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Entry
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- *601366 - SMAD FAMILY MEMBER 2; SMAD2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601366</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#nomenclature">Nomenclature</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601366">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000175387;t=ENST00000262160" 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=4087" 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=601366" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000175387;t=ENST00000262160" 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_001003652,NM_001135937,NM_005901,XM_017025749,XM_047437507,XM_047437508" 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_005901" 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=601366" 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=03221&isoform_id=03221_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/SMAD2" 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/1403713,1552530,1575530,2695663,5174511,13633914,15928762,19344008,30583683,32492944,51173730,119583318,119583319,119583320,119583321,189066552,209693426,221042588,1034604024,2217316819,2217316821,2462560456,2462560458,2462560460" 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/Q15796" 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=4087" 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=ENSG00000175387;t=ENST00000262160" 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=SMAD2" 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=SMAD2" 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+4087" 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/SMAD2" 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:4087" 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/4087" 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=chr18&hgg_gene=ENST00000262160.11&hgg_start=47808957&hgg_end=47930872&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:6768" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:6768" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601366[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=601366[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000175387" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=SMAD2" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=SMAD2" 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=SMAD2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SMAD2&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/PA134959722" 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:6768" 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/FBgn0025800.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:108051" 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/SMAD2#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:108051" 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/4087/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=4087" 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=WBGene00004856;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-990603-7" 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">
|
|
<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:4087" 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=SMAD2&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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601366
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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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SMAD FAMILY MEMBER 2; SMAD2
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 2; MADH2<br />
|
|
SMA- AND MAD-RELATED PROTEIN 2 MAD, DROSOPHILA, HOMOLOG OF<br />
|
|
MADR2
|
|
</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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SMAD2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SMAD2</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/18/169?start=-3&limit=10&highlight=169">18q21.1</a>
|
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr18:47808957-47930872&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'})">18:47,808,957-47,930,872</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=619657,619656" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/18/169?start=-3&limit=10&highlight=169">
|
|
18q21.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Congenital heart defects, multiple types, 8, with or without heterotaxy
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619657"> 619657 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Loeys-Dietz syndrome 6
|
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|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619656"> 619656 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
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</tbody>
|
|
</table>
|
|
</div>
|
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</div>
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<p><a href="#16" class="mim-tip-reference" title="Riggins, G. J., Thiagalingam, S., Rozenblum, E., Weinstein, C. L., Kern, S. E., Hamilton, S. R., Willson, J. K. V., Markowitz, S. D., Kinzler, K. W., Vogelstein, B. <strong>Mad-related genes in the human.</strong> Nature Genet. 13: 347-349, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673135</a>] [<a href="https://doi.org/10.1038/ng0796-347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673135">Riggins et al. (1996)</a> identified a homolog of the Drosophila 'mothers against decapentaplegic' (Mad) gene (also 'mothers against dpp'). The predicted 467-amino acid polypeptide, which the authors called JV18-1, shows maximal homology to Mad genes at the amino and carboxy termini of the protein, with 62% identity to Mad over 373 amino acids. Drosophila Mad apparently acts downstream of the TGF-beta receptor (<a href="/entry/190181">190181</a>) to transduce signals from the members of the TGF-beta gene family (<a href="/entry/190180">190180</a>). The gene product shows 44% identity over 158 amino acids to another Mad homolog, DPC4 (SMAD4; <a href="/entry/600993">600993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8673135" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Graff, J. M., Bansal, A., Melton, D. A. <strong>Xenopus Mad proteins transduce distinct subsets of signals for the TGF-beta superfamily.</strong> Cell 85: 479-487, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8653784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8653784</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81249-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8653784">Graff et al. (1996)</a> described a family of Xenopus proteins homologous to the Drosophila Mad and C. elegans CEM genes. MAD and MAD-related proteins are important components of the serine/threonine kinase receptor signal transduction pathways. <a href="#7" class="mim-tip-reference" title="Eppert, K., Scherer, S. W., Ozcelik, H., Pirone, R., Hoodless, P., Kim, H., Tsui, L.-C., Bapat, B., Gallinger, S., Andrulis, I. L., Thomsen, G. H., Wrana, J. L., Attisano, L. <strong>MADR2 maps to 18q21 and encodes a TGF-beta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma.</strong> Cell 86: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8752209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8752209</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80128-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8752209">Eppert et al. (1996)</a> cloned and characterized a member of this family, which they designated MADR2. The gene encodes a 467-amino acid protein that contains no common structural motifs known at that time. MADR2 shares high homology with MADR1 (<a href="/entry/601595">601595</a>) and significant homology with DPC4. They reported that MADR2 is rapidly phosphorylated by activation of the TGF-beta signaling pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8752209+8653784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By RT-PCR of human erythroleukemia cell mRNA using primers based on conserved regions between the Drosophila Mad and C. elegans Sma genes, <a href="#14" class="mim-tip-reference" title="Nakao, A., Roijer, E., Imamura, T., Souchelnytskyi, S., Stenman, G., Heldin, C.-H., ten Dijke, P. <strong>Identification of Smad2, a human Mad-related protein in the transforming growth factor-beta signaling pathway.</strong> J. Biol. Chem. 272: 2896-2900, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9006934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9006934</a>] [<a href="https://doi.org/10.1074/jbc.272.5.2896" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9006934">Nakao et al. (1997)</a> cloned a SMAD2 cDNA. Northern blot analysis of human tissues detected ubiquitously expressed 3.4- and 2.9-kb SMAD2 transcripts. The encoded protein has a molecular mass of 58 kD by SDS-PAGE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9006934" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Baker, J. C., Harland, R. M. <strong>A novel mesoderm inducer, Madr2, functions in the activin signal transduction pathway.</strong> Genes Dev. 10: 1880-1889, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8756346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8756346</a>] [<a href="https://doi.org/10.1101/gad.10.15.1880" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8756346">Baker and Harland (1996)</a> identified the mouse Madr2 gene using a functional assay to clone mouse mesoderm inducers from Xenopus ectoderm. The mouse amino acid sequence is 46% identical to the human tumor suppressor DPC4. Madr2 was expressed widely in the mouse embryo (with the exception of heart and the tail bud) from embryonic days 6.5 to 10.5. Madr2 was found to be confined to the nucleus in the deep anterior cells of the second axis, whereas it was localized in the cytoplasm in the epidermal and more posterior cells. Because Madr2 localized to the nucleus in response to activin (see <a href="/entry/147290">147290</a>) and because activin-like phenotypes were induced by overexpression of Madr2, <a href="#1" class="mim-tip-reference" title="Baker, J. C., Harland, R. M. <strong>A novel mesoderm inducer, Madr2, functions in the activin signal transduction pathway.</strong> Genes Dev. 10: 1880-1889, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8756346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8756346</a>] [<a href="https://doi.org/10.1101/gad.10.15.1880" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8756346">Baker and Harland (1996)</a> concluded that Madr2 is a signal transduction component that mediates the activity of activin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8756346" 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="#12" class="mim-tip-reference" title="Macias-Silva, M., Abdollah, S., Hoodless, P. A., Pirone, R., Attisano, L., Wrana, J. L. <strong>MADR2 is a substrate of the TGF-beta receptor and its phosphorylation is required for nuclear accumulation and signaling.</strong> Cell 87: 1215-1224, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8980228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8980228</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81817-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8980228">Macias-Silva et al. (1996)</a> demonstrated that MADR2 and not the related protein DPC4 transiently interacts with the TGF-beta receptor and is directly phosphorylated by the complex on C-terminal serines. Interaction of MADR2 with receptors and phosphorylation requires activation of receptor I by receptor II and is mediated by the receptor I kinase. Mutation of the phosphorylation sites generated a dominant-negative MADR2 that blocks TGF-beta-dependent transcriptional responses, stably associates with receptors, and fails to accumulate in the nucleus in response to TGF-beta signaling. Thus, <a href="#12" class="mim-tip-reference" title="Macias-Silva, M., Abdollah, S., Hoodless, P. A., Pirone, R., Attisano, L., Wrana, J. L. <strong>MADR2 is a substrate of the TGF-beta receptor and its phosphorylation is required for nuclear accumulation and signaling.</strong> Cell 87: 1215-1224, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8980228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8980228</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81817-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8980228">Macias-Silva et al. (1996)</a> concluded that transient association and phosphorylation of MADR2 by the TGF-beta receptor is necessary for nuclear accumulation and initiation of signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8980228" 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>SMAD proteins mediate TGF-beta signaling to regulate cell growth and differentiation. <a href="#18" class="mim-tip-reference" title="Stroschein, S. L., Wang, W., Zhou, S., Zhou, Q., Luo, K. <strong>Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein.</strong> Science 286: 771-774, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10531062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10531062</a>] [<a href="https://doi.org/10.1126/science.286.5440.771" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10531062">Stroschein et al. (1999)</a> identified SnoN (<a href="/entry/165340">165340</a>) as a component of the SMAD pathway. They proposed a model of regulation of TGF-beta signaling by SnoN in which SnoN maintains the repressed state of TGF-beta target genes in the absence of ligand and participates in the negative feedback regulation of TGF-beta signaling. In the absence of TGF-beta, SnoN binds to the nuclear SMAD4 (DPC4) and represses TGF-beta-responsive promoter activity through recruitment of a nuclear repressor complex. TGF-beta induces activation and nuclear translocation of SMAD2, SMAD3 (<a href="/entry/603109">603109</a>), and SMAD4. SMAD3 causes degradation of SnoN, allowing a SMAD2/SMAD4 complex to activate TGF-beta target genes. To initiate a negative feedback mechanism that permits a precise and timely regulation of TGF-beta signaling, TGF-beta also induces an increased expression of SnoN at a later stage, which in turn binds to SMAD heteromeric complexes and shuts off TGF-beta signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10531062" 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>SMADs mediate activin, TGF-beta, and BMP signaling from receptors to nuclei. According to the current model, activated activin/TGF-beta receptors phosphorylate the carboxyl-terminal serines of SMAD2 and SMAD3 (SSMS-COOH); phosphorylated SMAD2/SMAD3 oligomerizes with SMAD4, translocates to the nucleus, and modulates transcription of defined genes. To test key features of this model, <a href="#8" class="mim-tip-reference" title="Funaba, M., Mathews, L. S. <strong>Identification and characterization of constitutively active Smad2 mutants: evaluation of formation of Smad complex and subcellular distribution.</strong> Molec. Endocr. 14: 1583-1591, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11043574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11043574</a>] [<a href="https://doi.org/10.1210/mend.14.10.0537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11043574">Funaba and Mathews (2000)</a> explored the construction of constitutively active SMAD2 mutants. To mimic phosphorylated SMAD2, they made 2 SMAD2 mutants with acidic amino acid substitutions of carboxyl-terminal serines: SMAD2-2E and SMAD2-3E. The mutants enhanced basal transcriptional activity in a mink lung epithelial cell line, L17. In a SMAD4-deficient cell line, SMAD2-2E did not affect basal signaling; suggesting that the constitutively active SMAD2 mutant also requires SMAD4 for function. <a href="#8" class="mim-tip-reference" title="Funaba, M., Mathews, L. S. <strong>Identification and characterization of constitutively active Smad2 mutants: evaluation of formation of Smad complex and subcellular distribution.</strong> Molec. Endocr. 14: 1583-1591, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11043574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11043574</a>] [<a href="https://doi.org/10.1210/mend.14.10.0537" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11043574">Funaba and Mathews (2000)</a> concluded that SMAD2 phosphorylation results in both tighter binding to SMAD4 and increased nuclear concentration; those changes may be responsible for transcriptional activation by SMAD2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11043574" 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="#26" class="mim-tip-reference" title="You, L., Kruse, F. E. <strong>Differential effect of activin A and BMP-7 on myofibroblast differentiation and the role of the Smad signaling pathway.</strong> Invest. Ophthal. Vis. Sci. 43: 72-81, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11773015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11773015</a>]" pmid="11773015">You and Kruse (2002)</a> studied corneal myofibroblast differentiation and signal transduction induced by the TGFB family members activin A (<a href="/entry/147290">147290</a>) and bone morphogenetic protein-7 (BMP7; <a href="/entry/112267">112267</a>). They found that activin A induced phosphorylation of SMAD2, and BMP7 induced SMAD1 (<a href="/entry/601595">601595</a>), both of which were inhibited by follistatin (<a href="/entry/136470">136470</a>). Transfection with antisense SMAD2/SMAD3 prevented activin-induced expression and accumulation of alpha-smooth muscle actin. The authors concluded that TGFB proteins have different functions in the cornea. Activin A and TGFB1, but not BMP7, are regulators of keratocyte differentiation and might play a role during myofibroblast transdifferentiation. SMAD2/SMAD3 signal transduction appeared to be important in the regulation of muscle-specific genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11773015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Oft, M., Akhurst, R. J., Balmain, A. <strong>Metastasis is driven by sequential elevation of H-ras and Smad2 levels.</strong> Nature Cell Biol. 4: 487-494, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12105419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12105419</a>] [<a href="https://doi.org/10.1038/ncb807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12105419">Oft et al. (2002)</a> found that activation of Smad2 induced migration of mouse squamous carcinoma cells, but that elevated levels of H-ras (<a href="/entry/190020">190020</a>) were required for nuclear accumulation of Smad2. Elevated levels of both were required for induction of spindle-cell transformation and metastasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12105419" 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>SMAD2 is released from cytoplasmic retention by TGFB receptor-mediated phosphorylation and accumulates in the nucleus, where it associates with cofactors to regulate transcription. <a href="#25" class="mim-tip-reference" title="Xu, L., Kang, Y., Col, S., Massague, J. <strong>Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGF-beta signaling complexes in the cytoplasm and nucleus.</strong> Molec. Cell 10: 271-282, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12191473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12191473</a>] [<a href="https://doi.org/10.1016/s1097-2765(02)00586-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12191473">Xu et al. (2002)</a> uncovered direct interactions of SMAD2 with the nucleoporins NUP214 (<a href="/entry/114350">114350</a>) and NUP153 (<a href="/entry/603948">603948</a>). These interactions mediate constitutive nucleocytoplasmic shuttling of SMAD2. NUP214 and NUP153 compete with the cytoplasmic retention factor SARA (<a href="/entry/603755">603755</a>) and the nuclear SMAD2 partner FAST1 (<a href="/entry/603621">603621</a>) for binding to a hydrophobic corridor on the MH2 surface of SMAD2. TGFB receptor-mediated phosphorylation stimulates nuclear accumulation of SMAD2 by modifying its affinity for SARA and SMAD4 but not for NUP214 or NUP153. Thus, by directly contacting the nuclear pore complex, SMAD2 undergoes constant shuttling, providing a dynamic pool that is competitively drawn by cytoplasmic and nuclear signal transduction partners. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12191473" 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>TGFB stimulation leads to phosphorylation and activation of SMAD2 and SMAD3, which form complexes with SMAD4 that accumulate in the nucleus and regulate transcription of target genes. <a href="#11" class="mim-tip-reference" title="Inman, G. J., Nicolas, F. J., Hill, C. S. <strong>Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity.</strong> Molec. Cell 10: 283-294, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12191474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12191474</a>] [<a href="https://doi.org/10.1016/s1097-2765(02)00585-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12191474">Inman et al. (2002)</a> demonstrated that following TGFB stimulation of epithelial cells, receptors remain active for at least 3 to 4 hours, and continuous receptor activity is required to maintain active SMADs in the nucleus and for TGFB-induced transcription. Continuous nucleocytoplasmic shuttling of the SMADs during active TGFB signaling provides the mechanism whereby the intracellular transducers of the signal continuously monitor receptor activity. These data explain how, at all times, the concentration of active SMADs in the nucleus is directly dictated by the levels of activated receptors in the cytoplasm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12191474" 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 Xenopus embryo explants, whole zebrafish embryos, and mammalian cell lines, <a href="#2" class="mim-tip-reference" title="Batut, J., Howell, M., Hill, C. S. <strong>Kinesin-mediated transport of Smad2 is required for signaling in response to TGF-beta ligands.</strong> Dev. Cell 12: 261-274, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17276343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17276343</a>] [<a href="https://doi.org/10.1016/j.devcel.2007.01.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17276343">Batut et al. (2007)</a> showed that phosphorylation and nuclear accumulation of Smad2 required an intact microtubule network and the ATPase activity of the kinesin motor. Smad2 interacted directly with the kinesin-1 light chain subunit (KLC2), and interfering with kinesin activity in Xenopus and zebrafish embryos phenocopied loss of Nodal (<a href="/entry/601265">601265</a>) signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17276343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Davis, B. N., Hilyard, A. C., Lagna, G., Hata, A. <strong>SMAD proteins control DROSHA-mediated microRNA maturation.</strong> Nature 454: 56-61, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18548003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18548003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18548003[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/nature07086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18548003">Davis et al. (2008)</a> demonstrated that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta (<a href="/entry/190180">190180</a>) and BMPs is mediated by miR21 (<a href="/entry/611020">611020</a>). miR21 downregulates PDCD4 (<a href="/entry/608610">608610</a>), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-beta and BMP signaling promoted a rapid increase in expression of mature miR21 through a posttranscriptional step, promoting the processing of primary transcripts of miR21 (pri-miR21) into precursor miR21 (pre-miR21) by the Drosha complex (see <a href="/entry/608828">608828</a>). TGF-beta and BMP-specific SMAD signal transducers SMAD1, SMAD2, SMAD3 (<a href="/entry/603109">603109</a>), and SMAD5 (<a href="/entry/603110">603110</a>) are recruited to pri-miR21 in a complex with the RNA helicase p68 (DDX5; <a href="/entry/180630">180630</a>), a component of the Drosha microprocessor complex. The shared cofactor SMAD4 (<a href="/entry/600993">600993</a>) is not required for this process. Thus, <a href="#5" class="mim-tip-reference" title="Davis, B. N., Hilyard, A. C., Lagna, G., Hata, A. <strong>SMAD proteins control DROSHA-mediated microRNA maturation.</strong> Nature 454: 56-61, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18548003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18548003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18548003[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/nature07086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18548003">Davis et al. (2008)</a> concluded that regulation of microRNA biogenesis by ligand-specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4-independent responses mediated by the TGF-beta and BMP signaling pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18548003" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bertero, A., Brown, S., Madrigal, P., Osnato, A., Ortmann, D., Yiangou, L., Kadiwala, J., Hubner, N. C., de los Mozos, I. R., Sadee, C., Lenaerts, A.-S., Nakanoh, S., Grandy, R., Farnell, E., Ule, J., Stunnenberg, H. G., Mendjan, S., Vallier, L. <strong>The SMAD2/3 interactome reveals that TGF-beta controls m6A mRNA methylation in pluripotency.</strong> Nature 555: 256-259, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29489750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29489750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29489750[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/nature25784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29489750">Bertero et al. (2018)</a> described the interactome of SMAD2/3 in human pluripotent stem cells. This analysis revealed that SMAD2/3 is involved in multiple molecular processes in addition to its role in transcription. In particular, <a href="#3" class="mim-tip-reference" title="Bertero, A., Brown, S., Madrigal, P., Osnato, A., Ortmann, D., Yiangou, L., Kadiwala, J., Hubner, N. C., de los Mozos, I. R., Sadee, C., Lenaerts, A.-S., Nakanoh, S., Grandy, R., Farnell, E., Ule, J., Stunnenberg, H. G., Mendjan, S., Vallier, L. <strong>The SMAD2/3 interactome reveals that TGF-beta controls m6A mRNA methylation in pluripotency.</strong> Nature 555: 256-259, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29489750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29489750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29489750[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/nature25784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29489750">Bertero et al. (2018)</a> identified a functional interaction with the METTL3 (<a href="/entry/612472">612472</a>)-METTL14 (<a href="/entry/616504">616504</a>)-WTAP (<a href="/entry/605442">605442</a>) complex, which mediates the conversion of adenosine to N6-methyladenosine (m6A) on RNA. <a href="#3" class="mim-tip-reference" title="Bertero, A., Brown, S., Madrigal, P., Osnato, A., Ortmann, D., Yiangou, L., Kadiwala, J., Hubner, N. C., de los Mozos, I. R., Sadee, C., Lenaerts, A.-S., Nakanoh, S., Grandy, R., Farnell, E., Ule, J., Stunnenberg, H. G., Mendjan, S., Vallier, L. <strong>The SMAD2/3 interactome reveals that TGF-beta controls m6A mRNA methylation in pluripotency.</strong> Nature 555: 256-259, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29489750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29489750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29489750[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/nature25784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29489750">Bertero et al. (2018)</a> showed that SMAD2/3 promotes binding of the m6A methyltransferase complex to a subset of transcripts involved in early cell fate decisions. This mechanism destabilizes specific SMAD2/3 transcriptional targets, including the pluripotency factor gene NANOG (<a href="/entry/607937">607937</a>), priming them for rapid downregulation upon differentiation to enable timely exit from pluripotency. <a href="#3" class="mim-tip-reference" title="Bertero, A., Brown, S., Madrigal, P., Osnato, A., Ortmann, D., Yiangou, L., Kadiwala, J., Hubner, N. C., de los Mozos, I. R., Sadee, C., Lenaerts, A.-S., Nakanoh, S., Grandy, R., Farnell, E., Ule, J., Stunnenberg, H. G., Mendjan, S., Vallier, L. <strong>The SMAD2/3 interactome reveals that TGF-beta controls m6A mRNA methylation in pluripotency.</strong> Nature 555: 256-259, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29489750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29489750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29489750[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/nature25784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29489750">Bertero et al. (2018)</a> concluded that their findings revealed the mechanism by which extracellular signaling can induce rapid cellular responses through regulation of the epitranscriptome. They commented that these aspects of TGF-beta signaling could have far-reaching implications in many other cell types and in diseases such as cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29489750" 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="#23" class="mim-tip-reference" title="Wu, G., Chen, Y.-G., Ozdamar, B., Gyuricza, C. A., Chong, P. A., Wrana, J. L., Massague, J., Shi, Y. <strong>Structural basis of Smad2 recognition by the Smad anchor for receptor activation.</strong> Science 287: 92-97, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10615055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10615055</a>] [<a href="https://doi.org/10.1126/science.287.5450.92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10615055">Wu et al. (2000)</a> determined the crystal structure of a SMAD2 MH2 domain in complex with the SMAD-binding domain of SARA at 2.2-angstrom resolution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10615055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Wu, J.-W., Hu, M., Chai, J., Seoane, J., Huse, M., Li, C., Rigotti, D. J., Kyin, S., Muir, T. W., Fairman, R., Massague, J., Shi, Y. <strong>Crystal structure of a phosphorylated Smad2: recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling.</strong> Molec. Cell 8: 1277-1289, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11779503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11779503</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00421-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11779503">Wu et al. (2001)</a> determined the crystal structure of a phosphorylated SMAD2 at 1.8-angstrom resolution. The structure revealed the formation of a homotrimer mediated by the C-terminal phosphoserine residues. The phosphoserine-binding surface on the MH2 domain, which is frequently targeted for inactivation in cancers, is highly conserved among the comediator SMADs (Co-SMADs) and receptor-regulated SMADs (R-SMADs). This finding, together with mutagenesis data, pinpointed a functional interface between SMAD2 and SMAD4. In addition, the phosphoserine-binding surface on the MH2 domain coincides with the surface on R-SMADs that is required for docking interactions with the serine-phosphorylated receptor kinases. These observations defined a bifunctional role for the MH2 domain as a phosphoserine-X-phosphoserine-binding module in receptor ser/thr kinase signaling pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11779503" 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="#20" class="mim-tip-reference" title="Takenoshita, S., Mogi, A., Nagashima, M., Yang, K., Yagi, K., Hanyu, A., Nagamachi, Y., Miyazono, K., Hagiwara, K. <strong>Characterization of the MADH2/Smad2 gene, a human Mad homolog responsible for the transforming growth factor-beta and activin signal transduction pathway.</strong> Genomics 48: 1-11, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9503010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9503010</a>] [<a href="https://doi.org/10.1006/geno.1997.5149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9503010">Takenoshita et al. (1998)</a> determined the structure of the human MADH2 gene and characterized the 5-prime and 3-prime ends of MADH2 mRNAs. The MADH2 gene contains 12 exons, the first 2 (1a and 1b) of which are alternatively spliced such that they are used singly or in combination. In addition, RT-PCR showed that the fourth exon (exon 3), which encodes 30 amino acids, is spliced out in about 10% of MADH2 transcripts. The authors found that MADH2 mRNAs are transcribed from 2 different promoters located in 1 CpG island. The 3-prime ends of MADH2 mRNAs are heterogeneous, and <a href="#20" class="mim-tip-reference" title="Takenoshita, S., Mogi, A., Nagashima, M., Yang, K., Yagi, K., Hanyu, A., Nagamachi, Y., Miyazono, K., Hagiwara, K. <strong>Characterization of the MADH2/Smad2 gene, a human Mad homolog responsible for the transforming growth factor-beta and activin signal transduction pathway.</strong> Genomics 48: 1-11, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9503010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9503010</a>] [<a href="https://doi.org/10.1006/geno.1997.5149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9503010">Takenoshita et al. (1998)</a> identified several polyadenylation signals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9503010" 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="#7" class="mim-tip-reference" title="Eppert, K., Scherer, S. W., Ozcelik, H., Pirone, R., Hoodless, P., Kim, H., Tsui, L.-C., Bapat, B., Gallinger, S., Andrulis, I. L., Thomsen, G. H., Wrana, J. L., Attisano, L. <strong>MADR2 maps to 18q21 and encodes a TGF-beta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma.</strong> Cell 86: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8752209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8752209</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80128-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8752209">Eppert et al. (1996)</a> mapped the MADR2 gene close to DPC4 at 18q21, a region which is frequently deleted in colorectal cancers. <a href="#16" class="mim-tip-reference" title="Riggins, G. J., Thiagalingam, S., Rozenblum, E., Weinstein, C. L., Kern, S. E., Hamilton, S. R., Willson, J. K. V., Markowitz, S. D., Kinzler, K. W., Vogelstein, B. <strong>Mad-related genes in the human.</strong> Nature Genet. 13: 347-349, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673135</a>] [<a href="https://doi.org/10.1038/ng0796-347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673135">Riggins et al. (1996)</a> mapped the human MADH2 gene to 18q21. <a href="#14" class="mim-tip-reference" title="Nakao, A., Roijer, E., Imamura, T., Souchelnytskyi, S., Stenman, G., Heldin, C.-H., ten Dijke, P. <strong>Identification of Smad2, a human Mad-related protein in the transforming growth factor-beta signaling pathway.</strong> J. Biol. Chem. 272: 2896-2900, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9006934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9006934</a>] [<a href="https://doi.org/10.1074/jbc.272.5.2896" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9006934">Nakao et al. (1997)</a> refined the localization of the SMAD2 gene to 18q21.1, approximately 3 Mb proximal to DPC4, by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9006934+8752209+8673135" 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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From a cohort of 362 parent-offspring trios in which a child had severe congenital heart disease but no first-degree relative with structural heart disease, <a href="#27" class="mim-tip-reference" title="Zaidi, S., Choi, M., Wakimoto, H., Ma, L., Jiang, J., Overton, J. D., Romano-Adesman, A., Bjornson, R. D., Breitbart, R. E., Brown, K. K., Carriero, N. J., Cheung, Y. H., and 38 others. <strong>De novo mutations in histone-modifying genes in congenital heart disease.</strong> Nature 498: 220-223, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23665959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23665959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23665959[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/nature12141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23665959">Zaidi et al. (2013)</a> identified 2 unrelated patients with congenital heart defects and heterotaxy (CHTD8; <a href="/entry/619657">619657</a>) who were heterozygous for de novo mutations in the SMAD2 gene: a splice site variant (<a href="#0001">601366.0001</a>) and a missense variant (W244C; <a href="#0002">601366.0002</a>), respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23665959" 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 GeneMatcher, <a href="#10" class="mim-tip-reference" title="Granadillo, J. L., Chung, W. K., Hecht, L., Corsten-Janssen, N., Wegner, D., Nij Bijvank, S. W. A., Toler, T. L., Pineda-Alvarez, D. E., Douglas, G., Murphy, J. J., Shimony, J., Shinawi, M. <strong>Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants.</strong> Hum. Mutat. 39: 1875-1884, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30157302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30157302</a>] [<a href="https://doi.org/10.1002/humu.23627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30157302">Granadillo et al. (2018)</a> identified 3 patients with complex congenital heart defects, including 1 with heterotaxy, who had heterozygous mutations in the SMAD2 gene, including a nonsense mutation (Q159X; <a href="#0007">601366.0007</a>), a missense mutation (C312S; <a href="#0008">601366.0008</a>), and a splice site mutation (<a href="#0009">601366.0009</a>). The authors concluded that mutation in SMAD2 results in 2 distinct phenotypes: a cardiac phenotype with complex congenital defects, with or without heterotaxy, and a vascular phenotype characterized by adult-onset arterial aneurysms and features suggestive of a connective tissue disorder (Loeys-Dietz syndrome). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30157302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Loeys-Dietz Syndrome 6</em></strong></p><p>
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In a cohort of 365 patients with arterial aneurysm and/or dissection, who were 60 years of age or younger and negative for mutation in the FBN1 (<a href="/entry/134797">134797</a>), TGFBR1 (<a href="/entry/190181">190181</a>), TGFBR2 (<a href="/entry/190182">190182</a>), ACTA2 (<a href="/entry/102620">102620</a>), or MYH11 (<a href="/entry/160745">160745</a>) genes, <a href="#13" class="mim-tip-reference" title="Micha, D., Guo, D., Hilhorst-Hofstee, Y., van Kooten, F., Atmaja, D., Overwater, E., Cayami, F. K., Regalado, E. S., van Uffelen, R., Venselaar, H., Faradz, S. M. H., Vriend, G., Weiss, M. M., Sistermans, E. A., Maugeri, A., Milewicz, D. M., Pals, G., van Dijk, F. S. <strong>SMAD2 Mutations are associated with arterial aneurysms and dissections.</strong> Hum. Mutat. 36: 1145-1149, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26247899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26247899</a>] [<a href="https://doi.org/10.1002/humu.22854" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26247899">Micha et al. (2015)</a> sequenced the SMAD2 gene and identified 2 probands with heterozygous missense mutations that were not found in public variant databases: L449S (<a href="#0003">601366.0003</a>) and G457R (<a href="#0004">601366.0004</a>), respectively. Analysis of exome data from 211 families with thoracic aortic aneurysm identified another SMAD2 missense variant (Q388R; <a href="#0005">601366.0005</a>) in 2 affected sisters. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26247899" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By whole-exome sequencing in a 51-year-old Chinese man with thoracic and abdominal aortic aneurysm, <a href="#28" class="mim-tip-reference" title="Zhang, W., Zeng, Q., Xu, Y., Ying, H., Zhou, W., Cao, Q., Zhou, W. <strong>Exome sequencing identified a novel SMAD2 mutation in a Chinese family with early onset aortic aneurysms.</strong> Clin. Chim. Acta 468: 211-214, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28283438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28283438</a>] [<a href="https://doi.org/10.1016/j.cca.2017.03.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28283438">Zhang et al. (2017)</a> identified heterozygosity for a missense mutation in the SMAD2 gene (A278V; <a href="#0006">601366.0006</a>) that was not found in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28283438" 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 42-year-old woman with aortic root aneurysm and dilated and tortuous cerebral arteries, <a href="#10" class="mim-tip-reference" title="Granadillo, J. L., Chung, W. K., Hecht, L., Corsten-Janssen, N., Wegner, D., Nij Bijvank, S. W. A., Toler, T. L., Pineda-Alvarez, D. E., Douglas, G., Murphy, J. J., Shimony, J., Shinawi, M. <strong>Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants.</strong> Hum. Mutat. 39: 1875-1884, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30157302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30157302</a>] [<a href="https://doi.org/10.1002/humu.23627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30157302">Granadillo et al. (2018)</a> identified heterozygosity for a 1-bp duplication in the SMAD2 gene (<a href="#0010">601366.0010</a>) that was not found in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30157302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Cannaerts, E., Kempers, M., Maugeri, A., Marcelis, C., Gardeitchik, T., Richer, J., Micha, D., Beauchesne, L., Timmermans, J., Vermeersch, P., Meyten, N., Chenier, S., van de Beek, G., Peeters, N., Alaerts, M., Schepers, D., Van Laer, L., Verstraeten, A., Loeys, B. <strong>Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: further delineation of the phenotype.</strong> J. Med. Genet. 56: 220-227, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29967133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29967133</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29967133">Cannaerts et al. (2019)</a> identified heterozygous SMAD2 mutations in 9 patients from 5 unrelated families with thoracic aortic aneurysm and/or arterial tortuosity and connective tissue and skeletal anomalies (see, e.g., <a href="#0010">601366.0010</a> and <a href="#0011">601366.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29967133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Somatic Mutation in Colorectal Cancer</em></strong></p><p>
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In a screen of 66 sporadic colorectal carcinomas, <a href="#7" class="mim-tip-reference" title="Eppert, K., Scherer, S. W., Ozcelik, H., Pirone, R., Hoodless, P., Kim, H., Tsui, L.-C., Bapat, B., Gallinger, S., Andrulis, I. L., Thomsen, G. H., Wrana, J. L., Attisano, L. <strong>MADR2 maps to 18q21 and encodes a TGF-beta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma.</strong> Cell 86: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8752209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8752209</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80128-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8752209">Eppert et al. (1996)</a> identified 4 missense mutations in MADR2, 2 of which were associated with loss of heterozygosity (LOH) in 1 allele. These mutations were associated with loss of protein expression or loss of TGF-beta-regulated phosphorylation. <a href="#7" class="mim-tip-reference" title="Eppert, K., Scherer, S. W., Ozcelik, H., Pirone, R., Hoodless, P., Kim, H., Tsui, L.-C., Bapat, B., Gallinger, S., Andrulis, I. L., Thomsen, G. H., Wrana, J. L., Attisano, L. <strong>MADR2 maps to 18q21 and encodes a TGF-beta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma.</strong> Cell 86: 543-552, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8752209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8752209</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80128-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8752209">Eppert et al. (1996)</a> proposed that MADR2 is a tumor suppressor gene and that mutations acquired in colorectal cancer may function to disrupt TGF-beta signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8752209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Riggins, G. J., Thiagalingam, S., Rozenblum, E., Weinstein, C. L., Kern, S. E., Hamilton, S. R., Willson, J. K. V., Markowitz, S. D., Kinzler, K. W., Vogelstein, B. <strong>Mad-related genes in the human.</strong> Nature Genet. 13: 347-349, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673135</a>] [<a href="https://doi.org/10.1038/ng0796-347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673135">Riggins et al. (1996)</a> evaluated JV18-1 in a panel of 18 colorectal cancer cell lines, each containing allelic loss of the minimally lost region on chromosome 18q. RT-PCR studies revealed JV18-1 expression in normal colon, normal brain, and in 17 of 18 colorectal tumors. They identified 1 tumor in which there was a homozygous deletion of JV18-1 sequences. The deletion in this tumor did not extend proximally to include D18S535 or distally to DPC4. In another tumor, a smaller protein encoded by JV18-1 was present. The protein was shorter because of a deletion extending from codons 345 to 358. This deletion was somatic in origin. <a href="#16" class="mim-tip-reference" title="Riggins, G. J., Thiagalingam, S., Rozenblum, E., Weinstein, C. L., Kern, S. E., Hamilton, S. R., Willson, J. K. V., Markowitz, S. D., Kinzler, K. W., Vogelstein, B. <strong>Mad-related genes in the human.</strong> Nature Genet. 13: 347-349, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673135</a>] [<a href="https://doi.org/10.1038/ng0796-347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673135">Riggins et al. (1996)</a> concluded that this gene family may be important in the suppression of neoplasia, since its members transduce growth inhibitory signals from TGF-beta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8673135" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By PCR-SSCP analysis of the entire coding region of the SMAD2 gene using intron-based primers, <a href="#21" class="mim-tip-reference" title="Takenoshita, S., Tani, M., Mogi, A., Nagashima, M., Nagamachi, Y., Bennett, W. P., Hagiwara, K., Harris, C. C., Yokota, J. <strong>Mutation analysis of the Smad2 gene in human colon cancers using genomic DNA and intron primers.</strong> Carcinogenesis 19: 803-807, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9635866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9635866</a>] [<a href="https://doi.org/10.1093/carcin/19.5.803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9635866">Takenoshita et al. (1998)</a> screened genomic DNA sequences of colorectal cancers for mutations of the SMAD2 gene. Although no mutations were found within any exon of SMAD2, 2 of 60 sporadic colorectal cancers displayed deletions in the polypyrimidine tract preceding exon 4. Deletions of this region were also detected in colon cancer cell lines, and were clustered within cells exhibiting microsatellite instability. Deletions in the polypyrimidine tract had no effect on the splicing of the SMAD2 gene in these cases; however, the polypyrimidine tract in the splicing acceptor site may be a target for mutations in mismatch repair-deficient tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9635866" 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="Takagi, Y., Koumura, H., Futamura, M., Aoki, S., Ymaguchi, K., Kida, H., Tanemura, H., Shimokawa, K., Saji, S. <strong>Somatic alterations of the SMAD-2 gene in human colorectal cancers.</strong> Brit. J. Cancer 78: 1152-1155, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9820171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9820171</a>] [<a href="https://doi.org/10.1038/bjc.1998.645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9820171">Takagi et al. (1998)</a> carried out mutation analyses of the SMAD2 gene on cDNA sampled from 36 primary colorectal cancer specimens. Only 1 missense mutation (2.8%), producing an amino acid substitution in the highly conserved region, and 2 homozygous deletions (5.5%) of the total coding region of SMAD2 gene were detected. They concluded that the SMAD2 gene may play a role as a candidate tumor suppressor gene in a small fraction of colorectal cancers. Even in combination with changes in SMAD4, the observed frequency was not sufficient to account for all 18q21 deletions in colorectal cancers. Thus, another tumor suppressor gene, such as DCC (<a href="/entry/120470">120470</a>), discovered as the first tumor suppressor candidate in the region, may exist in the 18q21 region where LOH is often seen. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9820171" 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 cDNA, <a href="#17" class="mim-tip-reference" title="Roth, S., Johansson, M., Loukola, A., Peltomaki, P., Jarvinen, H., Mecklin, J.-P., Aaltonen, L. A. <strong>Mutation analysis of SMAD2, SMAD3, and SMAD4 genes in hereditary non-polyposis colorectal cancer.</strong> J. Med. Genet. 37: 298-300, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10819637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10819637</a>] [<a href="https://doi.org/10.1136/jmg.37.4.298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10819637">Roth et al. (2000)</a> conducted mutation analysis of the SMAD2, SMAD3, and SMAD4 genes in 14 Finnish kindreds with hereditary nonpolyposis colon cancer (see <a href="/entry/120435">120435</a>). They found no mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10819637" 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="#22" class="mim-tip-reference" title="Waldrip, W. R., Bikoff, E. K., Hoodless, P. A., Wrana, J. L., Robertson, E. J. <strong>Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo.</strong> Cell 92: 797-808, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529255</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81407-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529255">Waldrip et al. (1998)</a> studied the effect of Smad2 in mouse embryonic development by targeted disruption of the mouse Smad2 gene using embryonic stem cell technology. They found that Smad2 function was not required for mesoderm production per se, but, rather unexpectedly, in the absence of Smad2, the entire epiblast adopts a mesodermal fate giving rise to a normal yolk sac and fetal blood cells. In contrast, Smad2 mutant mouse embryos entirely lacked tissues of the embryonic germ layers. <a href="#22" class="mim-tip-reference" title="Waldrip, W. R., Bikoff, E. K., Hoodless, P. A., Wrana, J. L., Robertson, E. J. <strong>Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo.</strong> Cell 92: 797-808, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529255</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81407-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529255">Waldrip et al. (1998)</a> concluded that Smad2 signals serve to restrict the site of primitive streak formation and establish anterior-posterior identity within the epiblast. Chimera experiments demonstrated that these essential activities are contributed by the extraembryonic tissues. Thus, the extraembryonic tissues play critical roles in establishing the body plan during early mouse development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9529255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Derynck, R., Gelbart, W. M., Harland, R. M., Heldin, C.-H., Kern, S. E., Massague, J., Melton, D. A., Mlodzik, M., Padgett, R. W., Roberts, A. B., Smith, J., Thomsen, G. H., Vogelstein, B., Wang, X.-F. <strong>Nomenclature: vertebrate mediators of TGF-beta family signals. (Letter)</strong> Cell 87: 173 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8861901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8861901</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81335-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8861901">Derynck et al. (1996)</a> proposed a revised nomenclature for the Mad-related products and genes that are implicated in signal transduction by members of the TGF-beta family. As the root symbol they proposed SMAD, which is a merger of Sma (the gene in C. elegans) and Mad. SMAD serves to differentiate these proteins from unrelated gene products previously called MAD (see <a href="/entry/600021">600021</a>). JV18.1 became SMAD2 in their nomenclature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8861901" 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=601366[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">rs397509416 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509416;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=rs397509416" 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=rs397509416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient (1-02020) with complex congenital heart defects and heterotaxy (CHTD8; <a href="/entry/619657">619657</a>), <a href="#27" class="mim-tip-reference" title="Zaidi, S., Choi, M., Wakimoto, H., Ma, L., Jiang, J., Overton, J. D., Romano-Adesman, A., Bjornson, R. D., Breitbart, R. E., Brown, K. K., Carriero, N. J., Cheung, Y. H., and 38 others. <strong>De novo mutations in histone-modifying genes in congenital heart disease.</strong> Nature 498: 220-223, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23665959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23665959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23665959[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/nature12141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23665959">Zaidi et al. (2013)</a> identified a heterozygous de novo splice site mutation in intron 6 of the SMAD2 gene (p.IVS6+1G-A). Cardiovascular anomalies in the proband included dextrocardia, unbalanced complete atrioventricular canal, pulmonary stenosis, double-outlet right ventricle, dextroposition of the great arteries, and atrial septal defect; she also had asplenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23665959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs367537998 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs367537998;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=rs367537998" 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=rs367537998" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient (1-02621) with complex congenital heart defects and heterotaxy (CHTD8; <a href="/entry/619657">619657</a>), <a href="#27" class="mim-tip-reference" title="Zaidi, S., Choi, M., Wakimoto, H., Ma, L., Jiang, J., Overton, J. D., Romano-Adesman, A., Bjornson, R. D., Breitbart, R. E., Brown, K. K., Carriero, N. J., Cheung, Y. H., and 38 others. <strong>De novo mutations in histone-modifying genes in congenital heart disease.</strong> Nature 498: 220-223, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23665959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23665959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23665959[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/nature12141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23665959">Zaidi et al. (2013)</a> identified a heterozygous de novo missense mutation in the SMAD2 gene (trp244 to cys; W244C). Cardiovascular anomalies in the proband included dextrocardia, unbalanced right-dominant complete atrioventricular canal, pulmonary stenosis, left superior vena cava to left atrium, partial anomalous pulmonary venous return, and double-outlet right ventricle. She also exhibited abnormal nose, foot syndactyly, and gut malrotation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23665959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2144276501 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2144276501;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=rs2144276501" 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=rs2144276501" 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=RCV001789795 OR RCV005095151" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001789795, RCV005095151" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001789795...</a>
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<p>In a 51-year-old woman (family 1) with Loeys-Dietz syndrome-6 (LDS6; <a href="/entry/619656">619656</a>), <a href="#13" class="mim-tip-reference" title="Micha, D., Guo, D., Hilhorst-Hofstee, Y., van Kooten, F., Atmaja, D., Overwater, E., Cayami, F. K., Regalado, E. S., van Uffelen, R., Venselaar, H., Faradz, S. M. H., Vriend, G., Weiss, M. M., Sistermans, E. A., Maugeri, A., Milewicz, D. M., Pals, G., van Dijk, F. S. <strong>SMAD2 Mutations are associated with arterial aneurysms and dissections.</strong> Hum. Mutat. 36: 1145-1149, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26247899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26247899</a>] [<a href="https://doi.org/10.1002/humu.22854" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26247899">Micha et al. (2015)</a> identified heterozygosity for a c.1346T-C transition (c.1346T-C, NM_001003652.3) in the SMAD2 gene, resulting in a leu449-to-ser (L449S) substitution at a highly conserved residue within the MH2 domain. The mutation was not found in the 1000 Genomes Project, dbSNP137, ExAC, or NHLBI Go ESP databases. The proband had aneurysms and/or dissections of the left vertebral, internal carotid, and intracavernous carotid arteries, as well as bilateral dissection of the carotid arteries in the carotid canal and caliber changes of the left and right internal carotid arteries and left vertebral artery. CT of the thorax and abdomen revealed no aortic abnormalities; however, the proband's mother had thoracic and abdominal aneurysms as well as aortic tortuosity, and a maternal uncle died at age 50 due to dissection of the abdominal aorta. Familial segregation of the mutation was not reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26247899" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2144276285 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2144276285;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=rs2144276285" 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=rs2144276285" 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 30-year-old woman (family 2) with Loeys-Dietz syndrome-6 (LDS6; <a href="/entry/619656">619656</a>), <a href="#13" class="mim-tip-reference" title="Micha, D., Guo, D., Hilhorst-Hofstee, Y., van Kooten, F., Atmaja, D., Overwater, E., Cayami, F. K., Regalado, E. S., van Uffelen, R., Venselaar, H., Faradz, S. M. H., Vriend, G., Weiss, M. M., Sistermans, E. A., Maugeri, A., Milewicz, D. M., Pals, G., van Dijk, F. S. <strong>SMAD2 Mutations are associated with arterial aneurysms and dissections.</strong> Hum. Mutat. 36: 1145-1149, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26247899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26247899</a>] [<a href="https://doi.org/10.1002/humu.22854" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26247899">Micha et al. (2015)</a> identified heterozygosity for a c.1369G-A transition (c.1369G-A, NM_001003652.3) in the SMAD2 gene, resulting in a gly457-to-arg (G457R) substitution at a highly conserved residue within the MH2 domain. The mutation was not found in the 1000 Genomes Project, dbSNP137, ExAC, or NHLBI Go ESP databases. The proband was tall with long thin fingers, and had inguinal hernia repair and surgery for pes planus in childhood; at age 23, she was diagnosed with dilation of the aortic root and dural ectasia. Skeletal features included pain in multiple joints and mild scoliosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26247899" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs746828424 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs746828424;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs746828424?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs746828424" 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=rs746828424" 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=RCV001789797 OR RCV003560848" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001789797, RCV003560848" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001789797...</a>
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<p>In 2 sisters with Loeys-Dietz syndrome-6 (LDS6; <a href="/entry/619656">619656</a>), <a href="#13" class="mim-tip-reference" title="Micha, D., Guo, D., Hilhorst-Hofstee, Y., van Kooten, F., Atmaja, D., Overwater, E., Cayami, F. K., Regalado, E. S., van Uffelen, R., Venselaar, H., Faradz, S. M. H., Vriend, G., Weiss, M. M., Sistermans, E. A., Maugeri, A., Milewicz, D. M., Pals, G., van Dijk, F. S. <strong>SMAD2 Mutations are associated with arterial aneurysms and dissections.</strong> Hum. Mutat. 36: 1145-1149, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26247899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26247899</a>] [<a href="https://doi.org/10.1002/humu.22854" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26247899">Micha et al. (2015)</a> identified heterozygosity for a c.1163A-G transition (c.1163A-G, NM_001003652.3) in the SMAD2 gene, resulting in a gln388-to-arg (Q388R) substitution at a highly conserved residue within the MH2 domain. The mutation was not found in the 1000 Genomes Project, dbSNP137, ExAC, or NHLBI Go ESP databases. The sisters both had aneurysms of the ascending aorta, at ages 46 and 59 years, respectively, as well as striae and long toes. Other features included downslanting palpebral fissures, high-arched palate, and abdominal wall hernia. They also experienced joint pain and exhibited significant osteoarthritis, requiring replacement of some joints. Their mother died suddenly at age 56 of unknown cause, and their paternal grandfather was reported to have died at age 76 of aortic aneurysm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26247899" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2144300734 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2144300734;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=rs2144300734" 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=rs2144300734" 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=RCV001789798 OR RCV003136156" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001789798, RCV003136156" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001789798...</a>
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<p>In a 51-year-old Chinese man with thoracic and abdominal aortic aneurysm (LDS6; <a href="/entry/619656">619656</a>), <a href="#28" class="mim-tip-reference" title="Zhang, W., Zeng, Q., Xu, Y., Ying, H., Zhou, W., Cao, Q., Zhou, W. <strong>Exome sequencing identified a novel SMAD2 mutation in a Chinese family with early onset aortic aneurysms.</strong> Clin. Chim. Acta 468: 211-214, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28283438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28283438</a>] [<a href="https://doi.org/10.1016/j.cca.2017.03.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28283438">Zhang et al. (2017)</a> identified heterozygosity for a c.833C-T transition (c.833C-T, NM_001003652.3) in exon 8 of the SMAD2 gene, resulting in an ala278-to-val (A278V) substitution at a highly conserved residue within the MH2 domain. The mutation, which was not found in the dbSNP139, 1000 Genomes Project, ESP, or ExAC databases, was also not present in the proband's mother, suggesting that he inherited it from his father, who died at age 40 of thoracic aortic aneurysm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28283438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 8</strong>
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SMAD2, GLU159TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1064793873 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1064793873;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=rs1064793873" 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=rs1064793873" 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=RCV000480930 OR RCV001789776" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000480930, RCV001789776" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000480930...</a>
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<p>In a 2-year-old girl (patient 1) with complex congenital heart defects (CHTD8; <a href="/entry/619657">619657</a>), <a href="#10" class="mim-tip-reference" title="Granadillo, J. L., Chung, W. K., Hecht, L., Corsten-Janssen, N., Wegner, D., Nij Bijvank, S. W. A., Toler, T. L., Pineda-Alvarez, D. E., Douglas, G., Murphy, J. J., Shimony, J., Shinawi, M. <strong>Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants.</strong> Hum. Mutat. 39: 1875-1884, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30157302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30157302</a>] [<a href="https://doi.org/10.1002/humu.23627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30157302">Granadillo et al. (2018)</a> identified heterozygosity for a c.475G-T transversion (c.475G-T, NM_005901.5) in exon 3 of the SMAD2 gene, resulting in a glu159-to-ter (E159X) substitution within the MH1 domain. The mutation, which was not found in the NHLBI ESP, ExAC, or gnomAD databases, was not present in the mother; the father was unavailable for testing. Cardiovascular defects in the proband included atrial and ventricular septal defect, double-outlet right ventricle, dextroposition of the great arteries, patent ductus arteriosus, and valvular anomalies. Because the proband also exhibited a single central incisor, analysis of a holoprosencephaly panel revealed a known HPE-associated variant (see HPE4, <a href="/entry/142946">142946</a>) in the TGIF1 gene (Q107L; <a href="/entry/602630#0006">602630.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30157302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 8</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs797044882 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044882;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=rs797044882" 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=rs797044882" 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=RCV000190697 OR RCV001789764" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190697, RCV001789764" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190697...</a>
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<p>In a 10-year-old girl (patient 2) with complex congenital heart defects (CHTD8; <a href="/entry/619657">619657</a>), <a href="#10" class="mim-tip-reference" title="Granadillo, J. L., Chung, W. K., Hecht, L., Corsten-Janssen, N., Wegner, D., Nij Bijvank, S. W. A., Toler, T. L., Pineda-Alvarez, D. E., Douglas, G., Murphy, J. J., Shimony, J., Shinawi, M. <strong>Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants.</strong> Hum. Mutat. 39: 1875-1884, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30157302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30157302</a>] [<a href="https://doi.org/10.1002/humu.23627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30157302">Granadillo et al. (2018)</a> identified heterozygosity for a de novo c.935G-C transition (c.935G-C, NM_005901.5) in exon 8 of the SMAD2 gene, resulting in a cys312-to-ser (C312S) substitution at a highly conserved residue within the beta strand of the MH2 domain. The mutation was not found in the NHLBI ESP, ExAC, or gnomAD databases. Cardiovascular defects in the proband included atrial and ventricular septal defect, double-outlet right ventricle, dextroposition of the great arteries, patent ductus arteriosus, and mitral and pulmonary valve atresia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30157302" 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 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 8, WITH HETEROTAXY</strong>
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SMAD2, IVS2, A-G, -12
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1402819968 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1402819968;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1402819968?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1402819968" 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=rs1402819968" 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=RCV001789799" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001789799" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001789799</a>
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<p>In a female fetus (patient 3) with complex congenital heart defects and heterotaxy (CHTD8; <a href="/entry/619657">619657</a>), in whom no mutation was found in a panel of heterotaxy genes, <a href="#10" class="mim-tip-reference" title="Granadillo, J. L., Chung, W. K., Hecht, L., Corsten-Janssen, N., Wegner, D., Nij Bijvank, S. W. A., Toler, T. L., Pineda-Alvarez, D. E., Douglas, G., Murphy, J. J., Shimony, J., Shinawi, M. <strong>Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants.</strong> Hum. Mutat. 39: 1875-1884, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30157302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30157302</a>] [<a href="https://doi.org/10.1002/humu.23627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30157302">Granadillo et al. (2018)</a> identified heterozygosity for a de novo splice site mutation (c.237-12A-G, NM_005901.5) in intron 2 of the SMAD2 gene. RNA analysis revealed inclusion of 11 bp of intronic sequence before exon 3, causing a frameshift resulting in a premature termination codon (Thr80LeufsTer12). The splice variant was not found in the NHLBI ESP, ExAC, or gnomAD databases. Cardiovascular defects in the proband included dextrocardia, atrial isomerism, atrial and ventricular septal defect, unbalanced complete atrioventricular canal, hypoplastic left ventricle, and anomalous pulmonary venous return; she also had dextrogastria and left-sided gallbladder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30157302" 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="0010" class="mim-anchor"></a>
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<strong>.0010 LOEYS-DIETZ SYNDROME 6</strong>
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SMAD2, 1-BP DUP, 612T
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2144373131 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2144373131;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=rs2144373131" 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=rs2144373131" 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=RCV001789800 OR RCV004552023" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001789800, RCV004552023" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001789800...</a>
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<p>In a 42-year-old woman (patient 4) with aortic root aneurysm, bicuspid aortic valve, and dilated and tortuous cerebral arteries (LDS6; <a href="/entry/619656">619656</a>), <a href="#10" class="mim-tip-reference" title="Granadillo, J. L., Chung, W. K., Hecht, L., Corsten-Janssen, N., Wegner, D., Nij Bijvank, S. W. A., Toler, T. L., Pineda-Alvarez, D. E., Douglas, G., Murphy, J. J., Shimony, J., Shinawi, M. <strong>Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants.</strong> Hum. Mutat. 39: 1875-1884, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30157302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30157302</a>] [<a href="https://doi.org/10.1002/humu.23627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30157302">Granadillo et al. (2018)</a> identified heterozygosity for a de novo 1-bp duplication (c.612dupT, NM_005901.5) in exon 5 of the SMAD2 gene, causing a frameshift resulting in a premature termination codon (asn205-to-ter, N205X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30157302" 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 70-year-old father and his 30-year-old son (family1) with dilation of the aortic root, <a href="#4" class="mim-tip-reference" title="Cannaerts, E., Kempers, M., Maugeri, A., Marcelis, C., Gardeitchik, T., Richer, J., Micha, D., Beauchesne, L., Timmermans, J., Vermeersch, P., Meyten, N., Chenier, S., van de Beek, G., Peeters, N., Alaerts, M., Schepers, D., Van Laer, L., Verstraeten, A., Loeys, B. <strong>Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: further delineation of the phenotype.</strong> J. Med. Genet. 56: 220-227, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29967133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29967133</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29967133">Cannaerts et al. (2019)</a> identified heterozygosity for the 1-bp duplication in the SMAD2 gene resulting in introduction of the premature stop codon N205X. Both father and son exhibited tall stature and long fingers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29967133" 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>.0011 LOEYS-DIETZ SYNDROME 6</strong>
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SMAD2, ASN361THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2144290354 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2144290354;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=rs2144290354" 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=rs2144290354" 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=RCV001789801" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001789801" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001789801</a>
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<p>In a 51-year-old man (family 4) with spontaneous dissection of the left coronary artery, who also had tortuosity of the circle of Willis and iliac arteries (LDS6; <a href="/entry/619656">619656</a>), <a href="#4" class="mim-tip-reference" title="Cannaerts, E., Kempers, M., Maugeri, A., Marcelis, C., Gardeitchik, T., Richer, J., Micha, D., Beauchesne, L., Timmermans, J., Vermeersch, P., Meyten, N., Chenier, S., van de Beek, G., Peeters, N., Alaerts, M., Schepers, D., Van Laer, L., Verstraeten, A., Loeys, B. <strong>Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: further delineation of the phenotype.</strong> J. Med. Genet. 56: 220-227, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29967133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29967133</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29967133">Cannaerts et al. (2019)</a> identified heterozygosity for a c.1082A-C transversion in the SMAD2 gene, resulting in an asn361-to-thr (N361T) substitution within the MH2 domain. The mutation was not found in his unaffected sister or sons; DNA from his deceased parents was unavailable. Other features in the proband included broad uvula, pes planus, pectus asymmetry, mild scoliosis, generalized arthralgias with tendinopathies, and inguinal hernia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29967133" 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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Bertero, A., Brown, S., Madrigal, P., Osnato, A., Ortmann, D., Yiangou, L., Kadiwala, J., Hubner, N. C., de los Mozos, I. R., Sadee, C., Lenaerts, A.-S., Nakanoh, S., Grandy, R., Farnell, E., Ule, J., Stunnenberg, H. G., Mendjan, S., Vallier, L.
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<strong>The SMAD2/3 interactome reveals that TGF-beta controls m6A mRNA methylation in pluripotency.</strong>
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Nature 555: 256-259, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29489750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29489750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29489750[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=29489750" 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/nature25784" target="_blank">Full Text</a>]
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Cannaerts, E., Kempers, M., Maugeri, A., Marcelis, C., Gardeitchik, T., Richer, J., Micha, D., Beauchesne, L., Timmermans, J., Vermeersch, P., Meyten, N., Chenier, S., van de Beek, G., Peeters, N., Alaerts, M., Schepers, D., Van Laer, L., Verstraeten, A., Loeys, B.
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<strong>Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: further delineation of the phenotype.</strong>
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J. Med. Genet. 56: 220-227, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29967133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29967133</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29967133" 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/10.1136/jmedgenet-2018-105304" target="_blank">Full Text</a>]
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Davis, B. N., Hilyard, A. C., Lagna, G., Hata, A.
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<strong>SMAD proteins control DROSHA-mediated microRNA maturation.</strong>
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Nature 454: 56-61, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18548003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18548003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18548003[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=18548003" 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/nature07086" target="_blank">Full Text</a>]
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Derynck, R., Gelbart, W. M., Harland, R. M., Heldin, C.-H., Kern, S. E., Massague, J., Melton, D. A., Mlodzik, M., Padgett, R. W., Roberts, A. B., Smith, J., Thomsen, G. H., Vogelstein, B., Wang, X.-F.
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[<a href="https://doi.org/10.1016/s0092-8674(00)81335-5" target="_blank">Full Text</a>]
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Eppert, K., Scherer, S. W., Ozcelik, H., Pirone, R., Hoodless, P., Kim, H., Tsui, L.-C., Bapat, B., Gallinger, S., Andrulis, I. L., Thomsen, G. H., Wrana, J. L., Attisano, L.
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[<a href="https://doi.org/10.1016/s0092-8674(00)80128-2" target="_blank">Full Text</a>]
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Funaba, M., Mathews, L. S.
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Graff, J. M., Bansal, A., Melton, D. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8653784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8653784</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8653784" 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(00)81249-0" target="_blank">Full Text</a>]
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<a id="Zaidi2013" class="mim-anchor"></a>
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Zaidi, S., Choi, M., Wakimoto, H., Ma, L., Jiang, J., Overton, J. D., Romano-Adesman, A., Bjornson, R. D., Breitbart, R. E., Brown, K. K., Carriero, N. J., Cheung, Y. H., and 38 others.
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<strong>De novo mutations in histone-modifying genes in congenital heart disease.</strong>
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Nature 498: 220-223, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23665959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23665959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23665959[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=23665959" 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/nature12141" target="_blank">Full Text</a>]
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<a id="Zhang2017" class="mim-anchor"></a>
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Zhang, W., Zeng, Q., Xu, Y., Ying, H., Zhou, W., Cao, Q., Zhou, W.
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<strong>Exome sequencing identified a novel SMAD2 mutation in a Chinese family with early onset aortic aneurysms.</strong>
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Clin. Chim. Acta 468: 211-214, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28283438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28283438</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28283438" 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.cca.2017.03.007" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 12/10/2021
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Ada Hamosh - updated : 08/13/2018<br>Ada Hamosh - updated : 07/24/2013<br>Ada Hamosh - updated : 9/11/2008<br>Patricia A. Hartz - updated : 3/2/2007<br>Ada Hamosh - updated : 9/29/2004<br>Stylianos E. Antonarakis - updated : 9/11/2002<br>Patricia A. Hartz - updated : 8/5/2002<br>John A. Phillips, III - updated : 8/2/2002<br>Jane Kelly - updated : 7/8/2002<br>Matthew B. Gross - reorganized : 1/4/2002<br>Stylianos E. Antonarakis - updated : 1/4/2002<br>Michael J. Wright - updated : 1/8/2001<br>Patti M. Sherman - updated : 6/15/2000<br>Ada Hamosh - updated : 2/8/2000<br>Ada Hamosh - updated : 10/23/1999<br>Victor A. McKusick - updated : 2/3/1999<br>Victor A. McKusick - updated : 8/17/1998<br>Stylianos E. Antonarakis - updated : 5/20/1998<br>Rebekah S. Rasooly - updated : 4/6/1998<br>Ethylin Wang Jabs - updated : 11/18/1997<br>Victor A. McKusick - updated : 2/6/1997<br>Moyra Smith - updated : 12/20/1996
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Creation Date:
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<span class="mim-text-font">
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Moyra Smith : 8/8/1996
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alopez : 12/10/2021
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carol : 01/07/2020<br>carol : 01/06/2020<br>alopez : 08/13/2018<br>alopez : 07/24/2013<br>alopez : 9/11/2008<br>wwang : 12/28/2007<br>terry : 12/11/2007<br>mgross : 3/6/2007<br>terry : 3/2/2007<br>carol : 4/28/2005<br>mgross : 4/13/2005<br>terry : 9/29/2004<br>mgross : 10/7/2002<br>alopez : 9/16/2002<br>mgross : 9/11/2002<br>mgross : 9/11/2002<br>carol : 8/5/2002<br>cwells : 8/2/2002<br>mgross : 7/8/2002<br>mgross : 1/4/2002<br>mgross : 1/4/2002<br>mgross : 1/4/2002<br>alopez : 1/8/2001<br>mcapotos : 6/22/2000<br>psherman : 6/15/2000<br>alopez : 2/8/2000<br>alopez : 10/23/1999<br>carol : 2/11/1999<br>terry : 2/3/1999<br>dkim : 9/11/1998<br>carol : 8/20/1998<br>terry : 8/17/1998<br>carol : 5/20/1998<br>psherman : 4/6/1998<br>mark : 11/19/1997<br>jenny : 11/18/1997<br>jenny : 11/18/1997<br>terry : 2/6/1997<br>mark : 2/6/1997<br>terry : 2/6/1997<br>terry : 2/3/1997<br>mark : 12/20/1996<br>mark : 12/20/1996<br>terry : 12/9/1996<br>mark : 8/15/1996<br>mark : 8/15/1996<br>marlene : 8/9/1996<br>mark : 8/8/1996
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<strong>*</strong> 601366
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SMAD FAMILY MEMBER 2; SMAD2
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MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 2; MADH2<br />
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SMA- AND MAD-RELATED PROTEIN 2 MAD, DROSOPHILA, HOMOLOG OF<br />
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MADR2
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<strong><em>HGNC Approved Gene Symbol: SMAD2</em></strong>
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Cytogenetic location: 18q21.1
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Phenotype
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Inheritance
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Phenotype <br /> mapping key
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18q21.1
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Congenital heart defects, multiple types, 8, with or without heterotaxy
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619657
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Autosomal dominant
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3
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Loeys-Dietz syndrome 6
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619656
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Autosomal dominant
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Cloning and Expression</strong>
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<p>Riggins et al. (1996) identified a homolog of the Drosophila 'mothers against decapentaplegic' (Mad) gene (also 'mothers against dpp'). The predicted 467-amino acid polypeptide, which the authors called JV18-1, shows maximal homology to Mad genes at the amino and carboxy termini of the protein, with 62% identity to Mad over 373 amino acids. Drosophila Mad apparently acts downstream of the TGF-beta receptor (190181) to transduce signals from the members of the TGF-beta gene family (190180). The gene product shows 44% identity over 158 amino acids to another Mad homolog, DPC4 (SMAD4; 600993). </p><p>Graff et al. (1996) described a family of Xenopus proteins homologous to the Drosophila Mad and C. elegans CEM genes. MAD and MAD-related proteins are important components of the serine/threonine kinase receptor signal transduction pathways. Eppert et al. (1996) cloned and characterized a member of this family, which they designated MADR2. The gene encodes a 467-amino acid protein that contains no common structural motifs known at that time. MADR2 shares high homology with MADR1 (601595) and significant homology with DPC4. They reported that MADR2 is rapidly phosphorylated by activation of the TGF-beta signaling pathway. </p><p>By RT-PCR of human erythroleukemia cell mRNA using primers based on conserved regions between the Drosophila Mad and C. elegans Sma genes, Nakao et al. (1997) cloned a SMAD2 cDNA. Northern blot analysis of human tissues detected ubiquitously expressed 3.4- and 2.9-kb SMAD2 transcripts. The encoded protein has a molecular mass of 58 kD by SDS-PAGE. </p><p>Baker and Harland (1996) identified the mouse Madr2 gene using a functional assay to clone mouse mesoderm inducers from Xenopus ectoderm. The mouse amino acid sequence is 46% identical to the human tumor suppressor DPC4. Madr2 was expressed widely in the mouse embryo (with the exception of heart and the tail bud) from embryonic days 6.5 to 10.5. Madr2 was found to be confined to the nucleus in the deep anterior cells of the second axis, whereas it was localized in the cytoplasm in the epidermal and more posterior cells. Because Madr2 localized to the nucleus in response to activin (see 147290) and because activin-like phenotypes were induced by overexpression of Madr2, Baker and Harland (1996) concluded that Madr2 is a signal transduction component that mediates the activity of activin. </p>
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<strong>Gene Function</strong>
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<p>Macias-Silva et al. (1996) demonstrated that MADR2 and not the related protein DPC4 transiently interacts with the TGF-beta receptor and is directly phosphorylated by the complex on C-terminal serines. Interaction of MADR2 with receptors and phosphorylation requires activation of receptor I by receptor II and is mediated by the receptor I kinase. Mutation of the phosphorylation sites generated a dominant-negative MADR2 that blocks TGF-beta-dependent transcriptional responses, stably associates with receptors, and fails to accumulate in the nucleus in response to TGF-beta signaling. Thus, Macias-Silva et al. (1996) concluded that transient association and phosphorylation of MADR2 by the TGF-beta receptor is necessary for nuclear accumulation and initiation of signaling. </p><p>SMAD proteins mediate TGF-beta signaling to regulate cell growth and differentiation. Stroschein et al. (1999) identified SnoN (165340) as a component of the SMAD pathway. They proposed a model of regulation of TGF-beta signaling by SnoN in which SnoN maintains the repressed state of TGF-beta target genes in the absence of ligand and participates in the negative feedback regulation of TGF-beta signaling. In the absence of TGF-beta, SnoN binds to the nuclear SMAD4 (DPC4) and represses TGF-beta-responsive promoter activity through recruitment of a nuclear repressor complex. TGF-beta induces activation and nuclear translocation of SMAD2, SMAD3 (603109), and SMAD4. SMAD3 causes degradation of SnoN, allowing a SMAD2/SMAD4 complex to activate TGF-beta target genes. To initiate a negative feedback mechanism that permits a precise and timely regulation of TGF-beta signaling, TGF-beta also induces an increased expression of SnoN at a later stage, which in turn binds to SMAD heteromeric complexes and shuts off TGF-beta signaling. </p><p>SMADs mediate activin, TGF-beta, and BMP signaling from receptors to nuclei. According to the current model, activated activin/TGF-beta receptors phosphorylate the carboxyl-terminal serines of SMAD2 and SMAD3 (SSMS-COOH); phosphorylated SMAD2/SMAD3 oligomerizes with SMAD4, translocates to the nucleus, and modulates transcription of defined genes. To test key features of this model, Funaba and Mathews (2000) explored the construction of constitutively active SMAD2 mutants. To mimic phosphorylated SMAD2, they made 2 SMAD2 mutants with acidic amino acid substitutions of carboxyl-terminal serines: SMAD2-2E and SMAD2-3E. The mutants enhanced basal transcriptional activity in a mink lung epithelial cell line, L17. In a SMAD4-deficient cell line, SMAD2-2E did not affect basal signaling; suggesting that the constitutively active SMAD2 mutant also requires SMAD4 for function. Funaba and Mathews (2000) concluded that SMAD2 phosphorylation results in both tighter binding to SMAD4 and increased nuclear concentration; those changes may be responsible for transcriptional activation by SMAD2. </p><p>You and Kruse (2002) studied corneal myofibroblast differentiation and signal transduction induced by the TGFB family members activin A (147290) and bone morphogenetic protein-7 (BMP7; 112267). They found that activin A induced phosphorylation of SMAD2, and BMP7 induced SMAD1 (601595), both of which were inhibited by follistatin (136470). Transfection with antisense SMAD2/SMAD3 prevented activin-induced expression and accumulation of alpha-smooth muscle actin. The authors concluded that TGFB proteins have different functions in the cornea. Activin A and TGFB1, but not BMP7, are regulators of keratocyte differentiation and might play a role during myofibroblast transdifferentiation. SMAD2/SMAD3 signal transduction appeared to be important in the regulation of muscle-specific genes. </p><p>Oft et al. (2002) found that activation of Smad2 induced migration of mouse squamous carcinoma cells, but that elevated levels of H-ras (190020) were required for nuclear accumulation of Smad2. Elevated levels of both were required for induction of spindle-cell transformation and metastasis. </p><p>SMAD2 is released from cytoplasmic retention by TGFB receptor-mediated phosphorylation and accumulates in the nucleus, where it associates with cofactors to regulate transcription. Xu et al. (2002) uncovered direct interactions of SMAD2 with the nucleoporins NUP214 (114350) and NUP153 (603948). These interactions mediate constitutive nucleocytoplasmic shuttling of SMAD2. NUP214 and NUP153 compete with the cytoplasmic retention factor SARA (603755) and the nuclear SMAD2 partner FAST1 (603621) for binding to a hydrophobic corridor on the MH2 surface of SMAD2. TGFB receptor-mediated phosphorylation stimulates nuclear accumulation of SMAD2 by modifying its affinity for SARA and SMAD4 but not for NUP214 or NUP153. Thus, by directly contacting the nuclear pore complex, SMAD2 undergoes constant shuttling, providing a dynamic pool that is competitively drawn by cytoplasmic and nuclear signal transduction partners. </p><p>TGFB stimulation leads to phosphorylation and activation of SMAD2 and SMAD3, which form complexes with SMAD4 that accumulate in the nucleus and regulate transcription of target genes. Inman et al. (2002) demonstrated that following TGFB stimulation of epithelial cells, receptors remain active for at least 3 to 4 hours, and continuous receptor activity is required to maintain active SMADs in the nucleus and for TGFB-induced transcription. Continuous nucleocytoplasmic shuttling of the SMADs during active TGFB signaling provides the mechanism whereby the intracellular transducers of the signal continuously monitor receptor activity. These data explain how, at all times, the concentration of active SMADs in the nucleus is directly dictated by the levels of activated receptors in the cytoplasm. </p><p>Using Xenopus embryo explants, whole zebrafish embryos, and mammalian cell lines, Batut et al. (2007) showed that phosphorylation and nuclear accumulation of Smad2 required an intact microtubule network and the ATPase activity of the kinesin motor. Smad2 interacted directly with the kinesin-1 light chain subunit (KLC2), and interfering with kinesin activity in Xenopus and zebrafish embryos phenocopied loss of Nodal (601265) signaling. </p><p>Davis et al. (2008) demonstrated that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta (190180) and BMPs is mediated by miR21 (611020). miR21 downregulates PDCD4 (608610), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-beta and BMP signaling promoted a rapid increase in expression of mature miR21 through a posttranscriptional step, promoting the processing of primary transcripts of miR21 (pri-miR21) into precursor miR21 (pre-miR21) by the Drosha complex (see 608828). TGF-beta and BMP-specific SMAD signal transducers SMAD1, SMAD2, SMAD3 (603109), and SMAD5 (603110) are recruited to pri-miR21 in a complex with the RNA helicase p68 (DDX5; 180630), a component of the Drosha microprocessor complex. The shared cofactor SMAD4 (600993) is not required for this process. Thus, Davis et al. (2008) concluded that regulation of microRNA biogenesis by ligand-specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4-independent responses mediated by the TGF-beta and BMP signaling pathways. </p><p>Bertero et al. (2018) described the interactome of SMAD2/3 in human pluripotent stem cells. This analysis revealed that SMAD2/3 is involved in multiple molecular processes in addition to its role in transcription. In particular, Bertero et al. (2018) identified a functional interaction with the METTL3 (612472)-METTL14 (616504)-WTAP (605442) complex, which mediates the conversion of adenosine to N6-methyladenosine (m6A) on RNA. Bertero et al. (2018) showed that SMAD2/3 promotes binding of the m6A methyltransferase complex to a subset of transcripts involved in early cell fate decisions. This mechanism destabilizes specific SMAD2/3 transcriptional targets, including the pluripotency factor gene NANOG (607937), priming them for rapid downregulation upon differentiation to enable timely exit from pluripotency. Bertero et al. (2018) concluded that their findings revealed the mechanism by which extracellular signaling can induce rapid cellular responses through regulation of the epitranscriptome. They commented that these aspects of TGF-beta signaling could have far-reaching implications in many other cell types and in diseases such as cancer. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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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Wu et al. (2000) determined the crystal structure of a SMAD2 MH2 domain in complex with the SMAD-binding domain of SARA at 2.2-angstrom resolution. </p><p>Wu et al. (2001) determined the crystal structure of a phosphorylated SMAD2 at 1.8-angstrom resolution. The structure revealed the formation of a homotrimer mediated by the C-terminal phosphoserine residues. The phosphoserine-binding surface on the MH2 domain, which is frequently targeted for inactivation in cancers, is highly conserved among the comediator SMADs (Co-SMADs) and receptor-regulated SMADs (R-SMADs). This finding, together with mutagenesis data, pinpointed a functional interface between SMAD2 and SMAD4. In addition, the phosphoserine-binding surface on the MH2 domain coincides with the surface on R-SMADs that is required for docking interactions with the serine-phosphorylated receptor kinases. These observations defined a bifunctional role for the MH2 domain as a phosphoserine-X-phosphoserine-binding module in receptor ser/thr kinase signaling pathways. </p>
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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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<span class="mim-text-font">
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<p>Takenoshita et al. (1998) determined the structure of the human MADH2 gene and characterized the 5-prime and 3-prime ends of MADH2 mRNAs. The MADH2 gene contains 12 exons, the first 2 (1a and 1b) of which are alternatively spliced such that they are used singly or in combination. In addition, RT-PCR showed that the fourth exon (exon 3), which encodes 30 amino acids, is spliced out in about 10% of MADH2 transcripts. The authors found that MADH2 mRNAs are transcribed from 2 different promoters located in 1 CpG island. The 3-prime ends of MADH2 mRNAs are heterogeneous, and Takenoshita et al. (1998) identified several polyadenylation signals. </p>
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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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<span class="mim-text-font">
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<p>Eppert et al. (1996) mapped the MADR2 gene close to DPC4 at 18q21, a region which is frequently deleted in colorectal cancers. Riggins et al. (1996) mapped the human MADH2 gene to 18q21. Nakao et al. (1997) refined the localization of the SMAD2 gene to 18q21.1, approximately 3 Mb proximal to DPC4, by fluorescence in situ hybridization. </p>
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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 class="mim-text-font">
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<p><strong><em>Congenital Heart Defects, Multiple Types 8, With or Without Heterotaxy</em></strong></p><p>
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From a cohort of 362 parent-offspring trios in which a child had severe congenital heart disease but no first-degree relative with structural heart disease, Zaidi et al. (2013) identified 2 unrelated patients with congenital heart defects and heterotaxy (CHTD8; 619657) who were heterozygous for de novo mutations in the SMAD2 gene: a splice site variant (601366.0001) and a missense variant (W244C; 601366.0002), respectively. </p><p>Using GeneMatcher, Granadillo et al. (2018) identified 3 patients with complex congenital heart defects, including 1 with heterotaxy, who had heterozygous mutations in the SMAD2 gene, including a nonsense mutation (Q159X; 601366.0007), a missense mutation (C312S; 601366.0008), and a splice site mutation (601366.0009). The authors concluded that mutation in SMAD2 results in 2 distinct phenotypes: a cardiac phenotype with complex congenital defects, with or without heterotaxy, and a vascular phenotype characterized by adult-onset arterial aneurysms and features suggestive of a connective tissue disorder (Loeys-Dietz syndrome). </p><p><strong><em>Loeys-Dietz Syndrome 6</em></strong></p><p>
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In a cohort of 365 patients with arterial aneurysm and/or dissection, who were 60 years of age or younger and negative for mutation in the FBN1 (134797), TGFBR1 (190181), TGFBR2 (190182), ACTA2 (102620), or MYH11 (160745) genes, Micha et al. (2015) sequenced the SMAD2 gene and identified 2 probands with heterozygous missense mutations that were not found in public variant databases: L449S (601366.0003) and G457R (601366.0004), respectively. Analysis of exome data from 211 families with thoracic aortic aneurysm identified another SMAD2 missense variant (Q388R; 601366.0005) in 2 affected sisters. </p><p>By whole-exome sequencing in a 51-year-old Chinese man with thoracic and abdominal aortic aneurysm, Zhang et al. (2017) identified heterozygosity for a missense mutation in the SMAD2 gene (A278V; 601366.0006) that was not found in public variant databases. </p><p>In a 42-year-old woman with aortic root aneurysm and dilated and tortuous cerebral arteries, Granadillo et al. (2018) identified heterozygosity for a 1-bp duplication in the SMAD2 gene (601366.0010) that was not found in public variant databases. </p><p>Cannaerts et al. (2019) identified heterozygous SMAD2 mutations in 9 patients from 5 unrelated families with thoracic aortic aneurysm and/or arterial tortuosity and connective tissue and skeletal anomalies (see, e.g., 601366.0010 and 601366.0011). </p><p><strong><em>Somatic Mutation in Colorectal Cancer</em></strong></p><p>
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In a screen of 66 sporadic colorectal carcinomas, Eppert et al. (1996) identified 4 missense mutations in MADR2, 2 of which were associated with loss of heterozygosity (LOH) in 1 allele. These mutations were associated with loss of protein expression or loss of TGF-beta-regulated phosphorylation. Eppert et al. (1996) proposed that MADR2 is a tumor suppressor gene and that mutations acquired in colorectal cancer may function to disrupt TGF-beta signaling. </p><p>Riggins et al. (1996) evaluated JV18-1 in a panel of 18 colorectal cancer cell lines, each containing allelic loss of the minimally lost region on chromosome 18q. RT-PCR studies revealed JV18-1 expression in normal colon, normal brain, and in 17 of 18 colorectal tumors. They identified 1 tumor in which there was a homozygous deletion of JV18-1 sequences. The deletion in this tumor did not extend proximally to include D18S535 or distally to DPC4. In another tumor, a smaller protein encoded by JV18-1 was present. The protein was shorter because of a deletion extending from codons 345 to 358. This deletion was somatic in origin. Riggins et al. (1996) concluded that this gene family may be important in the suppression of neoplasia, since its members transduce growth inhibitory signals from TGF-beta. </p><p>By PCR-SSCP analysis of the entire coding region of the SMAD2 gene using intron-based primers, Takenoshita et al. (1998) screened genomic DNA sequences of colorectal cancers for mutations of the SMAD2 gene. Although no mutations were found within any exon of SMAD2, 2 of 60 sporadic colorectal cancers displayed deletions in the polypyrimidine tract preceding exon 4. Deletions of this region were also detected in colon cancer cell lines, and were clustered within cells exhibiting microsatellite instability. Deletions in the polypyrimidine tract had no effect on the splicing of the SMAD2 gene in these cases; however, the polypyrimidine tract in the splicing acceptor site may be a target for mutations in mismatch repair-deficient tumors. </p><p>Takagi et al. (1998) carried out mutation analyses of the SMAD2 gene on cDNA sampled from 36 primary colorectal cancer specimens. Only 1 missense mutation (2.8%), producing an amino acid substitution in the highly conserved region, and 2 homozygous deletions (5.5%) of the total coding region of SMAD2 gene were detected. They concluded that the SMAD2 gene may play a role as a candidate tumor suppressor gene in a small fraction of colorectal cancers. Even in combination with changes in SMAD4, the observed frequency was not sufficient to account for all 18q21 deletions in colorectal cancers. Thus, another tumor suppressor gene, such as DCC (120470), discovered as the first tumor suppressor candidate in the region, may exist in the 18q21 region where LOH is often seen. </p><p>Using cDNA, Roth et al. (2000) conducted mutation analysis of the SMAD2, SMAD3, and SMAD4 genes in 14 Finnish kindreds with hereditary nonpolyposis colon cancer (see 120435). They found no mutations. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Waldrip et al. (1998) studied the effect of Smad2 in mouse embryonic development by targeted disruption of the mouse Smad2 gene using embryonic stem cell technology. They found that Smad2 function was not required for mesoderm production per se, but, rather unexpectedly, in the absence of Smad2, the entire epiblast adopts a mesodermal fate giving rise to a normal yolk sac and fetal blood cells. In contrast, Smad2 mutant mouse embryos entirely lacked tissues of the embryonic germ layers. Waldrip et al. (1998) concluded that Smad2 signals serve to restrict the site of primitive streak formation and establish anterior-posterior identity within the epiblast. Chimera experiments demonstrated that these essential activities are contributed by the extraembryonic tissues. Thus, the extraembryonic tissues play critical roles in establishing the body plan during early mouse development. </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>Nomenclature</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>Derynck et al. (1996) proposed a revised nomenclature for the Mad-related products and genes that are implicated in signal transduction by members of the TGF-beta family. As the root symbol they proposed SMAD, which is a merger of Sma (the gene in C. elegans) and Mad. SMAD serves to differentiate these proteins from unrelated gene products previously called MAD (see 600021). JV18.1 became SMAD2 in their nomenclature. </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>11 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 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 8, WITH HETEROTAXY</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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SMAD2, IVS6, G-A, +1
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<br />
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SNP: rs397509416,
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ClinVar: RCV001789751
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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 patient (1-02020) with complex congenital heart defects and heterotaxy (CHTD8; 619657), Zaidi et al. (2013) identified a heterozygous de novo splice site mutation in intron 6 of the SMAD2 gene (p.IVS6+1G-A). Cardiovascular anomalies in the proband included dextrocardia, unbalanced complete atrioventricular canal, pulmonary stenosis, double-outlet right ventricle, dextroposition of the great arteries, and atrial septal defect; she also had asplenia. </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 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 8, WITH HETEROTAXY</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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SMAD2, TRP244CYS
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<br />
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SNP: rs367537998,
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ClinVar: RCV000122601, RCV002292376
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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 patient (1-02621) with complex congenital heart defects and heterotaxy (CHTD8; 619657), Zaidi et al. (2013) identified a heterozygous de novo missense mutation in the SMAD2 gene (trp244 to cys; W244C). Cardiovascular anomalies in the proband included dextrocardia, unbalanced right-dominant complete atrioventricular canal, pulmonary stenosis, left superior vena cava to left atrium, partial anomalous pulmonary venous return, and double-outlet right ventricle. She also exhibited abnormal nose, foot syndactyly, and gut malrotation. </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 LOEYS-DIETZ SYNDROME 6</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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SMAD2, LEU449SER
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<br />
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SNP: rs2144276501,
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ClinVar: RCV001789795, RCV005095151
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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 51-year-old woman (family 1) with Loeys-Dietz syndrome-6 (LDS6; 619656), Micha et al. (2015) identified heterozygosity for a c.1346T-C transition (c.1346T-C, NM_001003652.3) in the SMAD2 gene, resulting in a leu449-to-ser (L449S) substitution at a highly conserved residue within the MH2 domain. The mutation was not found in the 1000 Genomes Project, dbSNP137, ExAC, or NHLBI Go ESP databases. The proband had aneurysms and/or dissections of the left vertebral, internal carotid, and intracavernous carotid arteries, as well as bilateral dissection of the carotid arteries in the carotid canal and caliber changes of the left and right internal carotid arteries and left vertebral artery. CT of the thorax and abdomen revealed no aortic abnormalities; however, the proband's mother had thoracic and abdominal aneurysms as well as aortic tortuosity, and a maternal uncle died at age 50 due to dissection of the abdominal aorta. Familial segregation of the mutation was not reported. </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 LOEYS-DIETZ SYNDROME 6</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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SMAD2, GLY457ARG
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<br />
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SNP: rs2144276285,
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ClinVar: RCV001789796, RCV002544317
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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 30-year-old woman (family 2) with Loeys-Dietz syndrome-6 (LDS6; 619656), Micha et al. (2015) identified heterozygosity for a c.1369G-A transition (c.1369G-A, NM_001003652.3) in the SMAD2 gene, resulting in a gly457-to-arg (G457R) substitution at a highly conserved residue within the MH2 domain. The mutation was not found in the 1000 Genomes Project, dbSNP137, ExAC, or NHLBI Go ESP databases. The proband was tall with long thin fingers, and had inguinal hernia repair and surgery for pes planus in childhood; at age 23, she was diagnosed with dilation of the aortic root and dural ectasia. Skeletal features included pain in multiple joints and mild scoliosis. </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">
|
|
<strong>.0005 LOEYS-DIETZ SYNDROME 6</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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SMAD2, GLN388ARG
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<br />
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SNP: rs746828424,
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gnomAD: rs746828424,
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ClinVar: RCV001789797, RCV003560848
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sisters with Loeys-Dietz syndrome-6 (LDS6; 619656), Micha et al. (2015) identified heterozygosity for a c.1163A-G transition (c.1163A-G, NM_001003652.3) in the SMAD2 gene, resulting in a gln388-to-arg (Q388R) substitution at a highly conserved residue within the MH2 domain. The mutation was not found in the 1000 Genomes Project, dbSNP137, ExAC, or NHLBI Go ESP databases. The sisters both had aneurysms of the ascending aorta, at ages 46 and 59 years, respectively, as well as striae and long toes. Other features included downslanting palpebral fissures, high-arched palate, and abdominal wall hernia. They also experienced joint pain and exhibited significant osteoarthritis, requiring replacement of some joints. Their mother died suddenly at age 56 of unknown cause, and their paternal grandfather was reported to have died at age 76 of aortic aneurysm. </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 LOEYS-DIETZ SYNDROME 6</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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SMAD2, ALA278VAL
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<br />
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SNP: rs2144300734,
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ClinVar: RCV001789798, RCV003136156
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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 51-year-old Chinese man with thoracic and abdominal aortic aneurysm (LDS6; 619656), Zhang et al. (2017) identified heterozygosity for a c.833C-T transition (c.833C-T, NM_001003652.3) in exon 8 of the SMAD2 gene, resulting in an ala278-to-val (A278V) substitution at a highly conserved residue within the MH2 domain. The mutation, which was not found in the dbSNP139, 1000 Genomes Project, ESP, or ExAC databases, was also not present in the proband's mother, suggesting that he inherited it from his father, who died at age 40 of thoracic aortic aneurysm. </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 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 8</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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SMAD2, GLU159TER
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<br />
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SNP: rs1064793873,
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ClinVar: RCV000480930, RCV001789776
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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 2-year-old girl (patient 1) with complex congenital heart defects (CHTD8; 619657), Granadillo et al. (2018) identified heterozygosity for a c.475G-T transversion (c.475G-T, NM_005901.5) in exon 3 of the SMAD2 gene, resulting in a glu159-to-ter (E159X) substitution within the MH1 domain. The mutation, which was not found in the NHLBI ESP, ExAC, or gnomAD databases, was not present in the mother; the father was unavailable for testing. Cardiovascular defects in the proband included atrial and ventricular septal defect, double-outlet right ventricle, dextroposition of the great arteries, patent ductus arteriosus, and valvular anomalies. Because the proband also exhibited a single central incisor, analysis of a holoprosencephaly panel revealed a known HPE-associated variant (see HPE4, 142946) in the TGIF1 gene (Q107L; 602630.0006). </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">
|
|
<strong>.0008 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 8</strong>
|
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</span>
|
|
</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMAD2, CYS312SER
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<br />
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SNP: rs797044882,
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ClinVar: RCV000190697, RCV001789764
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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 10-year-old girl (patient 2) with complex congenital heart defects (CHTD8; 619657), Granadillo et al. (2018) identified heterozygosity for a de novo c.935G-C transition (c.935G-C, NM_005901.5) in exon 8 of the SMAD2 gene, resulting in a cys312-to-ser (C312S) substitution at a highly conserved residue within the beta strand of the MH2 domain. The mutation was not found in the NHLBI ESP, ExAC, or gnomAD databases. Cardiovascular defects in the proband included atrial and ventricular septal defect, double-outlet right ventricle, dextroposition of the great arteries, patent ductus arteriosus, and mitral and pulmonary valve atresia. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 8, WITH HETEROTAXY</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMAD2, IVS2, A-G, -12
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<br />
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SNP: rs1402819968,
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gnomAD: rs1402819968,
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ClinVar: RCV001789799
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a female fetus (patient 3) with complex congenital heart defects and heterotaxy (CHTD8; 619657), in whom no mutation was found in a panel of heterotaxy genes, Granadillo et al. (2018) identified heterozygosity for a de novo splice site mutation (c.237-12A-G, NM_005901.5) in intron 2 of the SMAD2 gene. RNA analysis revealed inclusion of 11 bp of intronic sequence before exon 3, causing a frameshift resulting in a premature termination codon (Thr80LeufsTer12). The splice variant was not found in the NHLBI ESP, ExAC, or gnomAD databases. Cardiovascular defects in the proband included dextrocardia, atrial isomerism, atrial and ventricular septal defect, unbalanced complete atrioventricular canal, hypoplastic left ventricle, and anomalous pulmonary venous return; she also had dextrogastria and left-sided gallbladder. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 LOEYS-DIETZ SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
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|
</div>
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<div>
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<span class="mim-text-font">
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SMAD2, 1-BP DUP, 612T
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<br />
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SNP: rs2144373131,
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ClinVar: RCV001789800, RCV004552023
|
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|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 42-year-old woman (patient 4) with aortic root aneurysm, bicuspid aortic valve, and dilated and tortuous cerebral arteries (LDS6; 619656), Granadillo et al. (2018) identified heterozygosity for a de novo 1-bp duplication (c.612dupT, NM_005901.5) in exon 5 of the SMAD2 gene, causing a frameshift resulting in a premature termination codon (asn205-to-ter, N205X). </p><p>In a 70-year-old father and his 30-year-old son (family1) with dilation of the aortic root, Cannaerts et al. (2019) identified heterozygosity for the 1-bp duplication in the SMAD2 gene resulting in introduction of the premature stop codon N205X. Both father and son exhibited tall stature and long fingers. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 LOEYS-DIETZ SYNDROME 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
SMAD2, ASN361THR
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<br />
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|
|
SNP: rs2144290354,
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|
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|
|
ClinVar: RCV001789801
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 51-year-old man (family 4) with spontaneous dissection of the left coronary artery, who also had tortuosity of the circle of Willis and iliac arteries (LDS6; 619656), Cannaerts et al. (2019) identified heterozygosity for a c.1082A-C transversion in the SMAD2 gene, resulting in an asn361-to-thr (N361T) substitution within the MH2 domain. The mutation was not found in his unaffected sister or sons; DNA from his deceased parents was unavailable. Other features in the proband included broad uvula, pes planus, pectus asymmetry, mild scoliosis, generalized arthralgias with tendinopathies, and inguinal hernia. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
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<p />
|
|
</div>
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|
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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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Baker, J. C., Harland, R. M.
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<strong>A novel mesoderm inducer, Madr2, functions in the activin signal transduction pathway.</strong>
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<li>
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<p class="mim-text-font">
|
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Batut, J., Howell, M., Hill, C. S.
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<strong>Kinesin-mediated transport of Smad2 is required for signaling in response to TGF-beta ligands.</strong>
|
|
Dev. Cell 12: 261-274, 2007.
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Bertero, A., Brown, S., Madrigal, P., Osnato, A., Ortmann, D., Yiangou, L., Kadiwala, J., Hubner, N. C., de los Mozos, I. R., Sadee, C., Lenaerts, A.-S., Nakanoh, S., Grandy, R., Farnell, E., Ule, J., Stunnenberg, H. G., Mendjan, S., Vallier, L.
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<strong>The SMAD2/3 interactome reveals that TGF-beta controls m6A mRNA methylation in pluripotency.</strong>
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<p class="mim-text-font">
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Cannaerts, E., Kempers, M., Maugeri, A., Marcelis, C., Gardeitchik, T., Richer, J., Micha, D., Beauchesne, L., Timmermans, J., Vermeersch, P., Meyten, N., Chenier, S., van de Beek, G., Peeters, N., Alaerts, M., Schepers, D., Van Laer, L., Verstraeten, A., Loeys, B.
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<strong>Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: further delineation of the phenotype.</strong>
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[PubMed: 29967133]
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<p class="mim-text-font">
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Davis, B. N., Hilyard, A. C., Lagna, G., Hata, A.
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<strong>SMAD proteins control DROSHA-mediated microRNA maturation.</strong>
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Nature 454: 56-61, 2008.
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[PubMed: 18548003]
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[Full Text: https://doi.org/10.1038/nature07086]
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Derynck, R., Gelbart, W. M., Harland, R. M., Heldin, C.-H., Kern, S. E., Massague, J., Melton, D. A., Mlodzik, M., Padgett, R. W., Roberts, A. B., Smith, J., Thomsen, G. H., Vogelstein, B., Wang, X.-F.
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<strong>Nomenclature: vertebrate mediators of TGF-beta family signals. (Letter)</strong>
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Cell 87: 173 only, 1996.
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[PubMed: 8861901]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)81335-5]
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Eppert, K., Scherer, S. W., Ozcelik, H., Pirone, R., Hoodless, P., Kim, H., Tsui, L.-C., Bapat, B., Gallinger, S., Andrulis, I. L., Thomsen, G. H., Wrana, J. L., Attisano, L.
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<strong>MADR2 maps to 18q21 and encodes a TGF-beta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma.</strong>
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Cell 86: 543-552, 1996.
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[PubMed: 8752209]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)80128-2]
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<p class="mim-text-font">
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Funaba, M., Mathews, L. S.
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<strong>Identification and characterization of constitutively active Smad2 mutants: evaluation of formation of Smad complex and subcellular distribution.</strong>
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Molec. Endocr. 14: 1583-1591, 2000.
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[PubMed: 11043574]
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<p class="mim-text-font">
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Graff, J. M., Bansal, A., Melton, D. A.
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<strong>Xenopus Mad proteins transduce distinct subsets of signals for the TGF-beta superfamily.</strong>
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Cell 85: 479-487, 1996.
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[PubMed: 8653784]
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<p class="mim-text-font">
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Granadillo, J. L., Chung, W. K., Hecht, L., Corsten-Janssen, N., Wegner, D., Nij Bijvank, S. W. A., Toler, T. L., Pineda-Alvarez, D. E., Douglas, G., Murphy, J. J., Shimony, J., Shinawi, M.
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<strong>Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants.</strong>
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Hum. Mutat. 39: 1875-1884, 2018.
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[PubMed: 30157302]
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<p class="mim-text-font">
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Inman, G. J., Nicolas, F. J., Hill, C. S.
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<strong>Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity.</strong>
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Molec. Cell 10: 283-294, 2002.
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[PubMed: 12191474]
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<li>
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<p class="mim-text-font">
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Macias-Silva, M., Abdollah, S., Hoodless, P. A., Pirone, R., Attisano, L., Wrana, J. L.
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<strong>MADR2 is a substrate of the TGF-beta receptor and its phosphorylation is required for nuclear accumulation and signaling.</strong>
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Cell 87: 1215-1224, 1996.
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[PubMed: 8980228]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)81817-6]
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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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Micha, D., Guo, D., Hilhorst-Hofstee, Y., van Kooten, F., Atmaja, D., Overwater, E., Cayami, F. K., Regalado, E. S., van Uffelen, R., Venselaar, H., Faradz, S. M. H., Vriend, G., Weiss, M. M., Sistermans, E. A., Maugeri, A., Milewicz, D. M., Pals, G., van Dijk, F. S.
|
|
<strong>SMAD2 Mutations are associated with arterial aneurysms and dissections.</strong>
|
|
Hum. Mutat. 36: 1145-1149, 2015.
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[PubMed: 26247899]
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[Full Text: https://doi.org/10.1002/humu.22854]
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<p class="mim-text-font">
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Nakao, A., Roijer, E., Imamura, T., Souchelnytskyi, S., Stenman, G., Heldin, C.-H., ten Dijke, P.
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<strong>Identification of Smad2, a human Mad-related protein in the transforming growth factor-beta signaling pathway.</strong>
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J. Biol. Chem. 272: 2896-2900, 1997.
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[PubMed: 9006934]
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[Full Text: https://doi.org/10.1074/jbc.272.5.2896]
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</p>
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<li>
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<p class="mim-text-font">
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Oft, M., Akhurst, R. J., Balmain, A.
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<strong>Metastasis is driven by sequential elevation of H-ras and Smad2 levels.</strong>
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Nature Cell Biol. 4: 487-494, 2002.
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[PubMed: 12105419]
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[Full Text: https://doi.org/10.1038/ncb807]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Riggins, G. J., Thiagalingam, S., Rozenblum, E., Weinstein, C. L., Kern, S. E., Hamilton, S. R., Willson, J. K. V., Markowitz, S. D., Kinzler, K. W., Vogelstein, B.
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<strong>Mad-related genes in the human.</strong>
|
|
Nature Genet. 13: 347-349, 1996.
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[PubMed: 8673135]
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[Full Text: https://doi.org/10.1038/ng0796-347]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Roth, S., Johansson, M., Loukola, A., Peltomaki, P., Jarvinen, H., Mecklin, J.-P., Aaltonen, L. A.
|
|
<strong>Mutation analysis of SMAD2, SMAD3, and SMAD4 genes in hereditary non-polyposis colorectal cancer.</strong>
|
|
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