. Moreover, the elevated frequency of these damaged cells in both progenitor and downstream compartments in double-null mouse skin coincided with delayed compensatory tissue renewal from residual ATR-expressing cells. <a href="#29" class="mim-tip-reference" title="Ruzankina, Y., Schoppy, D. W., Asare, A., Clark, C. E., Vonderheide, R. H., Brown, E. J. <strong>Tissue regenerative delays and synthetic lethality in adult mice after combined deletion of Atr and Trp53.</strong> Nature Genet. 41: 1144-1149, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19718024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19718024</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19718024[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19718024">Ruzankina et al. (2009)</a> concluded that, taken together, their results indicated that the combined loss of Atr and Trp53 in adult mice leads to the accumulation of highly damaged cells, which, consequently, impose a barrier to regeneration from undamaged progenitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19718024" 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="#23" class="mim-tip-reference" title="Murga, M., Bunting, S., Montana, M. F., Soria, R., Mulero, F., Canamero, M., Lee, Y., McKinnon, P. J., Nussenzweig, A., Fernandez-Capetillo, O. <strong>A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging.</strong> Nature Genet. 41: 891-898, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19620979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19620979</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19620979[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19620979">Murga et al. (2009)</a> developed a mouse model of Seckel syndrome by replacing exons 8, 9, and 10 of the mouse Atr gene with those from human, and then introducing the A-to-G transition into exon 9 of the humanized gene (<a href="#0001">601215.0001</a>). ATR Seckel homozygous mice were born at submendelian ratios and showed severe dwarfism that was already noticeable at birth. Mutant placentas showed an accumulation of necrotic areas and overall loss of cellularity. In addition to the overall dwarfism, Seckel mice showed microcephaly and facial dysmorphisms including micrognathia and receding foreheads. Seckel mice also had small brains, cysts, and agenesis of the corpus callosum. Seckel mice showed high levels of replicative stress during embryogenesis, when proliferation is widespread, but this was reduced to marginal amounts in postnatal life. In spite of this decrease, adult Seckel mice showed accelerated aging, which was further aggravated in the absence of p53. <a href="#23" class="mim-tip-reference" title="Murga, M., Bunting, S., Montana, M. F., Soria, R., Mulero, F., Canamero, M., Lee, Y., McKinnon, P. J., Nussenzweig, A., Fernandez-Capetillo, O. <strong>A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging.</strong> Nature Genet. 41: 891-898, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19620979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19620979</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19620979[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19620979">Murga et al. (2009)</a> concluded that their results supported a model whereby replicative stress, particularly in utero, contributes to the onset of aging in postnatal life, and this is balanced by the replicative stress-limiting role of the checkpoint proteins ATR and p53. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19620979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using the mouse model of Seckel syndrome developed by <a href="#23" class="mim-tip-reference" title="Murga, M., Bunting, S., Montana, M. F., Soria, R., Mulero, F., Canamero, M., Lee, Y., McKinnon, P. J., Nussenzweig, A., Fernandez-Capetillo, O. <strong>A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging.</strong> Nature Genet. 41: 891-898, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19620979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19620979</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19620979[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19620979">Murga et al. (2009)</a>, <a href="#34" class="mim-tip-reference" title="Valdes-Sanchez, L., De la Cerda, B., Diaz-Corrales, F. J., Massalini, S., Chakarova, C. F., Wright, A. F., Bhattacharya, S. S. <strong>ATR localizes to the photoreceptor connecting cilium and deficiency leads to severe photoreceptor degeneration in mice.</strong> Hum. Molec. Genet. 22: 1507-1515, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23297361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23297361</a>] [<a href="https://doi.org/10.1093/hmg/dds563" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23297361">Valdes-Sanchez et al. (2013)</a> found that heterozygous expression of humanized mutant ATR (ATR +/S) resulted in abnormal electroretinogram with photoreceptor and optic nerve degeneration. ATR +/S mice showed normal embryonic and retinal development, but lost rods by postnatal day 20 (P20) and cones by P25. In wildtype mice, Atr localized to the nonmotile connecting cilium between the outer photoreceptor segment and inner nuclear segment. Compared with wildtype, ATR +/S cilia were about 40% shorter. ATR deficiency was also associated with diminished levels of microtubule-interacting Map2c (<a href="/entry/157130">157130</a>) in photoreceptor inner segment. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19620979+23297361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 Pakistani families, <a href="#25" class="mim-tip-reference" title="O'Driscoll, M., Ruiz-Perez, V. L., Woods, C. G., Jeggo, P. A., Goodship, J. A. <strong>A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome.</strong> Nature Genet. 33: 497-501, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640452</a>] [<a href="https://doi.org/10.1038/ng1129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640452">O'Driscoll et al. (2003)</a> found that a homozygous translationally silent (synonymous) single base change, 2101A-G, segregated with Seckel syndrome (SCKL1; <a href="/entry/210600">210600</a>). The mutation resulted in the use of 2 cryptic splice-donor sites in exon 9. Loss of exon 9 and use of the cryptic splice-donor sites introduced a stop codon in the next exon. Because of the profound effect on splicing efficiency, there were reduced but residual levels of normal transcript and protein. The severity of this hypomorphic mutation was shown by the marked microcephaly and dwarfism observed in the affected individuals and was consistent with the embryonic and somatic lethality seen in the absence of ATR (<a href="#3" class="mim-tip-reference" title="Brown, E. J., Baltimore, D. <strong>ATR disruption leads to chromosomal fragmentation and early embryonic lethality.</strong> Genes Dev. 14: 397-402, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10691732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10691732</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10691732[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10691732">Brown and Baltimore, 2000</a>; <a href="#8" class="mim-tip-reference" title="Cortez, D., Guntuku, S., Qin, J., Elledge, S. J. <strong>ATR and ATRIP: partners in checkpoint signaling.</strong> Science 294: 1713-1716, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11721054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11721054</a>] [<a href="https://doi.org/10.1126/science.1065521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11721054">Cortez et al., 2001</a>). This was the first evidence of a clinical disorder associated with impaired ATR signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11721054+10691732+12640452" 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>.0002 CUTANEOUS TELANGIECTASIA AND CANCER SYNDROME, FAMILIAL (1 family)</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906797 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906797;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=rs387906797" 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=rs387906797" 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=RCV000023082 OR RCV003556071" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023082, RCV003556071" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023082...</a>
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<p>In affected members of a large 4-generation family with a syndrome involving early-onset cutaneous telangiectases, mild developmental anomalies of hair, teeth, and nails, and a predisposition to cancer (FCTCS; <a href="/entry/614564">614564</a>), predominantly oropharyngeal, <a href="#33" class="mim-tip-reference" title="Tanaka, A., Weinel, S., Nagy, N., O'Driscoll, M., Lai-Cheong, J. E., Kulp-Shorten, C. L., Knable, A., Carpenter, G., Fisher, S. A., Hiragun, M., Yanase, Y., Hide, M., Callen, J., McGrath, J. A. <strong>Germline mutation in ATR in autosomal-dominant oropharyngeal cancer syndrome.</strong> Am. J. Hum. Genet. 90: 511-517, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22341969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22341969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22341969[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.01.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22341969">Tanaka et al. (2012)</a> identified heterozygosity for a 6431A-G transition in the ATR gene, resulting in a gln2144-to-arg (Q2144R) substitution at a highly conserved residue within the FAT domain, immediately adjacent to a potential phosphorylation site (SQ/TQ motif) at ser2143. The mutation was not found in unaffected family members or in 220 ethnically matched control chromosomes. Immunoblotting of mutant fibroblast samples showed no reduction in ATR mRNA compared to controls; however, expression of p53 (TP53; <a href="/entry/191170">191170</a>) was found to be both constitutively reduced and reduced after ATR activation with hydroxyurea. Sequencing of DNA from an affected individual's oropharyngeal cancer lesion revealed loss of heterozygosity with allelic loss of the wildtype allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22341969" 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>.0003 SECKEL SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387907327 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907327;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/rs387907327?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=rs387907327" 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=rs387907327" 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=RCV000034827" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000034827" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000034827</a>
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<p>In a 9.5-year-old French girl with Seckel syndrome (SCKL1; <a href="/entry/210600">210600</a>), <a href="#22" class="mim-tip-reference" title="Mokrani-Benhelli, H., Gaillard, L., Biasutto, P., Le Guen, T., Touzot, F., Vasquez, N., Komatsu, J., Conseiller, E., Picard, C., Gluckman, E., Francannet, C., Fischer, A., Durandy, A., Soulier, J., de Villartay, J.-P., Cavazzana-Calvo, M. <strong>Primary microcephaly, impaired DNA replication, and genomic instability caused by compound heterozygous ATR mutations.</strong> Hum. Mutat. 34: 374-384, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23111928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23111928</a>] [<a href="https://doi.org/10.1002/humu.22245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23111928">Mokrani-Benhelli et al. (2013)</a> identified compound heterozygosity for a 5635G-T transversion in exon 33 of the ATR gene, resulting in an asp1879-to-tyr (D1879Y) substitution, and a 540-kb deletion on chromosome 3 encompassing ATR as well as 3 other genes. The missense mutation was inherited from her mother and the deletion from her father. Immunoblot of patient B-lymphoblastoid cell line (B-LCL) cells revealed a marked decrease in ATR expression compared to her parents and controls; her father also had a consistently reduced ATR level as well, likely reflecting his ATR hemizygous status. The missense mutation was predicted to disrupt an exon-splicing enhancer (ESE) site located in exon 33, and RT-PCR confirmed the occurrence of aberrant splicing events when the 5635G-T mutation was present. The patient's primary fibroblasts exhibited an increased sensitivity to UV irradiation, and ATR-dependent phosphorylation of H2AX (<a href="/entry/601772">601772</a>) in response to hydroxyurea and UV treatment was virtually absent in patient cells, whereas the ATM (<a href="/entry/607585">607585</a>)-dependent phosphorylation of H2AX following ionizing radiation was intact. In addition, analysis of DNA replication parameters during unperturbed cell cycles in patient B-LCL cells and fibroblasts revealed that fork speed and interorigin distance were significantly reduced and asymmetric replicons were increased in both cell types compared to controls. FISH analysis revealed spontaneously accumulated DNA damage in patient fibroblasts, in part at telomeres, that resulted in an ATM-dependent DNA-damage response. The patient's cells also spontaneously exhibited high levels of genomic instability that were partly counteracted by ATM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23111928" 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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ATR, MET1159ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777851 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777851;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=rs587777851" 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=rs587777851" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated English patients with Seckel syndrome (SCKL1; <a href="/entry/210600">210600</a>), <a href="#26" class="mim-tip-reference" title="Ogi, T., Walker, S., Stiff, T., Hobson, E., Limsirichaikul, S., Carpenter, G., Prescott, K., Suri, M., Byrd, P. J., Matsuse, M., Mitsutake, N., Nakazawa, Y., Vasudevan, P., Barrow, M., Stewart, G. S., Taylor, A. M. R., O'Driscoll, M., Jeggo, P. A. <strong>Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel syndrome.</strong> PLoS Genet. 8: e1002945, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23144622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23144622</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23144622[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/10.1371/journal.pgen.1002945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23144622">Ogi et al. (2012)</a> identified the same compound heterozygous mutations in the ATR gene: a c.3477G-T transversion, resulting in a met1159-to-ile (M1159I) substitution at a highly conserved residue in the UME domain, and a C-to-G transversion in intron 40 (c.6897+464C-G; <a href="#0005">601215.0005</a>), resulting in a splicing defect and premature termination (Val2300GlyfsTer75). Western blot analysis of patient cells showed decreased levels of ATR and ATRIP (<a href="/entry/606605">606605</a>). Studies of patient cells and in vitro functional expression studies showed impaired ATR-dependent G2/M cell cycle arrest after UV radiation, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23144622" 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> rs587777852 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777852;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/rs587777852?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=rs587777852" 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=rs587777852" 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=RCV000144693 OR RCV002514777 OR RCV004751286" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144693, RCV002514777, RCV004751286" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144693...</a>
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<p>For discussion of the splice site mutation in the ATR gene (c.6897+464C-G) that was found in compound heterozygous state in patients with Seckel syndrome (SCKL1; <a href="/entry/210600">210600</a>) by <a href="#26" class="mim-tip-reference" title="Ogi, T., Walker, S., Stiff, T., Hobson, E., Limsirichaikul, S., Carpenter, G., Prescott, K., Suri, M., Byrd, P. J., Matsuse, M., Mitsutake, N., Nakazawa, Y., Vasudevan, P., Barrow, M., Stewart, G. S., Taylor, A. M. R., O'Driscoll, M., Jeggo, P. A. <strong>Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel syndrome.</strong> PLoS Genet. 8: e1002945, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23144622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23144622</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23144622[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/10.1371/journal.pgen.1002945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23144622">Ogi et al. (2012)</a>, see <a href="#0004">601215.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23144622" 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 href="https://doi.org/10.1093/hmg/ddh335" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/35082110" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/422701" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(02)01113-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1071398" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.93.7.2850" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1065521" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0968-0004(00)89093-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature03442" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1257216" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg242" target="_blank">Full Text</a>]
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<a id="Glover1984" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1007/BF00272988" target="_blank">Full Text</a>]
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<a id="Glover1988" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1038/35106058" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29170278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29170278</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29170278[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=29170278" 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.aan6490" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature09350" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0378-1119(01)00543-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1140321" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.22245" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/518696" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1129" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1371/journal.pgen.1002945" target="_blank">Full Text</a>]
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Tanaka, A., Weinel, S., Nagy, N., O'Driscoll, M., Lai-Cheong, J. E., Kulp-Shorten, C. L., Knable, A., Carpenter, G., Fisher, S. A., Hiragun, M., Yanase, Y., Hide, M., Callen, J., McGrath, J. A.
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<strong>Germline mutation in ATR in autosomal-dominant oropharyngeal cancer syndrome.</strong>
|
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Am. J. Hum. Genet. 90: 511-517, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22341969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22341969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22341969[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=22341969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2012.01.007" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="34" class="mim-anchor"></a>
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<a id="Valdes-Sanchez2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Valdes-Sanchez, L., De la Cerda, B., Diaz-Corrales, F. J., Massalini, S., Chakarova, C. F., Wright, A. F., Bhattacharya, S. S.
|
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<strong>ATR localizes to the photoreceptor connecting cilium and deficiency leads to severe photoreceptor degeneration in mice.</strong>
|
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Hum. Molec. Genet. 22: 1507-1515, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23297361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23297361</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23297361" 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/dds563" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="35" class="mim-anchor"></a>
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<a id="Zou2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zou, L., Elledge, S. J.
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<strong>Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.</strong>
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Science 300: 1542-1548, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12791985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12791985</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12791985" 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.1083430" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 11/20/2018
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 08/14/2018<br>Ada Hamosh - updated : 02/01/2016<br>Cassandra L. Kniffin - updated : 10/20/2014<br>Matthew B. Gross - updated : 9/30/2014<br>Patricia A. Hartz - updated : 4/8/2014<br>Marla J. F. O'Neill - updated : 4/11/2013<br>Marla J. F. O'Neill - updated : 4/11/2012<br>Ada Hamosh - updated : 6/20/2011<br>Ada Hamosh - updated : 9/29/2010<br>Ada Hamosh - updated : 1/12/2010<br>Ada Hamosh - updated : 9/16/2009<br>Patricia A. Hartz - updated : 7/9/2007<br>Ada Hamosh - updated : 6/20/2007<br>Victor A. McKusick - updated : 6/18/2007<br>George E. Tiller - updated : 5/21/2007<br>George E. Tiller - updated : 9/9/2005<br>Patricia A. Hartz - updated : 6/7/2005<br>Ada Hamosh - updated : 5/25/2005<br>Victor A. McKusick - updated : 9/9/2004<br>Ada Hamosh - updated : 6/17/2003<br>Victor A. McKusick - updated : 3/18/2003<br>Patricia A. Hartz - updated : 1/21/2003<br>Stylianos E. Antonarakis - updated : 1/16/2003<br>Ada Hamosh - updated : 8/7/2002<br>Ada Hamosh - updated : 1/4/2002<br>Ada Hamosh - updated : 6/20/2001<br>Paul J. Converse - updated : 8/30/2000<br>Victor A. McKusick - updated : 4/28/1998
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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="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 4/19/1996
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</span>
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</div>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </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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carol : 01/15/2025
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/21/2020<br>carol : 07/29/2019<br>alopez : 11/20/2018<br>alopez : 08/14/2018<br>alopez : 02/01/2016<br>carol : 1/4/2016<br>mcolton : 5/22/2015<br>carol : 12/11/2014<br>carol : 10/20/2014<br>ckniffin : 10/20/2014<br>carol : 10/1/2014<br>mgross : 9/30/2014<br>mgross : 4/17/2014<br>mcolton : 4/8/2014<br>carol : 4/11/2013<br>terry : 4/12/2012<br>carol : 4/11/2012<br>alopez : 6/20/2011<br>alopez : 10/5/2010<br>terry : 9/29/2010<br>alopez : 1/14/2010<br>terry : 1/12/2010<br>alopez : 9/17/2009<br>alopez : 9/17/2009<br>terry : 9/16/2009<br>mgross : 10/4/2007<br>terry : 7/9/2007<br>alopez : 6/26/2007<br>terry : 6/20/2007<br>alopez : 6/19/2007<br>terry : 6/18/2007<br>wwang : 6/4/2007<br>terry : 5/21/2007<br>alopez : 9/27/2005<br>terry : 9/9/2005<br>wwang : 6/17/2005<br>wwang : 6/9/2005<br>terry : 6/7/2005<br>wwang : 5/27/2005<br>wwang : 5/25/2005<br>terry : 5/25/2005<br>tkritzer : 9/20/2004<br>terry : 9/9/2004<br>alopez : 6/19/2003<br>terry : 6/17/2003<br>alopez : 4/2/2003<br>alopez : 3/18/2003<br>terry : 3/18/2003<br>ckniffin : 3/11/2003<br>mgross : 1/21/2003<br>terry : 1/21/2003<br>mgross : 1/16/2003<br>alopez : 8/8/2002<br>terry : 8/7/2002<br>alopez : 1/10/2002<br>terry : 1/4/2002<br>terry : 12/7/2001<br>alopez : 6/21/2001<br>alopez : 6/21/2001<br>terry : 6/20/2001<br>mgross : 8/30/2000<br>alopez : 4/29/1998<br>terry : 4/28/1998<br>terry : 5/24/1996<br>mark : 4/29/1996<br>mark : 4/19/1996
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</span>
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</div>
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</div>
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</div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 601215
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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ATR SERINE/THREONINE KINASE; ATR
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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ATR GENE<br />
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ATAXIA-TELANGIECTASIA AND RAD3-RELATED<br />
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FRAP-RELATED PROTEIN 1; FRP1
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</span>
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</h4>
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</div>
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<div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ATR</em></strong>
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</span>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 3q23
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:142,449,235-142,578,733 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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3q23
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<td>
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<span class="mim-font">
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?Cutaneous telangiectasia and cancer syndrome, familial
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</span>
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</td>
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<td>
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<span class="mim-font">
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614564
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Seckel syndrome 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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210600
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tbody>
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</table>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
|
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>ATR, an essential regulator of genomic integrity, controls and coordinates DNA-replication origin firing, replication-fork stability, cell cycle checkpoints, and DNA repair (summary by Tanaka et al., 2012). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Members of the phosphatidylinositol kinase-related kinase (PIKK) family are high molecular mass kinases involved in cell cycle progression, DNA recombination, and the detection of DNA damage (Cimprich et al., 1996). The human ATM gene (607585), which is defective in cells of patients with ataxia-telangiectasia (208900) and is involved in detection and response of cells to damaged DNA (Enoch and Norbury, 1995), is a member of this family. Another is FRAP (601231), which is involved in a rapamycin-sensitive pathway leading to G1 cell cycle progression. Cimprich et al. (1996) cloned a human cDNA encoding a protein with significant homology to members of the PIK-related kinase family. Three overlapping clones isolated from a Jurkat T-cell cDNA library revealed a 7.9-kb open reading frame encoding a protein that they named FRP1 for FRAP-related protein 1. The deduced protein contained 2,644 amino acids and a predicted molecular mass of 301 kD. FRP1 is most closely related to 3 of the family members involved in checkpoint function--Mei-41 (Drosophila), Mec1 (S. cerevisiae), and Rad3 (Schizosaccharomyces)--and as such may be the functional human counterpart of these proteins. </p><p>By RT-PCR of cell lines originating from several human tissues, Mannino et al. (2001) found evidence for 2 ATR transcripts due to alternative splicing within the noncatalytic domain. RT-PCR of a human tissue panel indicated a single transcript in adult heart, testis, and ovary, and 2 or more transcripts in pancreas, placenta, and liver. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Mapping</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Using fluorescence in situ hybridization and a full-length cDNA FRP1 clone, Cimprich et al. (1996) mapped the FRP1 gene to 3q22-q24. </p><p>Gross (2014) mapped the ATR gene to chromosome 3q23 based on an alignment of the ATR sequence (GenBank AB208847) with the genomic sequence (GRCh38).</p>
|
|
</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Smith et al. (1998) referred to this gene as ATR, for 'ataxia telangiectasia' and 'rad3-related.' In a genetic screen for loci present in rhabdomyosarcomas, they identified an isochromosome 3q, i(3q), that inhibited muscle differentiation when transferred into myoblasts. Specifically, the i(3q) inhibited the function of myogenic differentiation antigen-1 (MYOD1; 159970), resulting in a nondifferentiating phenotype. Furthermore, the i(3q) induced a 'cut' ('cell untimely torn') phenotype in which cytokinesis occurred before nuclear division. These results indicated that introduction of the i(3q) into the test cells caused abnormal cell division resulting in aneuploidy. There was also loss of G1 arrest following gamma-irradiation. Smith et al. (1998) showed that forced expression of the ATR gene resulted in a phenocopy of the i(3q). Thus, genetic alteration of ATR leads to loss of differentiation as well as cell cycle abnormalities. </p><p>Bao et al. (2001) demonstrated a direct regulatory linkage between RAD17 (603139) and the checkpoint kinases ATM and ATR. Treatment of human cells with genotoxic agents induced ATM/ATR-phosphorylation of RAD17 at serine-635 and serine-645. Overexpression of a RAD17 mutant bearing alanine substitutions at both phosphorylation sites abrogated the DNA damage-induced G2 checkpoint and sensitized human fibroblasts to genotoxic stress. In contrast to wildtype RAD17, the RAD17 mutant showed no ionizing radiation-inducible association with RAD1 (603153), a component of the RAD1-RAD9 (603761)-HUS1 (603760) checkpoint complex. These findings demonstrated that ATR/ATM-dependent phosphorylation of RAD17 is a critical early event during checkpoint signaling in DNA-damaged cells. </p><p>Cortez et al. (2001) identified an ATR-interacting protein that is phosphorylated by ATR, regulates ATR expression, and is an essential component of the DNA damage checkpoint pathway. ATR and ATRIP (606605) both localize to intranuclear foci after DNA damage or inhibition of replication. Deletion of ATR mediated by the Cre recombinase caused the loss of ATR and ATRIP expression, loss of DNA damage checkpoint responses, and cell death. Therefore, Cortez et al. (2001) concluded that ATR is essential for the viability of human somatic cells. Small interfering RNA directed against ATRIP caused the loss of both ATRIP and ATR expression and the loss of checkpoint responses to DNA damage. Thus, ATRIP and ATR are mutually dependent partners in cell cycle checkpoint signaling pathways. </p><p>S. cerevisiae Mec1, homolog of mammalian ATR, is an essential protein that mediates S-phase checkpoint responses and meiotic recombination. Cha and Kleckner (2002) found that elimination of Mec1 function leads to genomewide fork stalling followed by chromosome breakage. Breaks do not result from stochastic collapse of stalled forks or other incidental lesions; instead, they occur in specific regions of the genome during a G2 chromosomal transition. Cha and Kleckner (2002) found break regions to be genetically encoded replication slow zones, a yeast chromosomal determinant. Thus, Cha and Kleckner (2002) concluded that Mec1 has important functions in normal S phase, and the genome instability of Mec1 (and, analogously, ATR -/-) mutants stems from defects in these basic roles. </p><p>Casper et al. (2002) demonstrated that ATR, but not ATM (607585), is critical for maintenance of fragile site stability. ATR deficiency resulted in fragile site expression with and without addition of replication inhibitors. The authors proposed that fragile sites are unreplicated chromosomal regions resulting from stalled forks that escape the ATR replication checkpoint. They stated that these findings have important implications for understanding both the mechanism of fragile site instability and the consequences of stalled replication in mammalian cells. </p><p>Common fragile sites are specific loci that preferentially exhibit gaps and breaks on metaphase chromosomes under conditions that partially inhibit DNA replication (Glover et al., 1984). Although they are normally stable in cultured human cells, under replicative stress, fragile sites are hotspots for sister chromatid exchanges (SCEs), translocations, and deletions (Glover and Stein (1987, 1988)), as well as integration of foreign DNA, and they may trigger some gene amplification events via a breakage-fusion-bridge cycle. Numerous studies have shown that fragile sites are unstable in tumors (review by Huebner and Croce, 2001). Casper et al. (2004) pursued further the relationship between ATR and instability at common chromosomal fragile sites by testing whether cells from patients with Seckel syndrome (SCKL1; 210600) caused by the 2101A-G transition in the ATR gene (601215.0001) showed increased chromosome breakage following replication stress. Compared with controls, there was greater chromosomal instability, particularly at fragile sites, in cells from patients with Seckel syndrome after treatment with aphidicolin, an inhibitor of DNA polymerase alpha (312040) and other polymerases. The difference in chromosomal instability between control and patient cells increased at higher levels of aphidicolin treatment, suggesting that the low level of ATR present in these patients was not sufficient to respond appropriately to replication stress. Casper et al. (2004) pointed out that this was the first human genetic syndrome associated with increased chromosome instability at fragile sites following replication stress, and suggested that these findings may be related to the phenotypic findings of patients with Seckel syndrome. </p><p>The function of the ATR-ATRIP protein kinase complex is crucial for the cellular response to replication stress and DNA damage. Zou and Elledge (2003) demonstrated that the replication protein A (RPA) complex (see 179835), which associates with single-stranded DNA, is required for recruitment of ATR to sites of DNA damage and for ATR-mediated CHK1 (603078) activation in human cells. In vitro, RPA stimulates the binding of ATRIP to single-stranded DNA. The binding of ATRIP to RPA-coated single-stranded DNA enables the ATR-ATRIP complex to associate with DNA and stimulates phosphorylation of the RAD17 protein that is bound to DNA. Furthermore, Ddc2, the budding yeast homolog of ATRIP, is specifically recruited to double-stranded DNA breaks in an RPA-dependent manner. A checkpoint-deficient mutant of RPA, rfa1-t11, is defective for recruiting Ddc2 to single-stranded DNA both in vivo and in vitro. Zou and Elledge (2003) concluded that RPA-coated single-stranded DNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling. </p><p>Giuliano et al. (2003) developed stable cell lines expressing GFP fusion proteins containing polyglutamine repeats of various lengths. The expression of the expanded (43Q) repeat protein resulted in aggregate formation in a time-dependent fashion, but did not induce apoptosis. However, the expression of 43Q expanded protein strongly activated the ATM/ATR-dependent DNA damage response, as shown by selective phosphorylation of ATM substrates. Similarly, Giuliano et al. (2003) found phosphorylated ATM substrates in fibroblasts from Huntington disease (143100) and SCA2 (183090) patients. Oxidative stress increased accumulation of these phosphorylated ATM substrates. The authors concluded that polyglutamine induces ATM/ATR-dependent DNA damage response through accumulation of reactive oxygen species. </p><p>Falck et al. (2005) identified related, conserved C-terminal motifs in human NBS1 (602667), ATRIP, and Ku80 (194364) proteins that are required for their interaction with ATM, ATR, and DNA-PKcs (600899), respectively. These EEXXXDDL motifs are essential not only for efficient recruitment of ATM, ATR, and DNA-PKcs to sites of damage, but are also critical for ATM-, ATR-, and DNA-PKcs-mediated signaling events that trigger cell cycle checkpoints and DNA repair. Falck et al. (2005) concluded that recruitment of these PIKKs to DNA lesions occurs by common mechanisms through an evolutionarily conserved motif, and provide direct evidence that PIKK recruitment is required for PIKK-dependent DNA-damage signaling. </p><p>Using yeast mutants, Saiardi et al. (2005) showed that inositol pyrophosphates physiologically antagonized the actions of Tel1 and Mec1, the yeast homologs of ATM (607585) and ATR, respectively. Mutants with reduced or elevated levels of inositol pyrophosphates displayed longer and shorter telomeres, respectively. </p><p>Matsuoka et al. (2007) performed a large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR and identified more than 900 regulated phosphorylation sites encompassing over 700 proteins. Functional analysis of a subset of this dataset indicated that this list was highly enriched for proteins involved in the DNA damage response. This set of proteins was highly interconnected, and Matsuoka et al. (2007) identified a large number of protein modules and networks not previously linked to the DNA damage response. Matsuoka et al. (2007) concluded that their database painted a much broader landscape for the DNA damage response than had been appreciated and opened new avenues of investigation into the responses to DNA damage in mammals. </p><p>Liu et al. (2010) assigned MLL (159555) as a novel effector in the mammalian S-phase checkpoint network and identified checkpoint dysfunction as an underlying mechanism of MLL leukemias. MLL is phosphorylated at ser516 by ATR in response to genotoxic stress in the S phase, which disrupts its interaction with, and hence its degradation by, the SCF(Skp2) (601436) E3 ligase, leading to its accumulation. Stabilized MLL protein accumulates on chromatin, methylates histone H3 lysine-4 (H3K4) at late replication origins, and inhibits the loading of CDC45 (603465) to delay DNA replication. </p><p>Robert et al. (2011) showed that histone deacetylase (HDAC) inhibition/ablation specifically counteracts yeast Mec1 (ortholog of human ATR) activation, double-strand break processing, and single-strand DNA-RFA nucleofilament formation. Moreover, the recombination protein Sae2 (human CTIP; 604124) is acetylated and degraded after HDAC inhibition. Two HDACs, Hda1 (see HDAC4, 605314) and Rpd3 (HDAC1; 601241) and 1 histone acetyltransferase (HAT), Gcn5 (GCN5L2; 602301), have key roles in these processes. Robert et al. (2011) also found that HDAC inhibition triggers Sae2 degradation by promoting autophagy that affects the DNA damage sensitivity of Hda1 and Rpd3 mutants. Rapamycin, which stimulates autophagy by inhibiting Tor (MTOR; 601231), also causes Sae2 degradation. Robert et al. (2011) proposed that Rpd3, Hda1, and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand break processing with autophagy. </p><p>Flynn et al. (2015) showed that loss of ATRX (300032) compromises cell-cycle regulation of the telomeric noncoding RNA TERRA and leads to persistent association of replication protein A (RPA; see 179835) with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of the protein kinase ATR, a critical regulator of recombination recruited by RPA, disrupts alternative lengthening of telomeres (ALT) and triggers chromosome fragmentation and apoptosis in ALT cells. The cell death induced by ATR inhibitors is highly selective for cancer cells that rely on ALT, suggesting that such inhibitors may be useful for treatment of ALT-positive cancers. </p><p>Kabeche et al. (2018) described an unexpected role of ATR in mitosis. Acute inhibition or degradation of ATR in mitosis induces whole-chromosome missegregation. The effect of ATR ablation is not due to altered cyclin-dependent kinase-1 (CDK1; 116940) activity, DNA damage responses, or unscheduled DNA synthesis, but to loss of an ATR function at centromeres. In mitosis, ATR localizes to centromeres through Aurora A (603072)-regulated association with centromere protein F (CENPF; 600236), allowing ATR to engage RPA-coated centromeric R loops. As ATR is activated at centromeres, it stimulates Aurora B (604970) through Chk1, preventing formation of lagging chromosomes. Thus, a mitosis-specific and R loop-driven ATR pathway acts at centromeres to promote faithful chromosome segregation, revealing functions of R loops and ATR in suppressing chromosome instability. </p><p>Saldivar et al. (2018) demonstrated that cells transactivate the mitotic gene network as they exit the S phase through a CDK1 (116940)-directed FOXM1 (602341) phosphorylation switch. During normal DNA replication, the checkpoint kinase ATR is activated by ETAA1 (613196) to block this switch until the S phase ends. ATR inhibition prematurely activates FOXM1, deregulating the S/G2 transition and leading to early mitosis, underreplicated DNA, and DNA damage. Thus, ATR couples DNA replication with mitosis and preserves genome integrity by enforcing an S/G2 checkpoint. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Seckel Syndrome 1</em></strong></p><p>
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Seckel syndrome (see 210600) is an autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly, and mental retardation. Clinically, Seckel syndrome shares features in common with disorders involving impaired DNA-damage responses, such as Nijmegen breakage syndrome (251260) and LIG4 syndrome (606593). O'Driscoll et al. (2003) investigated the ATR gene, which maps to the Seckel syndrome-1 critical region, and found a synonymous (translationally silent) mutation (601215.0001) in affected individuals that alters ATR splicing. </p><p>Alderton et al. (2004) reported that ATR-Seckel cells displayed impaired phosphorylation of ATR-dependent substrates, impaired G2/M checkpoint arrest, and elevated micronucleus (MN) formation following exposure to UV and agents that cause replication stalling. Nuclear fragmentation (NF) occurred following replication arrest. ATR-Seckel cells also had an endogenously increased number of centrosomes in mitotic cells, suggesting a role for ATR in regulating centrosome stability. Among 7 unrelated Seckel syndrome cell lines, impaired phosphorylation of ATR-dependent substrates was a common but not invariant feature. In contrast, all cell lines displayed defective G2/M arrest, increased levels of NF and MN formation following exposure to agents that cause replication stalling, and increased endogenous centrosome numbers. </p><p>In 2 unrelated English patients with Seckel syndrome-1, Ogi et al. (2012) identified the same compound heterozygous mutations in the ATR gene (601215.0004 and 601215.0005). </p><p><strong><em>Familial Cutaneous Telangiectasia and Cancer Syndrome</em></strong></p><p>
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In a large 4-generation family with a syndrome involving early-onset cutaneous telangiectases, mild developmental anomalies of hair, teeth, and nails, and a predisposition to cancer mapping to chromosome 3q22-q24 (FCTCS; 614564), Tanaka et al. (2012) analyzed 42 candidate genes and identified a heterozygous missense mutation in the ATR gene (Q2144R; 601215.0002) that segregated with the disorder and was not found in 220 ethnically matched control chromosomes. Analysis of DNA from an affected family member's oropharyngeal cancer lesion showed loss of heterozygosity for the wildtype ATR allele, implicating ATR in the pathophysiology of oropharyngeal cancer and indicating a tumor-suppressing role for ATR. </p><p><strong><em>Impaired ATR Signaling in Other Disorders</em></strong></p><p>
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In addition to ATR-Seckel syndrome, impaired ATR signaling is also observed in cell lines from other disorders characterized by microcephaly and growth delay, including non-ATR Seckel syndrome (606744), Nijmegen breakage syndrome, and primary autosomal recessive microcephaly (MCPH1; 251200). O'Driscoll et al. (2007) examined ATR pathway function in cell lines from 3 haploinsufficient contiguous gene deletion disorders: a subset of blepharophimosis-ptosis-epicanthus inversus syndrome (BPES; 110100), Miller-Dieker lissencephaly syndrome (247200), and Williams-Beuren syndrome (194050). In these 3 syndromes the deleted region encompasses ATR, RPA1 (179835), and RFC2 (600404), respectively. These 3 genes function in ATR signaling. Cell lines from these disorders displayed an impaired ATR-dependent DNA damage response. Thus, O'Driscoll et al. (2007) described ATR signaling as a pathway unusually sensitive to haploinsufficiency and identified 3 further human disorders displaying a defective ATR-dependent DNA damage response. The striking correlation of ATR pathway dysfunction with the presence of microcephaly and growth delay strongly suggested a causal relationship. </p><p>In a 9.5-year-old French girl with Seckel syndrome, Mokrani-Benhelli et al. (2013) identified compound heterozygosity for a missense mutation in the ATR gene (D1879Y; 601215.0003) and a 540-kb deletion on chromosome 3 encompassing ATR as well as 3 other genes, XRN1 (607994), PLS1 (602734), and TRPC1 (602343). DNA combing technology revealed a profound spontaneous alteration of several DNA replication parameters in patient cells, and FISH analysis demonstrated the genomic instability caused by ATR deficiency. Mokrani-Benhelli et al. (2013) stated that these results emphasized the crucial role for ATR in the control of DNA replication, and reinforced the complementary and nonredundant contributions of ATM and ATR. </p>
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<strong>Animal Model</strong>
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<p>Brown and Baltimore (2000) noted that ATM and ATR belong to a conserved family of high molecular weight kinases. They generated mice with a targeted disruption of the Atr gene by deleting 3 exons encoding the initiating met and the following 90 amino acids. Atr +/- mice survived nearly as long as ATR +/+ mice but had an increase in tumor incidence. In contrast, and unlike Atm -/- or p53 (191170) -/- mice, Atr -/- embryos survived to the blastocyst stage at day 3.5 postcoitum but not to day 7.5. In culture, wildtype and heterozygous blastocysts were initially indistinguishable from the Atr -/- cells, but the Atr -/- cells then died, suffering from chromosomal fragmentation. TUNEL analysis revealed widespread apoptosis after 3 days of culture, and the apoptosis could be blocked by inhibition of Casp3 (600636). The authors speculated that ATR may be particularly essential in the early embryo to sense incomplete DNA replication and prevent mitotic catastrophe. </p><p>Ruzankina et al. (2007) found that deletion of Atr in adult mice led to defects in tissue homeostasis and rapid appearance of age-related phenotypes. Histologic and genetic analysis indicated that Atr deletion caused acute cellular loss in tissues that require continuous cell proliferation for maintenance. Thymic involution, alopecia, and hair graying in Atr-knockout mice were associated with dramatic reductions in tissue-specific stem and progenitor cells and exhaustion of tissue renewal and homeostatic capacity. </p><p>Ruzankina et al. (2009) reported that p53 deficiency severely exacerbates tissue degeneration caused by mosaic deletion of the essential genome maintenance regulator Atr. Combined loss of Atr and p53 led to severe defects in hair follicle regeneration, localized inflammation (Mac1+Gr1+ infiltrates), accelerated deterioration of the intestinal epithelium, and synthetic lethality in adult mice. Tissue degeneration in double-null mice was characterized by the accumulation of cells maintaining high levels of DNA damage. Moreover, the elevated frequency of these damaged cells in both progenitor and downstream compartments in double-null mouse skin coincided with delayed compensatory tissue renewal from residual ATR-expressing cells. Ruzankina et al. (2009) concluded that, taken together, their results indicated that the combined loss of Atr and Trp53 in adult mice leads to the accumulation of highly damaged cells, which, consequently, impose a barrier to regeneration from undamaged progenitors. </p><p>Murga et al. (2009) developed a mouse model of Seckel syndrome by replacing exons 8, 9, and 10 of the mouse Atr gene with those from human, and then introducing the A-to-G transition into exon 9 of the humanized gene (601215.0001). ATR Seckel homozygous mice were born at submendelian ratios and showed severe dwarfism that was already noticeable at birth. Mutant placentas showed an accumulation of necrotic areas and overall loss of cellularity. In addition to the overall dwarfism, Seckel mice showed microcephaly and facial dysmorphisms including micrognathia and receding foreheads. Seckel mice also had small brains, cysts, and agenesis of the corpus callosum. Seckel mice showed high levels of replicative stress during embryogenesis, when proliferation is widespread, but this was reduced to marginal amounts in postnatal life. In spite of this decrease, adult Seckel mice showed accelerated aging, which was further aggravated in the absence of p53. Murga et al. (2009) concluded that their results supported a model whereby replicative stress, particularly in utero, contributes to the onset of aging in postnatal life, and this is balanced by the replicative stress-limiting role of the checkpoint proteins ATR and p53. </p><p>Using the mouse model of Seckel syndrome developed by Murga et al. (2009), Valdes-Sanchez et al. (2013) found that heterozygous expression of humanized mutant ATR (ATR +/S) resulted in abnormal electroretinogram with photoreceptor and optic nerve degeneration. ATR +/S mice showed normal embryonic and retinal development, but lost rods by postnatal day 20 (P20) and cones by P25. In wildtype mice, Atr localized to the nonmotile connecting cilium between the outer photoreceptor segment and inner nuclear segment. Compared with wildtype, ATR +/S cilia were about 40% shorter. ATR deficiency was also associated with diminished levels of microtubule-interacting Map2c (157130) in photoreceptor inner segment. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>5 Selected Examples):</strong>
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</h4>
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<span class="mim-font">
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<strong>.0001 SECKEL SYNDROME 1</strong>
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ATR, 2101A-G
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SNP: rs587776690,
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ClinVar: RCV000008805, RCV002415405
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<p>In 2 Pakistani families, O'Driscoll et al. (2003) found that a homozygous translationally silent (synonymous) single base change, 2101A-G, segregated with Seckel syndrome (SCKL1; 210600). The mutation resulted in the use of 2 cryptic splice-donor sites in exon 9. Loss of exon 9 and use of the cryptic splice-donor sites introduced a stop codon in the next exon. Because of the profound effect on splicing efficiency, there were reduced but residual levels of normal transcript and protein. The severity of this hypomorphic mutation was shown by the marked microcephaly and dwarfism observed in the affected individuals and was consistent with the embryonic and somatic lethality seen in the absence of ATR (Brown and Baltimore, 2000; Cortez et al., 2001). This was the first evidence of a clinical disorder associated with impaired ATR signaling. </p>
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<span class="mim-font">
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<strong>.0002 CUTANEOUS TELANGIECTASIA AND CANCER SYNDROME, FAMILIAL (1 family)</strong>
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ATR, GLN2144ARG
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SNP: rs387906797,
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ClinVar: RCV000023082, RCV003556071
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<p>In affected members of a large 4-generation family with a syndrome involving early-onset cutaneous telangiectases, mild developmental anomalies of hair, teeth, and nails, and a predisposition to cancer (FCTCS; 614564), predominantly oropharyngeal, Tanaka et al. (2012) identified heterozygosity for a 6431A-G transition in the ATR gene, resulting in a gln2144-to-arg (Q2144R) substitution at a highly conserved residue within the FAT domain, immediately adjacent to a potential phosphorylation site (SQ/TQ motif) at ser2143. The mutation was not found in unaffected family members or in 220 ethnically matched control chromosomes. Immunoblotting of mutant fibroblast samples showed no reduction in ATR mRNA compared to controls; however, expression of p53 (TP53; 191170) was found to be both constitutively reduced and reduced after ATR activation with hydroxyurea. Sequencing of DNA from an affected individual's oropharyngeal cancer lesion revealed loss of heterozygosity with allelic loss of the wildtype allele. </p>
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<span class="mim-font">
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<strong>.0003 SECKEL SYNDROME 1</strong>
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ATR, ASP1879TYR
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SNP: rs387907327,
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gnomAD: rs387907327,
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ClinVar: RCV000034827
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<p>In a 9.5-year-old French girl with Seckel syndrome (SCKL1; 210600), Mokrani-Benhelli et al. (2013) identified compound heterozygosity for a 5635G-T transversion in exon 33 of the ATR gene, resulting in an asp1879-to-tyr (D1879Y) substitution, and a 540-kb deletion on chromosome 3 encompassing ATR as well as 3 other genes. The missense mutation was inherited from her mother and the deletion from her father. Immunoblot of patient B-lymphoblastoid cell line (B-LCL) cells revealed a marked decrease in ATR expression compared to her parents and controls; her father also had a consistently reduced ATR level as well, likely reflecting his ATR hemizygous status. The missense mutation was predicted to disrupt an exon-splicing enhancer (ESE) site located in exon 33, and RT-PCR confirmed the occurrence of aberrant splicing events when the 5635G-T mutation was present. The patient's primary fibroblasts exhibited an increased sensitivity to UV irradiation, and ATR-dependent phosphorylation of H2AX (601772) in response to hydroxyurea and UV treatment was virtually absent in patient cells, whereas the ATM (607585)-dependent phosphorylation of H2AX following ionizing radiation was intact. In addition, analysis of DNA replication parameters during unperturbed cell cycles in patient B-LCL cells and fibroblasts revealed that fork speed and interorigin distance were significantly reduced and asymmetric replicons were increased in both cell types compared to controls. FISH analysis revealed spontaneously accumulated DNA damage in patient fibroblasts, in part at telomeres, that resulted in an ATM-dependent DNA-damage response. The patient's cells also spontaneously exhibited high levels of genomic instability that were partly counteracted by ATM. </p>
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<span class="mim-font">
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<strong>.0004 SECKEL SYNDROME 1</strong>
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</span>
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</h4>
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ATR, MET1159ILE
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<br />
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SNP: rs587777851,
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ClinVar: RCV000144692, RCV002512562
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated English patients with Seckel syndrome (SCKL1; 210600), Ogi et al. (2012) identified the same compound heterozygous mutations in the ATR gene: a c.3477G-T transversion, resulting in a met1159-to-ile (M1159I) substitution at a highly conserved residue in the UME domain, and a C-to-G transversion in intron 40 (c.6897+464C-G; 601215.0005), resulting in a splicing defect and premature termination (Val2300GlyfsTer75). Western blot analysis of patient cells showed decreased levels of ATR and ATRIP (606605). Studies of patient cells and in vitro functional expression studies showed impaired ATR-dependent G2/M cell cycle arrest after UV radiation, consistent with a loss of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 SECKEL SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ATR, IVS40, C-G, +464
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<br />
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SNP: rs587777852,
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gnomAD: rs587777852,
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ClinVar: RCV000144693, RCV002514777, RCV004751286
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the splice site mutation in the ATR gene (c.6897+464C-G) that was found in compound heterozygous state in patients with Seckel syndrome (SCKL1; 210600) by Ogi et al. (2012), see 601215.0004. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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Alderton, G. K., Joenje, H., Varon, R., Borglum, A. D., Jeggo, P. A., O'Driscoll, M.
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<strong>Seckel syndrome exhibits cellular features demonstrating defects in the ATR-signalling pathway.</strong>
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<p class="mim-text-font">
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Bao, S., Tibbetts, R. S., Brumbaugh, K. M., Fang, Y., Richardson, D. A., Ali, A., Chen, S. M., Abraham, R. T., Wang, X.-F.
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<strong>ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses.</strong>
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Nature 411: 969-974, 2001.
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Brown, E. J., Baltimore, D.
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<strong>ATR disruption leads to chromosomal fragmentation and early embryonic lethality.</strong>
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Casper, A. M., Nghiem, P., Arlt, M. F., Glover, T. W.
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<strong>ATR regulates fragile site stability.</strong>
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Cell 111: 779-789, 2002.
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<strong>cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein.</strong>
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[PubMed: 8610130]
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[Full Text: https://doi.org/10.1073/pnas.93.7.2850]
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Cortez, D., Guntuku, S., Qin, J., Elledge, S. J.
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<strong>ATR and ATRIP: partners in checkpoint signaling.</strong>
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Science 294: 1713-1716, 2001.
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[PubMed: 11721054]
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[Full Text: https://doi.org/10.1126/science.1065521]
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Enoch, T., Norbury, C.
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<strong>Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM.</strong>
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[PubMed: 8533157]
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<p class="mim-text-font">
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Falck, J., Coates, J., Jackson, S. P.
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<strong>Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage.</strong>
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Nature 434: 605-611, 2005.
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[PubMed: 15758953]
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Flynn, R. L., Cox, K. E., Jeitany, M., Wakimoto, H., Bryll, A. R., Ganem, N. J., Bersani, F., Pineda, J. R., Suva, M. L., Benes, C. H., Haber, D. A., Boussin, F. D., Zou, L.
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<strong>Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.</strong>
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Science 347: 273-277, 2015.
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[PubMed: 25593184]
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Giuliano, P., de Cristofaro, T., Affaitati, A., Pizzulo, G. M., Feliciello, A., Criscuolo, C., De Michele, G., Filla, A., Avvedimento, E. V., Varrone, S.
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<strong>DNA damage induced by polyglutamine-expanded proteins.</strong>
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Glover, T. W., Berger, C., Coyle, J., Echo, B.
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<strong>DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes.</strong>
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Hum. Genet. 67: 136-142, 1984.
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Glover, T. W., Stein, C. K.
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<strong>Induction of sister chromatid exchanges at common fragile sites.</strong>
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[PubMed: 3674017]
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Kabeche, L., Nguyen, H. D., Buisson, R., Zou, L.
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Science 359: 108-114, 2018.
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Ogi, T., Walker, S., Stiff, T., Hobson, E., Limsirichaikul, S., Carpenter, G., Prescott, K., Suri, M., Byrd, P. J., Matsuse, M., Mitsutake, N., Nakazawa, Y., Vasudevan, P., Barrow, M., Stewart, G. S., Taylor, A. M. R., O'Driscoll, M., Jeggo, P. A.
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<strong>Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel syndrome.</strong>
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<p class="mim-text-font">
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Robert, T., Vanoli, F., Chiolo, I., Shubassi, G., Bernstein, K. A., Rothstein, R., Botrugno, O. A., Parazzoli, D., Oldani, A., Minucci, S., Foiani, M.
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<strong>HDACs link the DNA damage response, processing of double-strand breaks and autophagy.</strong>
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[PubMed: 21368826]
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Ruzankina, Y., Pinzon-Guzman, C., Asare, A., Ong, T., Pontano, L., Cotsarelis, G., Zediak, V. P., Velez, M., Bhandoola, A., Brown, E. J.
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<strong>Deletion of developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss.</strong>
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|
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[PubMed: 18371340]
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Ruzankina, Y., Schoppy, D. W., Asare, A., Clark, C. E., Vonderheide, R. H., Brown, E. J.
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<strong>Tissue regenerative delays and synthetic lethality in adult mice after combined deletion of Atr and Trp53.</strong>
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[PubMed: 19718024]
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<p class="mim-text-font">
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Saiardi, A., Resnick, A. C., Snowman, A. M., Wendland, B., Snyder, S. H.
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<strong>Inositol pyrophosphates regulate cell death and telomere length through phosphoinositide 3-kinase-related protein kinases.</strong>
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[PubMed: 15665079]
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Saldivar, J. C., Hamperl, S., Bocek, M. J., Chung, M., Bass, T. E., Cisneros-Soberanis, F., Samejima, K., Xie, L., Paulson, J. R., Earnshaw, W. C., Cortez, D., Meyer, T., Cimprich, K. A.
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Smith, L., Liu, S. J., Goodrich, L., Jacobson, D., Degnin, C., Bentley, N., Carr, A., Flaggs, G., Keegan, K., Hoekstra, M., Thayer, M. J.
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<strong>Duplication of ATR inhibits MyoD, induces aneuploidy and eliminates radiation-induced G1 arrest.</strong>
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Tanaka, A., Weinel, S., Nagy, N., O'Driscoll, M., Lai-Cheong, J. E., Kulp-Shorten, C. L., Knable, A., Carpenter, G., Fisher, S. A., Hiragun, M., Yanase, Y., Hide, M., Callen, J., McGrath, J. A.
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Valdes-Sanchez, L., De la Cerda, B., Diaz-Corrales, F. J., Massalini, S., Chakarova, C. F., Wright, A. F., Bhattacharya, S. S.
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<strong>Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.</strong>
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Ada Hamosh - updated : 11/20/2018<br>Ada Hamosh - updated : 08/14/2018<br>Ada Hamosh - updated : 02/01/2016<br>Cassandra L. Kniffin - updated : 10/20/2014<br>Matthew B. Gross - updated : 9/30/2014<br>Patricia A. Hartz - updated : 4/8/2014<br>Marla J. F. O'Neill - updated : 4/11/2013<br>Marla J. F. O'Neill - updated : 4/11/2012<br>Ada Hamosh - updated : 6/20/2011<br>Ada Hamosh - updated : 9/29/2010<br>Ada Hamosh - updated : 1/12/2010<br>Ada Hamosh - updated : 9/16/2009<br>Patricia A. Hartz - updated : 7/9/2007<br>Ada Hamosh - updated : 6/20/2007<br>Victor A. McKusick - updated : 6/18/2007<br>George E. Tiller - updated : 5/21/2007<br>George E. Tiller - updated : 9/9/2005<br>Patricia A. Hartz - updated : 6/7/2005<br>Ada Hamosh - updated : 5/25/2005<br>Victor A. McKusick - updated : 9/9/2004<br>Ada Hamosh - updated : 6/17/2003<br>Victor A. McKusick - updated : 3/18/2003<br>Patricia A. Hartz - updated : 1/21/2003<br>Stylianos E. Antonarakis - updated : 1/16/2003<br>Ada Hamosh - updated : 8/7/2002<br>Ada Hamosh - updated : 1/4/2002<br>Ada Hamosh - updated : 6/20/2001<br>Paul J. Converse - updated : 8/30/2000<br>Victor A. McKusick - updated : 4/28/1998
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