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Entry
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- *606462 - RAD21 COHESIN COMPLEX COMPONENT; RAD21
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- OMIM
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<p>
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<span class="h4">*606462</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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 role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606462">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<h4 class="panel-title">
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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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<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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</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=ENSG00000164754;t=ENST00000297338" 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=5885" 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=606462" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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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=ENSG00000164754;t=ENST00000297338" 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_006265" 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_006265" 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=606462" 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=05924&isoform_id=05924_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/RAD21" 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/1620398,5453994,25091097,29791830,50234989,119612369,119612370,119612371,158260033,193783639,929653768" 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/O60216" 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=5885" 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=ENSG00000164754;t=ENST00000297338" 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=RAD21" 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=RAD21" 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+5885" 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/RAD21" 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:5885" 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/5885" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr8&hgg_gene=ENST00000297338.7&hgg_start=116845934&hgg_end=116874776&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:9811" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:9811" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/rad21" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=606462[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=606462[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/RAD21/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000164754" 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=RAD21" 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=RAD21" 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=RAD21" 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=RAD21&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/PA34170" 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:9811" 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/FBgn0260987.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:108016" 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/RAD21#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:108016" 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/5885/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=5885" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000591;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000591 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00004737;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00004737 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-994" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5885" 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=RAD21&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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606462
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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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RAD21 COHESIN COMPLEX COMPONENT; RAD21
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
RAD21, S. POMBE, HOMOLOG OF<br />
|
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NUCLEAR MATRIX PROTEIN 1; NXP1<br />
|
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SISTER CHROMATID COHESION 1; SCC1<br />
|
|
HR21<br />
|
|
KIAA0078
|
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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=RAD21" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">RAD21</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>
|
|
<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/8/500?start=-3&limit=10&highlight=500">8q24.11</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr8:116845934-116874776&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">8:116,845,934-116,874,776</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=611376,614701" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/8/500?start=-3&limit=10&highlight=500">
|
|
8q24.11
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Mungan syndrome
|
|
|
|
<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/611376"> 611376 </a>
|
|
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>Eukaryotic sister chromatids remain connected from the time of synthesis until they are separated in anaphase. This cohesion depends on a complex of proteins known as cohesins. In vertebrates, unlike in yeast, the cohesins dissociate from chromosome arms earlier in M phase, during prophase. Small amounts of cohesin remain near the centromere until metaphase, with complete removal at the beginning of anaphase. Cohesin complexes contain SCC1 (RAD21), SMC1 (<a href="/entry/300040">300040</a>), SMC3 (<a href="/entry/606062">606062</a>), and either SA1 (STAG1; <a href="/entry/604358">604358</a>) or SA2 (STAG2; <a href="/entry/300826">300826</a>). The complexes, in turn, interact with PDS5 (see <a href="/entry/613200">613200</a>), a protein implicated in chromosome cohesion, condensation, and recombination in yeast (summary by <a href="#23" class="mim-tip-reference" title="Sumara, I., Vorlaufer, E., Gieffers, C., Peters, B. H., Peters, J.-M. <strong>Characterization of vertebrate cohesin complexes and their regulation in prophase.</strong> J. Cell Biol. 151: 749-761, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11076961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11076961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11076961[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/10.1083/jcb.151.4.749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11076961">Sumara et al., 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11076961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By sequencing cDNAs randomly selected from a cDNA library derived from a human immature myeloid cell line, <a href="#20" class="mim-tip-reference" title="Nomura, N., Nagase, T., Miyajima, N., Sazuka, T., Tanaka, A., Sato, S., Seki, N., Kawarabayasi, Y., Ishikawa, K., Tabata, S. <strong>Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1.</strong> DNA Res. 1: 223-229, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7584044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7584044</a>] [<a href="https://doi.org/10.1093/dnares/1.5.223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7584044">Nomura et al. (1994)</a> identified a cDNA encoding a homolog of S. pombe Rad21 that they termed KIAA0078. The deduced KIAA0078 protein has 631 amino acids. Northern blot analysis detected equivalent expression of KIAA0078 in all tissues tested. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7584044" 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 searching EST databases for sequences similar to yeast Rad21 and subsequently searching with the worm and fly sequences these searches identified, <a href="#17" class="mim-tip-reference" title="McKay, M. J., Troelstra, C., van der Spek, P., Kanaar, R., Smit, B., Hagemeijer, A., Bootsma, D., Hoeijmakers, J. H. J. <strong>Sequence conservation of the rad21 Schizosaccharomyces pombe DNA double-strand break repair gene in human and mouse.</strong> Genomics 36: 305-315, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8812457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8812457</a>] [<a href="https://doi.org/10.1006/geno.1996.0466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8812457">McKay et al. (1996)</a> isolated a cDNA encoding a mouse homolog of Rad21. By probing a testis cDNA library with the mouse sequence, they obtained a cDNA encoding human RAD21, which they termed HR21. Sequence analysis predicted that the 631-amino acid phosphoprotein is 96% and 25% identical to the mouse and yeast proteins, respectively, and that they are most conserved at the N and C termini. These proteins all have 2 nuclear localization signals and an acidic stretch consistent with a chromatin-binding role. Northern blot analysis revealed ubiquitous expression of a 3.1-kb transcript in mouse tissues, with highest expression in testis and thymus. Testis also expressed a 2.2-kb transcript in postmeiotic cells. Northern blot analysis determined that expression increases during S phase and peaks in G2 phase in HeLa cells. There was no increase in expression after ionizing radiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8812457" 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 immunoscreening a placenta cDNA expression library, <a href="#21" class="mim-tip-reference" title="Sadano, H., Sugimoto, H., Sakai, F., Nomura, N., Osumi, T. <strong>NXP-1, a human protein related to Rad21/Scc1/Mcd1, is a component of the nuclear matrix.</strong> Biochem. Biophys. Res. Commun. 267: 418-422, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10623634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10623634</a>] [<a href="https://doi.org/10.1006/bbrc.1999.1969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10623634">Sadano et al. (2000)</a> cloned RAD21, which they designated NXP1. Western blot analysis and immunofluorescence microscopy showed nuclear expression of a 110-kD protein, which was higher than the predicted 70 kD most likely due to phosphorylation. Mutation and immunoprecipitation analyses with truncated proteins indicated that the N terminus of RAD21 is responsible for the nuclear localization and binding to a 28-kD nuclear matrix protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10623634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By immunoblot analysis, <a href="#12" class="mim-tip-reference" title="Hoque, M. T., Ishikawa, F. <strong>Human chromatid cohesin component hRad21 is phosphorylated in M phase and associated with metaphase centromeres.</strong> J. Biol. Chem. 276: 5059-5067, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11073952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11073952</a>] [<a href="https://doi.org/10.1074/jbc.M007809200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11073952">Hoque and Ishikawa (2001)</a> showed that the approximately 120-kD RAD21 protein is expressed in the nucleus at the same level throughout the cell cycle and that it becomes hyperphosphorylated during M phase. Immunofluorescence microscopy demonstrated that RAD21 begins to dissociate from arm region chromatin during prophase and from centromere regions during metaphase and anaphase and is associated with spindles. In telophase and cytokinesis, RAD21 is associated with microtubules and then resumes association with chromatin during cytokinesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11073952" 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="Hauf, S., Waizenegger, I. C., Peters, J.-M. <strong>Cohesin cleavage by separase required for anaphase and cytokinesis in human cells.</strong> Science 293: 1320-1323, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11509732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11509732</a>] [<a href="https://doi.org/10.1126/science.1061376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11509732">Hauf et al. (2001)</a> identified separase (see <a href="/entry/604143">604143</a>) cleavage sites in SCC1/RAD21 after arg172 and after arg450. Immunofluorescence microscopy demonstrated that cleavage-site mutant RAD21 dissociated from chromosomes by prophase, like wildtype, but was associated with multiple mitotic abnormalities. Flow cytometric and video microscopic analyses showed that cells with noncleavable RAD21 tend to express aneuploidy in interphase and that they initiate cytokinesis without segregating chromosomes. Analysis of metaphase cells suggested that these cells reenter interphase with sister chromatids still connected and form diplochromosomes in the subsequent mitosis. <a href="#11" class="mim-tip-reference" title="Hauf, S., Waizenegger, I. C., Peters, J.-M. <strong>Cohesin cleavage by separase required for anaphase and cytokinesis in human cells.</strong> Science 293: 1320-1323, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11509732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11509732</a>] [<a href="https://doi.org/10.1126/science.1061376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11509732">Hauf et al. (2001)</a> proposed that anaphase defects may be caused by RAD21 cleavage defects as well as by securin (PTTG1; <a href="/entry/604147">604147</a>) overexpression or deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11509732" 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="Hakimi, M.-A., Bochar, D. A., Schmiesing, J. A., Dong, Y., Barak, O. G., Speicher, D. W., Yokomori, K., Shiekhattar, R. <strong>A chromatin remodelling complex that loads cohesin onto human chromosomes.</strong> Nature 418: 994-998, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198550</a>] [<a href="https://doi.org/10.1038/nature01024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198550">Hakimi et al. (2002)</a> reported the isolation of a human SNF2 (<a href="/entry/600014">600014</a>)-containing chromatin remodeling complex that encompasses components of the cohesin and NURD (see <a href="/entry/603526">603526</a>) complexes. They showed that the RAD21 subunit of the cohesin complex directly interacts with the ATPase subunit SNF2. Mapping of RAD21, SNF2, and Mi2 (see <a href="/entry/603277">603277</a>) binding sites by chromatin immunoprecipitation experiments revealed the specific association of these 3 proteins with human DNA elements containing alu sequences. <a href="#10" class="mim-tip-reference" title="Hakimi, M.-A., Bochar, D. A., Schmiesing, J. A., Dong, Y., Barak, O. G., Speicher, D. W., Yokomori, K., Shiekhattar, R. <strong>A chromatin remodelling complex that loads cohesin onto human chromosomes.</strong> Nature 418: 994-998, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198550</a>] [<a href="https://doi.org/10.1038/nature01024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198550">Hakimi et al. (2002)</a> found a correlation between modification of histone tails and association of the SNF2/cohesin complex with chromatin. In addition, they showed that the association of the cohesin complex with chromatin can be regulated by the state of DNA methylation. Finally, they presented evidence pointing to a role for the ATPase activity of SNF2 in the loading of RAD21 on chromatin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12198550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Hoque, M. T., Ishikawa, F. <strong>Cohesin defects lead to premature sister chromatid separation, kinetochore dysfunction, and spindle-assembly checkpoint activation.</strong> J. Biol. Chem. 277: 42306-42314, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12200439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12200439</a>] [<a href="https://doi.org/10.1074/jbc.M206836200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12200439">Hoque and Ishikawa (2002)</a> found that expression of N-terminally truncated SCC1 had a dominant-negative effect on SCC1 function in several human cell lines. Cells expressing the N-terminally truncated protein showed impaired cell growth. Within mitotic cells, chromatids condensed normally, but the 2 pairs of sister chromatids were disjoined, separated prematurely, and became positioned randomly within nuclei. Spindle assembly checkpoint was activated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12200439" 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 yeast, the cohesin complex is essential for sister chromatid cohesion during mitosis. The Smc1 (<a href="/entry/300040">300040</a>) and Smc3 (<a href="/entry/606062">606062</a>) subunits are rod-shaped molecules with globular ABC-like ATPases at one end and dimerization domains at the other, connected by long coiled coils. Smc1 and Smc3 associate to form V-shaped heterodimers. Their ATPase heads are thought to be bridged by a third subunit, Scc1, creating a huge triangular ring that can trap sister DNA molecules. <a href="#7" class="mim-tip-reference" title="Gruber, S., Haering, C. H., Nasmyth, K. <strong>Chromosomal cohesin forms a ring.</strong> Cell 112: 765-777, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12654244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12654244</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00162-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12654244">Gruber et al. (2003)</a> studied whether cohesin forms such rings in vivo. Proteolytic cleavage of Scc1 by separase at the onset of anaphase triggers its dissociation from chromosomes. The authors showed that N- and C-terminal Scc1 cleavage fragments remain connected due to their association with different heads of a single Smc1/Smc3 heterodimer. Cleavage of the Smc3 coiled coil was sufficient to trigger cohesin release from chromosomes and loss of sister cohesion, consistent with a topologic association with chromatin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12654244" 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="#24" class="mim-tip-reference" title="Wendt, K. S., Yoshida, K., Itoh, T., Bando, M., Koch, B., Schirghuber, E., Tsutsumi, S., Nagae, G., Ishihara, K., Mishiro, T., Yahata, K., Imamoto, F., Aburatani, H., Nakao, M., Imamoto, N., Maeshima, K., Shirahige, K., Peters, J.-M. <strong>Cohesin mediates transcriptional insulation by CCCTC-binding factor.</strong> Nature 451: 796-801, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18235444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18235444</a>] [<a href="https://doi.org/10.1038/nature06634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18235444">Wendt et al. (2008)</a> described cohesin-binding sites in the human genome and showed that most of these are associated with the CCCTC-binding factor (CTCF; <a href="/entry/604167">604167</a>), a zinc finger protein required for transcriptional insulation. CTCF is dispensable for cohesin loading onto DNA, but is needed to enrich cohesin at specific binding sites. Cohesin enables CTCF to insulate promoters from distant enhancers and controls transcription at the H19 (<a href="/entry/103280">103280</a>)/IGF2 (<a href="/entry/147470">147470</a>) locus. This role of cohesin seems to be independent of its role in cohesion. <a href="#24" class="mim-tip-reference" title="Wendt, K. S., Yoshida, K., Itoh, T., Bando, M., Koch, B., Schirghuber, E., Tsutsumi, S., Nagae, G., Ishihara, K., Mishiro, T., Yahata, K., Imamoto, F., Aburatani, H., Nakao, M., Imamoto, N., Maeshima, K., Shirahige, K., Peters, J.-M. <strong>Cohesin mediates transcriptional insulation by CCCTC-binding factor.</strong> Nature 451: 796-801, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18235444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18235444</a>] [<a href="https://doi.org/10.1038/nature06634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18235444">Wendt et al. (2008)</a> proposed that cohesin functions as a transcriptional insulator, and speculated that subtle deficiencies in this function contribute to 'cohesinopathies' such as Cornelia de Lange syndrome (see <a href="/entry/122470">122470</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18235444" 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>Cohesin's Scc1, Smc1, and Smc3 subunits form a tripartite ring structure, and it had been proposed that cohesin holds sister DNA molecules together by trapping them inside its ring. To test this, <a href="#9" class="mim-tip-reference" title="Haering, C. H., Farcas, A.-M., Arumugam, P., Metson, J., Nasmyth, K. <strong>The cohesin ring concatenates sister DNA molecules.</strong> Nature 454: 297-301, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18596691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18596691</a>] [<a href="https://doi.org/10.1038/nature07098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18596691">Haering et al. (2008)</a> used site-specific crosslinking to create chemical connections at the 3 interfaces between the 3 constituent polypeptides of the ring, thereby creating covalently closed cohesin rings. As predicted by the ring entrapment model, this procedure produced dimeric DNA-cohesin structures that are resistant to protein denaturation. <a href="#9" class="mim-tip-reference" title="Haering, C. H., Farcas, A.-M., Arumugam, P., Metson, J., Nasmyth, K. <strong>The cohesin ring concatenates sister DNA molecules.</strong> Nature 454: 297-301, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18596691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18596691</a>] [<a href="https://doi.org/10.1038/nature07098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18596691">Haering et al. (2008)</a> concluded that cohesin rings concatenate individual sister minichromosome DNA molecules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18596691" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Seitan, V. C., Hao, B., Tachibana-Konwalski, K., Lavagnolli, T., Mira-Bontenbal, H., Brown, K. E., Teng, G., Carroll, T., Terry, A., Horan, K., Marks, H., Adams, D. J., Schatz, D. G., Aragon, L., Fisher, A. G., Krangel, M. S., Nasmyth, K., Merkenschlager, M. <strong>A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation.</strong> Nature 476: 467-471, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21832993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21832993</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21832993[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/nature10312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21832993">Seitan et al. (2011)</a> deleted the cohesin locus Rad21 in mouse thymocytes at a time in development when these cells stop cycling and rearrange their T-cell receptor alpha locus (TCRA; see <a href="/entry/186880">186880</a>). Rad21-deficient thymocytes had a normal life span and retained the ability to differentiate, albeit with reduced efficiency. Loss of Rad21 led to defective chromatin architecture at the Tcra locus, where cohesin-binding sites flank the TEA promoter and the E-alpha enhancer, and demarcate Tcra from interspersed Tcrd (see <a href="/entry/186810">186810</a>) elements and neighboring housekeeping genes. Cohesin was required for long-range promoter-enhancer interactions, Tcra transcription, H3K4me3 histone modifications that recruit the recombination machinery, and Tcra rearrangement. Provision of prearranged TCR transgenes largely rescued thymocyte differentiation, demonstrating that among thousands of potential target genes across the genome, defective Tcra rearrangement was limiting for the differentiation of cohesin-deficient thymocytes. <a href="#22" class="mim-tip-reference" title="Seitan, V. C., Hao, B., Tachibana-Konwalski, K., Lavagnolli, T., Mira-Bontenbal, H., Brown, K. E., Teng, G., Carroll, T., Terry, A., Horan, K., Marks, H., Adams, D. J., Schatz, D. G., Aragon, L., Fisher, A. G., Krangel, M. S., Nasmyth, K., Merkenschlager, M. <strong>A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation.</strong> Nature 476: 467-471, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21832993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21832993</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21832993[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/nature10312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21832993">Seitan et al. (2011)</a> concluded that their findings firmly established a cell division-independent role for cohesin in Tcra locus rearrangement and provided a comprehensive account of the mechanisms by which cohesin enables cellular differentiation in a well-characterized mammalian system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21832993" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Huis in 't Veld, P. J., Herzog, F., Ladurner, R., Davidson, I. F., Piric, S., Kreidl, E., Bhaskara, V., Aebersold, R., Peters, J.-M. <strong>Characterization of a DNA exit gate in the human cohesin ring.</strong> Science 346: 968-972, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25414306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25414306</a>] [<a href="https://doi.org/10.1126/science.1256904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25414306">Huis in 't Veld et al. (2014)</a> found that cohesin's proposed DNA exit gate is formed by interactions between SCC1 and the coiled-coil region of SMC3. Mutation of this interface abolished cohesin's ability to stably associate with chromatin and to mediate cohesion. Electron microscopy revealed that weakening of the SMC3-SCC1 interface resulted in opening of cohesin rings, as did proteolytic cleavage of SCC1. <a href="#14" class="mim-tip-reference" title="Huis in 't Veld, P. J., Herzog, F., Ladurner, R., Davidson, I. F., Piric, S., Kreidl, E., Bhaskara, V., Aebersold, R., Peters, J.-M. <strong>Characterization of a DNA exit gate in the human cohesin ring.</strong> Science 346: 968-972, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25414306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25414306</a>] [<a href="https://doi.org/10.1126/science.1256904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25414306">Huis in 't Veld et al. (2014)</a> suggested that these open forms may resemble intermediate states of cohesin normally generated by the release factor WAPL (<a href="/entry/610754">610754</a>) and the protease separase (ESPL1; <a href="/entry/604143">604143</a>), respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25414306" 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="Liu, N. Q., Maresca, M., van den Brand, T., Braccioli, L., Schijns, M. M. G. A., Teunissen, H., Bruneau, B. G., Nora, E. P., de Wit, E. <strong>WAPL maintains a cohesin loading cycle to preserve cell-type-specific distal gene regulation.</strong> Nature Genet. 53: 100-109, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33318687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33318687</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33318687[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/s41588-020-00744-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33318687">Liu et al. (2021)</a> found that Wapl was required for maintaining the pluripotent transcriptional state of mouse embryonic stem cells (mESCs), as acute depletion of Wapl resulted in cohesin redistribution and mESC differentiation. RNA-sequencing analysis revealed differential expression of genes in Wapl-depleted mESCs, with 80% being associated with embryonic tissue development, embryonic morphogenesis, and cell differentiation. Cohesin was required for maintaining pluripotency-specific gene expression by binding to specific regions in mESCs in a Wapl-dependent manner, and redistribution of cohesin binding was a unique feature in differentiated cells. As a result, mESC differentiation upon Wapl depletion was accompanied by global redistribution of cohesin from mESC type-specific binding regions to regions specific to differentiated cells. This cohesin redistribution affected local chromatin interactions and gene expression in a reversible manner. Cohesin binding to pluripotency-specific sites was dependent on the pioneer transcription factors Oct4 (POU5F1; <a href="/entry/164177">164177</a>) and Sox2 (<a href="/entry/184429">184429</a>), as these factors created an open chromatin platform for cohesin binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33318687" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Xie, L., Dong, P., Qi, Y., Hsieh, T. S., English, B. P., Jung, S., Chen, X., De Marzio, M., Casellas, R., Chang, H. Y., Zhang, B., Tjian, R., Liu, Z. <strong>BRD2 compartmentalizes the accessible genome.</strong> Nature Genet. 54: 481-491, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35410381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35410381</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35410381[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/s41588-022-01044-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35410381">Xie et al. (2022)</a> found that depletion of the cohesin complex component Rad21 triggered spatial mixing of accessible chromatin domains (ACDs) without affecting their compaction in mouse ESCs. Moreover, spatial mixing of ACDs was independent of transcription, but it involved the bromodomain and extraterminal (BET) protein family. Depletion analysis in mouse ESCs identified Brd2 (<a href="/entry/601540">601540</a>) as a BET protein involved in organizing accessible chromatin and showed that Brd2 maintained compaction of ACDs and promoted their interactions in the absence of cohesin. The interplay between Brd2 and cohesin regulated genome topology in the nucleus, and cohesin antagonized Brd2 binding to chromatin and counteracted its ability to promote interactions between ACDs. In the absence of cohesin, the affinity of Brd2 for active chromatin increased. In addition to cohesin, Brd4 (<a href="/entry/608749">608749</a>) competed with Brd2 to inhibit its activities in genome organization, implying a division of labor for BET proteins to govern distinct regulatory processes in the accessible genome. Polymer simulation supported a model of Brd2-cohesin interplay for nuclear topology, where genome compartmentalization resulted from competition between loop extrusion and chromatin state-specific affinity interactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35410381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#5" class="mim-tip-reference" title="Gligoris, T. G., Scheinost, J. C., Burmann, F., Petela, N., Chan, K.-L., Uluocak, P., Beckouet, F., Gruber, S., Nasmyth, K., Lowe, J. <strong>Closing the cohesin ring: structure and function of its Smc3-kleisin interface.</strong> Science 346: 963-967, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25414305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25414305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25414305[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.1256917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25414305">Gligoris et al. (2014)</a> showed that the N-terminal domain of yeast Scc1 contains 2 alpha-helices, forming a 4-helix bundle with the coiled coil emerging from the adenosine triphosphatase head of Smc3 (<a href="/entry/606062">606062</a>). Mutations affecting this interaction compromise cohesin's association with chromosomes. The interface is far from Smc3 residues, whose acetylation prevents cohesin's dissociation from chromosomes. <a href="#5" class="mim-tip-reference" title="Gligoris, T. G., Scheinost, J. C., Burmann, F., Petela, N., Chan, K.-L., Uluocak, P., Beckouet, F., Gruber, S., Nasmyth, K., Lowe, J. <strong>Closing the cohesin ring: structure and function of its Smc3-kleisin interface.</strong> Science 346: 963-967, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25414305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25414305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25414305[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.1256917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25414305">Gligoris et al. (2014)</a> concluded that cohesin complexes holding chromatids together in vivo do indeed have the configuration of heterotrimeric rings, and sister DNAs are entrapped within these. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25414305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By somatic cell hybrid analysis, <a href="#20" class="mim-tip-reference" title="Nomura, N., Nagase, T., Miyajima, N., Sazuka, T., Tanaka, A., Sato, S., Seki, N., Kawarabayasi, Y., Ishikawa, K., Tabata, S. <strong>Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1.</strong> DNA Res. 1: 223-229, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7584044/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7584044</a>] [<a href="https://doi.org/10.1093/dnares/1.5.223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7584044">Nomura et al. (1994)</a> mapped the RAD21 gene to chromosome 8. Using FISH, <a href="#17" class="mim-tip-reference" title="McKay, M. J., Troelstra, C., van der Spek, P., Kanaar, R., Smit, B., Hagemeijer, A., Bootsma, D., Hoeijmakers, J. H. J. <strong>Sequence conservation of the rad21 Schizosaccharomyces pombe DNA double-strand break repair gene in human and mouse.</strong> Genomics 36: 305-315, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8812457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8812457</a>] [<a href="https://doi.org/10.1006/geno.1996.0466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8812457">McKay et al. (1996)</a> refined the localization to 8q24. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7584044+8812457" 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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In 2 unrelated patients with Cornelia de Lange syndrome-4 (CDLS4; <a href="/entry/614701">614701</a>), <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Wilde, J. J., Albrecht, M., Dickinson, E., Tennstedt, S., Braunholz, D., Monnich, M., Yan, Y., Xu, W., Gil-Rodriguez, M. C., Clark, D., Hakonarson, H., and 15 others. <strong>RAD21 mutations cause a human cohesinopathy.</strong> Am. J. Hum. Genet. 90: 1014-1027, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22633399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22633399</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22633399[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.2012.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22633399">Deardorff et al. (2012)</a> identified different de novo heterozygous mutations in the RAD21 gene (P376R; <a href="#0001">606462.0001</a> and C585R; <a href="#0002">606462.0002</a>). These mutations were identified by screening of the RAD21 gene in 258 individuals with a CDLS-like phenotype after genomewide copy-number analysis had identified a different patient with a de novo deletion of chromosome 8q24.1 that included RAD21. In vitro studies showed that the P376R mutation resulted in altered activity of the mutant protein rather than a loss of function. Patient cells showed decreased sister chromatid separation, increased aneuploidy, and defective DNA repair, as well as abnormal transcriptional activity in a zebrafish model. In contrast, functional studies of the C585R mutation suggested a loss of function, similar to patients with deletion of the RAD21 gene. Three additional patients with overlapping deletions were also studied. Although the phenotype of all patients overlapped that of CDLS, there was some divergence in facial features and the cognitive defects in most were not as severe. Common features included short stature, synophrys, micrognathia, brachydactyly, mild radioulnar differences, vertebral anomalies, and mild cognitive involvement, although the boy with the P376R mutation had more severe mental retardation, tetralogy of Fallot, and hearing loss. <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Wilde, J. J., Albrecht, M., Dickinson, E., Tennstedt, S., Braunholz, D., Monnich, M., Yan, Y., Xu, W., Gil-Rodriguez, M. C., Clark, D., Hakonarson, H., and 15 others. <strong>RAD21 mutations cause a human cohesinopathy.</strong> Am. J. Hum. Genet. 90: 1014-1027, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22633399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22633399</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22633399[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.2012.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22633399">Deardorff et al. (2012)</a> concluded that dominant RAD21 missense mutations result in more severe functional defects and a worse phenotype than loss-of-function (LOF) mutations or deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22633399" 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 3 unrelated patients with CDLS4 with midline brain defects in the holoprosencephaly (HPE) spectrum, <a href="#15" class="mim-tip-reference" title="Kruszka, P., Berger, S. I., Casa, V., Dekker, M. R., Gaesser, J., Weiss, K., Martinez, A. F., Murdock, D. R, Louie, R. J., Prijoles, E. J., Lichty, A. W., Brouwer, O. F., and 23 others. <strong>Cohesin complex-associated holoprosencephaly.</strong> Brain 142: 2631-2643, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31334757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31334757</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31334757[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/10.1093/brain/awz210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31334757">Kruszka et al. (2019)</a> identified heterozygous frameshift or nonsense mutations in the RAD21 gene (<a href="#0004">606462.0004</a>-<a href="#0006">606462.0006</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were identified from a cohort of over 277 patients with HPE who underwent exome sequencing. All of the mutations were predicted to result in a loss of function, although functional studies of the variants and studies of patient cells were not performed. A father of 1 of the patients with milder symptoms also carried the heterozygous mutation; the inheritance pattern of the other 2 patients was unknown. The authors noted that the RAD21 gene is intolerant to LOF variation based on data from gnomAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31334757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Goel, H., Parasivam, G. <strong>Another case of holoprosencephaly associated with RAD21 loss-of-function variant. (Letter)</strong> Brain 143: e64, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32696056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32696056</a>] [<a href="https://doi.org/10.1093/brain/awaa173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32696056">Goel and Parasivam (2020)</a> identified a de novo heterozygous nonsense mutation in the RAD21 gene (E615X; <a href="#0007">606462.0007</a>) in a female fetus with CDLS4 and lobar holoprosencephaly. The mutation was identified by clinical exome analysis of 4,702 genes. No functional studies were performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32696056" 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 26-year-old woman with mild CDLS4, <a href="#2" class="mim-tip-reference" title="Boyle, M. I., Jespersgaard, C., Nazaryan, L., Bisgaard, A.-M., Tumer, Z. <strong>A novel RAD21 variant associated with intrafamilial phenotypic variation in Cornelia de Lange syndrome--review of the literature. (Letter)</strong> Clin. Genet. 91: 647-649, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27882533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27882533</a>] [<a href="https://doi.org/10.1111/cge.12863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27882533">Boyle et al. (2017)</a> identified a heterozygous mutation in the RAD21 gene (<a href="#0008">606462.0008</a>). The woman's mother and 2 maternal aunts, who were also heterozygous for the mutation, had variable, milder features seen in CDLS4 but did not meet clinical criteria for the disorder. <a href="#2" class="mim-tip-reference" title="Boyle, M. I., Jespersgaard, C., Nazaryan, L., Bisgaard, A.-M., Tumer, Z. <strong>A novel RAD21 variant associated with intrafamilial phenotypic variation in Cornelia de Lange syndrome--review of the literature. (Letter)</strong> Clin. Genet. 91: 647-649, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27882533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27882533</a>] [<a href="https://doi.org/10.1111/cge.12863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27882533">Boyle et al. (2017)</a> concluded that the intrafamilial phenotypic variation suggested incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27882533" 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 mother and son and an unrelated patient with CDLS4, <a href="#18" class="mim-tip-reference" title="Minor, A., Shinawi, M., Hogue, J. S., Vineyard, M., Hamlin, D. R., Tan, C., Donato, K., Wysinger, L., Botes, S., Das, S., del Gaudio, D. <strong>Two novel RAD 21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case.</strong> Gene 537: 279-284, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24378232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24378232</a>] [<a href="https://doi.org/10.1016/j.gene.2013.12.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24378232">Minor et al. (2014)</a> identified heterozygous mutations in the RAD21 gene (<a href="#0009">606462.0009</a> and <a href="#0010">606462.0010</a>, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24378232" 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 5-year-old boy with CDLS4, <a href="#4" class="mim-tip-reference" title="Dorval, S. Masciadri, M., Mathot, M., Russo, S., Revencu, N., Larizza, L. <strong>A novel RAD21 mutation in a boy with mild Cornelia de Lange presentation: further delineation of the phenotype.</strong> Europ. J. Med. Genet. 63: 103620, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30716475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30716475</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.01.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30716475">Dorval et al. (2020)</a> identified a heterozygous frameshift mutation in the RAD21 gene (<a href="#0011">606462.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30716475" 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 15-month-old boy with CDLS4, <a href="#8" class="mim-tip-reference" title="Gudmundsson, S., Anneren, G., Marcos-Alcalde, I., Wilbe, M., Melin, M., Gomez-Puertas, P., Bondeson, M.-L. <strong>A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4--review of the literature.</strong> Europ. J. Med. Genet. 62: 103526, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30125677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30125677</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.08.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30125677">Gudmundsson et al. (2019)</a> identified a de novo heterozygous mutation in the RAD21 gene (<a href="#0012">606462.0012</a>). Molecular modeling predicted that the mutation disrupted the interaction of RAD21 with SMC1A (<a href="/entry/300040">300040</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30125677" 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>Mungan Syndrome</em></strong></p><p>
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In a large Turkish family with intestinal pseudoobstruction mapping to chromosome 8q23-q24 (Mungan syndrome, MGS; <a href="/entry/611376">611376</a>), <a href="#1" class="mim-tip-reference" title="Bonora, E., Bianco, F., Cordeddu, L., Bamshad, M., Francescatto, L., Dowless, D., Stanghellini, V. Cogliandro, R. F., Lindberg, G., Mungan, Z., Cefle, K., Ozcelik, T., and 14 others. <strong>Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction.</strong> Gastroenterology 148: 771-782, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25575569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25575569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25575569[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/10.1053/j.gastro.2014.12.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25575569">Bonora et al. (2015)</a> identified homozygosity for a missense mutation in the RAD21 gene (A622T; <a href="#0003">606462.0003</a>) that segregated fully with disease in the family and was not found in 500 Turkish controls or in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25575569" 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="#1" class="mim-tip-reference" title="Bonora, E., Bianco, F., Cordeddu, L., Bamshad, M., Francescatto, L., Dowless, D., Stanghellini, V. Cogliandro, R. F., Lindberg, G., Mungan, Z., Cefle, K., Ozcelik, T., and 14 others. <strong>Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction.</strong> Gastroenterology 148: 771-782, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25575569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25575569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25575569[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/10.1053/j.gastro.2014.12.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25575569">Bonora et al. (2015)</a> injected zebrafish embryos with a rad21a slice-blocking morpholino and observed recapitulation of the chronic intestinal pseudoobstruction phenotype seen in their patients with Mungan syndrome. The morphants showed delayed food transit compared to wildtype zebrafish, and quantitative analysis of the zebrafish gut revealed marked depletion of enteric neurons at 4 and 5 days postfertilization in the morphants compared to controls, suggesting a neurogenic cause of the observed motility defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25575569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a boy with Cornelia de Lange syndrome-4 (CDLS4; <a href="/entry/614701">614701</a>), <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Wilde, J. J., Albrecht, M., Dickinson, E., Tennstedt, S., Braunholz, D., Monnich, M., Yan, Y., Xu, W., Gil-Rodriguez, M. C., Clark, D., Hakonarson, H., and 15 others. <strong>RAD21 mutations cause a human cohesinopathy.</strong> Am. J. Hum. Genet. 90: 1014-1027, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22633399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22633399</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22633399[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.2012.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22633399">Deardorff et al. (2012)</a> identified a de novo heterozygous 1127C-G transversion in the RAD21 gene, resulting in a pro376-to-arg (P376R) substitution in a highly conserved residue within a region essential for the interaction of RAD21 with STAG proteins. The mutation was not found in 600 control chromosomes. The patient had microcephaly and a characteristic facial appearance, with thick, bushy, arched eyebrows, synophrys, prominent eyelashes, broad nasal bridge, smooth philtrum, upturned nose, and thin upper lip. He also had a number of additional congenital anomalies, including submucosal cleft palate, stapes fixation and hearing loss, thin fingers, left radioulnar synostosis, delayed skeletal age, vertebral clefting, pectus carinatum, short femoral neck, tetralogy of Fallot, intestinal malrotation, gastroesophageal reflux, and severe cognitive delay. In vitro studies showed that the P376R mutation resulted in an increased interaction of RAD21 with STAG1 (<a href="/entry/604358">604358</a>) and STAG2 (<a href="/entry/300826">300826</a>), potentially causing delayed sister chromatid separation or altered transcription. Analysis of metaphase spreads from the patient showed a higher percentage of sister chromatids with a closed-arm phenotype compared to controls. Patient cells showed increased aneuploidy, with a substantial gain or loss of 1 or more chromosomes compared to controls, causing a delay in cell cycle progression during mitosis from G2/M to G1 phase. Patient lymphoblastoid cells also showed decreased survival, increased chromosome breakage, and defective DNA repair after irradiation compared to control cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22633399" 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>Rad21-null zebrafish show absent tissue-specific expression of Runx1 (<a href="/entry/151385">151385</a>). <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Wilde, J. J., Albrecht, M., Dickinson, E., Tennstedt, S., Braunholz, D., Monnich, M., Yan, Y., Xu, W., Gil-Rodriguez, M. C., Clark, D., Hakonarson, H., and 15 others. <strong>RAD21 mutations cause a human cohesinopathy.</strong> Am. J. Hum. Genet. 90: 1014-1027, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22633399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22633399</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22633399[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.2012.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22633399">Deardorff et al. (2012)</a> showed that zebrafish P377R (corresponding to human P376R) rescued transcriptional expression of Runx1 in 65% of Rad21-null zebrafish embryos, indicating partial function. However, this variant also caused altered transcription in wildtype embryos, causing 50% more atypical Runx1 expression than wildtype Rad21. These findings suggested altered activity of the mutant protein rather than a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22633399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a girl with Cornelia de Lange syndrome-4 (CDLS4; <a href="/entry/614701">614701</a>), <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Wilde, J. J., Albrecht, M., Dickinson, E., Tennstedt, S., Braunholz, D., Monnich, M., Yan, Y., Xu, W., Gil-Rodriguez, M. C., Clark, D., Hakonarson, H., and 15 others. <strong>RAD21 mutations cause a human cohesinopathy.</strong> Am. J. Hum. Genet. 90: 1014-1027, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22633399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22633399</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22633399[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.2012.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22633399">Deardorff et al. (2012)</a> identified a de novo heterozygous 1753T-C transition in the RAD21 gene, resulting in a cys585-to-arg (C585R) substitution in a residue conserved in vertebrates. The mutation was not found in 600 control chromosomes. Structural modeling suggested that the C585R mutation is within the C terminus of RAD21 positioned near the interface of RAD21 and the C-terminal residues of SMC1 (<a href="/entry/300040">300040</a>), and may interfere with the interaction between these 2 cohesion proteins, causing a defect in formation of functional cohesin complexes. The patient had microcephaly and a characteristic facial appearance, with thick, bushy, arched eyebrows, synophrys, long eyelashes, broad nasal bridge, smooth philtrum, thin upper lip, short nose, and upslanted palpebral fissures. Other features included short fingers, fifth finger clinodactyly, small prominent first toe, long fourth metacarpal, cutis marmorata, and mild neurodevelopmental defects. Zebrafish C597R (corresponding to human C585R) failed to rescue Runx1 expression in Rad21-null embryos and showed only background levels of activity in wildtype embryos, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22633399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a large Turkish family with intestinal pseudoobstruction (MGS; <a href="/entry/611376">611376</a>), originally described by <a href="#19" class="mim-tip-reference" title="Mungan, Z., Akyuz, F., Bugra, Z., Yonal, O., Ozturk, S., Acar, A., Cevikbas, U. <strong>Familial visceral myopathy with pseudo-obstruction, megaduodenum, Barrett's esophagus, and cardiac abnormalities.</strong> Am. J. Gastroent. 98: 2556-2560, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14638363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14638363</a>] [<a href="https://doi.org/10.1111/j.1572-0241.2003.08707.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14638363">Mungan et al. (2003)</a>, <a href="#1" class="mim-tip-reference" title="Bonora, E., Bianco, F., Cordeddu, L., Bamshad, M., Francescatto, L., Dowless, D., Stanghellini, V. Cogliandro, R. F., Lindberg, G., Mungan, Z., Cefle, K., Ozcelik, T., and 14 others. <strong>Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction.</strong> Gastroenterology 148: 771-782, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25575569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25575569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25575569[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/10.1053/j.gastro.2014.12.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25575569">Bonora et al. (2015)</a> identified homozygosity for a c.1864G-A transition (c.1864G-A, NM_006265.2) in the RAD21 gene, resulting in an ala622-to-thr (A622T) substitution at a highly conserved residue. The mutation segregated fully with disease in the family and was not found in 500 Turkish controls or in the dbSNP, 1000 Genomes Project, or NHLBI Exome Sequencing Project databases. Although expression of RAD21 in patient lymphoblastoid cells was similar to that of controls, expression of the RAD21 target gene RUNX1 (<a href="/entry/151385">151385</a>) was significantly reduced both in patient cells and in HEK293 cells transfected with the A622T mutant. Zebrafish embryos injected with a morpholino blocking the ortholog gene rad21a showed partial or complete absence of runx1 expression, which could not be rescued with coinjection of the A622T mutant, indicating a loss-of-function effect in vivo. <a href="#1" class="mim-tip-reference" title="Bonora, E., Bianco, F., Cordeddu, L., Bamshad, M., Francescatto, L., Dowless, D., Stanghellini, V. Cogliandro, R. F., Lindberg, G., Mungan, Z., Cefle, K., Ozcelik, T., and 14 others. <strong>Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction.</strong> Gastroenterology 148: 771-782, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25575569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25575569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25575569[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/10.1053/j.gastro.2014.12.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25575569">Bonora et al. (2015)</a> identified 2 RAD21 binding sites in the APOB (<a href="/entry/107730">107730</a>) proximal promoter and observed that nuclear extracts from wildtype cells formed a specific complex with either region, whereas no complex was observed in the presence of mutant RAD21. In addition, gut-specific APOB48 levels were increased in patient serum compared to controls; however, sera from sporadic patients with intestinal pseudoobstruction who were negative for mutation in RAD21 also showed consistently increased APOB48 levels compared to controls. <a href="#1" class="mim-tip-reference" title="Bonora, E., Bianco, F., Cordeddu, L., Bamshad, M., Francescatto, L., Dowless, D., Stanghellini, V. Cogliandro, R. F., Lindberg, G., Mungan, Z., Cefle, K., Ozcelik, T., and 14 others. <strong>Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction.</strong> Gastroenterology 148: 771-782, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25575569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25575569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25575569[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/10.1053/j.gastro.2014.12.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25575569">Bonora et al. (2015)</a> suggested that APOB48 expression might represent a marker for the degree of neuronal loss or symptom severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14638363+25575569" 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">rs1812331711 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1812331711;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=rs1812331711" 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=rs1812331711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 7-year-old girl (patient 12) with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; <a href="/entry/614701">614701</a>), <a href="#15" class="mim-tip-reference" title="Kruszka, P., Berger, S. I., Casa, V., Dekker, M. R., Gaesser, J., Weiss, K., Martinez, A. F., Murdock, D. R, Louie, R. J., Prijoles, E. J., Lichty, A. W., Brouwer, O. F., and 23 others. <strong>Cohesin complex-associated holoprosencephaly.</strong> Brain 142: 2631-2643, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31334757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31334757</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31334757[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/10.1093/brain/awz210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31334757">Kruszka et al. (2019)</a> identified a heterozygous c.1548delinsTC mutation in the RAD21 gene, predicted to result in a frameshift and premature termination (Glu518ArgfsTer19). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from her mildly affected father. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function (LOF). The authors noted that the RAD21 gene is intolerant to LOF variation based on data from gnomAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31334757" 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> rs1352385210 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1352385210;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/rs1352385210?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=rs1352385210" 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=rs1352385210" 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=RCV001072118" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001072118" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001072118</a>
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<p>In a 14-year-old boy (patient 13) with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; <a href="/entry/614701">614701</a>), <a href="#15" class="mim-tip-reference" title="Kruszka, P., Berger, S. I., Casa, V., Dekker, M. R., Gaesser, J., Weiss, K., Martinez, A. F., Murdock, D. R, Louie, R. J., Prijoles, E. J., Lichty, A. W., Brouwer, O. F., and 23 others. <strong>Cohesin complex-associated holoprosencephaly.</strong> Brain 142: 2631-2643, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31334757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31334757</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31334757[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/10.1093/brain/awz210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31334757">Kruszka et al. (2019)</a> identified a heterozygous c.589C-T transition (chr8.117869605G-A, GRCh37) in the RAD21 gene, resulting in a gln197-to-ter (Q197X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was predicted to result in a loss of function (LOF), although functional studies of the variant and studies of patient cells were not performed. The inheritance pattern could not be determined because parental DNA was unavailable. The authors noted that the RAD21 gene is intolerant to LOF variation based on data from gnomAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31334757" 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>.0006 CORNELIA DE LANGE SYNDROME 4 WITH MIDLINE BRAIN DEFECTS</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">rs1812376090 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1812376090;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=rs1812376090" 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=rs1812376090" 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=RCV001072119 OR RCV002286809" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001072119, RCV002286809" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001072119...</a>
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<p>In a 2-year-old boy (patient 14) with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; <a href="/entry/614701">614701</a>), <a href="#15" class="mim-tip-reference" title="Kruszka, P., Berger, S. I., Casa, V., Dekker, M. R., Gaesser, J., Weiss, K., Martinez, A. F., Murdock, D. R, Louie, R. J., Prijoles, E. J., Lichty, A. W., Brouwer, O. F., and 23 others. <strong>Cohesin complex-associated holoprosencephaly.</strong> Brain 142: 2631-2643, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31334757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31334757</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31334757[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/10.1093/brain/awz210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31334757">Kruszka et al. (2019)</a> identified a heterozygous 8-bp deletion (c.1217_1224del; chr8.117,864,885del8, GRCh37), predicted to result in a frameshift and premature termination (Lys406ArgfsTer4). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was predicted to result in a loss of function (LOF), although functional studies of the variant and studies of patient cells were not performed. The inheritance pattern could not be determined because parental DNA was unavailable. The authors noted that the RAD21 gene is intolerant to LOF variation based on data from gnomAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31334757" 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>.0007 CORNELIA DE LANGE SYNDROME 4 WITH MIDLINE BRAIN DEFECTS</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> rs1425483905 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1425483905;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/rs1425483905?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=rs1425483905" 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=rs1425483905" 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=RCV001260876" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001260876" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001260876</a>
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<p>In a female fetus with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; <a href="/entry/614701">614701</a>), <a href="#6" class="mim-tip-reference" title="Goel, H., Parasivam, G. <strong>Another case of holoprosencephaly associated with RAD21 loss-of-function variant. (Letter)</strong> Brain 143: e64, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32696056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32696056</a>] [<a href="https://doi.org/10.1093/brain/awaa173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32696056">Goel and Parasivam (2020)</a> identified a de novo heterozygous c.1843G-T transversion in the RAD21 gene, resulting in a glu615-to-ter (E615X) substitution. The mutation was identified by clinical whole-exome sequencing. Functional studies were not performed. The patient had lobar holoprosencephaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32696056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 CORNELIA DE LANGE SYNDROME 4</strong>
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RAD21, 1-BP DEL, 704G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1812478613 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1812478613;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=rs1812478613" 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=rs1812478613" 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=RCV001281378" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001281378" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001281378</a>
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<p>In a 26-year-old woman with mild Cornelia de Lange syndrome-4 (CDLS4; <a href="/entry/614701">614701</a>), <a href="#2" class="mim-tip-reference" title="Boyle, M. I., Jespersgaard, C., Nazaryan, L., Bisgaard, A.-M., Tumer, Z. <strong>A novel RAD21 variant associated with intrafamilial phenotypic variation in Cornelia de Lange syndrome--review of the literature. (Letter)</strong> Clin. Genet. 91: 647-649, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27882533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27882533</a>] [<a href="https://doi.org/10.1111/cge.12863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27882533">Boyle et al. (2017)</a> identified heterozygosity for a 1-bp deletion (c.704delG, NM_0062625.2) in exon 13 of the RAD21 gene, predicted to result in a frameshift and premature termination (Ser235IlefsTer19), leading to a nonfunctional protein or nonsense-mediated mRNA decay. The mutation, which was identified by targeted next-generation sequencing, was also present in heterozygous state in the patient's mother and 2 maternal aunts, who had variable, milder features seen in CDLS4 but did not fulfill the clinical criteria for CDLS. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27882533" 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>.0009 CORNELIA DE LANGE SYNDROME 4</strong>
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RAD21, 665-BP DEL, EX13DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001543703" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001543703" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001543703</a>
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<p>In a 3-year-old boy (patient 1) and his mother with mild Cornelia de Lange syndrome-4 (CDLS4; <a href="/entry/614701">614701</a>), <a href="#18" class="mim-tip-reference" title="Minor, A., Shinawi, M., Hogue, J. S., Vineyard, M., Hamlin, D. R., Tan, C., Donato, K., Wysinger, L., Botes, S., Das, S., del Gaudio, D. <strong>Two novel RAD 21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case.</strong> Gene 537: 279-284, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24378232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24378232</a>] [<a href="https://doi.org/10.1016/j.gene.2013.12.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24378232">Minor et al. (2014)</a> identified a heterozygous 665-bp deletion (chr8.(117,860,090_117,861,110)_(117,861,670_117,861,700)del) in the RAD21 gene with a 2-bp microhomology (TT) at the breakpoint junction, resulting in an in-frame deletion of exon 13. The deletion was identified by targeted array-CGH and confirmed by real-time quantitative PCR and breakpoint sequencing. The deletion was not detected in an in-house database of 452 patients tested for diagnostic purposes. The mutation was predicted to affect the interaction of RAD21 with SMC1A (<a href="/entry/300040">300040</a>) and alter the function of the cohesion complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24378232" 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">rs2130469261 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2130469261;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=rs2130469261" 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=rs2130469261" 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=RCV001543704" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001543704" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001543704</a>
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<p>In a 12-year-old boy (patient 2) with mild Cornelia de Lange syndrome-4 (CDLS4; <a href="/entry/614701">614701</a>), <a href="#18" class="mim-tip-reference" title="Minor, A., Shinawi, M., Hogue, J. S., Vineyard, M., Hamlin, D. R., Tan, C., Donato, K., Wysinger, L., Botes, S., Das, S., del Gaudio, D. <strong>Two novel RAD 21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case.</strong> Gene 537: 279-284, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24378232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24378232</a>] [<a href="https://doi.org/10.1016/j.gene.2013.12.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24378232">Minor et al. (2014)</a> identified a heterozygous 2-bp duplication (c.592_593dup, NM_006265) in exon 6 of the RAD21 gene, resulting in a frameshift and premature termination (Ser198ArgfsTer6). The mutation was identified by sequence analysis of the RAD21 gene. The mutation was not present in the mother, but the father was not available for testing. The mutation was predicted to result in either nonsense-mediated decay or a truncated protein missing functional domains necessary for the interaction with WAPL (<a href="/entry/610754">610754</a>), PDS5B (<a href="/entry/605333">605333</a>), and STAG1 (<a href="/entry/604358">604358</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24378232" 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">rs2130463115 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2130463115;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=rs2130463115" 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=rs2130463115" 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=RCV001543705" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001543705" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001543705</a>
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<p>In a 5-year-old by with mild Cornelia de Lange syndrome-4 (CDLS4; <a href="/entry/614701">614701</a>), <a href="#4" class="mim-tip-reference" title="Dorval, S. Masciadri, M., Mathot, M., Russo, S., Revencu, N., Larizza, L. <strong>A novel RAD21 mutation in a boy with mild Cornelia de Lange presentation: further delineation of the phenotype.</strong> Europ. J. Med. Genet. 63: 103620, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30716475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30716475</a>] [<a href="https://doi.org/10.1016/j.ejmg.2019.01.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30716475">Dorval et al. (2020)</a> identified a de novo heterozygous 4-bp deletion (c.943_946del, NM_006265) in exon 9 of the RAD21 gene, resulting in a frameshift and premature termination (Glu315GlnfsTer9). The mutation was identified by sequencing of a multigene panel containing 5 known CDLS genes and confirmed by Sanger sequencing. The mutation was not present in the ExAC and gnomAD databases. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30716475" 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>.0012 CORNELIA DE LANGE SYNDROME 4</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">rs1563686762 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1563686762;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=rs1563686762" 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=rs1563686762" 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=RCV000680272 OR RCV004721527" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000680272, RCV004721527" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000680272...</a>
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<p>In a 15-month-old boy with mild Cornelia de Lange syndrome-4 (CDLS4; <a href="/entry/614701">614701</a>), <a href="#8" class="mim-tip-reference" title="Gudmundsson, S., Anneren, G., Marcos-Alcalde, I., Wilbe, M., Melin, M., Gomez-Puertas, P., Bondeson, M.-L. <strong>A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4--review of the literature.</strong> Europ. J. Med. Genet. 62: 103526, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30125677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30125677</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.08.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30125677">Gudmundsson et al. (2019)</a> identified a de novo heterozygous 3-bp deletion (c.1774_1776del, NM_006265) in the RAD21 gene, resulting in deletion of Gln592, a conserved residue. The de novo mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. The mutation was not present in the ExAC, SweGen, and gnomAD databases. Molecular modeling predicted that the mutation disrupted the interaction of RAD21 with SMC1A (<a href="/entry/300040">300040</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30125677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Bonora2015" class="mim-anchor"></a>
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Bonora, E., Bianco, F., Cordeddu, L., Bamshad, M., Francescatto, L., Dowless, D., Stanghellini, V. Cogliandro, R. F., Lindberg, G., Mungan, Z., Cefle, K., Ozcelik, T., and 14 others.
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<strong>Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction.</strong>
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Gastroenterology 148: 771-782, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25575569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25575569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25575569[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=25575569" 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/10.1053/j.gastro.2014.12.034" target="_blank">Full Text</a>]
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Boyle, M. I., Jespersgaard, C., Nazaryan, L., Bisgaard, A.-M., Tumer, Z.
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<strong>A novel RAD21 variant associated with intrafamilial phenotypic variation in Cornelia de Lange syndrome--review of the literature. (Letter)</strong>
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Clin. Genet. 91: 647-649, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27882533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27882533</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27882533" 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/10.1111/cge.12863" target="_blank">Full Text</a>]
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Deardorff, M. A., Wilde, J. J., Albrecht, M., Dickinson, E., Tennstedt, S., Braunholz, D., Monnich, M., Yan, Y., Xu, W., Gil-Rodriguez, M. C., Clark, D., Hakonarson, H., and 15 others.
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<strong>RAD21 mutations cause a human cohesinopathy.</strong>
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Am. J. Hum. Genet. 90: 1014-1027, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22633399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22633399</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22633399[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=22633399" 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.2012.04.019" target="_blank">Full Text</a>]
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<a id="Dorval2020" class="mim-anchor"></a>
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Dorval, S. Masciadri, M., Mathot, M., Russo, S., Revencu, N., Larizza, L.
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<strong>A novel RAD21 mutation in a boy with mild Cornelia de Lange presentation: further delineation of the phenotype.</strong>
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Europ. J. Med. Genet. 63: 103620, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30716475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30716475</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30716475" 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.ejmg.2019.01.010" target="_blank">Full Text</a>]
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Gligoris, T. G., Scheinost, J. C., Burmann, F., Petela, N., Chan, K.-L., Uluocak, P., Beckouet, F., Gruber, S., Nasmyth, K., Lowe, J.
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<strong>Closing the cohesin ring: structure and function of its Smc3-kleisin interface.</strong>
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Science 346: 963-967, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25414305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25414305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25414305[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=25414305" 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.1256917" target="_blank">Full Text</a>]
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<a id="Goel2020" class="mim-anchor"></a>
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Goel, H., Parasivam, G.
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<strong>Another case of holoprosencephaly associated with RAD21 loss-of-function variant. (Letter)</strong>
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Brain 143: e64, 2020. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32696056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32696056</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32696056" 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/brain/awaa173" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Gruber2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gruber, S., Haering, C. H., Nasmyth, K.
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<strong>Chromosomal cohesin forms a ring.</strong>
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Cell 112: 765-777, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12654244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12654244</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12654244" 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/s0092-8674(03)00162-4" target="_blank">Full Text</a>]
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Gudmundsson, S., Anneren, G., Marcos-Alcalde, I., Wilbe, M., Melin, M., Gomez-Puertas, P., Bondeson, M.-L.
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<strong>A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4--review of the literature.</strong>
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Europ. J. Med. Genet. 62: 103526, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30125677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30125677</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30125677" 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.ejmg.2018.08.007" target="_blank">Full Text</a>]
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Xie, L., Dong, P., Qi, Y., Hsieh, T. S., English, B. P., Jung, S., Chen, X., De Marzio, M., Casellas, R., Chang, H. Y., Zhang, B., Tjian, R., Liu, Z.
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<strong>BRD2 compartmentalizes the accessible genome.</strong>
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Nature Genet. 54: 481-491, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35410381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35410381</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35410381[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=35410381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41588-022-01044-9" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 02/01/2023
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Hilary J. Vernon - updated : 07/29/2021<br>Bao Lige - updated : 04/28/2021<br>Hilary J. Vernon - updated : 01/11/2021<br>Hilary J. Vernon - updated : 10/09/2020<br>Cassandra L. Kniffin - updated : 04/10/2020<br>Marla J. F. O'Neill - updated : 09/06/2018<br>Ada Hamosh - updated : 01/14/2015<br>Ada Hamosh - updated : 1/14/2015<br>Cassandra L. Kniffin - updated : 7/5/2012<br>Ada Hamosh - updated : 9/21/2011<br>Ada Hamosh - updated : 8/12/2008<br>Ada Hamosh - updated : 3/7/2008<br>Stylianos E. Antonarakis - updated : 4/14/2003<br>Patricia A. Hartz - updated : 12/17/2002<br>Ada Hamosh - updated : 9/17/2002
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Paul J. Converse : 11/15/2001
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alopez : 03/20/2023
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mgross : 02/01/2023<br>carol : 08/02/2021<br>carol : 07/30/2021<br>carol : 07/29/2021<br>mgross : 04/28/2021<br>carol : 01/11/2021<br>carol : 10/09/2020<br>carol : 04/14/2020<br>carol : 04/13/2020<br>ckniffin : 04/10/2020<br>carol : 08/21/2019<br>carol : 09/06/2018<br>alopez : 01/14/2015<br>alopez : 1/14/2015<br>mgross : 10/4/2013<br>joanna : 8/29/2013<br>carol : 7/6/2012<br>terry : 7/6/2012<br>ckniffin : 7/5/2012<br>carol : 11/23/2011<br>carol : 11/22/2011<br>alopez : 9/23/2011<br>alopez : 9/23/2011<br>terry : 9/21/2011<br>carol : 11/8/2010<br>wwang : 12/30/2009<br>alopez : 8/25/2008<br>terry : 8/12/2008<br>alopez : 3/20/2008<br>terry : 3/7/2008<br>mgross : 4/14/2003<br>mgross : 12/18/2002<br>terry : 12/17/2002<br>alopez : 9/17/2002<br>mgross : 11/15/2001
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<span class="mim-font">
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<strong>*</strong> 606462
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RAD21 COHESIN COMPLEX COMPONENT; RAD21
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<em>Alternative titles; symbols</em>
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RAD21, S. POMBE, HOMOLOG OF<br />
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NUCLEAR MATRIX PROTEIN 1; NXP1<br />
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SISTER CHROMATID COHESION 1; SCC1<br />
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HR21<br />
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KIAA0078
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<strong><em>HGNC Approved Gene Symbol: RAD21</em></strong>
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Cytogenetic location: 8q24.11
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Genomic coordinates <span class="small">(GRCh38)</span> : 8:116,845,934-116,874,776 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Phenotype
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Inheritance
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8q24.11
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?Mungan syndrome
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611376
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Autosomal recessive
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3
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Cornelia de Lange syndrome 4
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614701
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<p>Eukaryotic sister chromatids remain connected from the time of synthesis until they are separated in anaphase. This cohesion depends on a complex of proteins known as cohesins. In vertebrates, unlike in yeast, the cohesins dissociate from chromosome arms earlier in M phase, during prophase. Small amounts of cohesin remain near the centromere until metaphase, with complete removal at the beginning of anaphase. Cohesin complexes contain SCC1 (RAD21), SMC1 (300040), SMC3 (606062), and either SA1 (STAG1; 604358) or SA2 (STAG2; 300826). The complexes, in turn, interact with PDS5 (see 613200), a protein implicated in chromosome cohesion, condensation, and recombination in yeast (summary by Sumara et al., 2000). </p>
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<strong>Cloning and Expression</strong>
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<p>By sequencing cDNAs randomly selected from a cDNA library derived from a human immature myeloid cell line, Nomura et al. (1994) identified a cDNA encoding a homolog of S. pombe Rad21 that they termed KIAA0078. The deduced KIAA0078 protein has 631 amino acids. Northern blot analysis detected equivalent expression of KIAA0078 in all tissues tested. </p><p>By searching EST databases for sequences similar to yeast Rad21 and subsequently searching with the worm and fly sequences these searches identified, McKay et al. (1996) isolated a cDNA encoding a mouse homolog of Rad21. By probing a testis cDNA library with the mouse sequence, they obtained a cDNA encoding human RAD21, which they termed HR21. Sequence analysis predicted that the 631-amino acid phosphoprotein is 96% and 25% identical to the mouse and yeast proteins, respectively, and that they are most conserved at the N and C termini. These proteins all have 2 nuclear localization signals and an acidic stretch consistent with a chromatin-binding role. Northern blot analysis revealed ubiquitous expression of a 3.1-kb transcript in mouse tissues, with highest expression in testis and thymus. Testis also expressed a 2.2-kb transcript in postmeiotic cells. Northern blot analysis determined that expression increases during S phase and peaks in G2 phase in HeLa cells. There was no increase in expression after ionizing radiation. </p><p>By immunoscreening a placenta cDNA expression library, Sadano et al. (2000) cloned RAD21, which they designated NXP1. Western blot analysis and immunofluorescence microscopy showed nuclear expression of a 110-kD protein, which was higher than the predicted 70 kD most likely due to phosphorylation. Mutation and immunoprecipitation analyses with truncated proteins indicated that the N terminus of RAD21 is responsible for the nuclear localization and binding to a 28-kD nuclear matrix protein. </p>
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<h4>
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>By immunoblot analysis, Hoque and Ishikawa (2001) showed that the approximately 120-kD RAD21 protein is expressed in the nucleus at the same level throughout the cell cycle and that it becomes hyperphosphorylated during M phase. Immunofluorescence microscopy demonstrated that RAD21 begins to dissociate from arm region chromatin during prophase and from centromere regions during metaphase and anaphase and is associated with spindles. In telophase and cytokinesis, RAD21 is associated with microtubules and then resumes association with chromatin during cytokinesis. </p><p>Hauf et al. (2001) identified separase (see 604143) cleavage sites in SCC1/RAD21 after arg172 and after arg450. Immunofluorescence microscopy demonstrated that cleavage-site mutant RAD21 dissociated from chromosomes by prophase, like wildtype, but was associated with multiple mitotic abnormalities. Flow cytometric and video microscopic analyses showed that cells with noncleavable RAD21 tend to express aneuploidy in interphase and that they initiate cytokinesis without segregating chromosomes. Analysis of metaphase cells suggested that these cells reenter interphase with sister chromatids still connected and form diplochromosomes in the subsequent mitosis. Hauf et al. (2001) proposed that anaphase defects may be caused by RAD21 cleavage defects as well as by securin (PTTG1; 604147) overexpression or deletion. </p><p>Hakimi et al. (2002) reported the isolation of a human SNF2 (600014)-containing chromatin remodeling complex that encompasses components of the cohesin and NURD (see 603526) complexes. They showed that the RAD21 subunit of the cohesin complex directly interacts with the ATPase subunit SNF2. Mapping of RAD21, SNF2, and Mi2 (see 603277) binding sites by chromatin immunoprecipitation experiments revealed the specific association of these 3 proteins with human DNA elements containing alu sequences. Hakimi et al. (2002) found a correlation between modification of histone tails and association of the SNF2/cohesin complex with chromatin. In addition, they showed that the association of the cohesin complex with chromatin can be regulated by the state of DNA methylation. Finally, they presented evidence pointing to a role for the ATPase activity of SNF2 in the loading of RAD21 on chromatin. </p><p>Hoque and Ishikawa (2002) found that expression of N-terminally truncated SCC1 had a dominant-negative effect on SCC1 function in several human cell lines. Cells expressing the N-terminally truncated protein showed impaired cell growth. Within mitotic cells, chromatids condensed normally, but the 2 pairs of sister chromatids were disjoined, separated prematurely, and became positioned randomly within nuclei. Spindle assembly checkpoint was activated. </p><p>In yeast, the cohesin complex is essential for sister chromatid cohesion during mitosis. The Smc1 (300040) and Smc3 (606062) subunits are rod-shaped molecules with globular ABC-like ATPases at one end and dimerization domains at the other, connected by long coiled coils. Smc1 and Smc3 associate to form V-shaped heterodimers. Their ATPase heads are thought to be bridged by a third subunit, Scc1, creating a huge triangular ring that can trap sister DNA molecules. Gruber et al. (2003) studied whether cohesin forms such rings in vivo. Proteolytic cleavage of Scc1 by separase at the onset of anaphase triggers its dissociation from chromosomes. The authors showed that N- and C-terminal Scc1 cleavage fragments remain connected due to their association with different heads of a single Smc1/Smc3 heterodimer. Cleavage of the Smc3 coiled coil was sufficient to trigger cohesin release from chromosomes and loss of sister cohesion, consistent with a topologic association with chromatin. </p><p>Wendt et al. (2008) described cohesin-binding sites in the human genome and showed that most of these are associated with the CCCTC-binding factor (CTCF; 604167), a zinc finger protein required for transcriptional insulation. CTCF is dispensable for cohesin loading onto DNA, but is needed to enrich cohesin at specific binding sites. Cohesin enables CTCF to insulate promoters from distant enhancers and controls transcription at the H19 (103280)/IGF2 (147470) locus. This role of cohesin seems to be independent of its role in cohesion. Wendt et al. (2008) proposed that cohesin functions as a transcriptional insulator, and speculated that subtle deficiencies in this function contribute to 'cohesinopathies' such as Cornelia de Lange syndrome (see 122470). </p><p>Cohesin's Scc1, Smc1, and Smc3 subunits form a tripartite ring structure, and it had been proposed that cohesin holds sister DNA molecules together by trapping them inside its ring. To test this, Haering et al. (2008) used site-specific crosslinking to create chemical connections at the 3 interfaces between the 3 constituent polypeptides of the ring, thereby creating covalently closed cohesin rings. As predicted by the ring entrapment model, this procedure produced dimeric DNA-cohesin structures that are resistant to protein denaturation. Haering et al. (2008) concluded that cohesin rings concatenate individual sister minichromosome DNA molecules. </p><p>Seitan et al. (2011) deleted the cohesin locus Rad21 in mouse thymocytes at a time in development when these cells stop cycling and rearrange their T-cell receptor alpha locus (TCRA; see 186880). Rad21-deficient thymocytes had a normal life span and retained the ability to differentiate, albeit with reduced efficiency. Loss of Rad21 led to defective chromatin architecture at the Tcra locus, where cohesin-binding sites flank the TEA promoter and the E-alpha enhancer, and demarcate Tcra from interspersed Tcrd (see 186810) elements and neighboring housekeeping genes. Cohesin was required for long-range promoter-enhancer interactions, Tcra transcription, H3K4me3 histone modifications that recruit the recombination machinery, and Tcra rearrangement. Provision of prearranged TCR transgenes largely rescued thymocyte differentiation, demonstrating that among thousands of potential target genes across the genome, defective Tcra rearrangement was limiting for the differentiation of cohesin-deficient thymocytes. Seitan et al. (2011) concluded that their findings firmly established a cell division-independent role for cohesin in Tcra locus rearrangement and provided a comprehensive account of the mechanisms by which cohesin enables cellular differentiation in a well-characterized mammalian system. </p><p>Huis in 't Veld et al. (2014) found that cohesin's proposed DNA exit gate is formed by interactions between SCC1 and the coiled-coil region of SMC3. Mutation of this interface abolished cohesin's ability to stably associate with chromatin and to mediate cohesion. Electron microscopy revealed that weakening of the SMC3-SCC1 interface resulted in opening of cohesin rings, as did proteolytic cleavage of SCC1. Huis in 't Veld et al. (2014) suggested that these open forms may resemble intermediate states of cohesin normally generated by the release factor WAPL (610754) and the protease separase (ESPL1; 604143), respectively. </p><p>Liu et al. (2021) found that Wapl was required for maintaining the pluripotent transcriptional state of mouse embryonic stem cells (mESCs), as acute depletion of Wapl resulted in cohesin redistribution and mESC differentiation. RNA-sequencing analysis revealed differential expression of genes in Wapl-depleted mESCs, with 80% being associated with embryonic tissue development, embryonic morphogenesis, and cell differentiation. Cohesin was required for maintaining pluripotency-specific gene expression by binding to specific regions in mESCs in a Wapl-dependent manner, and redistribution of cohesin binding was a unique feature in differentiated cells. As a result, mESC differentiation upon Wapl depletion was accompanied by global redistribution of cohesin from mESC type-specific binding regions to regions specific to differentiated cells. This cohesin redistribution affected local chromatin interactions and gene expression in a reversible manner. Cohesin binding to pluripotency-specific sites was dependent on the pioneer transcription factors Oct4 (POU5F1; 164177) and Sox2 (184429), as these factors created an open chromatin platform for cohesin binding. </p><p>Xie et al. (2022) found that depletion of the cohesin complex component Rad21 triggered spatial mixing of accessible chromatin domains (ACDs) without affecting their compaction in mouse ESCs. Moreover, spatial mixing of ACDs was independent of transcription, but it involved the bromodomain and extraterminal (BET) protein family. Depletion analysis in mouse ESCs identified Brd2 (601540) as a BET protein involved in organizing accessible chromatin and showed that Brd2 maintained compaction of ACDs and promoted their interactions in the absence of cohesin. The interplay between Brd2 and cohesin regulated genome topology in the nucleus, and cohesin antagonized Brd2 binding to chromatin and counteracted its ability to promote interactions between ACDs. In the absence of cohesin, the affinity of Brd2 for active chromatin increased. In addition to cohesin, Brd4 (608749) competed with Brd2 to inhibit its activities in genome organization, implying a division of labor for BET proteins to govern distinct regulatory processes in the accessible genome. Polymer simulation supported a model of Brd2-cohesin interplay for nuclear topology, where genome compartmentalization resulted from competition between loop extrusion and chromatin state-specific affinity interactions. </p>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Gligoris et al. (2014) showed that the N-terminal domain of yeast Scc1 contains 2 alpha-helices, forming a 4-helix bundle with the coiled coil emerging from the adenosine triphosphatase head of Smc3 (606062). Mutations affecting this interaction compromise cohesin's association with chromosomes. The interface is far from Smc3 residues, whose acetylation prevents cohesin's dissociation from chromosomes. Gligoris et al. (2014) concluded that cohesin complexes holding chromatids together in vivo do indeed have the configuration of heterotrimeric rings, and sister DNAs are entrapped within these. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By somatic cell hybrid analysis, Nomura et al. (1994) mapped the RAD21 gene to chromosome 8. Using FISH, McKay et al. (1996) refined the localization to 8q24. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Cornelia de Lange Syndrome 4 with or without Midline Brain Defects</em></strong></p><p>
|
|
In 2 unrelated patients with Cornelia de Lange syndrome-4 (CDLS4; 614701), Deardorff et al. (2012) identified different de novo heterozygous mutations in the RAD21 gene (P376R; 606462.0001 and C585R; 606462.0002). These mutations were identified by screening of the RAD21 gene in 258 individuals with a CDLS-like phenotype after genomewide copy-number analysis had identified a different patient with a de novo deletion of chromosome 8q24.1 that included RAD21. In vitro studies showed that the P376R mutation resulted in altered activity of the mutant protein rather than a loss of function. Patient cells showed decreased sister chromatid separation, increased aneuploidy, and defective DNA repair, as well as abnormal transcriptional activity in a zebrafish model. In contrast, functional studies of the C585R mutation suggested a loss of function, similar to patients with deletion of the RAD21 gene. Three additional patients with overlapping deletions were also studied. Although the phenotype of all patients overlapped that of CDLS, there was some divergence in facial features and the cognitive defects in most were not as severe. Common features included short stature, synophrys, micrognathia, brachydactyly, mild radioulnar differences, vertebral anomalies, and mild cognitive involvement, although the boy with the P376R mutation had more severe mental retardation, tetralogy of Fallot, and hearing loss. Deardorff et al. (2012) concluded that dominant RAD21 missense mutations result in more severe functional defects and a worse phenotype than loss-of-function (LOF) mutations or deletions. </p><p>In 3 unrelated patients with CDLS4 with midline brain defects in the holoprosencephaly (HPE) spectrum, Kruszka et al. (2019) identified heterozygous frameshift or nonsense mutations in the RAD21 gene (606462.0004-606462.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were identified from a cohort of over 277 patients with HPE who underwent exome sequencing. All of the mutations were predicted to result in a loss of function, although functional studies of the variants and studies of patient cells were not performed. A father of 1 of the patients with milder symptoms also carried the heterozygous mutation; the inheritance pattern of the other 2 patients was unknown. The authors noted that the RAD21 gene is intolerant to LOF variation based on data from gnomAD. </p><p>Goel and Parasivam (2020) identified a de novo heterozygous nonsense mutation in the RAD21 gene (E615X; 606462.0007) in a female fetus with CDLS4 and lobar holoprosencephaly. The mutation was identified by clinical exome analysis of 4,702 genes. No functional studies were performed. </p><p>In a 26-year-old woman with mild CDLS4, Boyle et al. (2017) identified a heterozygous mutation in the RAD21 gene (606462.0008). The woman's mother and 2 maternal aunts, who were also heterozygous for the mutation, had variable, milder features seen in CDLS4 but did not meet clinical criteria for the disorder. Boyle et al. (2017) concluded that the intrafamilial phenotypic variation suggested incomplete penetrance. </p><p>In a mother and son and an unrelated patient with CDLS4, Minor et al. (2014) identified heterozygous mutations in the RAD21 gene (606462.0009 and 606462.0010, respectively). </p><p>In a 5-year-old boy with CDLS4, Dorval et al. (2020) identified a heterozygous frameshift mutation in the RAD21 gene (606462.0011). </p><p>In a 15-month-old boy with CDLS4, Gudmundsson et al. (2019) identified a de novo heterozygous mutation in the RAD21 gene (606462.0012). Molecular modeling predicted that the mutation disrupted the interaction of RAD21 with SMC1A (300040). </p><p><strong><em>Mungan Syndrome</em></strong></p><p>
|
|
In a large Turkish family with intestinal pseudoobstruction mapping to chromosome 8q23-q24 (Mungan syndrome, MGS; 611376), Bonora et al. (2015) identified homozygosity for a missense mutation in the RAD21 gene (A622T; 606462.0003) that segregated fully with disease in the family and was not found in 500 Turkish controls or in public variant databases. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Bonora et al. (2015) injected zebrafish embryos with a rad21a slice-blocking morpholino and observed recapitulation of the chronic intestinal pseudoobstruction phenotype seen in their patients with Mungan syndrome. The morphants showed delayed food transit compared to wildtype zebrafish, and quantitative analysis of the zebrafish gut revealed marked depletion of enteric neurons at 4 and 5 days postfertilization in the morphants compared to controls, suggesting a neurogenic cause of the observed motility defects. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
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</span>
|
|
<strong>12 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0001 CORNELIA DE LANGE SYNDROME 4</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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RAD21, PRO376ARG
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<br />
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SNP: rs387907212,
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ClinVar: RCV000029138
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a boy with Cornelia de Lange syndrome-4 (CDLS4; 614701), Deardorff et al. (2012) identified a de novo heterozygous 1127C-G transversion in the RAD21 gene, resulting in a pro376-to-arg (P376R) substitution in a highly conserved residue within a region essential for the interaction of RAD21 with STAG proteins. The mutation was not found in 600 control chromosomes. The patient had microcephaly and a characteristic facial appearance, with thick, bushy, arched eyebrows, synophrys, prominent eyelashes, broad nasal bridge, smooth philtrum, upturned nose, and thin upper lip. He also had a number of additional congenital anomalies, including submucosal cleft palate, stapes fixation and hearing loss, thin fingers, left radioulnar synostosis, delayed skeletal age, vertebral clefting, pectus carinatum, short femoral neck, tetralogy of Fallot, intestinal malrotation, gastroesophageal reflux, and severe cognitive delay. In vitro studies showed that the P376R mutation resulted in an increased interaction of RAD21 with STAG1 (604358) and STAG2 (300826), potentially causing delayed sister chromatid separation or altered transcription. Analysis of metaphase spreads from the patient showed a higher percentage of sister chromatids with a closed-arm phenotype compared to controls. Patient cells showed increased aneuploidy, with a substantial gain or loss of 1 or more chromosomes compared to controls, causing a delay in cell cycle progression during mitosis from G2/M to G1 phase. Patient lymphoblastoid cells also showed decreased survival, increased chromosome breakage, and defective DNA repair after irradiation compared to control cells. </p><p>Rad21-null zebrafish show absent tissue-specific expression of Runx1 (151385). Deardorff et al. (2012) showed that zebrafish P377R (corresponding to human P376R) rescued transcriptional expression of Runx1 in 65% of Rad21-null zebrafish embryos, indicating partial function. However, this variant also caused altered transcription in wildtype embryos, causing 50% more atypical Runx1 expression than wildtype Rad21. These findings suggested altered activity of the mutant protein rather than a loss of function. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 CORNELIA DE LANGE SYNDROME 4</strong>
|
|
</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
RAD21, CYS585ARG
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<br />
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SNP: rs387907213,
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|
|
ClinVar: RCV000029139, RCV003133119
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</span>
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|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with Cornelia de Lange syndrome-4 (CDLS4; 614701), Deardorff et al. (2012) identified a de novo heterozygous 1753T-C transition in the RAD21 gene, resulting in a cys585-to-arg (C585R) substitution in a residue conserved in vertebrates. The mutation was not found in 600 control chromosomes. Structural modeling suggested that the C585R mutation is within the C terminus of RAD21 positioned near the interface of RAD21 and the C-terminal residues of SMC1 (300040), and may interfere with the interaction between these 2 cohesion proteins, causing a defect in formation of functional cohesin complexes. The patient had microcephaly and a characteristic facial appearance, with thick, bushy, arched eyebrows, synophrys, long eyelashes, broad nasal bridge, smooth philtrum, thin upper lip, short nose, and upslanted palpebral fissures. Other features included short fingers, fifth finger clinodactyly, small prominent first toe, long fourth metacarpal, cutis marmorata, and mild neurodevelopmental defects. Zebrafish C597R (corresponding to human C585R) failed to rescue Runx1 expression in Rad21-null embryos and showed only background levels of activity in wildtype embryos, consistent with a loss of function. </p>
|
|
</span>
|
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</div>
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<div>
|
|
<br />
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|
</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 MUNGAN SYNDROME (1 family)</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
RAD21, ALA622THR
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|
<br />
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|
|
SNP: rs775266057,
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|
|
|
gnomAD: rs775266057,
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|
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|
|
|
ClinVar: RCV000678504
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|
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|
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</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large Turkish family with intestinal pseudoobstruction (MGS; 611376), originally described by Mungan et al. (2003), Bonora et al. (2015) identified homozygosity for a c.1864G-A transition (c.1864G-A, NM_006265.2) in the RAD21 gene, resulting in an ala622-to-thr (A622T) substitution at a highly conserved residue. The mutation segregated fully with disease in the family and was not found in 500 Turkish controls or in the dbSNP, 1000 Genomes Project, or NHLBI Exome Sequencing Project databases. Although expression of RAD21 in patient lymphoblastoid cells was similar to that of controls, expression of the RAD21 target gene RUNX1 (151385) was significantly reduced both in patient cells and in HEK293 cells transfected with the A622T mutant. Zebrafish embryos injected with a morpholino blocking the ortholog gene rad21a showed partial or complete absence of runx1 expression, which could not be rescued with coinjection of the A622T mutant, indicating a loss-of-function effect in vivo. Bonora et al. (2015) identified 2 RAD21 binding sites in the APOB (107730) proximal promoter and observed that nuclear extracts from wildtype cells formed a specific complex with either region, whereas no complex was observed in the presence of mutant RAD21. In addition, gut-specific APOB48 levels were increased in patient serum compared to controls; however, sera from sporadic patients with intestinal pseudoobstruction who were negative for mutation in RAD21 also showed consistently increased APOB48 levels compared to controls. Bonora et al. (2015) suggested that APOB48 expression might represent a marker for the degree of neuronal loss or symptom severity. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 CORNELIA DE LANGE SYNDROME 4 WITH MIDLINE BRAIN DEFECTS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RAD21, c.1548delinsTC
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs1812331711,
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|
|
|
|
|
|
|
ClinVar: RCV001072117
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 7-year-old girl (patient 12) with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; 614701), Kruszka et al. (2019) identified a heterozygous c.1548delinsTC mutation in the RAD21 gene, predicted to result in a frameshift and premature termination (Glu518ArgfsTer19). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from her mildly affected father. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function (LOF). The authors noted that the RAD21 gene is intolerant to LOF variation based on data from gnomAD. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CORNELIA DE LANGE SYNDROME 4 WITH MIDLINE BRAIN DEFECTS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
RAD21, GLN197TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1352385210,
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|
|
|
|
|
gnomAD: rs1352385210,
|
|
|
|
|
|
ClinVar: RCV001072118
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 14-year-old boy (patient 13) with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; 614701), Kruszka et al. (2019) identified a heterozygous c.589C-T transition (chr8.117869605G-A, GRCh37) in the RAD21 gene, resulting in a gln197-to-ter (Q197X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was predicted to result in a loss of function (LOF), although functional studies of the variant and studies of patient cells were not performed. The inheritance pattern could not be determined because parental DNA was unavailable. The authors noted that the RAD21 gene is intolerant to LOF variation based on data from gnomAD. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
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|
|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CORNELIA DE LANGE SYNDROME 4 WITH MIDLINE BRAIN DEFECTS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
RAD21, 8-BP DEL, NT1217
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<br />
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|
|
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SNP: rs1812376090,
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|
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ClinVar: RCV001072119, RCV002286809
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|
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</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 2-year-old boy (patient 14) with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; 614701), Kruszka et al. (2019) identified a heterozygous 8-bp deletion (c.1217_1224del; chr8.117,864,885del8, GRCh37), predicted to result in a frameshift and premature termination (Lys406ArgfsTer4). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was predicted to result in a loss of function (LOF), although functional studies of the variant and studies of patient cells were not performed. The inheritance pattern could not be determined because parental DNA was unavailable. The authors noted that the RAD21 gene is intolerant to LOF variation based on data from gnomAD. </p>
|
|
</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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CORNELIA DE LANGE SYNDROME 4 WITH MIDLINE BRAIN DEFECTS</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
RAD21, GLU615TER
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|
|
|
<br />
|
|
|
|
SNP: rs1425483905,
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|
|
|
gnomAD: rs1425483905,
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ClinVar: RCV001260876
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</span>
|
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</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female fetus with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; 614701), Goel and Parasivam (2020) identified a de novo heterozygous c.1843G-T transversion in the RAD21 gene, resulting in a glu615-to-ter (E615X) substitution. The mutation was identified by clinical whole-exome sequencing. Functional studies were not performed. The patient had lobar holoprosencephaly. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<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">
|
|
<strong>.0008 CORNELIA DE LANGE SYNDROME 4</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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RAD21, 1-BP DEL, 704G
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<br />
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SNP: rs1812478613,
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ClinVar: RCV001281378
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 26-year-old woman with mild Cornelia de Lange syndrome-4 (CDLS4; 614701), Boyle et al. (2017) identified heterozygosity for a 1-bp deletion (c.704delG, NM_0062625.2) in exon 13 of the RAD21 gene, predicted to result in a frameshift and premature termination (Ser235IlefsTer19), leading to a nonfunctional protein or nonsense-mediated mRNA decay. The mutation, which was identified by targeted next-generation sequencing, was also present in heterozygous state in the patient's mother and 2 maternal aunts, who had variable, milder features seen in CDLS4 but did not fulfill the clinical criteria for CDLS. Functional studies were not performed. </p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CORNELIA DE LANGE SYNDROME 4</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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RAD21, 665-BP DEL, EX13DEL
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<br />
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ClinVar: RCV001543703
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 3-year-old boy (patient 1) and his mother with mild Cornelia de Lange syndrome-4 (CDLS4; 614701), Minor et al. (2014) identified a heterozygous 665-bp deletion (chr8.(117,860,090_117,861,110)_(117,861,670_117,861,700)del) in the RAD21 gene with a 2-bp microhomology (TT) at the breakpoint junction, resulting in an in-frame deletion of exon 13. The deletion was identified by targeted array-CGH and confirmed by real-time quantitative PCR and breakpoint sequencing. The deletion was not detected in an in-house database of 452 patients tested for diagnostic purposes. The mutation was predicted to affect the interaction of RAD21 with SMC1A (300040) and alter the function of the cohesion complex. </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>.0010 CORNELIA DE LANGE SYNDROME 4</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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RAD21, 2-BP DUP, NT592
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<br />
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SNP: rs2130469261,
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ClinVar: RCV001543704
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 12-year-old boy (patient 2) with mild Cornelia de Lange syndrome-4 (CDLS4; 614701), Minor et al. (2014) identified a heterozygous 2-bp duplication (c.592_593dup, NM_006265) in exon 6 of the RAD21 gene, resulting in a frameshift and premature termination (Ser198ArgfsTer6). The mutation was identified by sequence analysis of the RAD21 gene. The mutation was not present in the mother, but the father was not available for testing. The mutation was predicted to result in either nonsense-mediated decay or a truncated protein missing functional domains necessary for the interaction with WAPL (610754), PDS5B (605333), and STAG1 (604358). </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>.0011 CORNELIA DE LANGE SYNDROME 4</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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RAD21, 4-BP DEL, NT943
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<br />
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SNP: rs2130463115,
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ClinVar: RCV001543705
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 5-year-old by with mild Cornelia de Lange syndrome-4 (CDLS4; 614701), Dorval et al. (2020) identified a de novo heterozygous 4-bp deletion (c.943_946del, NM_006265) in exon 9 of the RAD21 gene, resulting in a frameshift and premature termination (Glu315GlnfsTer9). The mutation was identified by sequencing of a multigene panel containing 5 known CDLS genes and confirmed by Sanger sequencing. The mutation was not present in the ExAC and gnomAD databases. Functional studies were not performed. </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>.0012 CORNELIA DE LANGE SYNDROME 4</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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RAD21, 3-BP DEL, 1774TTG
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<br />
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SNP: rs1563686762,
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ClinVar: RCV000680272, RCV004721527
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 15-month-old boy with mild Cornelia de Lange syndrome-4 (CDLS4; 614701), Gudmundsson et al. (2019) identified a de novo heterozygous 3-bp deletion (c.1774_1776del, NM_006265) in the RAD21 gene, resulting in deletion of Gln592, a conserved residue. The de novo mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. The mutation was not present in the ExAC, SweGen, and gnomAD databases. Molecular modeling predicted that the mutation disrupted the interaction of RAD21 with SMC1A (300040). </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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<ol>
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<li>
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Bonora, E., Bianco, F., Cordeddu, L., Bamshad, M., Francescatto, L., Dowless, D., Stanghellini, V. Cogliandro, R. F., Lindberg, G., Mungan, Z., Cefle, K., Ozcelik, T., and 14 others.
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<strong>Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction.</strong>
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Gastroenterology 148: 771-782, 2015.
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[Full Text: https://doi.org/10.1053/j.gastro.2014.12.034]
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Boyle, M. I., Jespersgaard, C., Nazaryan, L., Bisgaard, A.-M., Tumer, Z.
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<strong>RAD21 mutations cause a human cohesinopathy.</strong>
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<strong>Closing the cohesin ring: structure and function of its Smc3-kleisin interface.</strong>
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Goel, H., Parasivam, G.
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<strong>Another case of holoprosencephaly associated with RAD21 loss-of-function variant. (Letter)</strong>
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Brain 143: e64, 2020. Note: Electronic Article.
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Gruber, S., Haering, C. H., Nasmyth, K.
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<strong>Chromosomal cohesin forms a ring.</strong>
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Cell 112: 765-777, 2003.
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Gudmundsson, S., Anneren, G., Marcos-Alcalde, I., Wilbe, M., Melin, M., Gomez-Puertas, P., Bondeson, M.-L.
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<strong>A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4--review of the literature.</strong>
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Haering, C. H., Farcas, A.-M., Arumugam, P., Metson, J., Nasmyth, K.
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<strong>The cohesin ring concatenates sister DNA molecules.</strong>
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Nature 454: 297-301, 2008.
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Hakimi, M.-A., Bochar, D. A., Schmiesing, J. A., Dong, Y., Barak, O. G., Speicher, D. W., Yokomori, K., Shiekhattar, R.
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<strong>A chromatin remodelling complex that loads cohesin onto human chromosomes.</strong>
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Nature 418: 994-998, 2002.
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Science 293: 1320-1323, 2001.
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Hoque, M. T., Ishikawa, F.
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J. Biol. Chem. 276: 5059-5067, 2001.
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<p class="mim-text-font">
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Hoque, M. T., Ishikawa, F.
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Huis in 't Veld, P. J., Herzog, F., Ladurner, R., Davidson, I. F., Piric, S., Kreidl, E., Bhaskara, V., Aebersold, R., Peters, J.-M.
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<strong>Characterization of a DNA exit gate in the human cohesin ring.</strong>
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<p class="mim-text-font">
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Kruszka, P., Berger, S. I., Casa, V., Dekker, M. R., Gaesser, J., Weiss, K., Martinez, A. F., Murdock, D. R, Louie, R. J., Prijoles, E. J., Lichty, A. W., Brouwer, O. F., and 23 others.
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<strong>Cohesin complex-associated holoprosencephaly.</strong>
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Brain 142: 2631-2643, 2019.
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<p class="mim-text-font">
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Liu, N. Q., Maresca, M., van den Brand, T., Braccioli, L., Schijns, M. M. G. A., Teunissen, H., Bruneau, B. G., Nora, E. P., de Wit, E.
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<strong>WAPL maintains a cohesin loading cycle to preserve cell-type-specific distal gene regulation.</strong>
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Nature Genet. 53: 100-109, 2021.
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<p class="mim-text-font">
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McKay, M. J., Troelstra, C., van der Spek, P., Kanaar, R., Smit, B., Hagemeijer, A., Bootsma, D., Hoeijmakers, J. H. J.
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<strong>Sequence conservation of the rad21 Schizosaccharomyces pombe DNA double-strand break repair gene in human and mouse.</strong>
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[PubMed: 8812457]
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<p class="mim-text-font">
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Minor, A., Shinawi, M., Hogue, J. S., Vineyard, M., Hamlin, D. R., Tan, C., Donato, K., Wysinger, L., Botes, S., Das, S., del Gaudio, D.
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<strong>Two novel RAD 21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case.</strong>
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Gene 537: 279-284, 2014.
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[PubMed: 24378232]
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[Full Text: https://doi.org/10.1016/j.gene.2013.12.045]
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<p class="mim-text-font">
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Mungan, Z., Akyuz, F., Bugra, Z., Yonal, O., Ozturk, S., Acar, A., Cevikbas, U.
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<strong>Familial visceral myopathy with pseudo-obstruction, megaduodenum, Barrett's esophagus, and cardiac abnormalities.</strong>
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Am. J. Gastroent. 98: 2556-2560, 2003.
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[PubMed: 14638363]
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[Full Text: https://doi.org/10.1111/j.1572-0241.2003.08707.x]
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</p>
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<li>
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<p class="mim-text-font">
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Nomura, N., Nagase, T., Miyajima, N., Sazuka, T., Tanaka, A., Sato, S., Seki, N., Kawarabayasi, Y., Ishikawa, K., Tabata, S.
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<strong>Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1.</strong>
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DNA Res. 1: 223-229, 1994.
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[PubMed: 7584044]
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[Full Text: https://doi.org/10.1093/dnares/1.5.223]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Sadano, H., Sugimoto, H., Sakai, F., Nomura, N., Osumi, T.
|
|
<strong>NXP-1, a human protein related to Rad21/Scc1/Mcd1, is a component of the nuclear matrix.</strong>
|
|
Biochem. Biophys. Res. Commun. 267: 418-422, 2000.
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[PubMed: 10623634]
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[Full Text: https://doi.org/10.1006/bbrc.1999.1969]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Seitan, V. C., Hao, B., Tachibana-Konwalski, K., Lavagnolli, T., Mira-Bontenbal, H., Brown, K. E., Teng, G., Carroll, T., Terry, A., Horan, K., Marks, H., Adams, D. J., Schatz, D. G., Aragon, L., Fisher, A. G., Krangel, M. S., Nasmyth, K., Merkenschlager, M.
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|
<strong>A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation.</strong>
|
|
Nature 476: 467-471, 2011.
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|
[PubMed: 21832993]
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[Full Text: https://doi.org/10.1038/nature10312]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Sumara, I., Vorlaufer, E., Gieffers, C., Peters, B. H., Peters, J.-M.
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Wendt, K. S., Yoshida, K., Itoh, T., Bando, M., Koch, B., Schirghuber, E., Tsutsumi, S., Nagae, G., Ishihara, K., Mishiro, T., Yahata, K., Imamoto, F., Aburatani, H., Nakao, M., Imamoto, N., Maeshima, K., Shirahige, K., Peters, J.-M.
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<strong>Cohesin mediates transcriptional insulation by CCCTC-binding factor.</strong>
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Xie, L., Dong, P., Qi, Y., Hsieh, T. S., English, B. P., Jung, S., Chen, X., De Marzio, M., Casellas, R., Chang, H. Y., Zhang, B., Tjian, R., Liu, Z.
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[Full Text: https://doi.org/10.1038/s41588-022-01044-9]
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Bao Lige - updated : 02/01/2023<br>Hilary J. Vernon - updated : 07/29/2021<br>Bao Lige - updated : 04/28/2021<br>Hilary J. Vernon - updated : 01/11/2021<br>Hilary J. Vernon - updated : 10/09/2020<br>Cassandra L. Kniffin - updated : 04/10/2020<br>Marla J. F. O'Neill - updated : 09/06/2018<br>Ada Hamosh - updated : 01/14/2015<br>Ada Hamosh - updated : 1/14/2015<br>Cassandra L. Kniffin - updated : 7/5/2012<br>Ada Hamosh - updated : 9/21/2011<br>Ada Hamosh - updated : 8/12/2008<br>Ada Hamosh - updated : 3/7/2008<br>Stylianos E. Antonarakis - updated : 4/14/2003<br>Patricia A. Hartz - updated : 12/17/2002<br>Ada Hamosh - updated : 9/17/2002
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