4430 lines
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Entry
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- *603109 - SMAD FAMILY MEMBER 3; SMAD3
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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">*603109</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="#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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<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="#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="#history">History</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/603109">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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</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=ENSG00000166949;t=ENST00000327367" 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=4088" 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=603109" 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=ENSG00000166949;t=ENST00000327367" 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_001145102,NM_001145103,NM_001145104,NM_001407011,NM_001407012,NM_001407013,NM_001407014,NM_001407015,NM_001407016,NM_001407017,NM_005902" 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_005902" 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=603109" 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=04380&isoform_id=04380_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/SMAD3" 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/1673577,2351035,2522267,5174513,7106776,18418623,29792115,48146889,51338669,51476304,62088812,119598194,119598195,119598196,119598197,158255198,189054041,221042108,221043276,221043568,221045422,223029440,223029442,223029444,2243203117,2243207440,2243422394,2243422396,2243422398,2243422400,2243422405,2462544039,2462544041" 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/P84022" 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=4088" 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=ENSG00000166949;t=ENST00000327367" 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=SMAD3" 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=SMAD3" 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+4088" 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/SMAD3" 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:4088" 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/4088" 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=chr15&hgg_gene=ENST00000327367.9&hgg_start=67065602&hgg_end=67195169&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:6769" 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:6769" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/smad3" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603109[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=603109[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/SMAD3/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000166949" 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=SMAD3" 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=SMAD3" 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=SMAD3" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://lovd.bx.psu.edu/home.php?select_db=SMAD3" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SMAD3&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/PA30526" 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:6769" 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:1201674" 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/SMAD3#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:1201674" 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/4088/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=4088" 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-000509-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4088" 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=SMAD3&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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603109
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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 3; SMAD3
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 3; MADH3<br />
|
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SMA- AND MAD-RELATED PROTEIN 3
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SMAD3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SMAD3</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/15/317?start=-3&limit=10&highlight=317">15q22.33</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:67065602-67195169&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'})">15:67,065,602-67,195,169</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
|
<a href="/geneMap/15/317?start=-3&limit=10&highlight=317">
|
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15q22.33
|
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</a>
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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Loeys-Dietz syndrome 3
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/613795"> 613795 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/603109" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<p>Drosophila Mad is required for signaling by the TGF-beta (e.g., <a href="/entry/190180">190180</a>)-related factor decapentaplegic. <a href="#28" class="mim-tip-reference" title="Zhang, Y., Feng, X.-H., Wu, R.-Y., Derynck, R. <strong>Receptor-associated Mad homologues synergize as effectors of the TGF-beta response.</strong> Nature 383: 168-172, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8774881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8774881</a>] [<a href="https://doi.org/10.1038/383168a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8774881">Zhang et al. (1996)</a> cloned a human cDNA encoding MADH3, a homolog of Drosophila Mad. The deduced 425-amino acid MADH3 protein (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=2522267" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">2522267</a>) is 92% identical to MADH2 (<a href="/entry/601366">601366</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8774881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By searching an expressed sequence tag database with the protein sequences of Mad and Mad homologs, <a href="#18" 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> isolated human cDNAs encoding MADH3, which they called JV15-2. The C terminus of MADH3 shows significant homology to that of Drosophila Mad. <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>
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<p><a href="#1" class="mim-tip-reference" title="Arai, T., Akiyama, Y., Okabe, S., Ando, M., Endo, M., Yuasa, Y. <strong>Genomic structure of the human Smad3 gene and its infrequent alterations in colorectal cancers.</strong> Cancer Lett. 122: 157-163, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9464505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9464505</a>] [<a href="https://doi.org/10.1016/s0304-3835(97)00384-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9464505">Arai et al. (1998)</a> determined the genomic structure of SMAD3, which contains 9 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9464505" 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="#18" 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 MADH3 gene to 15q21-q22 by somatic cell hybrid analysis and screening of YAC clones. <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>
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<p><a href="#28" class="mim-tip-reference" title="Zhang, Y., Feng, X.-H., Wu, R.-Y., Derynck, R. <strong>Receptor-associated Mad homologues synergize as effectors of the TGF-beta response.</strong> Nature 383: 168-172, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8774881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8774881</a>] [<a href="https://doi.org/10.1038/383168a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8774881">Zhang et al. (1996)</a> showed that MADH3 and MADH4 (SMAD4; <a href="/entry/600993">600993</a>) synergized to induce strong ligand-independent TGF-beta-like responses. MADH3 containing a C-terminal truncation acted as a dominant-negative inhibitor of the normal TGF-beta response. The activity of MADH3 was regulated by the TGF-beta receptors (e.g., <a href="/entry/190181">190181</a>), and MADH3 was phosphorylated and associated with the ligand-bound receptor complex. <a href="#28" class="mim-tip-reference" title="Zhang, Y., Feng, X.-H., Wu, R.-Y., Derynck, R. <strong>Receptor-associated Mad homologues synergize as effectors of the TGF-beta response.</strong> Nature 383: 168-172, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8774881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8774881</a>] [<a href="https://doi.org/10.1038/383168a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8774881">Zhang et al. (1996)</a> stated that these results define MADH3 as an effector of the TGF-beta response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8774881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Zawel, L., Dai, J. L., Buckhaults, P., Zhou, S., Kinzler, K. W., Vogelstein, B., Kern, S. E. <strong>Human Smad3 and Smad4 are sequence-specific transcription activators.</strong> Molec. Cell 1: 611-617, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9660945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9660945</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80061-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9660945">Zawel et al. (1998)</a> found that human SMAD3 and SMAD4 proteins could specifically recognize an identical 8-bp palindromic sequence (GTCTAGAC). Tandem repeats of this palindrome conferred striking TGF-beta responsiveness to a minimal promoter. This responsiveness was abrogated by targeted deletion of the cellular SMAD4 gene. These results showed that SMAD proteins are involved in the biologic responses to TGF-beta and related ligands. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9660945" 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 (<a href="/entry/601366">601366</a>), 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>SMAD3 is a direct mediator of transcriptional activation by the TGF-beta receptor. Its target genes in epithelial cells include cyclin-dependent kinase (CDK; see <a href="/entry/116953">116953</a>) inhibitors that generate a cytostatic response. <a href="#6" class="mim-tip-reference" title="Chen, C.-R., Kang, Y., Siegel, P. M., Massague, J. <strong>E2F4/5 and p107 as Smad cofactors linking the TGF-beta receptor to c-myc repression.</strong> Cell 110: 19-32, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12150994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12150994</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00801-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12150994">Chen et al. (2002)</a> defined how, in the same context, SMAD3 can mediate transcriptional repression of the growth-promoting gene MYC (<a href="/entry/190080">190080</a>). A complex containing SMAD3, the transcription factors E2F4 (<a href="/entry/600659">600659</a>), E2F5 (<a href="/entry/600967">600967</a>), and DP1 (<a href="/entry/189902">189902</a>), and the corepressor p107 (<a href="/entry/116957">116957</a>) preexists in the cytoplasm. In response to TGF-beta, this complex moves into the nucleus and associates with SMAD4, recognizing a composite SMAD-E2F site on MYC for repression. Previously known as the ultimate recipients of CDK regulatory signals, E2F4/E2F5 and p107 act here as transducers of TGF-beta receptor signals upstream of CDK. SMAD proteins therefore mediate transcriptional activation or repression depending on their associated partners. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12150994" 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 (<a href="/entry/190180">190180</a>) 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="#12" 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>Based upon molecular allelotyping and comparative genomic hybridization studies, chromosome 15q is the likely location of a tumor suppressor gene important in the pathogeneses of sporadic enteropancreatic endocrine tumors and parathyroid adenomas. To determine whether SMAD3 plays a primary role in the development of these tumors, <a href="#21" class="mim-tip-reference" title="Shattuck, T. M., Costa, J., Bernstein, M., Jensen, R. T., Chung, D. C., Arnold, A. <strong>Mutational analysis of Smad3, a candidate tumor suppressor implicated in TGF-beta and menin pathways, in parathyroid adenomas and enteropancreatic endocrine tumors.</strong> J. Clin. Endocr. Metab. 87: 3911-3914, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12161532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12161532</a>] [<a href="https://doi.org/10.1210/jcem.87.8.8707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12161532">Shattuck et al. (2002)</a> investigated 20 enteropancreatic tumors and 67 parathyroid adenomas for LOH at DNA markers surrounding SMAD3. Twenty percent of enteropancreatic tumors and 24% of parathyroid adenomas showed loss. All 9 coding exons and intron-exon boundaries of the SMAD3 gene were then sequenced in genomic DNA from all 20 enteropancreatic and 25 parathyroid tumors, including every case with LOH. No acquired clonal mutations, insertions, or microdeletions in SMAD3 were detected in any tumors. Because inactivating somatic mutation is the hallmark of an authentic tumor suppressor, SMAD3 is unlikely to function as a classic tumor suppressor gene in the pathogenesis of sporadic parathyroid or enteropancreatic endocrine tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12161532" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Matsuura, I., Denissova, N. G., Wang, G., He, D., Long, J., Liu, F. <strong>Cyclin-dependent kinases regulate the antiproliferative function of Smads.</strong> Nature 430: 226-231, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15241418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15241418</a>] [<a href="https://doi.org/10.1038/nature02650" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15241418">Matsuura et al. (2004)</a> showed that SMAD3 is a major physiologic substrate of the G1 cyclin-dependent kinases CDK4 (<a href="/entry/123829">123829</a>) and CDK2 (<a href="/entry/116953">116953</a>). Except for the retinoblastoma protein family, SMAD3 was the only CDK4 substrate demonstrated to that time. <a href="#15" class="mim-tip-reference" title="Matsuura, I., Denissova, N. G., Wang, G., He, D., Long, J., Liu, F. <strong>Cyclin-dependent kinases regulate the antiproliferative function of Smads.</strong> Nature 430: 226-231, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15241418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15241418</a>] [<a href="https://doi.org/10.1038/nature02650" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15241418">Matsuura et al. (2004)</a> mapped CDK4 and CDK2 phosphorylation sites to thr8, thr178, and ser212 in SMAD3. Mutation of the CDK phosphorylation sites increased Smad3 transcriptional activity, leading to higher expression of the CDK inhibitor p15 (<a href="/entry/600431">600431</a>). Mutation of the CDK phosphorylation sites of Smad3 also increased its ability to downregulate the expression of c-myc. Using Smad3 knockout mouse embryonic fibroblasts and other epithelial cell lines, <a href="#15" class="mim-tip-reference" title="Matsuura, I., Denissova, N. G., Wang, G., He, D., Long, J., Liu, F. <strong>Cyclin-dependent kinases regulate the antiproliferative function of Smads.</strong> Nature 430: 226-231, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15241418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15241418</a>] [<a href="https://doi.org/10.1038/nature02650" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15241418">Matsuura et al. (2004)</a> further showed that Smad3 inhibits cell cycle progression from G1 to S phase and that mutation of the CDK phosphorylation sites in Smad3 increases this ability. They concluded that CDK phosphorylation of SMAD3 inhibits its transcriptional activity and antiproliferative function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15241418" 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>To determine the role of SMAD3 in the pathogenesis of lymphoid neoplasia, <a href="#24" class="mim-tip-reference" title="Wolfraim, L. A., Fernandez, T. M., Mamura, M., Fuller, W. L., Kumar, R., Cole, D. E., Byfield, S., Felici, A., Flanders, K. C., Walz, T. M., Roberts, A. B., Aplan, P. D., Balis, F. M., Letterio, J. J. <strong>Loss of Smad3 in acute T-cell lymphoblastic leukemia.</strong> New Eng. J. Med. 351: 552-559, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15295048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15295048</a>] [<a href="https://doi.org/10.1056/NEJMoa031197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15295048">Wolfraim et al. (2004)</a> measured SMAD3 mRNA and protein in leukemia cells obtained at diagnosis from 19 children with acute leukemia: 10 with T-cell acute lymphoblastic leukemia (ALL), 7 with pre-B-cell ALL, and 2 with acute nonlymphoblastic leukemia (ANLL). SMAD3 protein was absent in T-cell ALL but present in pre-B-cell ALL and ANLL. No mutations in the SMAD3 gene were identified in T-cell ALL, and SMAD3 mRNA was present in T-cell ALL and normal T cells at similar levels. <a href="#24" class="mim-tip-reference" title="Wolfraim, L. A., Fernandez, T. M., Mamura, M., Fuller, W. L., Kumar, R., Cole, D. E., Byfield, S., Felici, A., Flanders, K. C., Walz, T. M., Roberts, A. B., Aplan, P. D., Balis, F. M., Letterio, J. J. <strong>Loss of Smad3 in acute T-cell lymphoblastic leukemia.</strong> New Eng. J. Med. 351: 552-559, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15295048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15295048</a>] [<a href="https://doi.org/10.1056/NEJMoa031197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15295048">Wolfraim et al. (2004)</a> concluded that loss of SMAD3 protein is a specific feature of pediatric T-cell lymphoblastic leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15295048" 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 experiments using mouse muscle, <a href="#5" class="mim-tip-reference" title="Carlson, M. E., Hsu, M., Conboy, I. M. <strong>Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells.</strong> Nature 454: 528-532, 2008. Note: Erratum: Nature 538: 274 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18552838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18552838</a>] [<a href="https://doi.org/10.1038/nature07034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18552838">Carlson et al. (2008)</a> found that, in addition to the loss of Notch (<a href="/entry/190198">190198</a>) activation, old muscle produces excessive TGF-beta (but not myostatin, <a href="/entry/601788">601788</a>), which induces unusually high levels of Smad3 in resident satellite cells and interferes with the regenerative capacity. Importantly, endogenous Notch and Smad3 antagonize each other in the control of satellite cell proliferation, such that activation of Notch blocks the TGF-beta-dependent upregulation of the cyclin-dependent kinase (CDK) inhibitors p15, p16 (<a href="/entry/600160">600160</a>), p21 (<a href="/entry/116899">116899</a>), and p27 (<a href="/entry/600778">600778</a>), whereas inhibition of Notch induces them. Furthermore, in muscle stem cells, Notch activity determined the binding of Smad3 to the promoters of these negative regulators of cell cycle progression. Attenuation of TGF-beta/Smad3 in old, injured muscle restored regeneration to satellite cells in vivo. Thus, a balance between endogenous Smad3 and active Notch controls the regenerative competence of muscle stem cells, and deregulation of this balance in the old muscle microniche interferes with regeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18552838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="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 (see <a href="/entry/112264">112264</a>) 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 (<a href="/entry/601595">601595</a>), SMAD2 (<a href="/entry/601366">601366</a>), SMAD3, 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="#8" 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="#7" class="mim-tip-reference" title="Chuderland, D., Konson, A., Seger, R. <strong>Identification and characterization of a general nuclear translocation signal in signaling proteins.</strong> Molec. Cell 31: 850-861, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760948</a>] [<a href="https://doi.org/10.1016/j.molcel.2008.08.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18760948">Chuderland et al. (2008)</a> identified an SPS motif in ERK2 (MAPK1; <a href="/entry/176948">176948</a>) and SMAD3 and a similar TPT motif in MEK1 (MAP2K1; <a href="/entry/176872">176872</a>) that directed protein nuclear accumulation when phosphorylated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18760948" 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 coimmunoprecipitation and in vitro binding assays, <a href="#14" class="mim-tip-reference" title="Liu, T., Zhao, M., Liu, J., He, Z., Zhang, Y., You, H., Huang, J., Lin, X., Feng, X.-H. <strong>Tumor suppressor bromodomain-containing protein 7 cooperates with Smads to promote transforming growth factor-beta responses.</strong> Oncogene 36: 362-372, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27270427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27270427</a>] [<a href="https://doi.org/10.1038/onc.2016.204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27270427">Liu et al. (2017)</a> found that human BRD7 (<a href="/entry/618489">618489</a>) interacted with SMAD3 and SMAD4 in HEK293T cells. The MH1 and MH2 domains of the SMADs were sufficient for BRD7 binding, and the N-terminal region preceding the bromodomain in BRD7 was required for SMAD binding. Overexpression of BRD7 significantly increased TGF-beta-induced transcriptional activation of p21, whereas knockdown of BRD7 reduced it. Chromatin immunoprecipitation assays demonstrated that, via its bromodomain, BRD7 increased SMAD3/SMAD4 binding to the p21 promoter in the presence of TGF-beta. BRD7 also enhanced TGF-beta-induced transcriptional activity of SMAD4 by interacting and cooperating with p300 (EP300; <a href="/entry/602700">602700</a>). BRD7 knockdown attenuated the TGF-beta-induced antiproliferation phenotype in tumor cells, whereas expression of BRD7 had a suppressive effect on tumor formation and enhanced TGF-beta-mediated epithelial-mesenchymal transition responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27270427" 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="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://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="#4" 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://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="#4" 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://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="#4" 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://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. 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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<p><strong><em>Loeys-Dietz Syndrome 3</em></strong></p><p>
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In a 4-generation Dutch family with arterial aneurysms and dissections and early-onset osteoarthritis mapping to chromosome 15q22.2-q24.2, <a href="#22" class="mim-tip-reference" title="van de Laar, I. M. B. H., Oldenburg, R. A., Pals, G., Roos-Hesselink, J. W., de Graaf, B. M., Verhagen, J. M. A., Hoedemaekers, Y. M., Willemsen, R., Severijnen, L.-A., Venselaar, H., Vriend, G., Pattynama, P. M., and 14 others. <strong>Mutations in SMAD3 cause a syndrome form of aortic aneurysms and dissections with early-onset osteoarthritis.</strong> Nature Genet. 43: 121-126, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21217753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21217753</a>] [<a href="https://doi.org/10.1038/ng.744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21217753">van de Laar et al. (2011)</a> analyzed the candidate gene SMAD3 and identified heterozygosity for a missense mutation (R287W; <a href="#0001">603109.0001</a>) that segregated with disease. The authors designated the disorder aneurysms-osteoarthritis syndrome (AOS), but it is here incorporated into the Loeys-Dietz phenotypic series as Loeys-Dietz syndrome-3 (LDS3; <a href="/entry/613795">613795</a>). Analysis of SMAD3 in 99 patients with thoracic aortic aneurysms and dissections and Marfan-like features, who were known to be negative for mutation in the FBN1 (<a href="/entry/134797">134797</a>), TGFBR1 (<a href="/entry/190181">190181</a>), and TGFBR2 (<a href="/entry/190182">190182</a>) genes, revealed 2 additional probands with heterozygous SMAD3 mutations (<a href="#0002">603109.0002</a>; <a href="#0003">603109.0003</a>). All 3 mutations were located in the MH2 domain, which mediates oligomerization of SMAD3 with SMAD4 (<a href="/entry/600993">600993</a>) and SMAD-dependent transcriptional activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21217753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Regalado, E. S., Guo, D., Villamizar, C., Avidan, N., Gilchrist, D., McGillivray, B., Clarke, L., Bernier, F., Santos-Cortez, R. L., Leal, S. M., Bertoli-Avella, A. M., Shendure, J., Rieder, M. J., Nickerson, D. A., NHLBI GO Exome Sequencing Project, Milewicz, D. M. <strong>Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.</strong> Circ. Res. 109: 680-686, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21778426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21778426</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21778426[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/10.1161/CIRCRESAHA.111.248161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21778426">Regalado et al. (2011)</a> reported 4 new mutations in SMAD3. One mutation (<a href="#0004">603109.0004</a>) was a frameshift mutation in exon 5 segregating in a family with LDS3 phenotype. The other 3 were missense mutations in invariant codons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21778426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="van de Laar, I. M. B. H., van der Linde, D., Oei, E. H. G., Bos, P. K., Bessems, J. H., Bierma-Zeinstra, S. M., van Meer, B. L., Pals, G., Oldenburg, R. A., Bekkers, J. A., Moelker, A., de Graaf, B. M., and 17 others. <strong>Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome.</strong> J. Med. Genet. 49: 47-57, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22167769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22167769</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100382" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22167769">Van de Laar et al. (2012)</a> identified 5 novel SMAD3 mutations in 5 additional families with aneurysms-osteoarthritis syndrome (see, e.g., <a href="#0008">603109.0008</a>-<a href="#0010">603109.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22167769" 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>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation in the SMAD3 gene and dizygotic twinning, see <a href="/entry/276400">276400</a>.</p><p><strong><em>Exclusion Studies</em></strong></p><p>
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Using cDNA, <a href="#19" 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="#29" class="mim-tip-reference" title="Zhu, Y., Richardson, J. A., Parada, L. F., Graff, J. M. <strong>Smad3 mutant mice develop metastatic colorectal cancer.</strong> Cell 94: 703-714, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9753318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9753318</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81730-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9753318">Zhu et al. (1998)</a> reported the targeted disruption of the mouse Smad3 gene. Smad3 mutant mice were viable and fertile. Between 4 and 6 months of age, the Smad3 mutant mice became moribund with colorectal adenocarcinomas. The neoplasms penetrated through the intestinal wall and metastasized to lymph nodes. Since TGF-beta transduces its signal to the interior of the cell via Smad2, Smad3, and Smad4, these results directly implicate TGF-beta signaling in the pathogenesis of colorectal cancer and provide a compelling animal model for the study of human colorectal cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9753318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Yang, X., Letterio, J. J., Lechleider, R. J., Chen, L., Hayman, R., Gu, H., Roberts, A. B., Deng, C. <strong>Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta.</strong> EMBO J. 18: 1280-1291, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10064594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10064594</a>] [<a href="https://doi.org/10.1093/emboj/18.5.1280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10064594">Yang et al. (1999)</a> found that Smad3-null (ex8/ex8) mice died between 1 and 8 months due to a primary defect in immune function. The mice exhibited inflammatory lesions in a number of organs, including the nasal mucosa, stomach, pancreas, colon, and small intestine, as well as enlarged lymph nodes, an involuted thymus, and the formation of bacterial abscesses adjacent to mucosal surfaces. Immunostaining revealed a significant increase in T-cell activation, suggesting that Smad3 has a role in TGFB-mediated regulation of T-cell activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10064594" 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>Renal tubulointerstitial fibrosis is a chronic inflammatory condition in which renal fibrosis is associated with epithelial-mesenchymal transition of the renal tubules and synthesis of extracellular matrix in response to multiple entities, including ureteral obstruction. TGFB plays a pivotal role in the disease process. <a href="#20" class="mim-tip-reference" title="Sato, M., Muragaki, Y., Saika, S., Roberts, A. B., Ooshima, A. <strong>Targeted disruption of TGF-beta-1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction.</strong> J. Clin. Invest. 112: 1486-1494, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14617750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14617750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14617750[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/10.1172/JCI19270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14617750">Sato et al. (2003)</a> found that Smad3-null mice with ureteral obstruction were protected against tubulointerstitial fibrosis, presumably by blocking the downstream effects of TGFB. Levels of TGFB mRNA and mature protein were decreased in the mutant animals compared to experimental controls, indicating that the Smad3 pathway is also essential for autoinduction of TGFB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14617750" 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="Wolfraim, L. A., Fernandez, T. M., Mamura, M., Fuller, W. L., Kumar, R., Cole, D. E., Byfield, S., Felici, A., Flanders, K. C., Walz, T. M., Roberts, A. B., Aplan, P. D., Balis, F. M., Letterio, J. J. <strong>Loss of Smad3 in acute T-cell lymphoblastic leukemia.</strong> New Eng. J. Med. 351: 552-559, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15295048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15295048</a>] [<a href="https://doi.org/10.1056/NEJMoa031197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15295048">Wolfraim et al. (2004)</a> used mice in which 1 or both alleles of Smad3 were inactivated to evaluate the role of Smad3 in the response of normal T cells to TGF-beta and in the susceptibility to spontaneous leukemogenesis in mice in which both alleles of the tumor suppressor p27(Kip1) (CDKN1B; <a href="/entry/600778">600778</a>) were deleted. The loss of 1 allele for Smad3 impaired the inhibitory effect of TGF-beta on the proliferation of normal T cells and worked in tandem with the homozygous inactivation of p27(Kip1) to promote T-cell leukemogenesis. <a href="#24" class="mim-tip-reference" title="Wolfraim, L. A., Fernandez, T. M., Mamura, M., Fuller, W. L., Kumar, R., Cole, D. E., Byfield, S., Felici, A., Flanders, K. C., Walz, T. M., Roberts, A. B., Aplan, P. D., Balis, F. M., Letterio, J. J. <strong>Loss of Smad3 in acute T-cell lymphoblastic leukemia.</strong> New Eng. J. Med. 351: 552-559, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15295048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15295048</a>] [<a href="https://doi.org/10.1056/NEJMoa031197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15295048">Wolfraim et al. (2004)</a> concluded that a reduction in Smad3 expression and the loss of p27(Kip1) work synergistically to promote T-cell leukemogenesis in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15295048" 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="Ashcroft, G. S., Yang, X., Glick, A. B., Weinstein, M., Letterio, J. L., Mizel, D. E., Anzano, M., Greenwell-Wild, T., Wahl, S. M., Deng, C., Roberts, A. B. <strong>Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response.</strong> Nature Cell Biol. 1: 260-266, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10559937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10559937</a>] [<a href="https://doi.org/10.1038/12971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10559937">Ashcroft et al. (1999)</a> generated Smad3-null mice and observed accelerated cutaneous wound healing, with complete reepithelialization by day 2 compared to day 5 in wildtype mice, and significantly reduced local infiltration of monocytes. Smad3 -/- keratinocytes showed altered patterns of growth and migration, and Smad3 -/- monocytes exhibited a selectively blunted chemotactic response to TGF-beta (<a href="/entry/190180">190180</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10559937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Arany, P. R., Flanders, K. C., Kobayashi, T., Kuo, C. K., Stuelten, C., Desai, K. V., Tuan, R., Rennard, S. I., Roberts, A. B. <strong>Smad3 deficiency alters key structural elements of the extracellular matrix and mechanotransduction of wound closure.</strong> Proc. Nat. Acad. Sci. 103: 9250-9255, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16754864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16754864</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16754864[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0602473103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16754864">Arany et al. (2006)</a> created excisional ear wounds in Smad3 -/- mice and observed wound enlargement compared to wildtype controls. Levels of elastin and glycosaminoglycans were increased, collagen fibers were more compactly organized, and integrins, TGFB1, and matrix metalloproteinases were altered both basally and after wounding in Smad3-knockout mice. Mechanical testing revealed an increased modulus of elasticity, suggesting an imbalance of tissue forces. <a href="#2" class="mim-tip-reference" title="Arany, P. R., Flanders, K. C., Kobayashi, T., Kuo, C. K., Stuelten, C., Desai, K. V., Tuan, R., Rennard, S. I., Roberts, A. B. <strong>Smad3 deficiency alters key structural elements of the extracellular matrix and mechanotransduction of wound closure.</strong> Proc. Nat. Acad. Sci. 103: 9250-9255, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16754864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16754864</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16754864[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0602473103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16754864">Arany et al. (2006)</a> proposed that the altered mechanical elastic properties lead to a persistent retractile force that is opposed by decreased wound contractile forces. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16754864" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Kanamaru, Y., Sumiyoshi, K., Ushio, H., Ogawa, H., Okumura, K., Nakao, A. <strong>Smad3 deficiency in mast cells provides efficient host protection against acute septic peritonitis.</strong> J. Immun. 174: 4193-4197, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15778380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15778380</a>] [<a href="https://doi.org/10.4049/jimmunol.174.7.4193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15778380">Kanamaru et al. (2005)</a> found that bone marrow-derived mast cells (BMMCs) from Smad3-null mice had an augmented capacity to produce proinflammatory cytokines upon stimulation with lipopolysaccharide. Mast cell-deficient mice reconstituted with Smad3-null BMMCs survived significantly longer in an acute peritonitis model than mast cell-deficient mice reconstituted with wildtype BMMCs. <a href="#13" class="mim-tip-reference" title="Kanamaru, Y., Sumiyoshi, K., Ushio, H., Ogawa, H., Okumura, K., Nakao, A. <strong>Smad3 deficiency in mast cells provides efficient host protection against acute septic peritonitis.</strong> J. Immun. 174: 4193-4197, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15778380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15778380</a>] [<a href="https://doi.org/10.4049/jimmunol.174.7.4193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15778380">Kanamaru et al. (2005)</a> proposed that SMAD3 in mast cells inhibits mast cell-mediated immune responses against gram-negative bacteria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15778380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 20 affected members of a 4-generation Dutch family with arterial aneurysms and dissections and early-onset osteoarthritis (LDS3; <a href="/entry/613795">613795</a>), <a href="#22" class="mim-tip-reference" title="van de Laar, I. M. B. H., Oldenburg, R. A., Pals, G., Roos-Hesselink, J. W., de Graaf, B. M., Verhagen, J. M. A., Hoedemaekers, Y. M., Willemsen, R., Severijnen, L.-A., Venselaar, H., Vriend, G., Pattynama, P. M., and 14 others. <strong>Mutations in SMAD3 cause a syndrome form of aortic aneurysms and dissections with early-onset osteoarthritis.</strong> Nature Genet. 43: 121-126, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21217753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21217753</a>] [<a href="https://doi.org/10.1038/ng.744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21217753">van de Laar et al. (2011)</a> identified heterozygosity for an 859C-T transition in exon 6 of the SMAD3 gene, resulting in an arg287-to-trp (R287W) substitution at a highly conserved residue within the MH2 domain. The mutation was not found in 7 unaffected family members or in 544 Dutch control chromosomes. Immunohistochemical analysis of aortic wall tissue from 2 patients showed increased expression of key proteins in the TGF-beta (see TGFB1, <a href="/entry/190180">190180</a>) pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21217753" 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">rs587776880 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776880;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=rs587776880" 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=rs587776880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 Dutch sibs with arterial aneurysms and dissections and early-onset osteoarthritis (LDS3; <a href="/entry/613795">613795</a>), <a href="#22" class="mim-tip-reference" title="van de Laar, I. M. B. H., Oldenburg, R. A., Pals, G., Roos-Hesselink, J. W., de Graaf, B. M., Verhagen, J. M. A., Hoedemaekers, Y. M., Willemsen, R., Severijnen, L.-A., Venselaar, H., Vriend, G., Pattynama, P. M., and 14 others. <strong>Mutations in SMAD3 cause a syndrome form of aortic aneurysms and dissections with early-onset osteoarthritis.</strong> Nature Genet. 43: 121-126, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21217753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21217753</a>] [<a href="https://doi.org/10.1038/ng.744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21217753">van de Laar et al. (2011)</a> identified heterozygosity for a 2-bp deletion (741delAT) in exon 6 of the SMAD3 gene, resulting in a frameshift and a premature termination sequence at codon 309 in exon 7 that removes nearly the complete MH2 domain (Thr247ProfsTer61). The deletion, which was presumably present in their affected deceased father, was not found in their unaffected mother or in 544 Dutch control chromosomes. Analysis of patient cDNA showed very weak mutant signal compared to wildtype, and treatment of patient fibroblast cultures with cycloheximide markedly increased the mutant signal, indicating that most of the abnormal RNA was subjected to nonsense messenger RNA decay and that a truncated SMAD3 protein was barely formed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21217753" 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">rs387906851 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906851;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=rs387906851" 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=rs387906851" 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 Dutch male patient with arterial aneurysm and early-onset osteoarthritis (LDS3; <a href="/entry/613795">613795</a>), <a href="#22" class="mim-tip-reference" title="van de Laar, I. M. B. H., Oldenburg, R. A., Pals, G., Roos-Hesselink, J. W., de Graaf, B. M., Verhagen, J. M. A., Hoedemaekers, Y. M., Willemsen, R., Severijnen, L.-A., Venselaar, H., Vriend, G., Pattynama, P. M., and 14 others. <strong>Mutations in SMAD3 cause a syndrome form of aortic aneurysms and dissections with early-onset osteoarthritis.</strong> Nature Genet. 43: 121-126, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21217753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21217753</a>] [<a href="https://doi.org/10.1038/ng.744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21217753">van de Laar et al. (2011)</a> identified heterozygosity for a 783C-T transition in exon 6 of the SMAD3 gene, resulting in a thr261-to-ile (T261I) substitution at a highly conserved residue in the MH2 domain. The mutation was not found in 544 Dutch control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21217753" 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">rs587776881 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776881;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=rs587776881" 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=rs587776881" 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=RCV000023244 OR RCV001385143" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023244, RCV001385143" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023244...</a>
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<p>In a 3-generation pedigree segregating autosomal dominant thoracic aortic aneurysms and dissections with intracranial and other arterial aneurysms (LDS3; <a href="/entry/613795">613795</a>), <a href="#17" class="mim-tip-reference" title="Regalado, E. S., Guo, D., Villamizar, C., Avidan, N., Gilchrist, D., McGillivray, B., Clarke, L., Bernier, F., Santos-Cortez, R. L., Leal, S. M., Bertoli-Avella, A. M., Shendure, J., Rieder, M. J., Nickerson, D. A., NHLBI GO Exome Sequencing Project, Milewicz, D. M. <strong>Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.</strong> Circ. Res. 109: 680-686, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21778426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21778426</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21778426[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/10.1161/CIRCRESAHA.111.248161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21778426">Regalado et al. (2011)</a> identified a deletion of an A at nucleotide 652 in exon 5 of the SMAD3 gene, resulting in frameshift leading to premature termination following asparagine-218 (N218fs). This mutation was present in all individuals with vascular disease in the family and segregated with a lod score of 2.52. The pedigree had originally been reported by <a href="#16" class="mim-tip-reference" title="Regalado, E., Medrek, S., Tran-Fadulu, V., Guo, D.-C., Pannu, H., Golabbakhsh, H., Smart, S., Chen, J. H., Shete, S., Kim, D. H., Stern, R., Braverman, A. C., Milewicz, D. M. <strong>Autosomal dominant inheritance of a predisposition to thoracic aortic aneurysms and dissections and intracranial saccular aneurysms.</strong> Am. J. Med. Genet. 155A: 2125-2130, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21815248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21815248</a>] [<a href="https://doi.org/10.1002/ajmg.a.34050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21815248">Regalado et al. (2011)</a>. The mutation was absent from 2,300 control exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21815248+21778426" 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">rs387906852 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906852;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=rs387906852" 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=rs387906852" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated families of European descent with autosomal dominant thoracic aortic and other aneurysms (LDS3; <a href="/entry/613795">613795</a>), <a href="#17" class="mim-tip-reference" title="Regalado, E. S., Guo, D., Villamizar, C., Avidan, N., Gilchrist, D., McGillivray, B., Clarke, L., Bernier, F., Santos-Cortez, R. L., Leal, S. M., Bertoli-Avella, A. M., Shendure, J., Rieder, M. J., Nickerson, D. A., NHLBI GO Exome Sequencing Project, Milewicz, D. M. <strong>Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.</strong> Circ. Res. 109: 680-686, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21778426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21778426</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21778426[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/10.1161/CIRCRESAHA.111.248161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21778426">Regalado et al. (2011)</a> identified a G-to-A transition at nucleotide 836 in exon 6 of the SMAD3 gene, resulting in an arg-to-lys substitution at codon 279 (R279K). Arg279 is completely conserved from human to Drosophila, and the R279K mutation was predicted to disrupt protein function. The mutation was not identified in 2,300 control exomes. There was decreased penetrance in younger family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21778426" 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">rs387906853 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906853;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=rs387906853" 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=rs387906853" 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=RCV000023246 OR RCV001703421 OR RCV003528136" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023246, RCV001703421, RCV003528136" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023246...</a>
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<p>In a small family with 3 sibs affected with thoracic aortic aneurysm and dissection (LDS3; <a href="/entry/613795">613795</a>), <a href="#17" class="mim-tip-reference" title="Regalado, E. S., Guo, D., Villamizar, C., Avidan, N., Gilchrist, D., McGillivray, B., Clarke, L., Bernier, F., Santos-Cortez, R. L., Leal, S. M., Bertoli-Avella, A. M., Shendure, J., Rieder, M. J., Nickerson, D. A., NHLBI GO Exome Sequencing Project, Milewicz, D. M. <strong>Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.</strong> Circ. Res. 109: 680-686, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21778426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21778426</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21778426[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/10.1161/CIRCRESAHA.111.248161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21778426">Regalado et al. (2011)</a> identified a G-to-A transition at nucleotide 715 in exon 6 of the SMAD3 gene, resulting in a glutamine-to-lysine substitution at codon 239 (E239K). Exon 6 encodes the MH2 protein-protein binding domain. Glu239 is completely conserved from human to Drosophila, and the E239K mutation was predicted to disrupt protein function. The mutation was not identified in 2,300 control exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21778426" 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">rs387906854 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906854;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=rs387906854" 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=rs387906854" 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=RCV000023247 OR RCV002313719" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023247, RCV002313719" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023247...</a>
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<p>In a family segregating autosomal dominant thoracic aortic aneurysm with dissection as well as other features of Loeys-Dietz syndrome (LDS3; <a href="/entry/613795">613795</a>) including bifid uvula and scoliosis, and early-onset osteoarthritis, <a href="#17" class="mim-tip-reference" title="Regalado, E. S., Guo, D., Villamizar, C., Avidan, N., Gilchrist, D., McGillivray, B., Clarke, L., Bernier, F., Santos-Cortez, R. L., Leal, S. M., Bertoli-Avella, A. M., Shendure, J., Rieder, M. J., Nickerson, D. A., NHLBI GO Exome Sequencing Project, Milewicz, D. M. <strong>Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.</strong> Circ. Res. 109: 680-686, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21778426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21778426</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21778426[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/10.1161/CIRCRESAHA.111.248161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21778426">Regalado et al. (2011)</a> identified a heterozygous alanine-to-valine substitution at codon 112 (A112V). The mutation segregated with disease with reduced penetrance in this family and was not identified in 2,300 control exomes. <a href="#10" class="mim-tip-reference" title="Guo, D.-C. <strong>Personal Communication.</strong> Houston, Tex. 2/7/2012."None>Guo (2012)</a> stated that the correct nucleotide change for the A112V mutation is 335C-T in exon 2 rather than 235C-T as cited in <a href="#17" class="mim-tip-reference" title="Regalado, E. S., Guo, D., Villamizar, C., Avidan, N., Gilchrist, D., McGillivray, B., Clarke, L., Bernier, F., Santos-Cortez, R. L., Leal, S. M., Bertoli-Avella, A. M., Shendure, J., Rieder, M. J., Nickerson, D. A., NHLBI GO Exome Sequencing Project, Milewicz, D. M. <strong>Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.</strong> Circ. Res. 109: 680-686, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21778426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21778426</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21778426[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/10.1161/CIRCRESAHA.111.248161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21778426">Regalado et al. (2011)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21778426" 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">rs587776882 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776882;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=rs587776882" 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=rs587776882" 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 with aneurysms-osteoarthritis syndrome (LCS3; <a href="/entry/613795">613795</a>), <a href="#23" class="mim-tip-reference" title="van de Laar, I. M. B. H., van der Linde, D., Oei, E. H. G., Bos, P. K., Bessems, J. H., Bierma-Zeinstra, S. M., van Meer, B. L., Pals, G., Oldenburg, R. A., Bekkers, J. A., Moelker, A., de Graaf, B. M., and 17 others. <strong>Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome.</strong> J. Med. Genet. 49: 47-57, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22167769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22167769</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100382" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22167769">van de Laar et al. (2012)</a> identified a 1-bp deletion at nucleotide 313 of the SMAD3 gene (313delG), resulting in a frameshift (Ala105ProfsTer11). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22167769" 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">rs387906855 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906855;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=rs387906855" 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=rs387906855" 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=RCV000023249 OR RCV002313720" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023249, RCV002313720" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023249...</a>
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<p>In a patient with aneurysms-osteoarthritis syndrome (LCS3; <a href="/entry/613795">613795</a>), <a href="#23" class="mim-tip-reference" title="van de Laar, I. M. B. H., van der Linde, D., Oei, E. H. G., Bos, P. K., Bessems, J. H., Bierma-Zeinstra, S. M., van Meer, B. L., Pals, G., Oldenburg, R. A., Bekkers, J. A., Moelker, A., de Graaf, B. M., and 17 others. <strong>Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome.</strong> J. Med. Genet. 49: 47-57, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22167769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22167769</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100382" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22167769">van de Laar et al. (2012)</a> identified a 788C-T transition in the SMAD3 gene, resulting in a pro263-to-leu (P263L) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22167769" 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">rs387906856 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906856;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=rs387906856" 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=rs387906856" 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=RCV000023250" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023250" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023250</a>
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<p>In affected members of a family segregating aneurysms-osteoarthritis syndrome (LCS3; <a href="/entry/613795">613795</a>), <a href="#23" class="mim-tip-reference" title="van de Laar, I. M. B. H., van der Linde, D., Oei, E. H. G., Bos, P. K., Bessems, J. H., Bierma-Zeinstra, S. M., van Meer, B. L., Pals, G., Oldenburg, R. A., Bekkers, J. A., Moelker, A., de Graaf, B. M., and 17 others. <strong>Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome.</strong> J. Med. Genet. 49: 47-57, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22167769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22167769</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100382" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22167769">van de Laar et al. (2012)</a> identified a 1-bp duplication at nucleotide 1080 in the SMAD3 gene (1080dupT), resulting in a glu361-to-ter (E361X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22167769" 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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Arai, T., Akiyama, Y., Okabe, S., Ando, M., Endo, M., Yuasa, Y.
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<strong>Genomic structure of the human Smad3 gene and its infrequent alterations in colorectal cancers.</strong>
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Cancer Lett. 122: 157-163, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9464505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9464505</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9464505" 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/s0304-3835(97)00384-4" target="_blank">Full Text</a>]
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<a id="Roth2000" class="mim-anchor"></a>
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Roth, S., Johansson, M., Loukola, A., Peltomaki, P., Jarvinen, H., Mecklin, J.-P., Aaltonen, L. A.
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<strong>Mutation analysis of SMAD2, SMAD3, and SMAD4 genes in hereditary non-polyposis colorectal cancer.</strong>
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J. Med. Genet. 37: 298-300, 2000.
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.37.4.298" target="_blank">Full Text</a>]
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<a id="Sato2003" class="mim-anchor"></a>
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Sato, M., Muragaki, Y., Saika, S., Roberts, A. B., Ooshima, A.
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<strong>Targeted disruption of TGF-beta-1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction.</strong>
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J. Clin. Invest. 112: 1486-1494, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14617750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14617750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14617750[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=14617750" 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/10.1172/JCI19270" target="_blank">Full Text</a>]
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<a id="Shattuck2002" class="mim-anchor"></a>
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Shattuck, T. M., Costa, J., Bernstein, M., Jensen, R. T., Chung, D. C., Arnold, A.
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<strong>Mutational analysis of Smad3, a candidate tumor suppressor implicated in TGF-beta and menin pathways, in parathyroid adenomas and enteropancreatic endocrine tumors.</strong>
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J. Clin. Endocr. Metab. 87: 3911-3914, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12161532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12161532</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12161532" 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/10.1210/jcem.87.8.8707" target="_blank">Full Text</a>]
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<a id="van de Laar2011" class="mim-anchor"></a>
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van de Laar, I. M. B. H., Oldenburg, R. A., Pals, G., Roos-Hesselink, J. W., de Graaf, B. M., Verhagen, J. M. A., Hoedemaekers, Y. M., Willemsen, R., Severijnen, L.-A., Venselaar, H., Vriend, G., Pattynama, P. M., and 14 others.
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<strong>Mutations in SMAD3 cause a syndrome form of aortic aneurysms and dissections with early-onset osteoarthritis.</strong>
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Nature Genet. 43: 121-126, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21217753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21217753</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21217753" 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/ng.744" target="_blank">Full Text</a>]
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<a id="van de Laar2012" class="mim-anchor"></a>
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van de Laar, I. M. B. H., van der Linde, D., Oei, E. H. G., Bos, P. K., Bessems, J. H., Bierma-Zeinstra, S. M., van Meer, B. L., Pals, G., Oldenburg, R. A., Bekkers, J. A., Moelker, A., de Graaf, B. M., and 17 others.
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<strong>Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome.</strong>
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J. Med. Genet. 49: 47-57, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22167769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22167769</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22167769" 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-2011-100382" target="_blank">Full Text</a>]
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Wolfraim, L. A., Fernandez, T. M., Mamura, M., Fuller, W. L., Kumar, R., Cole, D. E., Byfield, S., Felici, A., Flanders, K. C., Walz, T. M., Roberts, A. B., Aplan, P. D., Balis, F. M., Letterio, J. J.
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<strong>Loss of Smad3 in acute T-cell lymphoblastic leukemia.</strong>
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New Eng. J. Med. 351: 552-559, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15295048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15295048</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15295048" 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/10.1056/NEJMoa031197" target="_blank">Full Text</a>]
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<a id="25" class="mim-anchor"></a>
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<a id="Yang1999" class="mim-anchor"></a>
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Yang, X., Letterio, J. J., Lechleider, R. J., Chen, L., Hayman, R., Gu, H., Roberts, A. B., Deng, C.
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<strong>Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta.</strong>
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EMBO J. 18: 1280-1291, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10064594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10064594</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10064594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/emboj/18.5.1280" target="_blank">Full Text</a>]
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<a id="26" class="mim-anchor"></a>
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<a id="You2002" class="mim-anchor"></a>
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<p class="mim-text-font">
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You, L., Kruse, F. E.
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<strong>Differential effect of activin A and BMP-7 on myofibroblast differentiation and the role of the Smad signaling pathway.</strong>
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Invest. Ophthal. Vis. Sci. 43: 72-81, 2002.
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[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>, <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'})">related citations</a>]
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<a id="Zawel1998" class="mim-anchor"></a>
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Zawel, L., Dai, J. L., Buckhaults, P., Zhou, S., Kinzler, K. W., Vogelstein, B., Kern, S. E.
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<strong>Human Smad3 and Smad4 are sequence-specific transcription activators.</strong>
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Molec. Cell 1: 611-617, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9660945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9660945</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9660945" 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/s1097-2765(00)80061-1" target="_blank">Full Text</a>]
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<a id="Zhang1996" class="mim-anchor"></a>
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Zhang, Y., Feng, X.-H., Wu, R.-Y., Derynck, R.
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<strong>Receptor-associated Mad homologues synergize as effectors of the TGF-beta response.</strong>
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Nature 383: 168-172, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8774881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8774881</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8774881" 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/10.1038/383168a0" target="_blank">Full Text</a>]
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Zhu, Y., Richardson, J. A., Parada, L. F., Graff, J. M.
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<strong>Smad3 mutant mice develop metastatic colorectal cancer.</strong>
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Cell 94: 703-714, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9753318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9753318</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9753318" 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)81730-4" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 06/28/2019
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<span class="mim-text-font">
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Ada Hamosh - updated : 08/13/2018<br>Marla J. F. O'Neill - updated : 6/14/2016<br>Ada Hamosh - updated : 2/6/2012<br>Ada Hamosh - updated : 9/26/2011<br>Marla J. F. O'Neill - updated : 3/7/2011<br>Patricia A. Hartz - updated : 5/29/2009<br>Ada Hamosh - updated : 8/29/2008<br>Ada Hamosh - updated : 8/13/2008<br>Ada Hamosh - updated : 4/4/2008<br>Paul J. Converse - updated : 11/1/2006<br>Marla J. F. O'Neill - updated : 7/28/2006<br>Patricia A. Hartz - updated : 7/20/2006<br>Ada Hamosh - updated : 9/29/2004<br>Victor A. McKusick - updated : 9/13/2004<br>Ada Hamosh - updated : 8/26/2004<br>Cassandra L. Kniffin - updated : 12/4/2003<br>John A. Phillips, III - updated : 4/8/2003<br>Stylianos E. Antonarakis - updated : 9/11/2002<br>Stylianos E. Antonarakis - updated : 7/26/2002<br>Jane Kelly - updated : 7/8/2002<br>Victor A. McKusick - updated : 4/25/2002<br>Michael J. Wright - updated : 1/8/2001<br>Ada Hamosh - updated : 8/31/2000<br>Stylianos E. Antonarakis - updated : 1/31/1999<br>Stylianos E. Antonarakis - updated : 10/13/1998
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Patti M. Sherman : 10/9/1998
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carol : 01/08/2020
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mgross : 06/28/2019<br>alopez : 08/13/2018<br>carol : 08/17/2017<br>alopez : 12/19/2016<br>carol : 06/20/2016<br>carol : 6/17/2016<br>carol : 6/14/2016<br>carol : 11/14/2014<br>alopez : 4/22/2014<br>carol : 9/6/2012<br>carol : 2/27/2012<br>terry : 2/7/2012<br>carol : 2/7/2012<br>terry : 2/6/2012<br>alopez : 10/24/2011<br>alopez : 10/5/2011<br>terry : 9/26/2011<br>carol : 3/7/2011<br>terry : 3/7/2011<br>terry : 6/3/2009<br>mgross : 6/2/2009<br>terry : 5/29/2009<br>alopez : 9/11/2008<br>terry : 8/29/2008<br>alopez : 8/20/2008<br>terry : 8/13/2008<br>alopez : 4/14/2008<br>terry : 4/4/2008<br>wwang : 12/28/2007<br>terry : 12/11/2007<br>mgross : 11/7/2006<br>terry : 11/1/2006<br>wwang : 8/7/2006<br>terry : 7/28/2006<br>mgross : 7/20/2006<br>carol : 4/28/2005<br>carol : 4/28/2005<br>mgross : 4/13/2005<br>terry : 9/29/2004<br>tkritzer : 9/14/2004<br>terry : 9/13/2004<br>tkritzer : 8/30/2004<br>terry : 8/26/2004<br>carol : 12/8/2003<br>ckniffin : 12/4/2003<br>cwells : 4/29/2003<br>terry : 4/8/2003<br>mgross : 9/11/2002<br>mgross : 7/26/2002<br>mgross : 7/26/2002<br>mgross : 7/8/2002<br>mgross : 4/25/2002<br>alopez : 1/8/2001<br>alopez : 9/5/2000<br>terry : 8/31/2000<br>carol : 1/31/1999<br>carol : 10/13/1998<br>carol : 10/13/1998
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<strong>*</strong> 603109
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SMAD FAMILY MEMBER 3; SMAD3
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 3; MADH3<br />
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SMA- AND MAD-RELATED PROTEIN 3
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SMAD3</em></strong>
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</span>
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</p>
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<strong>
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<em>
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Cytogenetic location: 15q22.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:67,065,602-67,195,169 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<tbody>
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<td rowspan="1">
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<span class="mim-font">
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15q22.33
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<td>
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<span class="mim-font">
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Loeys-Dietz syndrome 3
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</td>
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<td>
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<span class="mim-font">
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613795
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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</table>
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<span class="mim-font">
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<strong>TEXT</strong>
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<strong>Cloning and Expression</strong>
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<p>Drosophila Mad is required for signaling by the TGF-beta (e.g., 190180)-related factor decapentaplegic. Zhang et al. (1996) cloned a human cDNA encoding MADH3, a homolog of Drosophila Mad. The deduced 425-amino acid MADH3 protein (GenBank 2522267) is 92% identical to MADH2 (601366). </p><p>By searching an expressed sequence tag database with the protein sequences of Mad and Mad homologs, Riggins et al. (1996) isolated human cDNAs encoding MADH3, which they called JV15-2. The C terminus of MADH3 shows significant homology to that of Drosophila Mad. </p>
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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 class="mim-text-font">
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<p>Arai et al. (1998) determined the genomic structure of SMAD3, which contains 9 exons. </p>
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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>Riggins et al. (1996) mapped the MADH3 gene to 15q21-q22 by somatic cell hybrid analysis and screening of YAC clones. </p>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</h4>
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<p>Zhang et al. (1996) showed that MADH3 and MADH4 (SMAD4; 600993) synergized to induce strong ligand-independent TGF-beta-like responses. MADH3 containing a C-terminal truncation acted as a dominant-negative inhibitor of the normal TGF-beta response. The activity of MADH3 was regulated by the TGF-beta receptors (e.g., 190181), and MADH3 was phosphorylated and associated with the ligand-bound receptor complex. Zhang et al. (1996) stated that these results define MADH3 as an effector of the TGF-beta response. </p><p>Zawel et al. (1998) found that human SMAD3 and SMAD4 proteins could specifically recognize an identical 8-bp palindromic sequence (GTCTAGAC). Tandem repeats of this palindrome conferred striking TGF-beta responsiveness to a minimal promoter. This responsiveness was abrogated by targeted deletion of the cellular SMAD4 gene. These results showed that SMAD proteins are involved in the biologic responses to TGF-beta and related ligands. </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 (601366), 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>SMAD3 is a direct mediator of transcriptional activation by the TGF-beta receptor. Its target genes in epithelial cells include cyclin-dependent kinase (CDK; see 116953) inhibitors that generate a cytostatic response. Chen et al. (2002) defined how, in the same context, SMAD3 can mediate transcriptional repression of the growth-promoting gene MYC (190080). A complex containing SMAD3, the transcription factors E2F4 (600659), E2F5 (600967), and DP1 (189902), and the corepressor p107 (116957) preexists in the cytoplasm. In response to TGF-beta, this complex moves into the nucleus and associates with SMAD4, recognizing a composite SMAD-E2F site on MYC for repression. Previously known as the ultimate recipients of CDK regulatory signals, E2F4/E2F5 and p107 act here as transducers of TGF-beta receptor signals upstream of CDK. SMAD proteins therefore mediate transcriptional activation or repression depending on their associated partners. </p><p>TGFB (190180) 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>Based upon molecular allelotyping and comparative genomic hybridization studies, chromosome 15q is the likely location of a tumor suppressor gene important in the pathogeneses of sporadic enteropancreatic endocrine tumors and parathyroid adenomas. To determine whether SMAD3 plays a primary role in the development of these tumors, Shattuck et al. (2002) investigated 20 enteropancreatic tumors and 67 parathyroid adenomas for LOH at DNA markers surrounding SMAD3. Twenty percent of enteropancreatic tumors and 24% of parathyroid adenomas showed loss. All 9 coding exons and intron-exon boundaries of the SMAD3 gene were then sequenced in genomic DNA from all 20 enteropancreatic and 25 parathyroid tumors, including every case with LOH. No acquired clonal mutations, insertions, or microdeletions in SMAD3 were detected in any tumors. Because inactivating somatic mutation is the hallmark of an authentic tumor suppressor, SMAD3 is unlikely to function as a classic tumor suppressor gene in the pathogenesis of sporadic parathyroid or enteropancreatic endocrine tumors. </p><p>Matsuura et al. (2004) showed that SMAD3 is a major physiologic substrate of the G1 cyclin-dependent kinases CDK4 (123829) and CDK2 (116953). Except for the retinoblastoma protein family, SMAD3 was the only CDK4 substrate demonstrated to that time. Matsuura et al. (2004) mapped CDK4 and CDK2 phosphorylation sites to thr8, thr178, and ser212 in SMAD3. Mutation of the CDK phosphorylation sites increased Smad3 transcriptional activity, leading to higher expression of the CDK inhibitor p15 (600431). Mutation of the CDK phosphorylation sites of Smad3 also increased its ability to downregulate the expression of c-myc. Using Smad3 knockout mouse embryonic fibroblasts and other epithelial cell lines, Matsuura et al. (2004) further showed that Smad3 inhibits cell cycle progression from G1 to S phase and that mutation of the CDK phosphorylation sites in Smad3 increases this ability. They concluded that CDK phosphorylation of SMAD3 inhibits its transcriptional activity and antiproliferative function. </p><p>To determine the role of SMAD3 in the pathogenesis of lymphoid neoplasia, Wolfraim et al. (2004) measured SMAD3 mRNA and protein in leukemia cells obtained at diagnosis from 19 children with acute leukemia: 10 with T-cell acute lymphoblastic leukemia (ALL), 7 with pre-B-cell ALL, and 2 with acute nonlymphoblastic leukemia (ANLL). SMAD3 protein was absent in T-cell ALL but present in pre-B-cell ALL and ANLL. No mutations in the SMAD3 gene were identified in T-cell ALL, and SMAD3 mRNA was present in T-cell ALL and normal T cells at similar levels. Wolfraim et al. (2004) concluded that loss of SMAD3 protein is a specific feature of pediatric T-cell lymphoblastic leukemia. </p><p>In experiments using mouse muscle, Carlson et al. (2008) found that, in addition to the loss of Notch (190198) activation, old muscle produces excessive TGF-beta (but not myostatin, 601788), which induces unusually high levels of Smad3 in resident satellite cells and interferes with the regenerative capacity. Importantly, endogenous Notch and Smad3 antagonize each other in the control of satellite cell proliferation, such that activation of Notch blocks the TGF-beta-dependent upregulation of the cyclin-dependent kinase (CDK) inhibitors p15, p16 (600160), p21 (116899), and p27 (600778), whereas inhibition of Notch induces them. Furthermore, in muscle stem cells, Notch activity determined the binding of Smad3 to the promoters of these negative regulators of cell cycle progression. Attenuation of TGF-beta/Smad3 in old, injured muscle restored regeneration to satellite cells in vivo. Thus, a balance between endogenous Smad3 and active Notch controls the regenerative competence of muscle stem cells, and deregulation of this balance in the old muscle microniche interferes with regeneration. </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 (see 112264) 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 (601595), SMAD2 (601366), SMAD3, 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>Chuderland et al. (2008) identified an SPS motif in ERK2 (MAPK1; 176948) and SMAD3 and a similar TPT motif in MEK1 (MAP2K1; 176872) that directed protein nuclear accumulation when phosphorylated. </p><p>Using coimmunoprecipitation and in vitro binding assays, Liu et al. (2017) found that human BRD7 (618489) interacted with SMAD3 and SMAD4 in HEK293T cells. The MH1 and MH2 domains of the SMADs were sufficient for BRD7 binding, and the N-terminal region preceding the bromodomain in BRD7 was required for SMAD binding. Overexpression of BRD7 significantly increased TGF-beta-induced transcriptional activation of p21, whereas knockdown of BRD7 reduced it. Chromatin immunoprecipitation assays demonstrated that, via its bromodomain, BRD7 increased SMAD3/SMAD4 binding to the p21 promoter in the presence of TGF-beta. BRD7 also enhanced TGF-beta-induced transcriptional activity of SMAD4 by interacting and cooperating with p300 (EP300; 602700). BRD7 knockdown attenuated the TGF-beta-induced antiproliferation phenotype in tumor cells, whereas expression of BRD7 had a suppressive effect on tumor formation and enhanced TGF-beta-mediated epithelial-mesenchymal transition responses. </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. 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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<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>Loeys-Dietz Syndrome 3</em></strong></p><p>
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In a 4-generation Dutch family with arterial aneurysms and dissections and early-onset osteoarthritis mapping to chromosome 15q22.2-q24.2, van de Laar et al. (2011) analyzed the candidate gene SMAD3 and identified heterozygosity for a missense mutation (R287W; 603109.0001) that segregated with disease. The authors designated the disorder aneurysms-osteoarthritis syndrome (AOS), but it is here incorporated into the Loeys-Dietz phenotypic series as Loeys-Dietz syndrome-3 (LDS3; 613795). Analysis of SMAD3 in 99 patients with thoracic aortic aneurysms and dissections and Marfan-like features, who were known to be negative for mutation in the FBN1 (134797), TGFBR1 (190181), and TGFBR2 (190182) genes, revealed 2 additional probands with heterozygous SMAD3 mutations (603109.0002; 603109.0003). All 3 mutations were located in the MH2 domain, which mediates oligomerization of SMAD3 with SMAD4 (600993) and SMAD-dependent transcriptional activation. </p><p>Regalado et al. (2011) reported 4 new mutations in SMAD3. One mutation (603109.0004) was a frameshift mutation in exon 5 segregating in a family with LDS3 phenotype. The other 3 were missense mutations in invariant codons. </p><p>Van de Laar et al. (2012) identified 5 novel SMAD3 mutations in 5 additional families with aneurysms-osteoarthritis syndrome (see, e.g., 603109.0008-603109.0010). </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation in the SMAD3 gene and dizygotic twinning, see 276400.</p><p><strong><em>Exclusion Studies</em></strong></p><p>
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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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<span class="mim-font">
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<strong>Animal Model</strong>
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<span class="mim-text-font">
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<p>Zhu et al. (1998) reported the targeted disruption of the mouse Smad3 gene. Smad3 mutant mice were viable and fertile. Between 4 and 6 months of age, the Smad3 mutant mice became moribund with colorectal adenocarcinomas. The neoplasms penetrated through the intestinal wall and metastasized to lymph nodes. Since TGF-beta transduces its signal to the interior of the cell via Smad2, Smad3, and Smad4, these results directly implicate TGF-beta signaling in the pathogenesis of colorectal cancer and provide a compelling animal model for the study of human colorectal cancer. </p><p>Yang et al. (1999) found that Smad3-null (ex8/ex8) mice died between 1 and 8 months due to a primary defect in immune function. The mice exhibited inflammatory lesions in a number of organs, including the nasal mucosa, stomach, pancreas, colon, and small intestine, as well as enlarged lymph nodes, an involuted thymus, and the formation of bacterial abscesses adjacent to mucosal surfaces. Immunostaining revealed a significant increase in T-cell activation, suggesting that Smad3 has a role in TGFB-mediated regulation of T-cell activation. </p><p>Renal tubulointerstitial fibrosis is a chronic inflammatory condition in which renal fibrosis is associated with epithelial-mesenchymal transition of the renal tubules and synthesis of extracellular matrix in response to multiple entities, including ureteral obstruction. TGFB plays a pivotal role in the disease process. Sato et al. (2003) found that Smad3-null mice with ureteral obstruction were protected against tubulointerstitial fibrosis, presumably by blocking the downstream effects of TGFB. Levels of TGFB mRNA and mature protein were decreased in the mutant animals compared to experimental controls, indicating that the Smad3 pathway is also essential for autoinduction of TGFB. </p><p>Wolfraim et al. (2004) used mice in which 1 or both alleles of Smad3 were inactivated to evaluate the role of Smad3 in the response of normal T cells to TGF-beta and in the susceptibility to spontaneous leukemogenesis in mice in which both alleles of the tumor suppressor p27(Kip1) (CDKN1B; 600778) were deleted. The loss of 1 allele for Smad3 impaired the inhibitory effect of TGF-beta on the proliferation of normal T cells and worked in tandem with the homozygous inactivation of p27(Kip1) to promote T-cell leukemogenesis. Wolfraim et al. (2004) concluded that a reduction in Smad3 expression and the loss of p27(Kip1) work synergistically to promote T-cell leukemogenesis in mice. </p><p>Ashcroft et al. (1999) generated Smad3-null mice and observed accelerated cutaneous wound healing, with complete reepithelialization by day 2 compared to day 5 in wildtype mice, and significantly reduced local infiltration of monocytes. Smad3 -/- keratinocytes showed altered patterns of growth and migration, and Smad3 -/- monocytes exhibited a selectively blunted chemotactic response to TGF-beta (190180). </p><p>Arany et al. (2006) created excisional ear wounds in Smad3 -/- mice and observed wound enlargement compared to wildtype controls. Levels of elastin and glycosaminoglycans were increased, collagen fibers were more compactly organized, and integrins, TGFB1, and matrix metalloproteinases were altered both basally and after wounding in Smad3-knockout mice. Mechanical testing revealed an increased modulus of elasticity, suggesting an imbalance of tissue forces. Arany et al. (2006) proposed that the altered mechanical elastic properties lead to a persistent retractile force that is opposed by decreased wound contractile forces. </p><p>Kanamaru et al. (2005) found that bone marrow-derived mast cells (BMMCs) from Smad3-null mice had an augmented capacity to produce proinflammatory cytokines upon stimulation with lipopolysaccharide. Mast cell-deficient mice reconstituted with Smad3-null BMMCs survived significantly longer in an acute peritonitis model than mast cell-deficient mice reconstituted with wildtype BMMCs. Kanamaru et al. (2005) proposed that SMAD3 in mast cells inhibits mast cell-mediated immune responses against gram-negative bacteria. </p>
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</span>
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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>History</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>Gupta et al. (2006) retracted their paper describing the identification of a microRNA in the latency-associated transcript (Lat) of herpes simplex virus (HSV)-1 (miR-Lat) that targets TGFB and SMAD3 via sequences in their 3-prime UTRs that show partial homology to miR-Lat. </p><p>The article in which Dong et al. (2002) suggested that alterations in the SMAD pathway, including marked SMAD7 (602932) deficiency and SMAD3 upregulation, may be responsible for the TGFB1 (191080) hyperresponsiveness observed in scleroderma (181750) was retracted because some of the elements in figure 3 may have been fabricated. </p>
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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>10 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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<h4>
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<span class="mim-font">
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<strong>.0001 LOEYS-DIETZ SYNDROME 3</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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SMAD3, ARG287TRP
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<br />
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SNP: rs387906850,
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ClinVar: RCV000023241, RCV000195645, RCV000699559, RCV002276569
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<span class="mim-text-font">
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<p>In 20 affected members of a 4-generation Dutch family with arterial aneurysms and dissections and early-onset osteoarthritis (LDS3; 613795), van de Laar et al. (2011) identified heterozygosity for an 859C-T transition in exon 6 of the SMAD3 gene, resulting in an arg287-to-trp (R287W) substitution at a highly conserved residue within the MH2 domain. The mutation was not found in 7 unaffected family members or in 544 Dutch control chromosomes. Immunohistochemical analysis of aortic wall tissue from 2 patients showed increased expression of key proteins in the TGF-beta (see TGFB1, 190180) pathway. </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>
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<span class="mim-font">
|
|
<strong>.0002 LOEYS-DIETZ SYNDROME 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMAD3, 2-BP DEL, 741AT
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<br />
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SNP: rs587776880,
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ClinVar: RCV000023242
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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 3 Dutch sibs with arterial aneurysms and dissections and early-onset osteoarthritis (LDS3; 613795), van de Laar et al. (2011) identified heterozygosity for a 2-bp deletion (741delAT) in exon 6 of the SMAD3 gene, resulting in a frameshift and a premature termination sequence at codon 309 in exon 7 that removes nearly the complete MH2 domain (Thr247ProfsTer61). The deletion, which was presumably present in their affected deceased father, was not found in their unaffected mother or in 544 Dutch control chromosomes. Analysis of patient cDNA showed very weak mutant signal compared to wildtype, and treatment of patient fibroblast cultures with cycloheximide markedly increased the mutant signal, indicating that most of the abnormal RNA was subjected to nonsense messenger RNA decay and that a truncated SMAD3 protein was barely formed. </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>.0003 LOEYS-DIETZ SYNDROME 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMAD3, THR261ILE
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<br />
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SNP: rs387906851,
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ClinVar: RCV000023243
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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 Dutch male patient with arterial aneurysm and early-onset osteoarthritis (LDS3; 613795), van de Laar et al. (2011) identified heterozygosity for a 783C-T transition in exon 6 of the SMAD3 gene, resulting in a thr261-to-ile (T261I) substitution at a highly conserved residue in the MH2 domain. The mutation was not found in 544 Dutch control chromosomes. </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>
|
|
<span class="mim-font">
|
|
<strong>.0004 LOEYS-DIETZ SYNDROME 3</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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SMAD3, 1-BP DEL, 652A
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<br />
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SNP: rs587776881,
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ClinVar: RCV000023244, RCV001385143
|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-generation pedigree segregating autosomal dominant thoracic aortic aneurysms and dissections with intracranial and other arterial aneurysms (LDS3; 613795), Regalado et al. (2011) identified a deletion of an A at nucleotide 652 in exon 5 of the SMAD3 gene, resulting in frameshift leading to premature termination following asparagine-218 (N218fs). This mutation was present in all individuals with vascular disease in the family and segregated with a lod score of 2.52. The pedigree had originally been reported by Regalado et al. (2011). The mutation was absent from 2,300 control exomes. </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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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 LOEYS-DIETZ SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
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SMAD3, ARG279LYS
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<br />
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|
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SNP: rs387906852,
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|
|
|
ClinVar: RCV000023245
|
|
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|
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated families of European descent with autosomal dominant thoracic aortic and other aneurysms (LDS3; 613795), Regalado et al. (2011) identified a G-to-A transition at nucleotide 836 in exon 6 of the SMAD3 gene, resulting in an arg-to-lys substitution at codon 279 (R279K). Arg279 is completely conserved from human to Drosophila, and the R279K mutation was predicted to disrupt protein function. The mutation was not identified in 2,300 control exomes. There was decreased penetrance in younger family members. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LOEYS-DIETZ SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
SMAD3, GLU239LYS
|
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|
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<br />
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|
|
SNP: rs387906853,
|
|
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|
|
|
|
ClinVar: RCV000023246, RCV001703421, RCV003528136
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a small family with 3 sibs affected with thoracic aortic aneurysm and dissection (LDS3; 613795), Regalado et al. (2011) identified a G-to-A transition at nucleotide 715 in exon 6 of the SMAD3 gene, resulting in a glutamine-to-lysine substitution at codon 239 (E239K). Exon 6 encodes the MH2 protein-protein binding domain. Glu239 is completely conserved from human to Drosophila, and the E239K mutation was predicted to disrupt protein function. The mutation was not identified in 2,300 control exomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 LOEYS-DIETZ SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMAD3, ALA112VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906854,
|
|
|
|
|
|
|
|
ClinVar: RCV000023247, RCV002313719
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family segregating autosomal dominant thoracic aortic aneurysm with dissection as well as other features of Loeys-Dietz syndrome (LDS3; 613795) including bifid uvula and scoliosis, and early-onset osteoarthritis, Regalado et al. (2011) identified a heterozygous alanine-to-valine substitution at codon 112 (A112V). The mutation segregated with disease with reduced penetrance in this family and was not identified in 2,300 control exomes. Guo (2012) stated that the correct nucleotide change for the A112V mutation is 335C-T in exon 2 rather than 235C-T as cited in Regalado et al. (2011). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LOEYS-DIETZ SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMAD3, 1-BP DEL, 313G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776882,
|
|
|
|
|
|
|
|
ClinVar: RCV000023248, RCV000767318
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with aneurysms-osteoarthritis syndrome (LCS3; 613795), van de Laar et al. (2012) identified a 1-bp deletion at nucleotide 313 of the SMAD3 gene (313delG), resulting in a frameshift (Ala105ProfsTer11). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 LOEYS-DIETZ SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMAD3, PRO263LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906855,
|
|
|
|
|
|
|
|
ClinVar: RCV000023249, RCV002313720
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with aneurysms-osteoarthritis syndrome (LCS3; 613795), van de Laar et al. (2012) identified a 788C-T transition in the SMAD3 gene, resulting in a pro263-to-leu (P263L) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 LOEYS-DIETZ SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMAD3, GLU361TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906856,
|
|
|
|
|
|
|
|
ClinVar: RCV000023250
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family segregating aneurysms-osteoarthritis syndrome (LCS3; 613795), van de Laar et al. (2012) identified a 1-bp duplication at nucleotide 1080 in the SMAD3 gene (1080dupT), resulting in a glu361-to-ter (E361X) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Arai, T., Akiyama, Y., Okabe, S., Ando, M., Endo, M., Yuasa, Y.
|
|
<strong>Genomic structure of the human Smad3 gene and its infrequent alterations in colorectal cancers.</strong>
|
|
Cancer Lett. 122: 157-163, 1998.
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|
|
[PubMed: 9464505]
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|
[Full Text: https://doi.org/10.1016/s0304-3835(97)00384-4]
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|
</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Arany, P. R., Flanders, K. C., Kobayashi, T., Kuo, C. K., Stuelten, C., Desai, K. V., Tuan, R., Rennard, S. I., Roberts, A. B.
|
|
<strong>Smad3 deficiency alters key structural elements of the extracellular matrix and mechanotransduction of wound closure.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 9250-9255, 2006.
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|
|
[PubMed: 16754864]
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[Full Text: https://doi.org/10.1073/pnas.0602473103]
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Ashcroft, G. S., Yang, X., Glick, A. B., Weinstein, M., Letterio, J. L., Mizel, D. E., Anzano, M., Greenwell-Wild, T., Wahl, S. M., Deng, C., Roberts, A. B.
|
|
<strong>Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response.</strong>
|
|
Nature Cell Biol. 1: 260-266, 1999.
|
|
|
|
|
|
[PubMed: 10559937]
|
|
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|
|
[Full Text: https://doi.org/10.1038/12971]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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: 29489750]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature25784]
|
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|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Carlson, M. E., Hsu, M., Conboy, I. M.
|
|
<strong>Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells.</strong>
|
|
Nature 454: 528-532, 2008. Note: Erratum: Nature 538: 274 only, 2016.
|
|
|
|
|
|
[PubMed: 18552838]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature07034]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Chen, C.-R., Kang, Y., Siegel, P. M., Massague, J.
|
|
<strong>E2F4/5 and p107 as Smad cofactors linking the TGF-beta receptor to c-myc repression.</strong>
|
|
Cell 110: 19-32, 2002.
|
|
|
|
|
|
[PubMed: 12150994]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0092-8674(02)00801-2]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Chuderland, D., Konson, A., Seger, R.
|
|
<strong>Identification and characterization of a general nuclear translocation signal in signaling proteins.</strong>
|
|
Molec. Cell 31: 850-861, 2008.
|
|
|
|
|
|
[PubMed: 18760948]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.molcel.2008.08.007]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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: 18548003]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature07086]
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dong, C., Zhu, S., Wang, T., Yoon, W., Li, Z., Alvarez, R. J., ten Dijke, P., White, B., Wigley, F. M., Goldschmidt-Clermont, P. J.
|
|
<strong>Deficient Smad7 expression: a putative molecular defect in scleroderma.</strong>
|
|
Proc. Nat. Acad. Sci. 99: 3908-3913, 2002. Note: Retraction: Proc. Nat. Acad. Sci. 113: E2208, 2016.
|
|
|
|
|
|
[PubMed: 11904440]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.062010399]
|
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|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Guo, D.-C.
|
|
<strong>Personal Communication.</strong>
|
|
Houston, Tex. 2/7/2012.
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gupta, A., Gartner, J. J., Sethupathy, P., Hatzigeorgiou, A. G., Fraser, N. W.
|
|
<strong>Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript.</strong>
|
|
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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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<strong>Mutation analysis of SMAD2, SMAD3, and SMAD4 genes in hereditary non-polyposis colorectal cancer.</strong>
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<strong>Targeted disruption of TGF-beta-1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction.</strong>
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Wolfraim, L. A., Fernandez, T. M., Mamura, M., Fuller, W. L., Kumar, R., Cole, D. E., Byfield, S., Felici, A., Flanders, K. C., Walz, T. M., Roberts, A. B., Aplan, P. D., Balis, F. M., Letterio, J. J.
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Yang, X., Letterio, J. J., Lechleider, R. J., Chen, L., Hayman, R., Gu, H., Roberts, A. B., Deng, C.
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<strong>Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta.</strong>
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You, L., Kruse, F. E.
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<strong>Differential effect of activin A and BMP-7 on myofibroblast differentiation and the role of the Smad signaling pathway.</strong>
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Zhang, Y., Feng, X.-H., Wu, R.-Y., Derynck, R.
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<strong>Receptor-associated Mad homologues synergize as effectors of the TGF-beta response.</strong>
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Zhu, Y., Richardson, J. A., Parada, L. F., Graff, J. M.
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<strong>Smad3 mutant mice develop metastatic colorectal cancer.</strong>
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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