3964 lines
321 KiB
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3964 lines
321 KiB
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- *606062 - STRUCTURAL MAINTENANCE OF CHROMOSOMES 3; SMC3
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- OMIM
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<p>
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<span class="h4">*606062</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606062">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000108055;t=ENST00000361804" 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=9126" 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=606062" 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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<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=ENSG00000108055;t=ENST00000361804" 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_005445" 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_005445" 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=606062" 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=05829&isoform_id=05829_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/SMC3" 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/3005929,3089368,4885399,4894360,28958118,29337005,119569942,119569943,158260565,164691107" 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/Q9UQE7" 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=9126" 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=ENSG00000108055;t=ENST00000361804" 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=SMC3" 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=SMC3" 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+9126" 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/SMC3" 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:9126" 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/9126" 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=chr10&hgg_gene=ENST00000361804.5&hgg_start=110567695&hgg_end=110606048&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/genes/HGNC:2468" 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/smc3" 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=606062[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=606062[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/SMC3/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/ENSG00000108055" 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.gwascentral.org/search?q=SMC3" 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=SMC3" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/SMC3" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SMC3&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/PA26966" 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:2468" 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/FBgn0015615.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:1339795" 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/SMC3#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:1339795" 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/9126/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=9126" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00004873;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-3196" 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:9126" 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=SMC3&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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606062
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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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STRUCTURAL MAINTENANCE OF CHROMOSOMES 3; SMC3
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
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CHONDROITIN SULFATE PROTEOGLYCAN 6; CSPG6<br />
|
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BAMACAN; BAM<br />
|
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HUMAN CHROMOSOME-ASSOCIATED POLYPEPTIDE; HCAP
|
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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=SMC3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SMC3</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/10/559?start=-3&limit=10&highlight=559">10q25.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr10:110567695-110606048&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'})">10:110,567,695-110,606,048</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
|
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
|
<a href="/geneMap/10/559?start=-3&limit=10&highlight=559">
|
|
10q25.2
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Cornelia de Lange syndrome 3
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/610759"> 610759 </a>
|
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|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/606062" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/606062" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<p>The SMC3 gene encodes a subunit of the evolutionarily conserved multimeric cohesin complex, which has been implicated in a wide range of functions, including sister chromatid cohesion, DNA repair mechanisms, gene regulation, and maintenance of genome stability (summary by <a href="#6" class="mim-tip-reference" title="Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J., and 50 others. <strong>De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.</strong> Hum. Mutat. 36: 454-462, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25655089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25655089</a>] [<a href="https://doi.org/10.1002/humu.22761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25655089">Gil-Rodriguez et al., 2015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25655089" 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>Proteoglycans are specialized glycoproteins with heterogeneous structures that are found in all connective tissues and on cell surfaces. SMC3, or bamacan (BAM), which was originally isolated from embryonic parietal yolk sac, is an abundant secreted chondroitin sulfate proteoglycan in basement membranes and an intracellular protein. See SCC1 (<a href="/entry/606462">606462</a>) and <a href="#16" 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> for information on the role of SMC3 in cohesin association with and dissociation from chromosomes. <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>Using a yeast 2-hybrid screen of a B-cell cDNA library with SMAP (<a href="/entry/601836">601836</a>) as bait, followed by probing a brain cDNA library, <a href="#15" class="mim-tip-reference" title="Shimizu, K., Shirataki, H., Honda, T., Minami, S., Takai, Y. <strong>Complex formation of SMAP/KAP3, a KIF3A/B ATPase motor-associated protein, with a human chromosome-associated polypeptide.</strong> J. Biol. Chem. 273: 6591-6594, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9506951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9506951</a>] [<a href="https://doi.org/10.1074/jbc.273.12.6591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9506951">Shimizu et al. (1998)</a> obtained a cDNA encoding SMC3, which they termed HCAP. Sequence analysis predicted that the 1,217-amino acid HCAP protein is 98% identical to rat Cspg6 and is homologous to frog and fly Cap proteins. HCAP has a head-rod-tail organization, which is common in SMC family members. The head contains an NTP-binding motif and the tail has a DA box. Western blot analysis showed expression of an approximately 140-kD nuclear protein. GST-pull down analysis confirmed the specific interaction between SMAP and HCAP. Fluorescence microscopy demonstrated an association of HCAP with mitotic chromosomes. Coimmunoprecipitation analysis indicated that HCAP is associated with SMAP and KIF3A (<a href="/entry/604683">604683</a>)/KIF3B (<a href="/entry/603754">603754</a>) in the nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9506951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Northern blot analysis, <a href="#5" class="mim-tip-reference" title="Ghiselli, G., Siracusa, L. D., Iozzo, R. V. <strong>Complete cDNA cloning, genomic organization, chromosomal assignment, functional characterization of the promoter, and expression of the murine bamacan gene.</strong> J. Biol. Chem. 274: 17384-17393, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10358101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10358101</a>] [<a href="https://doi.org/10.1074/jbc.274.24.17384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10358101">Ghiselli et al. (1999)</a> detected ubiquitous expression of a 4.2-kb Bam transcript in mouse, with highest levels in testis and brain, lower levels in muscle, heart, lung, kidney, colon, and thymus, and much lower levels in spleen, kidney, and liver. <a href="#4" class="mim-tip-reference" title="Ghiselli, G., Iozzo, R. V. <strong>Overexpression of bamacan/SMC3 causes transformation.</strong> J. Biol. Chem. 275: 20235-20238, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10801778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10801778</a>] [<a href="https://doi.org/10.1074/jbc.C000213200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10801778">Ghiselli and Iozzo (2000)</a> detected high levels of BAM expression in spontaneously transformed human and mouse colon carcinoma cells. They proposed that deregulated BAM/SMC3 expression may be directly linked to oncogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10358101+10801778" 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 genomic sequence analysis, <a href="#5" class="mim-tip-reference" title="Ghiselli, G., Siracusa, L. D., Iozzo, R. V. <strong>Complete cDNA cloning, genomic organization, chromosomal assignment, functional characterization of the promoter, and expression of the murine bamacan gene.</strong> J. Biol. Chem. 274: 17384-17393, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10358101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10358101</a>] [<a href="https://doi.org/10.1074/jbc.274.24.17384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10358101">Ghiselli et al. (1999)</a> determined that the mouse Smc3 gene contains 31 exons and is driven by a promoter enriched in GC sequences and lacking TATA and CAAT boxes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10358101" 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="#8" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 11/11/2015."None>Gross (2015)</a> mapped the SMC3 gene to chromosome 10q25.2 based on an alignment of the SMC3 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF020043" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF020043</a>) with the genomic sequence (GRCh38).</p><p><a href="#5" class="mim-tip-reference" title="Ghiselli, G., Siracusa, L. D., Iozzo, R. V. <strong>Complete cDNA cloning, genomic organization, chromosomal assignment, functional characterization of the promoter, and expression of the murine bamacan gene.</strong> J. Biol. Chem. 274: 17384-17393, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10358101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10358101</a>] [<a href="https://doi.org/10.1074/jbc.274.24.17384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10358101">Ghiselli et al. (1999)</a> mapped the mouse Smc3 gene to chromosome 19, in a region showing homology of synteny to human 10q25. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10358101" 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 yeast, the cohesin complex is essential for sister chromatid cohesion during mitosis. The Smc1 (<a href="/entry/300040">300040</a>) and Smc3 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="#9" 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>Cohesin's Scc1 (<a href="/entry/606462">606462</a>), 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="#10" 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="#10" 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="#14" class="mim-tip-reference" title="Rolef Ben-Shahar, T. R., Heeger, S., Lehane, C., East, P., Flynn, H., Skehel, M., Uhlmann, F. <strong>Eco1-dependent cohesin acetylation during establishment of sister chromatid cohesion.</strong> Science 321: 563-566, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18653893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18653893</a>] [<a href="https://doi.org/10.1126/science.1157774" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18653893">Rolef Ben-Shahar et al. (2008)</a> identified spontaneous suppressors of the thermosensitive eco1-1 allele (see <a href="/entry/609674">609674</a>) in budding yeast. An acetylation-mimicking mutation of a conserved lysine in cohesin's Smc3 subunit makes Eco1 dispensable for cell growth, and <a href="#14" class="mim-tip-reference" title="Rolef Ben-Shahar, T. R., Heeger, S., Lehane, C., East, P., Flynn, H., Skehel, M., Uhlmann, F. <strong>Eco1-dependent cohesin acetylation during establishment of sister chromatid cohesion.</strong> Science 321: 563-566, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18653893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18653893</a>] [<a href="https://doi.org/10.1126/science.1157774" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18653893">Rolef Ben-Shahar et al. (2008)</a> showed that Smc3 is acetylated in an Eco1-dependent manner during DNA replication to promote sister chromatid cohesion. A second set of eco1-1 suppressors inactivate the budding yeast ortholog of the cohesin destabilizer Wapl (<a href="/entry/610754">610754</a>). <a href="#14" class="mim-tip-reference" title="Rolef Ben-Shahar, T. R., Heeger, S., Lehane, C., East, P., Flynn, H., Skehel, M., Uhlmann, F. <strong>Eco1-dependent cohesin acetylation during establishment of sister chromatid cohesion.</strong> Science 321: 563-566, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18653893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18653893</a>] [<a href="https://doi.org/10.1126/science.1157774" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18653893">Rolef Ben-Shahar et al. (2008)</a> concluded that Eco1 modifies cohesin to stabilize sister chromatid cohesion in parallel with a cohesion establishment reaction that is in principle Eco1-independent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18653893" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Unal, E., Heidinger-Pauli, J. M., Kim, W., Guacci, V., Onn, I., Gygi, S. P., Koshland, D. E. <strong>A molecular determinant for the establishment of sister chromatid cohesion.</strong> Science 321: 566-569, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18653894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18653894</a>] [<a href="https://doi.org/10.1126/science.1157880" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18653894">Unal et al. (2008)</a> found that in budding yeast, the head domain of the Smc3 protein subunit of cohesin is acetylated by the Eco1p protein acetyltransferase at 2 evolutionarily conserved residues, promoting the chromatin-bound cohesin to tether sister chromatids. Smc3 protein acetylation is induced in S phase after the chromatin loading of cohesin and is suppressed in G1 and G2/M. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18653894" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Zhang, J., Shi, X., Li, Y., Kim, B.-J., Jia, J., Huang, Z., Yang, T., Fu, X., Jung, S. Y., Wang, Y., Zhang, P., Kim, S.-T., Pan, X., Qin, J. <strong>Acetylation of Smc3 by Eco1 is required for S phase sister chromatid cohesion in both human and yeast.</strong> Molec. Cell 31: 143-151, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18614053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18614053</a>] [<a href="https://doi.org/10.1016/j.molcel.2008.06.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18614053">Zhang et al. (2008)</a> showed that acetylation of SMC3 by ESCO1 was required for S phase sister chromatid cohesion in human cells and in yeast. In HeLa cells, ESCO1 acetylated SMC3 on lys105 and lys106, and knockdown of ESCO1 expression via small interfering RNA significantly decreased SMC3 acetylation. Expression of a dominant-negative nonacetylatable SMC3 mutant in HEK293T cells permitted SMC3 incorporation into the cohesin complex, but it interfered with sister chromatid cohesion and resulted in scattered chromosomes and chromosome breakage. <a href="#19" class="mim-tip-reference" title="Zhang, J., Shi, X., Li, Y., Kim, B.-J., Jia, J., Huang, Z., Yang, T., Fu, X., Jung, S. Y., Wang, Y., Zhang, P., Kim, S.-T., Pan, X., Qin, J. <strong>Acetylation of Smc3 by Eco1 is required for S phase sister chromatid cohesion in both human and yeast.</strong> Molec. Cell 31: 143-151, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18614053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18614053</a>] [<a href="https://doi.org/10.1016/j.molcel.2008.06.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18614053">Zhang et al. (2008)</a> concluded that ESCO1 is the major acetyltransferase required for SMC3 acetylation, and that SMC3 acetylation is required for sister chromatid cohesion and maintenance of genomic stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18614053" 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>Through single-molecule analysis, <a href="#17" class="mim-tip-reference" title="Terret, M.-E., Sherwood, R., Rahman, S., Qin, J., Jallepalli, P. V. <strong>Cohesin acetylation speeds the replication fork.</strong> Nature 462: 231-234, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19907496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19907496</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19907496[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/nature08550" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19907496">Terret et al. (2009)</a> demonstrated that a replication complex, the RFC-CTF18 clamp loader (see <a href="/entry/613201">613201</a>), controls the velocity spacing and restart activity of replication forks in human cells and is required for robust acetylation of cohesin's SMC3 subunit and sister chromatid cohesion. Unexpectedly, <a href="#17" class="mim-tip-reference" title="Terret, M.-E., Sherwood, R., Rahman, S., Qin, J., Jallepalli, P. V. <strong>Cohesin acetylation speeds the replication fork.</strong> Nature 462: 231-234, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19907496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19907496</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19907496[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/nature08550" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19907496">Terret et al. (2009)</a> discovered that cohesin acetylation itself is a central determinant of fork processivity, as slow-moving replication forks were found in cells lacking the Eco1-related acetyltransferases ESCO1 or ESCO2 (<a href="/entry/609353">609353</a>) (including those derived from Roberts syndrome (<a href="/entry/268300">268300</a>) patients, in whom ESCO2 is biallelically mutated), and in cells expressing a form of SMC3 that cannot be acetylated. This defect was a consequence of cohesin's hyperstable interaction with 2 regulatory cofactors, WAPL (<a href="/entry/610754">610754</a>) and PDS5A (<a href="/entry/613200">613200</a>); removal of either cofactor allowed forks to progress rapidly without ESCO1, ESCO2, or RFC-CTF18. <a href="#17" class="mim-tip-reference" title="Terret, M.-E., Sherwood, R., Rahman, S., Qin, J., Jallepalli, P. V. <strong>Cohesin acetylation speeds the replication fork.</strong> Nature 462: 231-234, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19907496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19907496</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19907496[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/nature08550" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19907496">Terret et al. (2009)</a> concluded that their results showed a novel mechanism for clamp loader-dependent fork progression, mediated by the posttranslational modification and structural remodeling of the cohesin ring. Loss of this regulatory mechanism leads to the spontaneous accrual of DNA damage and may contribute to the abnormalities of the Roberts syndrome cohesinopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19907496" 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="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 the proposed DNA exit gate of cohesin 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="#11" 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 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>Using biochemical reconstitution, <a href="#2" class="mim-tip-reference" title="Davidson, I. F., Bauer, B., Goetz, D., Tang, W., Wutz, G., Peters, J. M. <strong>DNA loop extrusion by human cohesin.</strong> Science 366: 1338-1345, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31753851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31753851</a>] [<a href="https://doi.org/10.1126/science.aaz3418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31753851">Davidson et al. (2019)</a> found that single human cohesin complexes form DNA loops symmetrically at rates up to 2.1 kilobase pairs per second. Loop formation and maintenance depend on cohesin's ATPase activity and on NIPBL (<a href="/entry/608667">608667</a>)-MAU2 (<a href="/entry/614560">614560</a>), but not on topologic entrapment of DNA by cohesin (components include SMC3; SMC1A, <a href="/entry/300040">300040</a>; STAG1, <a href="/entry/604358">604358</a>; STAG2, <a href="/entry/300826">300826</a>). During loop formation, cohesin and NIPBL-MAU2 reside at the base of loops, which indicates that they generate loops by extrusion. <a href="#2" class="mim-tip-reference" title="Davidson, I. F., Bauer, B., Goetz, D., Tang, W., Wutz, G., Peters, J. M. <strong>DNA loop extrusion by human cohesin.</strong> Science 366: 1338-1345, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31753851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31753851</a>] [<a href="https://doi.org/10.1126/science.aaz3418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31753851">Davidson et al. (2019)</a> concluded that their results showed that cohesin and NIPBL-MAU2 form an active holoenzyme that interacts with DNA either pseudotopologically or nontopologically to extrude genomic interphase DNA into loops. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31753851" 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="#7" 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 (<a href="/entry/606462">606462</a>) contains 2 alpha-helices, forming a 4-helix bundle with the coiled coil emerging from the adenosine triphosphatase head of Smc3. 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="#7" 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>Cornelia de Lange syndrome (CDLS; see <a href="/entry/122470">122470</a>) is a multisystem developmental disorder including craniofacial dysmorphia, hirsutism, malformations of the upper limbs, and neurodevelopmental delay. Because mutations in the cohesin complex member NIPBL (<a href="/entry/608667">608667</a>) result in CDLS, <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D. <strong>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.</strong> Am. J. Hum. Genet. 80: 485-494, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273969[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/511888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273969">Deardorff et al. (2007)</a> screened 115 NIPBL mutation-negative individuals with sporadic or familial CDLS and probands with CDLS-variant phenotypes for mutations in the cohesin complex component genes SMC3 and SMC1A (<a href="/entry/300040">300040</a>). They found 1 mutation in SMC3 (<a href="#0001">606062.0001</a>) in a patient with a milder CDLS phenotype (CDLS3; <a href="/entry/610759">610759</a>). Structural analysis of the mutant SMC3 protein indicated that it was likely to produce a functional cohesin complex, but <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D. <strong>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.</strong> Am. J. Hum. Genet. 80: 485-494, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273969[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/511888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273969">Deardorff et al. (2007)</a> posited that the mutation may alter the chromosome binding dynamics of the protein. Additionally, the authors found 14 additional mutations in the SMC1A gene in patients with X-linked CDLS (CDLS2; <a href="/entry/300590">300590</a>). The data indicated that SMC3 and SMC1A mutations contribute to approximately 5% of cases of CDLS, resulting in a consistently mild phenotype with absence of major structural anomalies typically associated with CDLS, and in some instances, resulted in a phenotype that approached that of apparently nonsyndromic mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17273969" 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 5 unrelated patients with CDLS3, <a href="#1" class="mim-tip-reference" title="Ansari, M., Poke, G., Ferry, Q., Williamson, K., Aldridge, R., Meynert, A. M., Bengani, H., Chan, C. Y., Kayserili, H., Avci, S., Hennekam, R. C. M., Lampe, A. K., and 63 others. <strong>Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.</strong> J. Med. Genet. 51: 659-668, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25125236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25125236</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25125236[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25125236">Ansari et al. (2014)</a> identified 5 different heterozygous mutations in the SMC3 gene (see, e.g., <a href="#0002">606062.0002</a> and <a href="#0003">606062.0003</a>). The mutations were shown to occur de novo in those with available parental DNA. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25125236" 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="Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J., and 50 others. <strong>De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.</strong> Hum. Mutat. 36: 454-462, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25655089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25655089</a>] [<a href="https://doi.org/10.1002/humu.22761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25655089">Gil-Rodriguez et al. (2015)</a> identified heterozygous mutations in the SMC3 gene (see, e.g., <a href="#0001">606062.0001</a>; <a href="#0004">606062.0004</a>-<a href="#0008">606062.0008</a>) in 10 unrelated patients with CDLS3. The mutations were shown to occur de novo in those with available parental DNA. The mutations were found either by gene panel sequencing or by exome sequencing, and none were found in 100 control alleles of publicly available databases. Functional studies were not performed. Based on their studies and previous reports, <a href="#6" class="mim-tip-reference" title="Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J., and 50 others. <strong>De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.</strong> Hum. Mutat. 36: 454-462, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25655089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25655089</a>] [<a href="https://doi.org/10.1002/humu.22761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25655089">Gil-Rodriguez et al. (2015)</a> estimated that SMC3 mutations account for about 1 to 2% of patients with features of CDLS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25655089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a male fetus with a severe form of CDLS3 with midline brain defects manifest as semilobar holoprosencephaly, <a href="#12" 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 de novo heterozygous 15-bp in-frame deletion in the SMC3 gene (<a href="#0009">606062.0009</a>). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; the patient was ascertained from a large cohort of over 277 patients with holoprosencephaly. 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 SMC3 gene is intolerant to LOF mutations based on data from the gnomAD database. <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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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=606062[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863223279 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863223279;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=rs863223279" 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=rs863223279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a male with a mild variant form of Cornelia de Lange syndrome (CDLS3; <a href="/entry/610759">610759</a>), <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D. <strong>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.</strong> Am. J. Hum. Genet. 80: 485-494, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273969[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/511888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273969">Deardorff et al. (2007)</a> found a 3-bp deletion in the SMC3 gene (1464_1466delAGA), resulting in deletion of glu488 (E488del). The mutation occurred in the junction of the N-terminal coiled-coil and the hinge domain, a region conserved from bacteria to human. Neither parent carried the mutation, indicating that it was a de novo event. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17273969" 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="Revenkova, E., Focarelli, M. L., Susani, L., Paulis, M., Bassi, M. T., Mannini, L., Frattini, A., Delia, D., Krantz, I., Vezzoni, P., Jessberger, R., Musio, A. <strong>Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA.</strong> Hum. Molec. Genet. 18: 418-427, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18996922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18996922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18996922[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/hmg/ddn369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18996922">Revenkova et al. (2009)</a> showed that E488del-mutant SMC3 affected the affinity of SMC hinge dimers for DNA. Mutated hinge dimers bound DNA with higher affinity than wildtype proteins, and SMC3-mutated Cornelia de Lange syndrome cell lines displayed genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18996922" 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="Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J., and 50 others. <strong>De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.</strong> Hum. Mutat. 36: 454-462, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25655089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25655089</a>] [<a href="https://doi.org/10.1002/humu.22761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25655089">Gil-Rodriguez et al. (2015)</a> identified a de novo heterozygous E488del mutation in a boy with a moderate form of CDLS3. The mutation was found by exome sequencing; functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25655089" 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 gene panel sequencing, <a href="#1" class="mim-tip-reference" title="Ansari, M., Poke, G., Ferry, Q., Williamson, K., Aldridge, R., Meynert, A. M., Bengani, H., Chan, C. Y., Kayserili, H., Avci, S., Hennekam, R. C. M., Lampe, A. K., and 63 others. <strong>Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.</strong> J. Med. Genet. 51: 659-668, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25125236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25125236</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25125236[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25125236">Ansari et al. (2014)</a> identified a heterozygous phe47-to-leu (F47L) mutation in the SMC3 gene in a patient with Cornelia de Lange syndrome-3 (CDLS3; <a href="/entry/610759">610759</a>). <a href="#6" class="mim-tip-reference" title="Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J., and 50 others. <strong>De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.</strong> Hum. Mutat. 36: 454-462, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25655089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25655089</a>] [<a href="https://doi.org/10.1002/humu.22761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25655089">Gil-Rodriguez et al. (2015)</a> reported that the mutation in this female patient with a mild form of CDLS3 was a c.139T-C transition in exon 4 of the SMC3 gene, resulting in an F47L substitution at a conserved residue in the N-terminal ATP-binding head domain. The mutation was not present in the mother; DNA from the father was not available. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25655089+25125236" 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 gene panel sequencing, <a href="#1" class="mim-tip-reference" title="Ansari, M., Poke, G., Ferry, Q., Williamson, K., Aldridge, R., Meynert, A. M., Bengani, H., Chan, C. Y., Kayserili, H., Avci, S., Hennekam, R. C. M., Lampe, A. K., and 63 others. <strong>Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.</strong> J. Med. Genet. 51: 659-668, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25125236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25125236</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25125236[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102573" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25125236">Ansari et al. (2014)</a> identified a 3-bp deletion (Thr1235del) in the SMC3 gene in a patient with Cornelia de Lange syndrome-3 (CDLS3; <a href="/entry/610759">610759</a>); the patient was somatic mosaic for the mutation. <a href="#6" class="mim-tip-reference" title="Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J., and 50 others. <strong>De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.</strong> Hum. Mutat. 36: 454-462, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25655089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25655089</a>] [<a href="https://doi.org/10.1002/humu.22761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25655089">Gil-Rodriguez et al. (2015)</a> reported that the mutation in this female patient with a moderate form of the disorder was a de novo heterozygous in-frame 3-bp deletion (c.703_705del) in exon 9 of the SMC3 gene, resulting in deletion of the conserved residue Thr235 in the coiled-coil region. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25655089+25125236" 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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SMC3, ARG236PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587784429 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587784429;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=rs587784429" 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=rs587784429" 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=RCV000147600 OR RCV004567165" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000147600, RCV004567165" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000147600...</a>
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<p>In a boy with a mild form of Cornelia de Lange syndrome-3 (CDLS3; <a href="/entry/610759">610759</a>), <a href="#6" class="mim-tip-reference" title="Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J., and 50 others. <strong>De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.</strong> Hum. Mutat. 36: 454-462, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25655089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25655089</a>] [<a href="https://doi.org/10.1002/humu.22761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25655089">Gil-Rodriguez et al. (2015)</a> identified a de novo heterozygous c.707G-C transversion in exon 9 of the SMC3 gene, resulting in an arg236-to-pro (R236P) substitution at a conserved residue in the coiled-coil domain. The mutation was found by gene panel sequencing. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25655089" 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>.0005 CORNELIA DE LANGE SYNDROME 3</strong>
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SMC3, GLU488LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863225260 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225260;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=rs863225260" 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=rs863225260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000201866" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201866" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201866</a>
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<span class="mim-text-font">
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<p>In a boy with a mild to moderate form of Cornelia de Lange syndrome-3 (CDLS3; <a href="/entry/610759">610759</a>), <a href="#6" class="mim-tip-reference" title="Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J., and 50 others. <strong>De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.</strong> Hum. Mutat. 36: 454-462, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25655089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25655089</a>] [<a href="https://doi.org/10.1002/humu.22761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25655089">Gil-Rodriguez et al. (2015)</a> identified a de novo heterozygous c.1462G-A transition in exon 15 of the SMC3 gene, resulting in a glu488-to-lys (E488K) substitution at a conserved residue in the coiled-coil domain. The mutation was found by gene panel sequencing. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25655089" 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 3</strong>
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SMC3, GLY655ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587784425 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587784425;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=rs587784425" 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=rs587784425" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000147580" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000147580" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000147580</a>
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<p>In a girl with a moderate form of Cornelia de Lange syndrome-3 (CDLS3; <a href="/entry/610759">610759</a>), <a href="#6" class="mim-tip-reference" title="Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J., and 50 others. <strong>De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.</strong> Hum. Mutat. 36: 454-462, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25655089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25655089</a>] [<a href="https://doi.org/10.1002/humu.22761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25655089">Gil-Rodriguez et al. (2015)</a> identified a de novo heterozygous c.1964G-A transition in exon 19 of the SMC3 gene, resulting in a gly655-to-asp (G655D) substitution at a conserved residue in the hinge domain. The mutation was found by gene panel sequencing. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25655089" 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 id="0007" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0007 CORNELIA DE LANGE SYNDROME 3</strong>
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SMC3, GLY666ALA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863225261 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225261;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=rs863225261" 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=rs863225261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000201859" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201859" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201859</a>
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<span class="mim-text-font">
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<p>In a boy with a mild to moderate form of Cornelia de Lange syndrome-3 (CDLS3; <a href="/entry/610759">610759</a>), <a href="#6" class="mim-tip-reference" title="Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J., and 50 others. <strong>De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.</strong> Hum. Mutat. 36: 454-462, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25655089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25655089</a>] [<a href="https://doi.org/10.1002/humu.22761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25655089">Gil-Rodriguez et al. (2015)</a> identified a de novo heterozygous c.1997G-C transversion in exon 19 of the SMC3 gene, resulting in a gly666-to-ala (G666A) substitution at a conserved residue in the hinge domain. The mutation was found by gene panel sequencing. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25655089" 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 id="0008" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0008 CORNELIA DE LANGE SYNDROME 3</strong>
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</h4>
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SMC3, HIS917PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs797044861 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044861;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=rs797044861" 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=rs797044861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000190665 OR RCV000201868" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190665, RCV000201868" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190665...</a>
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</span>
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<span class="mim-text-font">
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<p>In a girl with a moderate form of Cornelia de Lange syndrome-3 (CDLS3; <a href="/entry/610759">610759</a>), <a href="#6" class="mim-tip-reference" title="Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J., and 50 others. <strong>De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.</strong> Hum. Mutat. 36: 454-462, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25655089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25655089</a>] [<a href="https://doi.org/10.1002/humu.22761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25655089">Gil-Rodriguez et al. (2015)</a> identified a de novo heterozygous c.2750A-C transversion in exon 24 of the SMC3 gene, resulting in a his917-to-pro (H917P) substitution at a conserved residue in the coiled-coil domain. The mutation was found by exome sequencing. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25655089" 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 3 WITH MIDLINE BRAIN DEFECTS</strong>
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SMC3, 15-BP DEL, NT1138
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1861074646 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1861074646;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=rs1861074646" 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=rs1861074646" 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=RCV001072116" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001072116" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001072116</a>
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<p>In a male fetus with a severe form of Cornelia de Lange syndrome-3 with midline brain defects manifest as semilobar holoprosencephaly (CDLS3; <a href="/entry/610759">610759</a>), <a href="#12" 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 de novo heterozygous 15-bp in-frame deletion (c.1138_1152del) (chr10.112,343,987del15, GRCh37) in the SMC3 gene, predicted to result in the deletion of 5 amino acids (Gly380_Gln384del). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; the patient was ascertained from a large cohort of over 277 patients with holoprosencephaly. 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 SMC3 gene is intolerant to LOF mutations based on data from the gnomAD database. <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>REFERENCES</strong>
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<a id="Ansari2014" class="mim-anchor"></a>
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Ansari, M., Poke, G., Ferry, Q., Williamson, K., Aldridge, R., Meynert, A. M., Bengani, H., Chan, C. Y., Kayserili, H., Avci, S., Hennekam, R. C. M., Lampe, A. K., and 63 others.
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[<a href="https://doi.org/10.1136/jmedgenet-2014-102573" target="_blank">Full Text</a>]
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Davidson, I. F., Bauer, B., Goetz, D., Tang, W., Wutz, G., Peters, J. M.
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<strong>DNA loop extrusion by human cohesin.</strong>
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Science 366: 1338-1345, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31753851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31753851</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31753851" 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.aaz3418" target="_blank">Full Text</a>]
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<a id="Deardorff2007" class="mim-anchor"></a>
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Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D.
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<strong>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273969[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=17273969" 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/10.1086/511888" target="_blank">Full Text</a>]
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Ghiselli, G., Iozzo, R. V.
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<strong>Overexpression of bamacan/SMC3 causes transformation.</strong>
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J. Biol. Chem. 275: 20235-20238, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10801778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10801778</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10801778" 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/10.1074/jbc.C000213200" target="_blank">Full Text</a>]
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Ghiselli, G., Siracusa, L. D., Iozzo, R. V.
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<strong>Complete cDNA cloning, genomic organization, chromosomal assignment, functional characterization of the promoter, and expression of the murine bamacan gene.</strong>
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[<a href="https://doi.org/10.1074/jbc.274.24.17384" target="_blank">Full Text</a>]
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Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J., and 50 others.
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<strong>De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.</strong>
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Hum. Mutat. 36: 454-462, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25655089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25655089</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25655089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.22761" 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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[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="Gross2015" class="mim-anchor"></a>
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Gross, M. B.
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Baltimore, Md. 11/11/2015.
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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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Haering, C. H., Farcas, A.-M., Arumugam, P., Metson, J., Nasmyth, K.
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature07098" target="_blank">Full Text</a>]
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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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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1256904" target="_blank">Full Text</a>]
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<a id="Kruszka2019" class="mim-anchor"></a>
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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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|
[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://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'})">related citations</a>]
|
|
|
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|
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[<a href="https://doi.org/10.1093/brain/awz210" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
|
|
<a id="Revenkova2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Revenkova, E., Focarelli, M. L., Susani, L., Paulis, M., Bassi, M. T., Mannini, L., Frattini, A., Delia, D., Krantz, I., Vezzoni, P., Jessberger, R., Musio, A.
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|
<strong>Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA.</strong>
|
|
Hum. Molec. Genet. 18: 418-427, 2009.
|
|
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|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18996922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18996922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18996922[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=18996922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn369" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Rolef Ben-Shahar2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rolef Ben-Shahar, T. R., Heeger, S., Lehane, C., East, P., Flynn, H., Skehel, M., Uhlmann, F.
|
|
<strong>Eco1-dependent cohesin acetylation during establishment of sister chromatid cohesion.</strong>
|
|
Science 321: 563-566, 2008.
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18653893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18653893</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18653893" 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.1157774" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Shimizu1998" class="mim-anchor"></a>
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<div class="">
|
|
<p class="mim-text-font">
|
|
Shimizu, K., Shirataki, H., Honda, T., Minami, S., Takai, Y.
|
|
<strong>Complex formation of SMAP/KAP3, a KIF3A/B ATPase motor-associated protein, with a human chromosome-associated polypeptide.</strong>
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J. Biol. Chem. 273: 6591-6594, 1998.
|
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9506951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9506951</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9506951" 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/10.1074/jbc.273.12.6591" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Sumara2000" class="mim-anchor"></a>
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<div class="">
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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.
|
|
<strong>Characterization of vertebrate cohesin complexes and their regulation in prophase.</strong>
|
|
J. Cell Biol. 151: 749-761, 2000.
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1083/jcb.151.4.749" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Terret2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Terret, M.-E., Sherwood, R., Rahman, S., Qin, J., Jallepalli, P. V.
|
|
<strong>Cohesin acetylation speeds the replication fork.</strong>
|
|
Nature 462: 231-234, 2009.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19907496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19907496</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19907496[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=19907496" 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/nature08550" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Unal2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Unal, E., Heidinger-Pauli, J. M., Kim, W., Guacci, V., Onn, I., Gygi, S. P., Koshland, D. E.
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<strong>A molecular determinant for the establishment of sister chromatid cohesion.</strong>
|
|
Science 321: 566-569, 2008.
|
|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18653894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18653894</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18653894" 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.1157880" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Zhang2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, J., Shi, X., Li, Y., Kim, B.-J., Jia, J., Huang, Z., Yang, T., Fu, X., Jung, S. Y., Wang, Y., Zhang, P., Kim, S.-T., Pan, X., Qin, J.
|
|
<strong>Acetylation of Smc3 by Eco1 is required for S phase sister chromatid cohesion in both human and yeast.</strong>
|
|
Molec. Cell 31: 143-151, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18614053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18614053</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18614053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2008.06.006" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
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Ada Hamosh - updated : 05/06/2020
|
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</span>
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</div>
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</div>
|
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<div class="row collapse" id="mimCollapseContributors">
|
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
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Cassandra L. Kniffin - updated : 04/10/2020<br>Matthew B. Gross - updated : 11/11/2015<br>Cassandra L. Kniffin - updated : 11/3/2015<br>Ada Hamosh - updated : 1/14/2015<br>Ada Hamosh - updated : 1/14/2015<br>Ada Hamosh - updated : 1/6/2010<br>Ada Hamosh - updated : 12/29/2009<br>George E. Tiller - updated : 7/31/2009<br>Patricia A. Hartz - updated : 9/10/2008<br>Ada Hamosh - updated : 8/27/2008<br>Ada Hamosh - updated : 8/12/2008<br>Victor A. McKusick - updated : 2/8/2007<br>Stylianos E. Antonarakis - updated : 4/14/2003<br>Paul J. Converse - updated : 11/16/2001
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
|
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Creation Date:
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Paul J. Converse : 6/25/2001
|
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
|
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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|
alopez : 01/21/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
alopez : 05/06/2020<br>carol : 04/13/2020<br>ckniffin : 04/10/2020<br>mgross : 11/11/2015<br>carol : 11/11/2015<br>carol : 11/10/2015<br>ckniffin : 11/3/2015<br>alopez : 1/14/2015<br>alopez : 1/14/2015<br>wwang : 11/9/2010<br>alopez : 1/6/2010<br>terry : 12/29/2009<br>wwang : 8/13/2009<br>terry : 7/31/2009<br>mgross : 9/12/2008<br>terry : 9/10/2008<br>alopez : 8/27/2008<br>terry : 8/27/2008<br>alopez : 8/25/2008<br>terry : 8/12/2008<br>alopez : 3/20/2008<br>terry : 3/7/2008<br>mgross : 7/19/2007<br>alopez : 2/13/2007<br>alopez : 2/13/2007<br>terry : 2/8/2007<br>mgross : 4/14/2003<br>mgross : 11/16/2001<br>mgross : 6/25/2001<br>mgross : 6/25/2001<br>mgross : 6/25/2001
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 606062
|
|
</span>
|
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</h3>
|
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</div>
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<div>
|
|
<h3>
|
|
<span class="mim-font">
|
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|
|
STRUCTURAL MAINTENANCE OF CHROMOSOMES 3; SMC3
|
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|
|
</span>
|
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</h3>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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<div>
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<div >
|
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<p>
|
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<span class="mim-font">
|
|
<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">
|
|
CHONDROITIN SULFATE PROTEOGLYCAN 6; CSPG6<br />
|
|
BAMACAN; BAM<br />
|
|
HUMAN CHROMOSOME-ASSOCIATED POLYPEPTIDE; HCAP
|
|
</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: SMC3</em></strong>
|
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</span>
|
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: 10q25.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 10:110,567,695-110,606,048 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
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</p>
|
|
</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
10q25.2
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Cornelia de Lange syndrome 3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
610759
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
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|
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</tr>
|
|
|
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|
|
</tbody>
|
|
</table>
|
|
</div>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<span class="mim-text-font">
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<p>The SMC3 gene encodes a subunit of the evolutionarily conserved multimeric cohesin complex, which has been implicated in a wide range of functions, including sister chromatid cohesion, DNA repair mechanisms, gene regulation, and maintenance of genome stability (summary by Gil-Rodriguez et al., 2015). </p><p>Proteoglycans are specialized glycoproteins with heterogeneous structures that are found in all connective tissues and on cell surfaces. SMC3, or bamacan (BAM), which was originally isolated from embryonic parietal yolk sac, is an abundant secreted chondroitin sulfate proteoglycan in basement membranes and an intracellular protein. See SCC1 (606462) and Sumara et al. (2000) for information on the role of SMC3 in cohesin association with and dissociation from chromosomes. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using a yeast 2-hybrid screen of a B-cell cDNA library with SMAP (601836) as bait, followed by probing a brain cDNA library, Shimizu et al. (1998) obtained a cDNA encoding SMC3, which they termed HCAP. Sequence analysis predicted that the 1,217-amino acid HCAP protein is 98% identical to rat Cspg6 and is homologous to frog and fly Cap proteins. HCAP has a head-rod-tail organization, which is common in SMC family members. The head contains an NTP-binding motif and the tail has a DA box. Western blot analysis showed expression of an approximately 140-kD nuclear protein. GST-pull down analysis confirmed the specific interaction between SMAP and HCAP. Fluorescence microscopy demonstrated an association of HCAP with mitotic chromosomes. Coimmunoprecipitation analysis indicated that HCAP is associated with SMAP and KIF3A (604683)/KIF3B (603754) in the nucleus. </p><p>Using Northern blot analysis, Ghiselli et al. (1999) detected ubiquitous expression of a 4.2-kb Bam transcript in mouse, with highest levels in testis and brain, lower levels in muscle, heart, lung, kidney, colon, and thymus, and much lower levels in spleen, kidney, and liver. Ghiselli and Iozzo (2000) detected high levels of BAM expression in spontaneously transformed human and mouse colon carcinoma cells. They proposed that deregulated BAM/SMC3 expression may be directly linked to oncogenesis. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</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 genomic sequence analysis, Ghiselli et al. (1999) determined that the mouse Smc3 gene contains 31 exons and is driven by a promoter enriched in GC sequences and lacking TATA and CAAT boxes. </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>Gross (2015) mapped the SMC3 gene to chromosome 10q25.2 based on an alignment of the SMC3 sequence (GenBank AF020043) with the genomic sequence (GRCh38).</p><p>Ghiselli et al. (1999) mapped the mouse Smc3 gene to chromosome 19, in a region showing homology of synteny to human 10q25. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In yeast, the cohesin complex is essential for sister chromatid cohesion during mitosis. The Smc1 (300040) and Smc3 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>Cohesin's Scc1 (606462), 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>Rolef Ben-Shahar et al. (2008) identified spontaneous suppressors of the thermosensitive eco1-1 allele (see 609674) in budding yeast. An acetylation-mimicking mutation of a conserved lysine in cohesin's Smc3 subunit makes Eco1 dispensable for cell growth, and Rolef Ben-Shahar et al. (2008) showed that Smc3 is acetylated in an Eco1-dependent manner during DNA replication to promote sister chromatid cohesion. A second set of eco1-1 suppressors inactivate the budding yeast ortholog of the cohesin destabilizer Wapl (610754). Rolef Ben-Shahar et al. (2008) concluded that Eco1 modifies cohesin to stabilize sister chromatid cohesion in parallel with a cohesion establishment reaction that is in principle Eco1-independent. </p><p>Unal et al. (2008) found that in budding yeast, the head domain of the Smc3 protein subunit of cohesin is acetylated by the Eco1p protein acetyltransferase at 2 evolutionarily conserved residues, promoting the chromatin-bound cohesin to tether sister chromatids. Smc3 protein acetylation is induced in S phase after the chromatin loading of cohesin and is suppressed in G1 and G2/M. </p><p>Zhang et al. (2008) showed that acetylation of SMC3 by ESCO1 was required for S phase sister chromatid cohesion in human cells and in yeast. In HeLa cells, ESCO1 acetylated SMC3 on lys105 and lys106, and knockdown of ESCO1 expression via small interfering RNA significantly decreased SMC3 acetylation. Expression of a dominant-negative nonacetylatable SMC3 mutant in HEK293T cells permitted SMC3 incorporation into the cohesin complex, but it interfered with sister chromatid cohesion and resulted in scattered chromosomes and chromosome breakage. Zhang et al. (2008) concluded that ESCO1 is the major acetyltransferase required for SMC3 acetylation, and that SMC3 acetylation is required for sister chromatid cohesion and maintenance of genomic stability. </p><p>Through single-molecule analysis, Terret et al. (2009) demonstrated that a replication complex, the RFC-CTF18 clamp loader (see 613201), controls the velocity spacing and restart activity of replication forks in human cells and is required for robust acetylation of cohesin's SMC3 subunit and sister chromatid cohesion. Unexpectedly, Terret et al. (2009) discovered that cohesin acetylation itself is a central determinant of fork processivity, as slow-moving replication forks were found in cells lacking the Eco1-related acetyltransferases ESCO1 or ESCO2 (609353) (including those derived from Roberts syndrome (268300) patients, in whom ESCO2 is biallelically mutated), and in cells expressing a form of SMC3 that cannot be acetylated. This defect was a consequence of cohesin's hyperstable interaction with 2 regulatory cofactors, WAPL (610754) and PDS5A (613200); removal of either cofactor allowed forks to progress rapidly without ESCO1, ESCO2, or RFC-CTF18. Terret et al. (2009) concluded that their results showed a novel mechanism for clamp loader-dependent fork progression, mediated by the posttranslational modification and structural remodeling of the cohesin ring. Loss of this regulatory mechanism leads to the spontaneous accrual of DNA damage and may contribute to the abnormalities of the Roberts syndrome cohesinopathy. </p><p>Huis in 't Veld et al. (2014) found that the proposed DNA exit gate of cohesin 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 and the protease separase (ESPL1; 604143), respectively. </p><p>Using biochemical reconstitution, Davidson et al. (2019) found that single human cohesin complexes form DNA loops symmetrically at rates up to 2.1 kilobase pairs per second. Loop formation and maintenance depend on cohesin's ATPase activity and on NIPBL (608667)-MAU2 (614560), but not on topologic entrapment of DNA by cohesin (components include SMC3; SMC1A, 300040; STAG1, 604358; STAG2, 300826). During loop formation, cohesin and NIPBL-MAU2 reside at the base of loops, which indicates that they generate loops by extrusion. Davidson et al. (2019) concluded that their results showed that cohesin and NIPBL-MAU2 form an active holoenzyme that interacts with DNA either pseudotopologically or nontopologically to extrude genomic interphase DNA into loops. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Gligoris et al. (2014) showed that the N-terminal domain of yeast Scc1 (606462) contains 2 alpha-helices, forming a 4-helix bundle with the coiled coil emerging from the adenosine triphosphatase head of Smc3. 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>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>Cornelia de Lange syndrome (CDLS; see 122470) is a multisystem developmental disorder including craniofacial dysmorphia, hirsutism, malformations of the upper limbs, and neurodevelopmental delay. Because mutations in the cohesin complex member NIPBL (608667) result in CDLS, Deardorff et al. (2007) screened 115 NIPBL mutation-negative individuals with sporadic or familial CDLS and probands with CDLS-variant phenotypes for mutations in the cohesin complex component genes SMC3 and SMC1A (300040). They found 1 mutation in SMC3 (606062.0001) in a patient with a milder CDLS phenotype (CDLS3; 610759). Structural analysis of the mutant SMC3 protein indicated that it was likely to produce a functional cohesin complex, but Deardorff et al. (2007) posited that the mutation may alter the chromosome binding dynamics of the protein. Additionally, the authors found 14 additional mutations in the SMC1A gene in patients with X-linked CDLS (CDLS2; 300590). The data indicated that SMC3 and SMC1A mutations contribute to approximately 5% of cases of CDLS, resulting in a consistently mild phenotype with absence of major structural anomalies typically associated with CDLS, and in some instances, resulted in a phenotype that approached that of apparently nonsyndromic mental retardation. </p><p>In 5 unrelated patients with CDLS3, Ansari et al. (2014) identified 5 different heterozygous mutations in the SMC3 gene (see, e.g., 606062.0002 and 606062.0003). The mutations were shown to occur de novo in those with available parental DNA. Functional studies were not performed. </p><p>Gil-Rodriguez et al. (2015) identified heterozygous mutations in the SMC3 gene (see, e.g., 606062.0001; 606062.0004-606062.0008) in 10 unrelated patients with CDLS3. The mutations were shown to occur de novo in those with available parental DNA. The mutations were found either by gene panel sequencing or by exome sequencing, and none were found in 100 control alleles of publicly available databases. Functional studies were not performed. Based on their studies and previous reports, Gil-Rodriguez et al. (2015) estimated that SMC3 mutations account for about 1 to 2% of patients with features of CDLS. </p><p>In a male fetus with a severe form of CDLS3 with midline brain defects manifest as semilobar holoprosencephaly, Kruszka et al. (2019) identified a de novo heterozygous 15-bp in-frame deletion in the SMC3 gene (606062.0009). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; the patient was ascertained from a large cohort of over 277 patients with holoprosencephaly. 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 SMC3 gene is intolerant to LOF mutations based on data from the gnomAD database. </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">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 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">
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<strong>.0001 CORNELIA DE LANGE SYNDROME 3</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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SMC3, 3-BP DEL, 1464AGA
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<br />
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SNP: rs863223279,
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ClinVar: RCV000004894
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male with a mild variant form of Cornelia de Lange syndrome (CDLS3; 610759), Deardorff et al. (2007) found a 3-bp deletion in the SMC3 gene (1464_1466delAGA), resulting in deletion of glu488 (E488del). The mutation occurred in the junction of the N-terminal coiled-coil and the hinge domain, a region conserved from bacteria to human. Neither parent carried the mutation, indicating that it was a de novo event. </p><p>Revenkova et al. (2009) showed that E488del-mutant SMC3 affected the affinity of SMC hinge dimers for DNA. Mutated hinge dimers bound DNA with higher affinity than wildtype proteins, and SMC3-mutated Cornelia de Lange syndrome cell lines displayed genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents. </p><p>Gil-Rodriguez et al. (2015) identified a de novo heterozygous E488del mutation in a boy with a moderate form of CDLS3. The mutation was found by exome sequencing; 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>.0002 CORNELIA DE LANGE SYNDROME 3</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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SMC3, PHE47LEU
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<br />
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SNP: rs863225258,
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ClinVar: RCV000201864
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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>By gene panel sequencing, Ansari et al. (2014) identified a heterozygous phe47-to-leu (F47L) mutation in the SMC3 gene in a patient with Cornelia de Lange syndrome-3 (CDLS3; 610759). Gil-Rodriguez et al. (2015) reported that the mutation in this female patient with a mild form of CDLS3 was a c.139T-C transition in exon 4 of the SMC3 gene, resulting in an F47L substitution at a conserved residue in the N-terminal ATP-binding head domain. The mutation was not present in the mother; DNA from the father was not available. 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>.0003 CORNELIA DE LANGE SYNDROME 3</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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SMC3, 3-BP DEL, NT703
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<br />
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SNP: rs863225259,
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ClinVar: RCV000201849
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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>By gene panel sequencing, Ansari et al. (2014) identified a 3-bp deletion (Thr1235del) in the SMC3 gene in a patient with Cornelia de Lange syndrome-3 (CDLS3; 610759); the patient was somatic mosaic for the mutation. Gil-Rodriguez et al. (2015) reported that the mutation in this female patient with a moderate form of the disorder was a de novo heterozygous in-frame 3-bp deletion (c.703_705del) in exon 9 of the SMC3 gene, resulting in deletion of the conserved residue Thr235 in the coiled-coil region. 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>.0004 CORNELIA DE LANGE SYNDROME 3</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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SMC3, ARG236PRO
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<br />
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SNP: rs587784429,
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ClinVar: RCV000147600, RCV004567165
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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 boy with a mild form of Cornelia de Lange syndrome-3 (CDLS3; 610759), Gil-Rodriguez et al. (2015) identified a de novo heterozygous c.707G-C transversion in exon 9 of the SMC3 gene, resulting in an arg236-to-pro (R236P) substitution at a conserved residue in the coiled-coil domain. The mutation was found by gene panel sequencing. 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>.0005 CORNELIA DE LANGE SYNDROME 3</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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SMC3, GLU488LYS
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<br />
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SNP: rs863225260,
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ClinVar: RCV000201866
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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 boy with a mild to moderate form of Cornelia de Lange syndrome-3 (CDLS3; 610759), Gil-Rodriguez et al. (2015) identified a de novo heterozygous c.1462G-A transition in exon 15 of the SMC3 gene, resulting in a glu488-to-lys (E488K) substitution at a conserved residue in the coiled-coil domain. The mutation was found by gene panel sequencing. 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>.0006 CORNELIA DE LANGE SYNDROME 3</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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SMC3, GLY655ASP
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<br />
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SNP: rs587784425,
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ClinVar: RCV000147580
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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 girl with a moderate form of Cornelia de Lange syndrome-3 (CDLS3; 610759), Gil-Rodriguez et al. (2015) identified a de novo heterozygous c.1964G-A transition in exon 19 of the SMC3 gene, resulting in a gly655-to-asp (G655D) substitution at a conserved residue in the hinge domain. The mutation was found by gene panel sequencing. 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>.0007 CORNELIA DE LANGE SYNDROME 3</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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SMC3, GLY666ALA
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<br />
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SNP: rs863225261,
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ClinVar: RCV000201859
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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 boy with a mild to moderate form of Cornelia de Lange syndrome-3 (CDLS3; 610759), Gil-Rodriguez et al. (2015) identified a de novo heterozygous c.1997G-C transversion in exon 19 of the SMC3 gene, resulting in a gly666-to-ala (G666A) substitution at a conserved residue in the hinge domain. The mutation was found by gene panel sequencing. 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>.0008 CORNELIA DE LANGE SYNDROME 3</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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SMC3, HIS917PRO
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<br />
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SNP: rs797044861,
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ClinVar: RCV000190665, RCV000201868
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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 girl with a moderate form of Cornelia de Lange syndrome-3 (CDLS3; 610759), Gil-Rodriguez et al. (2015) identified a de novo heterozygous c.2750A-C transversion in exon 24 of the SMC3 gene, resulting in a his917-to-pro (H917P) substitution at a conserved residue in the coiled-coil domain. The mutation was found by exome sequencing. 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>.0009 CORNELIA DE LANGE SYNDROME 3 WITH MIDLINE BRAIN DEFECTS</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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SMC3, 15-BP DEL, NT1138
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<br />
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SNP: rs1861074646,
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ClinVar: RCV001072116
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male fetus with a severe form of Cornelia de Lange syndrome-3 with midline brain defects manifest as semilobar holoprosencephaly (CDLS3; 610759), Kruszka et al. (2019) identified a de novo heterozygous 15-bp in-frame deletion (c.1138_1152del) (chr10.112,343,987del15, GRCh37) in the SMC3 gene, predicted to result in the deletion of 5 amino acids (Gly380_Gln384del). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; the patient was ascertained from a large cohort of over 277 patients with holoprosencephaly. 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 SMC3 gene is intolerant to LOF mutations based on data from the gnomAD database. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Ansari, M., Poke, G., Ferry, Q., Williamson, K., Aldridge, R., Meynert, A. M., Bengani, H., Chan, C. Y., Kayserili, H., Avci, S., Hennekam, R. C. M., Lampe, A. K., and 63 others.
|
|
<strong>Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.</strong>
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J. Med. Genet. 51: 659-668, 2014.
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[PubMed: 25125236]
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[Full Text: https://doi.org/10.1136/jmedgenet-2014-102573]
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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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Davidson, I. F., Bauer, B., Goetz, D., Tang, W., Wutz, G., Peters, J. M.
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<strong>DNA loop extrusion by human cohesin.</strong>
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|
Science 366: 1338-1345, 2019.
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[PubMed: 31753851]
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[Full Text: https://doi.org/10.1126/science.aaz3418]
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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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Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D.
|
|
<strong>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.</strong>
|
|
Am. J. Hum. Genet. 80: 485-494, 2007.
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[PubMed: 17273969]
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[Full Text: https://doi.org/10.1086/511888]
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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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Ghiselli, G., Iozzo, R. V.
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<strong>Overexpression of bamacan/SMC3 causes transformation.</strong>
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J. Biol. Chem. 275: 20235-20238, 2000.
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[PubMed: 10801778]
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[Full Text: https://doi.org/10.1074/jbc.C000213200]
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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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Ghiselli, G., Siracusa, L. D., Iozzo, R. V.
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<strong>Complete cDNA cloning, genomic organization, chromosomal assignment, functional characterization of the promoter, and expression of the murine bamacan gene.</strong>
|
|
J. Biol. Chem. 274: 17384-17393, 1999.
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[PubMed: 10358101]
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[Full Text: https://doi.org/10.1074/jbc.274.24.17384]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J., and 50 others.
|
|
<strong>De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.</strong>
|
|
Hum. Mutat. 36: 454-462, 2015.
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[PubMed: 25655089]
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[Full Text: https://doi.org/10.1002/humu.22761]
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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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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.
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|
[PubMed: 25414305]
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[Full Text: https://doi.org/10.1126/science.1256917]
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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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Gross, M. B.
|
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<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 11/11/2015.
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Gruber, S., Haering, C. H., Nasmyth, K.
|
|
<strong>Chromosomal cohesin forms a ring.</strong>
|
|
Cell 112: 765-777, 2003.
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|
[PubMed: 12654244]
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[Full Text: https://doi.org/10.1016/s0092-8674(03)00162-4]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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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.
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|
|
[PubMed: 18596691]
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[Full Text: https://doi.org/10.1038/nature07098]
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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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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.
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|
[PubMed: 25414306]
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[Full Text: https://doi.org/10.1126/science.1256904]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
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.
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|
[PubMed: 31334757]
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[Full Text: https://doi.org/10.1093/brain/awz210]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Revenkova, E., Focarelli, M. L., Susani, L., Paulis, M., Bassi, M. T., Mannini, L., Frattini, A., Delia, D., Krantz, I., Vezzoni, P., Jessberger, R., Musio, A.
|
|
<strong>Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA.</strong>
|
|
Hum. Molec. Genet. 18: 418-427, 2009.
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[PubMed: 18996922]
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[Full Text: https://doi.org/10.1093/hmg/ddn369]
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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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Rolef Ben-Shahar, T. R., Heeger, S., Lehane, C., East, P., Flynn, H., Skehel, M., Uhlmann, F.
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<strong>Eco1-dependent cohesin acetylation during establishment of sister chromatid cohesion.</strong>
|
|
Science 321: 563-566, 2008.
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[PubMed: 18653893]
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[Full Text: https://doi.org/10.1126/science.1157774]
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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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Shimizu, K., Shirataki, H., Honda, T., Minami, S., Takai, Y.
|
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<strong>Complex formation of SMAP/KAP3, a KIF3A/B ATPase motor-associated protein, with a human chromosome-associated polypeptide.</strong>
|
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J. Biol. Chem. 273: 6591-6594, 1998.
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[PubMed: 9506951]
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[Full Text: https://doi.org/10.1074/jbc.273.12.6591]
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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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<strong>Characterization of vertebrate cohesin complexes and their regulation in prophase.</strong>
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[PubMed: 11076961]
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[Full Text: https://doi.org/10.1083/jcb.151.4.749]
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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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Terret, M.-E., Sherwood, R., Rahman, S., Qin, J., Jallepalli, P. V.
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<strong>Cohesin acetylation speeds the replication fork.</strong>
|
|
Nature 462: 231-234, 2009.
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[PubMed: 19907496]
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[Full Text: https://doi.org/10.1038/nature08550]
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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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Unal, E., Heidinger-Pauli, J. M., Kim, W., Guacci, V., Onn, I., Gygi, S. P., Koshland, D. E.
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<strong>A molecular determinant for the establishment of sister chromatid cohesion.</strong>
|
|
Science 321: 566-569, 2008.
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[PubMed: 18653894]
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[Full Text: https://doi.org/10.1126/science.1157880]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Zhang, J., Shi, X., Li, Y., Kim, B.-J., Jia, J., Huang, Z., Yang, T., Fu, X., Jung, S. Y., Wang, Y., Zhang, P., Kim, S.-T., Pan, X., Qin, J.
|
|
<strong>Acetylation of Smc3 by Eco1 is required for S phase sister chromatid cohesion in both human and yeast.</strong>
|
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Molec. Cell 31: 143-151, 2008.
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[PubMed: 18614053]
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[Full Text: https://doi.org/10.1016/j.molcel.2008.06.006]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 05/06/2020<br>Cassandra L. Kniffin - updated : 04/10/2020<br>Matthew B. Gross - updated : 11/11/2015<br>Cassandra L. Kniffin - updated : 11/3/2015<br>Ada Hamosh - updated : 1/14/2015<br>Ada Hamosh - updated : 1/14/2015<br>Ada Hamosh - updated : 1/6/2010<br>Ada Hamosh - updated : 12/29/2009<br>George E. Tiller - updated : 7/31/2009<br>Patricia A. Hartz - updated : 9/10/2008<br>Ada Hamosh - updated : 8/27/2008<br>Ada Hamosh - updated : 8/12/2008<br>Victor A. McKusick - updated : 2/8/2007<br>Stylianos E. Antonarakis - updated : 4/14/2003<br>Paul J. Converse - updated : 11/16/2001
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 6/25/2001
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Edit History:
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alopez : 01/21/2022<br>alopez : 05/06/2020<br>carol : 04/13/2020<br>ckniffin : 04/10/2020<br>mgross : 11/11/2015<br>carol : 11/11/2015<br>carol : 11/10/2015<br>ckniffin : 11/3/2015<br>alopez : 1/14/2015<br>alopez : 1/14/2015<br>wwang : 11/9/2010<br>alopez : 1/6/2010<br>terry : 12/29/2009<br>wwang : 8/13/2009<br>terry : 7/31/2009<br>mgross : 9/12/2008<br>terry : 9/10/2008<br>alopez : 8/27/2008<br>terry : 8/27/2008<br>alopez : 8/25/2008<br>terry : 8/12/2008<br>alopez : 3/20/2008<br>terry : 3/7/2008<br>mgross : 7/19/2007<br>alopez : 2/13/2007<br>alopez : 2/13/2007<br>terry : 2/8/2007<br>mgross : 4/14/2003<br>mgross : 11/16/2001<br>mgross : 6/25/2001<br>mgross : 6/25/2001<br>mgross : 6/25/2001
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OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
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