6471 lines
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Entry
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- *600993 - SMAD FAMILY MEMBER 4; SMAD4
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- OMIM
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<div class="container hidden-print">
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<div id="mimAlertBanner">
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600993</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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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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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="#biochemicalFeatures">Biochemical Features</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#nomenclature">Nomenclature</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600993">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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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=ENSG00000141646;t=ENST00000342988" 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=4089" 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=600993" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000141646;t=ENST00000342988" 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_001407041,NM_001407042,NM_001407043,NM_005359,NR_176264,NR_176265" 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_005359" 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=600993" 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=02995&isoform_id=02995_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/SMAD4" 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/1163234,2865657,4885457,12803151,13603414,13959561,119583389,119583390,119583391,158254976,557786683,557786685,557786687,957949704,957949707,2244985511,2244985823,2244986581" 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/Q13485" 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=4089" 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=ENSG00000141646;t=ENST00000342988" 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=SMAD4" 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=SMAD4" 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+4089" 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/SMAD4" 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:4089" 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/4089" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr18&hgg_gene=ENST00000590722.2&hgg_start=51030213&hgg_end=51085042&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:6770" 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:6770" 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/smad4" 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=600993[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=600993[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/SMAD4/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/ENSG00000141646" 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=SMAD4" 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=SMAD4" 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=SMAD4" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.arup.utah.edu/database/SMAD4/SMAD4_welcome.php" 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=SMAD4&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/PA30527" 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:6770" 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://www.mousephenotype.org/data/genes/MGI:894293" 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/SMAD4#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:894293" 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/4089/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=4089" 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=WBGene00004858;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-060130-140" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:600993" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4089" 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=SMAD4&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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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1149069001, 699316006, 9273005<br />
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">ICD+</a>
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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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600993
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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 4; SMAD4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 4; MADH4<br />
|
|
SMA- AND MAD-RELATED PROTEIN 4<br />
|
|
DELETED IN PANCREATIC CARCINOMA 4; DPC4
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SMAD4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SMAD4</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>
|
|
Cytogenetic location: <a href="/geneMap/18/189?start=-3&limit=10&highlight=189">18q21.2</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr18:51030213-51085042&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">18:51,030,213-51,085,042</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<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>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=175050,139210,260350,174900" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>The SMAD4 gene encodes a protein involved in signal transduction of the transforming growth factor-beta (see, e.g., TGFB1, <a href="/entry/190180">190180</a>) superfamily and bone morphogenic proteins (see, e.g., BMP1, <a href="/entry/112264">112264</a>) by mediating transcriptional activation of target genes. SMAD4 is the common SMAD protein required for most transcriptional responses to TGFB and BMP signaling (summary by <a href="#42" class="mim-tip-reference" title="Shioda, T., Lechleider, R. J., Dunwoodie, S. L., Li, H., Yahata, T., de Caestecker, M. P., Fenner, M. H., Roberts, A. B., Isselbacher, K. J. <strong>Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator.</strong> Proc. Nat. Acad. Sci. 95: 9785-9790, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9707553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9707553</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9707553[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.95.17.9785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9707553">Shioda et al., 1998</a> and <a href="#9" 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>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9707553+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>
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<p>About 90% of human pancreatic carcinomas show allelic loss at 18q. <a href="#17" class="mim-tip-reference" title="Hahn, S. A., Schutte, M., Hoque, T. M. S., Moskaluk, C. A., da Costa, L. T., Rozenblum, E., Weinstein, C. L., Fischer, A., Yeo, C. J., Hruban, R. H., Kern, S. E. <strong>DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.</strong> Science 271: 350-354, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8553070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8553070</a>] [<a href="https://doi.org/10.1126/science.271.5247.350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8553070">Hahn et al. (1996)</a> reported the identification of a putative tumor suppressor gene on chromosome 18q21.1 that may be a candidate for pancreatic carcinoma. The gene was homozygously deleted in 25 of 84 tumors and mutations were identified as somatic mutations in 6 of 27 carcinomas that lacked deletions. The gene was localized by deletion analysis of xenograft DNA. Markers absent in these samples were used to screen the CEPH mega-YAC library. YACs spanning the minimal deletion region were subcloned as cosmids for sequencing and recovery of cDNAs. A 2,680-bp cDNA was found and shown to code for a predicted 552-amino acid protein. The predicted protein shares blocks of as much as 85% similarity to the Drosophila Mad protein and the Caenorhabditis elegans sma-2,-3 and -4 proteins. In Drosophila, homozygous Mad mutants exhibit a variety of developmental defects. <a href="#17" class="mim-tip-reference" title="Hahn, S. A., Schutte, M., Hoque, T. M. S., Moskaluk, C. A., da Costa, L. T., Rozenblum, E., Weinstein, C. L., Fischer, A., Yeo, C. J., Hruban, R. H., Kern, S. E. <strong>DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.</strong> Science 271: 350-354, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8553070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8553070</a>] [<a href="https://doi.org/10.1126/science.271.5247.350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8553070">Hahn et al. (1996)</a> designated the gene DPC4 (for homozygously deleted in pancreatic carcinoma, locus 4). This region of chromosome 18q also contains a gene (DCC; <a href="/entry/120470">120470</a>) found to be deleted in colorectal cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8553070" 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="#17" class="mim-tip-reference" title="Hahn, S. A., Schutte, M., Hoque, T. M. S., Moskaluk, C. A., da Costa, L. T., Rozenblum, E., Weinstein, C. L., Fischer, A., Yeo, C. J., Hruban, R. H., Kern, S. E. <strong>DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.</strong> Science 271: 350-354, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8553070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8553070</a>] [<a href="https://doi.org/10.1126/science.271.5247.350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8553070">Hahn et al. (1996)</a> demonstrated that the SMAD4 gene contains 11 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8553070" 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="#17" class="mim-tip-reference" title="Hahn, S. A., Schutte, M., Hoque, T. M. S., Moskaluk, C. A., da Costa, L. T., Rozenblum, E., Weinstein, C. L., Fischer, A., Yeo, C. J., Hruban, R. H., Kern, S. E. <strong>DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.</strong> Science 271: 350-354, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8553070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8553070</a>] [<a href="https://doi.org/10.1126/science.271.5247.350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8553070">Hahn et al. (1996)</a> identified the SMAD4 gene on chromosome 18q21.1. <a href="#21" class="mim-tip-reference" title="Howe, J. R., Roth, S., Ringold, J. C., Summers, R. W., Jarvinen, H. J., Sistonen, P., Tomlinson, I. P. M., Houlston, R. S., Bevan, S., Mitros, F. A., Stone, E. M., Aaltonen, L. A. <strong>Mutations in the SMAD4/DPC4 gene in juvenile polyposis.</strong> Science 280: 1086-1088, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9582123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9582123</a>] [<a href="https://doi.org/10.1126/science.280.5366.1086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9582123">Howe et al. (1998)</a> identified the SMAD4 gene within a region on 18q21.1 defined by linkage analysis in a kindred with juvenile polyposis syndrome (<a href="/entry/174900">174900</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9582123+8553070" 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>To test directly the hypothesis that the SMAD4 gene is a tumor suppressor that is critical for transmitting signals from transforming growth factor-beta (TGFB1; <a href="/entry/190180">190180</a>) and related ligands, <a href="#53" class="mim-tip-reference" title="Zhou, S., Buckhaults, P., Zawel, L., Bunz, F., Riggins, G., Le Dai, J., Kern, S. E., Kinzler, K. W., Vogelstein, B. <strong>Targeted deletion of Smad4 shows it is required for transforming growth factor beta and activin signaling in colorectal cancer cells.</strong> Proc. Nat. Acad. Sci. 95: 2412-2416, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9482899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9482899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9482899[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.95.5.2412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9482899">Zhou et al. (1998)</a> deleted the SMAD4 gene through homologous recombination in human colorectal cancer cells. This deletion abrogated signaling from TGF-beta, as well as from the TGF-beta family member activin (<a href="/entry/147290">147290</a>). These results provided unequivocal evidence that mutational inactivation of SMAD4 causes TGF-beta unresponsiveness and gave a basis for understanding the physiologic role of this gene in tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9482899" 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>SMAD4 plays a pivotal role in signal transduction of the transforming growth factor beta superfamily cytokines by mediating transcriptional activation of target genes. <a href="#42" class="mim-tip-reference" title="Shioda, T., Lechleider, R. J., Dunwoodie, S. L., Li, H., Yahata, T., de Caestecker, M. P., Fenner, M. H., Roberts, A. B., Isselbacher, K. J. <strong>Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator.</strong> Proc. Nat. Acad. Sci. 95: 9785-9790, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9707553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9707553</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9707553[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.95.17.9785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9707553">Shioda et al. (1998)</a> presented results demonstrating additional roles of SMAD heterooligomerization in SMAD4-mediated transcriptional activation. The results also suggested that the transcriptional-activating activity observed in the presence of SMAD4 in mammalian cells may be derived, at least in part, from endogenously expressed separate transcriptional activators, such as MSG1 (<a href="/entry/300149">300149</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9707553" 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="#50" 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="#3" class="mim-tip-reference" title="Bai, R.-Y., Koester, C., Ouyang, T., Hahn, S. A., Hammerschmidt, M., Peschel, C., Duyster, J. <strong>SMIF, a Smad4-interacting protein that functions as a co-activator in TGF-beta signalling.</strong> Nature Cell Biol. 4: 181-190, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11836524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11836524</a>] [<a href="https://doi.org/10.1038/ncb753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11836524">Bai et al. (2002)</a> found that SMAD4 interacts directly with SMIF (<a href="/entry/607010">607010</a>). They found no interaction between other SMAD proteins and SMIF. By deletion analysis, they determined that tyr/phe301 and trp302 of SMAD4 and the N-terminal 100 amino acids of SMIF are required for this interaction. Cotransfection experiments demonstrated that treatment with TGF-beta or bone morphogenic protein-4 (BMP4; <a href="/entry/112262">112262</a>) resulted in SMAD4/SMIF interaction, followed by their nuclear translocation and accumulation. With use of several transient reporter assays to monitor TGF-beta-dependent transcriptional activity, <a href="#3" class="mim-tip-reference" title="Bai, R.-Y., Koester, C., Ouyang, T., Hahn, S. A., Hammerschmidt, M., Peschel, C., Duyster, J. <strong>SMIF, a Smad4-interacting protein that functions as a co-activator in TGF-beta signalling.</strong> Nature Cell Biol. 4: 181-190, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11836524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11836524</a>] [<a href="https://doi.org/10.1038/ncb753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11836524">Bai et al. (2002)</a> determined that the SMAD4/SMIF complex was the transcriptional unit, since neither protein alone was active. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11836524" 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="#8" 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 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="#24" 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><a href="#18" class="mim-tip-reference" title="He, W., Dorn, D. C., Erdjument-Bromage, H., Tempst, P., Moore, M. A. S., Massague, J. <strong>Hematopoiesis controlled by distinct TIF1-gamma and Smad4 branches of the TGF-beta pathway.</strong> Cell 125: 929-941, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16751102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16751102</a>] [<a href="https://doi.org/10.1016/j.cell.2006.03.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16751102">He et al. (2006)</a> found that TIF1-gamma (TRIM33; <a href="/entry/605769">605769</a>) competed with SMAD4 for selective binding of receptor-phosphorylated SMAD2 and SMAD3 in human cells. TGF-beta induced formation of endogenous SMAD2/3-TIF1-gamma and SMAD2/3-SMAD4 complexes in human and other mammalian hematopoietic, mesenchymal, and epithelial cells. In human CD34-positive hematopoietic stem/progenitor cells, where TGF-beta inhibits proliferation and stimulates erythroid differentiation, TIF1-gamma mediated the differentiation response, whereas SMAD4 mediated the antiproliferative response, with SMAD2 and SMAD3 participating in both responses. <a href="#18" class="mim-tip-reference" title="He, W., Dorn, D. C., Erdjument-Bromage, H., Tempst, P., Moore, M. A. S., Massague, J. <strong>Hematopoiesis controlled by distinct TIF1-gamma and Smad4 branches of the TGF-beta pathway.</strong> Cell 125: 929-941, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16751102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16751102</a>] [<a href="https://doi.org/10.1016/j.cell.2006.03.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16751102">He et al. (2006)</a> concluded that SMAD2/3-TIF1-gamma and SMAD2/3-SMAD4 function as complementary effector arms in the control of hematopoietic cell fate by the TGF-beta/SMAD pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16751102" 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="Kim, B.-G., Li, C., Qiao, W., Mamura, M., Kasprzak, B., Anver, M., Wolfraim, L., Hong, S., Mushinski, E., Potter, M., Kim, S.-J., Fu, X.-Y., Deng, C., Letterio, J. J. <strong>Smad4 signalling in T cells is required for suppression of gastrointestinal cancer.</strong> Nature 441: 1015-1019, 2006. Note: Erratum: Nature 444: 780 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791201/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791201</a>] [<a href="https://doi.org/10.1038/nature04846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16791201">Kim et al. (2006)</a> showed that selective loss of Smad4-dependent signaling in T cells leads to spontaneous epithelial cancers throughout the gastrointestinal tract in mice, whereas epithelial-specific deletion of the Smad4 gene does not. Tumors arising within the colon, rectum, duodenum, stomach, and oral cavity are stroma-rich with dense plasma cell infiltrates. Smad4-null T cells produce abundant TH2-type cytokines including IL5 (<a href="/entry/147850">147850</a>), IL6 (<a href="/entry/147620">147620</a>), and IL13 (<a href="/entry/147683">147683</a>), known mediators of plasma cell and stromal expression. <a href="#25" class="mim-tip-reference" title="Kim, B.-G., Li, C., Qiao, W., Mamura, M., Kasprzak, B., Anver, M., Wolfraim, L., Hong, S., Mushinski, E., Potter, M., Kim, S.-J., Fu, X.-Y., Deng, C., Letterio, J. J. <strong>Smad4 signalling in T cells is required for suppression of gastrointestinal cancer.</strong> Nature 441: 1015-1019, 2006. Note: Erratum: Nature 444: 780 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16791201/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16791201</a>] [<a href="https://doi.org/10.1038/nature04846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16791201">Kim et al. (2006)</a> concluded that their results support the concept that cancer, as an outcome, reflects the loss of normal communication between the cellular constituents of a given organ, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16791201" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="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> found that SMAD4, the common SMAD required for most transcriptional responses to BMP and TGFB signaling, is not required for processing of miR21 (<a href="/entry/611020">611020</a>) by BMP4 (<a href="/entry/112262">112262</a>) in primary pulmonary artery smooth muscle cells (PASMCs). <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="#5" class="mim-tip-reference" title="Bornstein, S., White, R., Malkoski, S., Oka, M., Han, G., Cleaver, T., Reh, D., Andersen, P., Gross, N., Olson, S., Deng, C., Lu, S.-L., Wang, X.-J. <strong>Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation.</strong> J. Clin. Invest. 119: 3408-3419, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19841536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19841536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19841536[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/JCI38854" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19841536">Bornstein et al. (2009)</a> found that expression of SMAD4 was downregulated in both malignant human head and neck squamous cell carcinomas (see <a href="/entry/275355">275355</a>) and in grossly normal adjacent buccal mucosa. Deletion of Smad4 specifically in mouse head and neck epithelia resulted in spontaneous head and neck squamous cell carcinomas with evidence of increased genomic instability and inflammation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19841536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Ding, Z., Wu, C.-J., Chu, G. C., Xiao, Y., Ho, D., Zhang, J., Perry, S. R., Labrot, E. S., Wu, X., Lis, R., Hoshida, Y., Hiller, D., and 16 others. <strong>SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression.</strong> Nature 470: 269-273, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21289624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21289624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21289624[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/nature09677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21289624">Ding et al. (2011)</a> exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten (<a href="/entry/601728">601728</a>)-null mouse prostate tumors and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonic pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFB/BMP-SMAD4 signaling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic, and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathologic and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumors identified cell proliferation and invasion as 2 cardinal tumor biologic features in the metastatic Smad4/Pten-null prostate cancer model. Follow-on pathologic and functional assessment confirmed cyclin D1 (<a href="/entry/168461">168461</a>) and SPP1 (<a href="/entry/166490">166490</a>) as key mediators of these biologic processes, which together with PTEN and SMAD4 form a 4-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human prostate cancer. <a href="#11" class="mim-tip-reference" title="Ding, Z., Wu, C.-J., Chu, G. C., Xiao, Y., Ho, D., Zhang, J., Perry, S. R., Labrot, E. S., Wu, X., Lis, R., Hoshida, Y., Hiller, D., and 16 others. <strong>SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression.</strong> Nature 470: 269-273, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21289624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21289624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21289624[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/nature09677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21289624">Ding et al. (2011)</a> concluded that this model-informed progression analysis, together with genetic, functional, and translational studies, established SMAD4 as a key regulator of prostate cancer progression in mice and humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21289624" 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="#37" class="mim-tip-reference" title="Qin, J., Wu, S.-P., Creighton, C. J., Dai, F., Xie, X., Cheng, C.-M., Frolov, A., Ayala, G., Lin, X., Feng, X.-H., Ittmann, M. M., Tsai, S.-J., Tsai, M.-J., Tsai, S. Y. <strong>COUP-TFII inhibits TGF-beta-induced growth barrier to promote prostate tumorigenesis.</strong> Nature 493: 236-240, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23201680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23201680</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23201680[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/nature11674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23201680">Qin et al. (2013)</a> demonstrated that COUP transcription factor-2, or COUP-TFII (NR2F2; <a href="/entry/107773">107773</a>), a member of the nuclear receptor superfamily, serves as a key regulator to inhibit SMAD4-dependent transcription, and consequently overrides the TGF-beta-dependent checkpoint for PTEN-null indolent tumors. Overexpression of COUP-TFII in the mouse prostate epithelium cooperates with PTEN deletion to augment malignant progression and produce an aggressive metastasis-prone tumor. The functional counteraction between COUP-TFII and SMAD4 is reinforced by genetically engineered mouse models in which conditional loss of SMAD4 diminishes the inhibitory effects elicited by COUP-TFII ablation. The biologic significance of COUP-TFII in prostate carcinogenesis is substantiated by patient sample analysis, in which COUP-TFII expression or activity is tightly correlated with tumor recurrence and disease progression, whereas it is inversely associated with TGF-beta signaling. <a href="#37" class="mim-tip-reference" title="Qin, J., Wu, S.-P., Creighton, C. J., Dai, F., Xie, X., Cheng, C.-M., Frolov, A., Ayala, G., Lin, X., Feng, X.-H., Ittmann, M. M., Tsai, S.-J., Tsai, M.-J., Tsai, S. Y. <strong>COUP-TFII inhibits TGF-beta-induced growth barrier to promote prostate tumorigenesis.</strong> Nature 493: 236-240, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23201680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23201680</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23201680[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/nature11674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23201680">Qin et al. (2013)</a> concluded that the destruction of the TGF-beta-dependent barrier by COUP-TFII is crucial for the progression of PTEN-mutant prostate cancer into a life-threatening disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23201680" 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="#52" class="mim-tip-reference" title="Zhang, S., Takaku, M., Zou, L., Gu, A., Chou, W., Zhang, G., Wu, B., Kong, Q., Thomas, S. Y., Serody, J. S., Chen, X., Xu, X., Wade, P. A., Cook, D. N., Ting, J. P. Y., Wan, Y. Y. <strong>Reversing SKI-SMAD4-mediated suppression is essential for T(H)17 cell differentiation.</strong> Nature 551: 105-109, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29072299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29072299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29072299[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/nature24283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29072299">Zhang et al. (2017)</a> demonstrated that TGF-beta (<a href="/entry/190180">190180</a>) enables TH17 cell differentiation by reversing SKI (<a href="/entry/164780">164780</a>)-SMAD4-mediated suppression of the retinoic acid receptor (RAR)-related orphan receptor ROR-gamma-t (RORC; <a href="/entry/602943">602943</a>). <a href="#52" class="mim-tip-reference" title="Zhang, S., Takaku, M., Zou, L., Gu, A., Chou, W., Zhang, G., Wu, B., Kong, Q., Thomas, S. Y., Serody, J. S., Chen, X., Xu, X., Wade, P. A., Cook, D. N., Ting, J. P. Y., Wan, Y. Y. <strong>Reversing SKI-SMAD4-mediated suppression is essential for T(H)17 cell differentiation.</strong> Nature 551: 105-109, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29072299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29072299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29072299[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/nature24283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29072299">Zhang et al. (2017)</a> found that, unlike wildtype T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGF-beta signaling in a RORC-dependent manner. Ectopic SMAD4 expression suppresses RORC expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGF-beta neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the RORC locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGF-beta stimulation. SKI controls histone acetylation and deacetylation of the RORC locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the RORC locus, RORC expression, and TH17 cell differentiation in a SMAD4-dependent manner. Therefore, <a href="#52" class="mim-tip-reference" title="Zhang, S., Takaku, M., Zou, L., Gu, A., Chou, W., Zhang, G., Wu, B., Kong, Q., Thomas, S. Y., Serody, J. S., Chen, X., Xu, X., Wade, P. A., Cook, D. N., Ting, J. P. Y., Wan, Y. Y. <strong>Reversing SKI-SMAD4-mediated suppression is essential for T(H)17 cell differentiation.</strong> Nature 551: 105-109, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29072299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29072299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29072299[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/nature24283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29072299">Zhang et al. (2017)</a> concluded that TGF-beta-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of ROR-gamma-t to enable TH17 cell differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29072299" 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="#33" 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://www.ncbi.nlm.nih.gov/pmc/?term=27270427[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/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 (<a href="/entry/116899">116899</a>), 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>
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<p><a href="#48" class="mim-tip-reference" title="Wu, J.-W., Krawitz, A. R., Chai, J., Li, W., Zhang, F., Luo, K., Shi, Y. <strong>Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: insights on Ski-mediated repression of TFG-beta signaling.</strong> Cell 111: 357-367, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12419246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12419246</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)01006-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12419246">Wu et al. (2002)</a> determined the crystal structure of the SMAD4-binding domain of SKI (<a href="/entry/164780">164780</a>) in complex with the MH2 domain of SMAD4 at 2.85-angstrom resolution. The structure revealed specific recognition of the SMAD4 L3 loop region by a highly conserved interaction loop (I loop) from SKI. The SKI-binding surface on SMAD4 was found to significantly overlap with that required for binding of the receptor-mediated SMADs (R-SMADs). Indeed, SKI disrupted the formation of a functional complex between the comediator SMADs (Co-SMADs) and R-SMADs, explaining how it could lead to repression of TGF-beta, activin, and BMP responses. The structure of the SKI fragment, stabilized by a bound zinc atom, resembled the SAND domain found in transcription factors and other nuclear proteins, in which the corresponding I loop is responsible for DNA binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12419246" 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>Juvenile Polyposis Syndrome</em></strong></p><p>
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In a large Iowa kindred with generalized juvenile polyposis and gastrointestinal cancer (JPS; <a href="/entry/174900">174900</a>), <a href="#20" class="mim-tip-reference" title="Howe, J. R., Ringold, J. C., Summers, R. W., Mitros, F. A., Nishimura, D. Y., Stone, E. M. <strong>A gene for familial juvenile polyposis maps to chromosome 18q21.1.</strong> Am. J. Hum. Genet. 62: 1129-1136, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9545410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9545410</a>] [<a href="https://doi.org/10.1086/301840" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9545410">Howe et al. (1998)</a> mapped a gene predisposing to JPS to chromosome 18q21.1, between markers D18S1118 and D18S487. This interval contains 2 putative tumor suppressor genes, DCC and SMAD4. The high incidence of colorectal cancer (as well as 1 case of pancreatic cancer) in affected members of the Iowa juvenile polyposis kindred displaying 18q21 linkage led <a href="#20" class="mim-tip-reference" title="Howe, J. R., Ringold, J. C., Summers, R. W., Mitros, F. A., Nishimura, D. Y., Stone, E. M. <strong>A gene for familial juvenile polyposis maps to chromosome 18q21.1.</strong> Am. J. Hum. Genet. 62: 1129-1136, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9545410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9545410</a>] [<a href="https://doi.org/10.1086/301840" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9545410">Howe et al. (1998)</a> to propose that one of these tumor suppressor genes predisposes to JPS. After sequencing 14 DCC exons and all 11 SMAD4 exons, they detected a 4-basepair deletion in exon 9 of SMAD4. Eight additional unrelated JPS patients were subsequently analyzed for mutations of all exons of SMAD4 by SSCP and genomic sequencing. In 2 JPS kindreds, a similar 4-bp deletion in exon 9 was segregating (<a href="#0005">600993.0005</a>). Because of the nature of the sequence in this region, these deletions can begin at any of 4 consecutive nucleotides and result in the same mutant sequence and new stop codon. The 3 kindreds segregating these deletions were all Caucasian and originated from Iowa, Mississippi, and Finland. There was no common ancestral haplotype, as assessed by analysis of microsatellite markers close to SMAD4. A patient with colonic and gastric JPS was found to have a 2-basepair deletion in exon 8 of SMAD4, at nucleotides 1170 to 1171 (codon 348) (<a href="#0006">600993.0006</a>). This deletion caused a frameshift that created a stop codon at nucleotides 1178 to 1180 (codon 350). Another patient with 30 to 40 colonic juvenile polyps at age 6 but with no family history of JPS was found to have a 1-bp insertion between nucleotides 815 and 820 of exon 5 (<a href="#0007">600993.0007</a>); this change added a guanine to a stretch of 6 sequential guanines in the wildtype sequence and created a frameshift and a new stop codon at nucleotides 830 to 832 (codon 235). No SMAD4 mutations were found in 4 other unrelated JPS patients. The mutant SMAD4 proteins were predicted to be truncated at the carboxy terminus and to lack sequences required for normal function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9545410" 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="Kinzler, K. W., Vogelstein, B. <strong>Landscaping the cancer terrain.</strong> Science 280: 1036-1037, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9616081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9616081</a>] [<a href="https://doi.org/10.1126/science.280.5366.1036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9616081">Kinzler and Vogelstein (1998)</a> referred to colorectal cancers developing on the basis of juvenile polyposis as 'landscaper defects.' This is following the designation 'gatekeeper defects' for the mutations in tumor suppressor genes that are known to prevent cancer through direct control of cell growth, including p53 (<a href="/entry/191170">191170</a>), RB1 (<a href="/entry/614041">614041</a>), VHL (<a href="/entry/608537">608537</a>), and APC (<a href="/entry/611731">611731</a>). Inactivation of these genes contributes directly to the neoplastic growth of the tumor; thus, they normally function as 'gatekeepers.' <a href="#27" class="mim-tip-reference" title="Kinzler, K. W., Vogelstein, B. <strong>Landscaping the cancer terrain.</strong> Science 280: 1036-1037, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9616081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9616081</a>] [<a href="https://doi.org/10.1126/science.280.5366.1036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9616081">Kinzler and Vogelstein (1998)</a> used the designation 'caretaker defects' for the susceptibility genes that indirectly suppress neoplasia (for example, XPB (<a href="/entry/133510">133510</a>), ATM (<a href="/entry/607585">607585</a>), MSH2 (<a href="/entry/609309">609309</a>), and MLH1 (<a href="/entry/120436">120436</a>)). A second class of indirectly acting cancer susceptibility genes was suggested by findings in juvenile polyposis, which carries an increased risk of colorectal cancer. The polyps in this situation are markedly different from the epithelium-rich adenomatous polyps that give rise to most cases of colorectal cancer. Polyps from JPS patients have a low potential to become malignant and are composed largely of stromal cells, comprising a mixture of mesenchymal and inflammatory elements in which epithelium is entrapped, often forming dilated cysts. The epithelial cells within and surrounding the polyp are initially devoid of neoplastic features but nonetheless are at increased risk of becoming malignant. <a href="#27" class="mim-tip-reference" title="Kinzler, K. W., Vogelstein, B. <strong>Landscaping the cancer terrain.</strong> Science 280: 1036-1037, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9616081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9616081</a>] [<a href="https://doi.org/10.1126/science.280.5366.1036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9616081">Kinzler and Vogelstein (1998)</a> proposed that the increased cancer susceptibility due to inherited mutations in juvenile polyposis is the product of an abnormal stromal environment. That an abnormal stroma can affect the development of adjacent epithelial cells is suggested by the experience with ulcerative colitis, which also leads to inflammation and cystic epithelium in the mucosa of the colon. Initially, the embedded epithelium shows no neoplastic changes, but foci of epithelial neoplasia and progression to cancer eventually develop in many cases. The regeneration that occurs to replace damaged epithelium may increase the probability of somatic mutations in this abnormal microenvironment. The increased risk of cancer in JPS and ulcerative colitis patients seems, therefore, primarily the result of an altered terrain for epithelial cell growth and thus can be thought of as a 'landscaper' defect. <a href="#27" class="mim-tip-reference" title="Kinzler, K. W., Vogelstein, B. <strong>Landscaping the cancer terrain.</strong> Science 280: 1036-1037, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9616081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9616081</a>] [<a href="https://doi.org/10.1126/science.280.5366.1036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9616081">Kinzler and Vogelstein (1998)</a> found it intriguing that the stromal cells, but not the epithelial cells, of most hamartomas from JPS patients contain a clonal genetic alteration. Similarly, clonal genetic changes have been demonstrated in the stroma, but not the epithelial cells, of endometrial polyps. In contrast, clonal genetic alterations have been demonstrated in epithelial cells, but not stromal cells, of polyps arising in patients with familial adenomatous polyposis (due to mutations in the APC gene) or Peutz-Jeghers syndrome (<a href="/entry/175200">175200</a>)--which are morphologically distinct from those of JPS patients. These results add to the emerging realization that solid tumors are not simply composed of neoplastic epithelial cells. Historically, the search for drugs that can modulate neoplasia has focused on such epithelial cells. Targeting specific stromal cells (such as those found in blood vessels) may be more valuable for therapeutic purposes. <a href="#27" class="mim-tip-reference" title="Kinzler, K. W., Vogelstein, B. <strong>Landscaping the cancer terrain.</strong> Science 280: 1036-1037, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9616081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9616081</a>] [<a href="https://doi.org/10.1126/science.280.5366.1036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9616081">Kinzler and Vogelstein (1998)</a> raised the question: 'Could drug targeting of the paracrine factors and other features of the stromal-epithelial interaction be similarly useful?' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9616081" 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="Friedl, W., Uhlhaas, S., Schulmann, K., Stolte, M., Loff, S., Back, W., Mangold, E., Stern, M., Knaebel, H. P., Sutter, C., Weber, R. G., Pistorius, S., Burger, B., Propping, P. <strong>Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers.</strong> Hum. Genet. 111: 108-111, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12136244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12136244</a>] [<a href="https://doi.org/10.1007/s00439-002-0748-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12136244">Friedl et al. (2002)</a> examined 29 patients with the clinical diagnosis of JPS for germline mutations in the MADH4 or BMPR1A (<a href="/entry/601299">601299</a>) genes and identified MADH4 mutations in 7 (24%) and BMPR1A mutations in 5 patients (17%). A remarkable prevalence of massive gastric polyposis was observed in patients with MADH4 mutations when compared with patients with BMPR1A mutations or without identified mutations. See, for example, <a href="#0009">600993.0009</a>. This was claimed to be the first genotype-phenotype correlation observed in JPS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12136244" 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 77 different familial and sporadic cases of juvenile polyposis, <a href="#22" class="mim-tip-reference" title="Howe, J. R., Sayed, M. G., Ahmed, A. F., Ringold, J., Larsen-Haidle, J., Merg, A., Mitros, F. A., Vaccaro, C. A., Petersen, G. M., Giardiello, F. M., Tinley, S. T., Aaltonen, L. A., Lynch, H. T. <strong>The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations.</strong> J. Med. Genet. 41: 484-491, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15235019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15235019</a>] [<a href="https://doi.org/10.1136/jmg.2004.018598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15235019">Howe et al. (2004)</a> identified germline SMAD4 mutations in 14 cases (18.2%) and BMPR1A mutations in 16 cases (20.8%). The authors noted that because mutations were not found in more than half of the patients with juvenile polyposis, either additional predisposing genes remain to be discovered or alternative means of inactivation of the 2 known genes account for these cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15235019" 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="#35" class="mim-tip-reference" title="Miyaki, M., Kuroki, T. <strong>Role of Smad4 (DPC4) inactivation in human cancer.</strong> Biochem. Biophys. Res. Commun. 306: 799-804, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12821112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12821112</a>] [<a href="https://doi.org/10.1016/s0006-291x(03)01066-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12821112">Miyaki and Kuroki (2003)</a> reviewed the role of SMAD4 inactivation in human cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12821112" 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>Juvenile Polyposis/Hereditary Hemorrhagic Telangiectasia Syndrome</em></strong></p><p>
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Juvenile polyposis (<a href="/entry/174900">174900</a>) and hereditary hemorrhagic telangiectasia (<a href="/entry/187300">187300</a>) are autosomal dominant disorders with distinct nonoverlapping clinical features. The former, an inherited predisposition to gastrointestinal malignancy, is caused by mutations in SMAD4 or BMPR1A (<a href="/entry/601299">601299</a>), and the latter is a vascular malformation disorder caused by mutations in ENG (<a href="/entry/131195">131195</a>) or ALK1 (<a href="/entry/601284">601284</a>). All 4 genes encode proteins involved in the transforming growth factor-beta signaling pathway (see <a href="/entry/190180">190180</a>). Although both of these disorders are uncommon, there are many reports of patients and families with both disorders or of patients with juvenile polyposis who show some symptoms of hereditary hemorrhagic telangiectasia; see JPHT, <a href="/entry/175050">175050</a>. <a href="#15" class="mim-tip-reference" title="Gallione, C. J., Repetto, G. M., Legius, E., Rustgi, A. K., Schelley, S. L., Tejpar, S., Mitchell, G., Drouin, E., Westermann, C. J. J., Marchuk, D. A. <strong>A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).</strong> Lancet 363: 852-859, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15031030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15031030</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)15732-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15031030">Gallione et al. (2004)</a> studied DNA from 6 unrelated families segregating both phenotypes and from an individual patient. No patient had mutations in the ENG or ALK1 genes; all had SMAD4 mutations. Three cases of de novo SMAD4 mutations were found. In 1, the mutation was passed on to a similarly affected child. Each mutation cosegregated with the syndromic phenotype in other affected family members. <a href="#15" class="mim-tip-reference" title="Gallione, C. J., Repetto, G. M., Legius, E., Rustgi, A. K., Schelley, S. L., Tejpar, S., Mitchell, G., Drouin, E., Westermann, C. J. J., Marchuk, D. A. <strong>A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).</strong> Lancet 363: 852-859, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15031030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15031030</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)15732-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15031030">Gallione et al. (2004)</a> concluded that patients with juvenile polyposis who had a SMAD4 mutation should be screened for the vascular lesions associated with hereditary hemorrhagic telangiectasia, especially occult arteriovenous malformations in visceral organs that may otherwise present suddenly with serious medical consequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15031030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Gallione, C. J., Richards, J. A., Letteboer, T. G. W., Rushlow, D., Prigoda, N. L., Leedom, T. P., Ganguly, A., Castells, A., Ploos van Amstel, J. K., Westermann, C. J. J., Pyeritz, R. E., Marchuk, D. A. <strong>SMAD4 mutations found in unselected HHT patients.</strong> J. Med. Genet. 43: 793-797, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16613914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16613914</a>] [<a href="https://doi.org/10.1136/jmg.2006.041517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16613914">Gallione et al. (2006)</a> screened the SMAD4 gene in 30 unrelated patients diagnosed with HHT who were negative for mutations in the ENG and ALK1 genes, and identified 3 who had mutations in SMAD4 (see <a href="#0008">600993.0008</a> and <a href="#0013">600993.0013</a>, respectively). None of the patients had a prior diagnosis of juvenile polyposis, but all 3 mutation-positive patients had colonic polyps, and 1 of the 3 had colorectal cancer. <a href="#16" class="mim-tip-reference" title="Gallione, C. J., Richards, J. A., Letteboer, T. G. W., Rushlow, D., Prigoda, N. L., Leedom, T. P., Ganguly, A., Castells, A., Ploos van Amstel, J. K., Westermann, C. J. J., Pyeritz, R. E., Marchuk, D. A. <strong>SMAD4 mutations found in unselected HHT patients.</strong> J. Med. Genet. 43: 793-797, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16613914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16613914</a>] [<a href="https://doi.org/10.1136/jmg.2006.041517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16613914">Gallione et al. (2006)</a> proposed that the SMAD4 gene should routinely be screened in HHT patients in whom mutations in neither ENG nor ALK1 are identified, and that HHT patients with SMAD4 mutations should be screened for colonic and gastric polyps. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16613914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Gallione, C., Aylsworth, A. S., Beis, J., Berk, T., Bernhardt, B., Clark, R. D., Clericuzio, C., Danesino, C., Drautz, J., Fahl, J., Fan, Z., Faughnan, M. E., and 19 others. <strong>Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome.</strong> Am. J. Med. Genet. 152A: 333-339, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20101697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20101697</a>] [<a href="https://doi.org/10.1002/ajmg.a.33206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20101697">Gallione et al. (2010)</a> identified heterozygous mutations in the SMAD4 gene in 15 of 19 patients with JP/HHT. Thirteen patients had mutations affecting the MH2 domain of the protein, but 2 others had mutations in the linker and MH1 domains, respectively. At least 1 mutation (R361C; <a href="/entry/600933#0008">600933.0008</a>) had also been found in patients with isolated JPS. Combined with a review of the literature, the findings indicated that there are no clear genotype/phenotype correlations when comparing JP/HHT to JPS alone. In addition, the mechanism for both disorders is consistent with a loss of function of SMAD4. <a href="#14" class="mim-tip-reference" title="Gallione, C., Aylsworth, A. S., Beis, J., Berk, T., Bernhardt, B., Clark, R. D., Clericuzio, C., Danesino, C., Drautz, J., Fahl, J., Fan, Z., Faughnan, M. E., and 19 others. <strong>Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome.</strong> Am. J. Med. Genet. 152A: 333-339, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20101697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20101697</a>] [<a href="https://doi.org/10.1002/ajmg.a.33206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20101697">Gallione et al. (2010)</a> emphasized that any JPS patient with a SMAD4 mutation is at risk for the visceral manifestations of HHT, and any HHT patient with SMAD4 mutation is at risk for early-onset gastrointestinal cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20101697" 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>Myhre Syndrome</em></strong></p><p>
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In each of 11 unrelated patients with Myhre syndrome (MYHRS; <a href="/entry/139210">139210</a>) tested, <a href="#29" class="mim-tip-reference" title="Le Goff, C., Mahaut, C., Abhyankar, A., Le Goff, W., Serre, V., Afenjar, A., Destree, A., di Rocco, M., Heron, D., Jacquemont, S., Marlin, S., Simon, M., Tolmie, J., Verloes, A., Casanova, J.-L., Munnich, A., Cormier-Daire, V. <strong>Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.</strong> Nature Genet. 44: 85-88, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22158539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22158539</a>] [<a href="https://doi.org/10.1038/ng.1016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22158539">Le Goff et al. (2012)</a> identified a heterozygous de novo mutation involving the same codon, ile500, of the SMAD4 gene (I500T, <a href="#0015">600993.0015</a>; I500V, <a href="#0016">600993.0016</a>; and I500M, <a href="#0017">600993.0017</a>). The mutations were identified by exome sequencing of 2 index patients and candidate gene analysis of SMAD4 because of its role in TFGB and BMP signaling. Fibroblast studies from 2 patients showed a defect in SMAD4 ubiquitination, resulting in stabilization of the mutant protein, as well as altered expression of downstream TGFB and BMP target genes associated with increased phosphorylation of multiple SMAD partners. Myhre syndrome is a developmental disorder characterized by pre- and postnatal short stature, brachydactyly, facial dysmorphism, thick skin, muscle hypertrophy, deafness, and developmental delay. The findings of <a href="#29" class="mim-tip-reference" title="Le Goff, C., Mahaut, C., Abhyankar, A., Le Goff, W., Serre, V., Afenjar, A., Destree, A., di Rocco, M., Heron, D., Jacquemont, S., Marlin, S., Simon, M., Tolmie, J., Verloes, A., Casanova, J.-L., Munnich, A., Cormier-Daire, V. <strong>Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.</strong> Nature Genet. 44: 85-88, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22158539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22158539</a>] [<a href="https://doi.org/10.1038/ng.1016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22158539">Le Goff et al. (2012)</a> indicated that defective transcriptional regulation during development plays a significant role in the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22158539" 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>Simultaneously and independently, <a href="#7" class="mim-tip-reference" title="Caputo, V., Cianetti, L., Niceta, M., Carta, C., Ciolfi, A., Bocchinfuso, G., Carrani, E., Dentici, M. L., Biamino, E., Belligni, E., Garavelli, L., Boccone, L., Melis, D., Andria, G., Gelb, B. D., Stella, L., Silengo, M., Dallapiccola, B., Tartaglia, M. <strong>A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome.</strong> Am. J. Hum. Genet. 90: 161-169, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22243968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22243968</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22243968[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.12.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22243968">Caputo et al. (2012)</a> identified 2 different heterozygous de novo mutations affecting residue ile500 in the SMAD4 gene in 8 unrelated patients with Myhre syndrome (I500T, <a href="#0015">600993.0015</a> and I500V, <a href="#0016">600993.0016</a>). <a href="#7" class="mim-tip-reference" title="Caputo, V., Cianetti, L., Niceta, M., Carta, C., Ciolfi, A., Bocchinfuso, G., Carrani, E., Dentici, M. L., Biamino, E., Belligni, E., Garavelli, L., Boccone, L., Melis, D., Andria, G., Gelb, B. D., Stella, L., Silengo, M., Dallapiccola, B., Tartaglia, M. <strong>A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome.</strong> Am. J. Hum. Genet. 90: 161-169, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22243968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22243968</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22243968[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.12.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22243968">Caputo et al. (2012)</a> specifically examined genes involved in the TGFB signaling network to identify SMAD4 as the causative gene, because the disorder GPHYSD (see <a href="/entry/231050">231050</a>) shows overlapping features. Both mutations occurred in the MH2 domain, which is necessary for SMAD oligomerization and TGFB/BMP signal transduction. Based on the role of SMAD4 in developmental processes, dysregulation of SMAD4 function was expected to have pleiotropic effects, as seen in Myhre syndrome. Affected individuals studied by <a href="#7" class="mim-tip-reference" title="Caputo, V., Cianetti, L., Niceta, M., Carta, C., Ciolfi, A., Bocchinfuso, G., Carrani, E., Dentici, M. L., Biamino, E., Belligni, E., Garavelli, L., Boccone, L., Melis, D., Andria, G., Gelb, B. D., Stella, L., Silengo, M., Dallapiccola, B., Tartaglia, M. <strong>A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome.</strong> Am. J. Hum. Genet. 90: 161-169, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22243968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22243968</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22243968[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.12.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22243968">Caputo et al. (2012)</a> presented with a homogeneous phenotype including short stature, a recognizable facial appearance, generalized muscular hypertrophy, hearing loss, short hands, distinctive skeletal anomalies, and joint stiffness. All subjects presented with low birth weight, but 5 became obese with age. Delayed psychomotor and/or language development and variable intellectual disability was documented in all but 1 individual. There was also a wide spectrum of congenital heart defects. None of the patients had any gross vascular anomaly or skin, pancreatic, or gastrointestinal malignancies. <a href="#7" class="mim-tip-reference" title="Caputo, V., Cianetti, L., Niceta, M., Carta, C., Ciolfi, A., Bocchinfuso, G., Carrani, E., Dentici, M. L., Biamino, E., Belligni, E., Garavelli, L., Boccone, L., Melis, D., Andria, G., Gelb, B. D., Stella, L., Silengo, M., Dallapiccola, B., Tartaglia, M. <strong>A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome.</strong> Am. J. Hum. Genet. 90: 161-169, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22243968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22243968</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22243968[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.12.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22243968">Caputo et al. (2012)</a> noted that the restrictive pattern of SMAD4 mutations suggested genetic homogeneity of Myhre syndrome, which was reflected in the clinically homogeneous presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22243968" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 female patients with laryngotracheal stenosis, arthropathy, prognathism, and short stature, originally described by <a href="#32" class="mim-tip-reference" title="Lindor, N. M., Kasperbauer, J. L., Hoffman, A. D., Parisi, J. E., Wang, H., Warman, M. <strong>Confirmation of existence of a new syndrome: LAPS syndrome.</strong> Am. J. Med. Genet. 109: 93-99, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11977156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11977156</a>] [<a href="https://doi.org/10.1002/ajmg.10316" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11977156">Lindor et al. (2002)</a> and believed to represent a distinct syndrome, <a href="#31" class="mim-tip-reference" title="Lindor, N. M., Gunawardena, S. R., Thibodeau, S. N. <strong>Mutations of SMAD4 account for both LAPS and Myhre syndromes.</strong> Am. J. Med. Genet. 158A: 1520-1521, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22585601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22585601</a>] [<a href="https://doi.org/10.1002/ajmg.a.35374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22585601">Lindor et al. (2012)</a> noted similarities to the Myhre syndrome phenotype and analyzed the SMAD4 gene. Both women were heterozygous for previously identified missense mutations in patients with Myhre syndrome (I500T, <a href="#0015">600993.0015</a>; I500V, <a href="#0016">600993.0016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22585601+11977156" 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="#30" class="mim-tip-reference" title="Lin, A. E., Scimone, E. R., Thom, R. P., Balaguru, D., Kinane, T. B., Moschovis, P. P., Cohen, M. S., Tan, W., Hague, C. D., Dannheim, K., Levitsky, L. L., Lilly, E., and 28 others. <strong>Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).</strong> Am. J. Med. Genet. 194: e63638, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38779990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38779990</a>] [<a href="https://doi.org/10.1002/ajmg.a.63638" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38779990">Lin et al. (2024)</a> reported the SMAD4 mutations identified in 47 patients with Myhre syndrome (including 4 who had previously been reported) from their clinic: 23 (49%) had an ile500-to-val (I500V) substitution (<a href="#0016">600993.0016</a>), 18 (38%) had an arg496-to-cys (R496C) substitution (<a href="#0018">600993.0018</a>), 5 (11%) had an ile500-to-thr substitution (<a href="#0015">600993.0015</a>), and 1 (2%) had an ile500-to-leu (I500L) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38779990" 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 16 trios in which a proband with Myhre syndrome had unaffected parents, <a href="#47" class="mim-tip-reference" title="Wood, K. A., Tong, R. S., Motta, M., Cordeddu, V., Scimone, E. R., Bush, S. J., Maxwell, D. W., Giannoulatou, E., Caputo, V., Traversa, A., Mancini, C., Ferrero, G. B., and 12 others. <strong>SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.</strong> Am. J. Hum. Genet. 111: 1953-1969, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39116879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39116879</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39116879[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2024.07.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39116879">Wood et al. (2024)</a> found that the SMAD4 mutation arose on the paternally derived allele. On average, these fathers were 6.3 years older than an age-matched population average, which suggested a paternal age effect for fathers of patients with Myhre syndrome. Deep sequencing analysis of sperm from men of different ages demonstrated that mutations affecting the Ile500 residue of SMAD4, including c.1498A-G (I500V), c.1499T-C (I500T), c.1498A-T (I500L), and c.1498A-C (I500L), were present in the sperm population. These mutations were not present in the donors' blood and were positively correlated with donor age. <a href="#47" class="mim-tip-reference" title="Wood, K. A., Tong, R. S., Motta, M., Cordeddu, V., Scimone, E. R., Bush, S. J., Maxwell, D. W., Giannoulatou, E., Caputo, V., Traversa, A., Mancini, C., Ferrero, G. B., and 12 others. <strong>SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.</strong> Am. J. Hum. Genet. 111: 1953-1969, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39116879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39116879</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39116879[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2024.07.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39116879">Wood et al. (2024)</a> concluded that this was consistent with clonal selection for the mutations, as opposed to hypermutability. Dual luciferase assays with SMAD4 with the I500V, I500T, and I500L mutations demonstrated that each mutation increased luciferase activity, and protein stability assays demonstrated that SMAD4 with each mutation had increased stability compared to wildtype. SMAD4 with the I500V and I500T mutations were expressed in HEK293 cells and resulted in increased ERK phosphorylation, indicating a gain-of-function mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39116879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Somatic Mutations in Cancer</em></strong></p><p>
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<a href="#46" class="mim-tip-reference" title="Thiagalingam, S., Lengauer, C., Leach, F. S., Schutte, M., Hahn, S. A., Overhauser, J., Willson, J. K. V., Markowitz, S., Hamilton, S. R., Kern, S. E., Kinzler, K. W., Vogelstein, B. <strong>Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers.</strong> Nature Genet. 13: 343-346, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673134</a>] [<a href="https://doi.org/10.1038/ng0796-343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673134">Thiagalingam et al. (1996)</a> evaluated sporadic colon cancer tumors for allelic deletions. They defined a minimally lost region (MLR) on chromosome 18q21 which extended between markers D18S535 and D18S858. It encompassed 16 cM between D18S535 and 20CO3 and included 2 candidate tumor suppressor genes: DPC4 and DCC. DPC4 was deleted in up to one-third of cases and DCC or a neighboring gene was deleted in the remaining tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8673134" 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="Kim, S. K., Fan, Y., Papadimitrakopoulou, V., Clayman, G., Hittelman, W. N., Hong, W. K., Lotan, R., Mao, L. <strong>DPC4, a candidate tumor suppressor gene, is altered infrequently in head and neck squamous cell carcinoma.</strong> Cancer Res. 56: 2519-2521, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8653689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8653689</a>]" pmid="8653689">Kim et al. (1996)</a> concluded that DPC4 is altered only infrequently in head and neck squamous cell carcinomas (HNSCCs), but may play some role in the tumorigenesis of a small set of HNSCC, because a nonsense gln526-to-ter mutation (Q526X) was found in the primary tumor and a lymph node metastasis from 1 of 11 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8653689" 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="#40" class="mim-tip-reference" title="Schutte, M., Hruban, R. H., Hedrick, L., Cho, K. R., Nadasdy, G. M., Weinstein, C. L., Bova, G. S., Isaacs, W. B., Cairns, P., Nawroz, H., Sidransky, D., Casero, R. A., Jr., Meltzer, P. S., Hahn, S. A., Kern, S. E. <strong>DPC4 gene in various tumor types.</strong> Cancer Res. 56: 2527-2530, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8653691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8653691</a>]" pmid="8653691">Schutte et al. (1996)</a> analyzed 338 tumors, originating from 12 distinct anatomic sites, for alterations in the DPC4 gene. DPC4 sequence alterations were sought in 64 specimens selected for the presence of allelic loss of 18q. An alteration of the DPC4 gene sequence was identified in 1 of 8 breast carcinomas and 1 of 8 ovarian carcinomas. These results indicated to them that whereas DPC4 inactivation is prevalent in pancreatic carcinoma (48%), it is distinctly uncommon (less than 10%) in other tumor types. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8653691" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using cDNA, <a href="#38" 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 (<a href="/entry/603109">603109</a>), 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>The Mad (for 'mothers against decapentaplegic') gene in Drosophila and the related Sma genes in C. elegans are implicated in signal transduction by members of the IGF-beta family in these organisms and also in vertebrates. <a href="#10" class="mim-tip-reference" title="Derynck, R., Gelbart, W. M., Harland, R. M., Heldin, C.-H., Kern, S. E., Massague, J., Melton, D. A., Mlodzik, M., Padgett, R. W., Roberts, A. B., Smith, J., Thomsen, G. H., Vogelstein, B., Wang, X.-F. <strong>Nomenclature: vertebrate mediators of TGF-beta family signals. (Letter)</strong> Cell 87: 173 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8861901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8861901</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81335-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8861901">Derynck et al. (1996)</a> proposed a revised nomenclature for the Mad-related products in vertebrates. Their proposed root symbol was SMAD, a merger of Sma and Mad, which serves to differentiate these proteins from unrelated gene products previously called Mad (see <a href="/entry/600021">600021</a>). DPC4 was to be designated SMAD4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8861901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#45" class="mim-tip-reference" title="Takaku, K., Oshima, M., Miyoshi, H., Matsui, M., Seldin, M. F., Taketo, M. M. <strong>Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes.</strong> Cell 92: 645-656, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9506519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9506519</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81132-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9506519">Takaku et al. (1998)</a> inactivated the mouse Dpc4 (Smad4) homolog. The homozygous mutants were embryonic lethal, whereas the heterozygotes showed no abnormality. The investigators then introduced the Dpc4 mutation into the knockout mice for the mouse homolog of the human APC (<a href="/entry/611731">611731</a>) gene, Apc-delta716, a model for human familial adenomatous polyposis. Because both Apc and Dpc4 are located on mouse chromosome 18, they constructed compound heterozygotes carrying both mutations on the same chromosome by meiotic recombination. In such mice, intestinal polyps developed into more malignant tumors than those in the simple Apc-delta716 heterozygotes, showing an extensive stromal cell proliferation, submucosal invasion, cell type heterogeneity, and in vivo transplantability. <a href="#45" class="mim-tip-reference" title="Takaku, K., Oshima, M., Miyoshi, H., Matsui, M., Seldin, M. F., Taketo, M. M. <strong>Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes.</strong> Cell 92: 645-656, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9506519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9506519</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81132-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9506519">Takaku et al. (1998)</a> suggested that mutations in DPC4 play a significant role in the malignant progression of colorectal tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9506519" 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="#43" class="mim-tip-reference" title="Sirard, C., de la Pompa, J. L., Elia, A., Itie, A., Mirtsos, C., Cheung, A., Hahn, S., Wakeham, A., Schwartz, L., Kern, S. E., Rossant, J., Mak, T. W. <strong>The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo.</strong> Genes Dev. 12: 107-119, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9420335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9420335</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9420335[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/10.1101/gad.12.1.107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9420335">Sirard et al. (1998)</a> demonstrated that homozygous Smad4 mutant mice died before embryonic day 7.5. Mutant embryos have reduced size, fail to gastrulate or express a mesodermal marker, and show abnormal visceral endoderm development. Growth retardation of the Smad4-deficient embryos results from reduced cell proliferation rather than increased apoptosis. Aggregation of mutant Smad4 embryonic stem cells with wildtype tetraploid morulae rescued the gastrulation defect. The results of <a href="#43" class="mim-tip-reference" title="Sirard, C., de la Pompa, J. L., Elia, A., Itie, A., Mirtsos, C., Cheung, A., Hahn, S., Wakeham, A., Schwartz, L., Kern, S. E., Rossant, J., Mak, T. W. <strong>The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo.</strong> Genes Dev. 12: 107-119, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9420335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9420335</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9420335[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/10.1101/gad.12.1.107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9420335">Sirard et al. (1998)</a> indicated that Smad4 is initially required for the differentiation of the visceral endoderm and that the gastrulation defect in the epiblast is secondary and non-cell autonomous. Rescued embryos showed severe anterior truncations, indicating a second important role for Smad4 in anterior patterning during embryogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9420335" 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="Bardeesy, N., Cheng, K., Berger, J. H., Chu, G. C., Pahler, J., Olson, P., Hezel, A. F., Horner, J., Lauwers, G. Y., Hanahan, D., DePinto, R. A. <strong>Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer.</strong> Genes Dev. 20: 3130-3146, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17114584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17114584</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17114584[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/10.1101/gad.1478706" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17114584">Bardeesy et al. (2006)</a> found that Smad4 deletion in mouse pancreatic epithelium had no impact on pancreatic development or physiology. However, when combined with an activated Kras (<a href="/entry/190070">190070</a>) allele, Smad4 deficiency enabled rapid progression to activated Kras-initiated neoplasm. Smad4 deficiency also altered the tumor phenotypes of mice with combined Kras activation and Ink4a/Arf (<a href="/entry/600160">600160</a>) deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17114584" 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 colon cancer, 38% of sporadic cases show loss of SMAD4 protein (<a href="#36" class="mim-tip-reference" title="Parsons, R., Myeroff, L. L., Liu, B., Willson, J. K. V., Markowitz, S. D., Kinzler, K. W., Vogelstein, B. <strong>Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer.</strong> Cancer Res. 55: 5548-5550, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7585632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7585632</a>]" pmid="7585632">Parsons et al., 1995</a>). To investigate the role of impaired TGF-beta family signaling in colon cancer progression, <a href="#45" class="mim-tip-reference" title="Takaku, K., Oshima, M., Miyoshi, H., Matsui, M., Seldin, M. F., Taketo, M. M. <strong>Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes.</strong> Cell 92: 645-656, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9506519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9506519</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81132-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9506519">Takaku et al. (1998)</a> constructed a compound mutant mouse strain that carries a knockout allele of Smad4 on the same chromatid as that of Apc. In the compound mutant, loss of Smad4-dependent TGF-beta family signaling caused intestinal adenomas to develop into adenocarcinomas, although Smad4-independent signaling remained unaffected. <a href="#28" class="mim-tip-reference" title="Kitamura, T., Kometani, K., Hashida, H., Matsunaga, A., Miyoshi, H., Hosogi, H., Aoki, M., Oshima, M., Hattori, M., Takabayashi, A., Minato, N., Taketo, M. M. <strong>SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion.</strong> Nature Genet. 39: 467-475, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17369830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17369830</a>] [<a href="https://doi.org/10.1038/ng1997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17369830">Kitamura et al. (2007)</a> showed that a new type of immature myeloid cell is recruited from the bone marrow to the tumor invasion front. These Cd34+ immature myeloid cells express the matrix metalloproteinases Mmp9 (<a href="/entry/120361">120361</a>) and Mmp2 (<a href="/entry/120360">120360</a>) and CC-chemokinin receptor-1 (CCR1; <a href="/entry/601159">601159</a>) and migrate toward the Ccr1 ligand Ccl9. In adenocarcinomas, expression of Ccl9 is increased in the tumor epithelium. By deleting Ccr1 in the background of the doubly mutant cis-Apc/Smad4, <a href="#28" class="mim-tip-reference" title="Kitamura, T., Kometani, K., Hashida, H., Matsunaga, A., Miyoshi, H., Hosogi, H., Aoki, M., Oshima, M., Hattori, M., Takabayashi, A., Minato, N., Taketo, M. M. <strong>SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion.</strong> Nature Genet. 39: 467-475, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17369830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17369830</a>] [<a href="https://doi.org/10.1038/ng1997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17369830">Kitamura et al. (2007)</a> showed that lack of Ccr1 prevents accumulation of Cd34+ immature myeloid cells at the tumor invasion front and suppresses tumor invasion. These results indicated that loss of TGF-beta family signaling in tumor epithelium causes accumulation of immature myeloid cells that promote tumor invasion. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9506519+7585632+17369830" 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 mice with skeletal muscle-specific knockout or knockdown of BMP signaling molecules, <a href="#39" class="mim-tip-reference" title="Sartori, R., Schirwis, E., Blaauw, B., Bortolanza, S., Zhao, J., Enzo, E., Stantzou, A., Mouisel, E., Toniolo, L., Ferry, A., Stricker, S., Goldberg, A. L., Dupont, S., Piccolo, S., Amthor, H., Sandri, M. <strong>BMP signaling controls muscle mass.</strong> Nature Genet. 45: 1309-1318, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24076600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24076600</a>] [<a href="https://doi.org/10.1038/ng.2772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24076600">Sartori et al. (2013)</a> found that BMP signaling, acting via Smad1 (<a href="/entry/601595">601595</a>), Smad5 (<a href="/entry/603110">603110</a>), and Smad8 (SMAD9; <a href="/entry/603295">603295</a>) (Smad1/5/8) and Smad4, regulated muscle mass. Inhibition of BMP signaling caused muscle atrophy, abolished the hypertrophic phenotype of myostatin (MSTN; <a href="/entry/601788">601788</a>)-deficient mice, and exacerbated the muscle-wasting effects of denervation and fasting. Bmp14 (GDF5; <a href="/entry/601146">601146</a>) was required to prevent excessive muscle loss following denervation. The BMP-Smad1/5/8-Smad4 pathway negatively regulated Fbxo30 (<a href="/entry/609101">609101</a>), a ubiquitin ligase required for muscle loss. Inhibition of Fbxo30 protected denervated muscle from atrophy and blunted atrophy in Smad4-deficient muscle. <a href="#39" class="mim-tip-reference" title="Sartori, R., Schirwis, E., Blaauw, B., Bortolanza, S., Zhao, J., Enzo, E., Stantzou, A., Mouisel, E., Toniolo, L., Ferry, A., Stricker, S., Goldberg, A. L., Dupont, S., Piccolo, S., Amthor, H., Sandri, M. <strong>BMP signaling controls muscle mass.</strong> Nature Genet. 45: 1309-1318, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24076600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24076600</a>] [<a href="https://doi.org/10.1038/ng.2772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24076600">Sartori et al. (2013)</a> concluded that BMP signaling is the dominant pathway controlling muscle mass and that the hypertrophic phenotype caused by myostatin inhibition results from unrestrained BMP signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24076600" 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="#51" class="mim-tip-reference" title="Zhang, P., Hou, S., Chen, J., Zhang, J., Lin, F., Ju, R., Cheng, X., Ma, X., Song, Y., Zhang, Y., Zhu, M., Du, J., Lan, Y., Yang, X. <strong>Smad4 deficiency in smooth muscle cells initiates the formation of aortic aneurysm.</strong> Circ. Res. 118: 388-399, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26699655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26699655</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.115.308040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26699655">Zhang et al. (2016)</a> found that mice with Smad4 deleted specifically in smooth muscle cells (SMCs) developed aortic aneurysm and died of dissection at 3 to 10 weeks of age. Smad4 mutant mice showed compromised TGF-beta superfamily signaling in aorta and upregulation of Ctss (<a href="/entry/116845">116845</a>) and Mmp12 (<a href="/entry/601046">601046</a>), proteases essential for elastin (ELN; <a href="/entry/130160">130160</a>) degradation. Deletion of Tgfbr2 (<a href="/entry/190182">190182</a>) in SMCs of mice led to aortic aneurysms similar to those observed in Smad4 mutant mice, accompanied by increased expression of Ctss and Mmp12. Immunohistochemical analysis revealed that macrophage infiltration contributed to progression of aortic aneurysms in Smad4 mutant mice, likely due to damage to elastic fibers by increased protease secretion. Microarray analysis showed excessive chemokine production and secretion, causing increased macrophage chemotaxis, in Smad4 mutants. Blocking chemokine signaling partially attenuated progression of aortic aneurysm in Smad4 mutant mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26699655" 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="#49" class="mim-tip-reference" title="Yan, J., Li, J., Hu, J., Zhang, L., Wei, C., Sultana, N., Cai, X., Zhang, W., Cai, C.-L. <strong>Smad4 deficiency impairs chondrocyte hypertrophy via the Runx2 transcription factor in mouse skeletal development.</strong> J. Biol. Chem. 293: 9162-9175, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29735531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29735531</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29735531[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/10.1074/jbc.RA118.001825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29735531">Yan et al. (2018)</a> found that mice with Smad4 conditional knockout (CKO) in chondrocytes died shortly after birth with impaired skeletal development. Quantitative RT-PCR of younger stage mouse embryos showed that Smad4 was essential for chondrocyte differentiation and that loss of Smad4 caused chondrodysplasia in limb development. Humerus of Smad4-CKO mice lacked chondrocyte hypertrophy, as primary chondrocytes failed to undergo hypertrophic differentiation during limb formation. Moreover, the proliferation rate of chondrocyte cells in humerus was decreased. In situ hybridization analysis revealed that Runx2 (<a href="/entry/600211">600211</a>) expression was dramatically downregulated in Smad4-deficient humerus, and chromatin immunoprecipitation-sequencing analysis demonstrated that Smad4 bound directly to Runx2 regulatory elements to control chondrocyte hypertrophy during mouse limb development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29735531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600993[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p><a href="#40" class="mim-tip-reference" title="Schutte, M., Hruban, R. H., Hedrick, L., Cho, K. R., Nadasdy, G. M., Weinstein, C. L., Bova, G. S., Isaacs, W. B., Cairns, P., Nawroz, H., Sidransky, D., Casero, R. A., Jr., Meltzer, P. S., Hahn, S. A., Kern, S. E. <strong>DPC4 gene in various tumor types.</strong> Cancer Res. 56: 2527-2530, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8653691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8653691</a>]" pmid="8653691">Schutte et al. (1996)</a> analyzed 11 DPC4 exons for 27 pancreatic tumors that did not have a homozygous deletion of the gene. Six mutations were identified. One of these was a GGA-to-TGA transversion in codon 358 changing gly to stop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8653691" 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 pancreatic cancer (<a href="/entry/260350">260350</a>) tumor DNA, <a href="#40" class="mim-tip-reference" title="Schutte, M., Hruban, R. H., Hedrick, L., Cho, K. R., Nadasdy, G. M., Weinstein, C. L., Bova, G. S., Isaacs, W. B., Cairns, P., Nawroz, H., Sidransky, D., Casero, R. A., Jr., Meltzer, P. S., Hahn, S. A., Kern, S. E. <strong>DPC4 gene in various tumor types.</strong> Cancer Res. 56: 2527-2530, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8653691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8653691</a>]" pmid="8653691">Schutte et al. (1996)</a> detected a somatic mutation, a transversion of codon 493 from GAT to CAT, resulting in substitution of his for asp. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8653691" 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">rs121912579 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912579;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=rs121912579" 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=rs121912579" 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=RCV000009065" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009065" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009065</a>
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<p>In pancreatic cancer (<a href="/entry/260350">260350</a>) tumor DNA, <a href="#40" class="mim-tip-reference" title="Schutte, M., Hruban, R. H., Hedrick, L., Cho, K. R., Nadasdy, G. M., Weinstein, C. L., Bova, G. S., Isaacs, W. B., Cairns, P., Nawroz, H., Sidransky, D., Casero, R. A., Jr., Meltzer, P. S., Hahn, S. A., Kern, S. E. <strong>DPC4 gene in various tumor types.</strong> Cancer Res. 56: 2527-2530, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8653691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8653691</a>]" pmid="8653691">Schutte et al. (1996)</a> detected a change of codon 515 from AGA to TGA, resulting in change of arg to stop. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8653691" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 JUVENILE POLYPOSIS SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338965 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338965;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=rs80338965" 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=rs80338965" 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=RCV000131266 OR RCV000205495 OR RCV000254690 OR RCV000768095 OR RCV001357425 OR RCV001376606 OR RCV002311019 OR RCV003227672 OR RCV003485541 OR RCV004745209" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000131266, RCV000205495, RCV000254690, RCV000768095, RCV001357425, RCV001376606, RCV002311019, RCV003227672, RCV003485541, RCV004745209" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000131266...</a>
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<p>In 3 unrelated cases of familial juvenile polyposis (JPS; <a href="/entry/174900">174900</a>), <a href="#21" class="mim-tip-reference" title="Howe, J. R., Roth, S., Ringold, J. C., Summers, R. W., Jarvinen, H. J., Sistonen, P., Tomlinson, I. P. M., Houlston, R. S., Bevan, S., Mitros, F. A., Stone, E. M., Aaltonen, L. A. <strong>Mutations in the SMAD4/DPC4 gene in juvenile polyposis.</strong> Science 280: 1086-1088, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9582123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9582123</a>] [<a href="https://doi.org/10.1126/science.280.5366.1086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9582123">Howe et al. (1998)</a> identified a 4-bp deletion involving codons 414 to 416 in exon 9 of the MADH4 gene and resulting in a frameshift with a premature stop at codon 434. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9582123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Friedl, W., Kruse, R., Uhlhaas, S., Stolte, M., Schartmann, B., Keller, K. M., Jungck, M., Stern, M., Loff, S., Back, W., Propping, P., Jenne, D. E. <strong>Frequent 4-bp deletion in exon 9 of the SMAD4/MADH4 gene in familial juvenile polyposis patients.</strong> Genes Chromosomes Cancer 25: 403-406, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10398437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10398437</a>]" pmid="10398437">Friedl et al. (1999)</a> examined 11 unrelated patients with juvenile polyposis for MADH4 germline mutations by direct sequencing of genomic DNA encompassing all 11 exons of the gene. They observed a 4-bp deletion of nucleotides 1372-1375, ACAG, in exon 9 in 2 unrelated patients. Examination with microsatellite markers flanking MADH4 supported an independent origin of the mutation in these 2 families. Combined with previous data (<a href="#21" class="mim-tip-reference" title="Howe, J. R., Roth, S., Ringold, J. C., Summers, R. W., Jarvinen, H. J., Sistonen, P., Tomlinson, I. P. M., Houlston, R. S., Bevan, S., Mitros, F. A., Stone, E. M., Aaltonen, L. A. <strong>Mutations in the SMAD4/DPC4 gene in juvenile polyposis.</strong> Science 280: 1086-1088, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9582123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9582123</a>] [<a href="https://doi.org/10.1126/science.280.5366.1086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9582123">Howe et al., 1998</a>), the results of <a href="#12" class="mim-tip-reference" title="Friedl, W., Kruse, R., Uhlhaas, S., Stolte, M., Schartmann, B., Keller, K. M., Jungck, M., Stern, M., Loff, S., Back, W., Propping, P., Jenne, D. E. <strong>Frequent 4-bp deletion in exon 9 of the SMAD4/MADH4 gene in familial juvenile polyposis patients.</strong> Genes Chromosomes Cancer 25: 403-406, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10398437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10398437</a>]" pmid="10398437">Friedl et al. (1999)</a> indicated that the 4-bp deletion accounts for about one-fourth of all juvenile polyposis cases and that other MADH4 mutations occur in an additional 15% of patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9582123+10398437" 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="Howe, J. R., Shellnut, J., Wagner, B., Ringold, J. C., Sayed, M. G., Ahmed, A. F., Lynch, P. M., Amos, C. I., Sistonen, P., Aaltonen, L. A. <strong>Common deletion of SMAD4 in juvenile polyposis is a mutational hotspot.</strong> Am. J. Hum. Genet. 70: 1357-1362, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11920286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11920286</a>] [<a href="https://doi.org/10.1086/340258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11920286">Howe et al. (2002)</a> did a haplotype analysis on 4 families with juvenile polyposis that had been described as having the same SMAD4 deletion (1244-1247delAGAC). The families came from Iowa, Mississippi, Texas, and Finland. No common haplotype was observed in these families. A 14-bp region containing the deletion had 4 direct repeats and 1 inverted repeat. Because no common ancestor was suggested by haplotype analysis and the sequence flanking the deletion contains repeats frequently associated with microdeletions, this common SMAD4 deletion most probably represents a mutation hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11920286" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 JUVENILE POLYPOSIS SYNDROME</strong>
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SMAD4, 2-BP DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs377767344 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs377767344;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=rs377767344" 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=rs377767344" 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=RCV001797982" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001797982" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001797982</a>
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<p>In a sporadic case of juvenile polyposis (JPS; <a href="/entry/174900">174900</a>), <a href="#21" class="mim-tip-reference" title="Howe, J. R., Roth, S., Ringold, J. C., Summers, R. W., Jarvinen, H. J., Sistonen, P., Tomlinson, I. P. M., Houlston, R. S., Bevan, S., Mitros, F. A., Stone, E. M., Aaltonen, L. A. <strong>Mutations in the SMAD4/DPC4 gene in juvenile polyposis.</strong> Science 280: 1086-1088, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9582123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9582123</a>] [<a href="https://doi.org/10.1126/science.280.5366.1086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9582123">Howe et al. (1998)</a> identified a 2-bp deletion in codon 348 of exon 8, resulting in frameshift and a premature stop at codon 350. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9582123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 JUVENILE POLYPOSIS SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs377767334 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs377767334;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=rs377767334" 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=rs377767334" 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=RCV000009069 OR RCV000021692 OR RCV000214505 OR RCV001386505 OR RCV002054467 OR RCV002310633" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009069, RCV000021692, RCV000214505, RCV001386505, RCV002054467, RCV002310633" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009069...</a>
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<p>In a sporadic case of juvenile polyposis (JPS; <a href="/entry/174900">174900</a>), <a href="#21" class="mim-tip-reference" title="Howe, J. R., Roth, S., Ringold, J. C., Summers, R. W., Jarvinen, H. J., Sistonen, P., Tomlinson, I. P. M., Houlston, R. S., Bevan, S., Mitros, F. A., Stone, E. M., Aaltonen, L. A. <strong>Mutations in the SMAD4/DPC4 gene in juvenile polyposis.</strong> Science 280: 1086-1088, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9582123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9582123</a>] [<a href="https://doi.org/10.1126/science.280.5366.1086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9582123">Howe et al. (1998)</a> described a 1-bp insertion between nucleotides 815 and 820 of exon 5; this change added a guanine to a stretch of 6 sequential guanines in the wildtype sequence and created a frameshift and new stop at codon 235. The patient had been found to have 30 to 40 colonic juvenile polyps at age 6 years. Four sibs and both parents were unaffected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9582123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Japanese woman with gastric juvenile polyposis (see <a href="/entry/174900">174900</a>), <a href="#41" class="mim-tip-reference" title="Shikata, K., Kukita, Y., Matsumoto, T., Esaki, M., Yao, T., Mochizuki, Y., Hayashi, K., Iida, M. <strong>Gastric juvenile polyposis associated with germline SMAD4 mutation.</strong> Am. J. Med. Genet. 134A: 326-329, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15754356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15754356</a>] [<a href="https://doi.org/10.1002/ajmg.a.30482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15754356">Shikata et al. (2005)</a> identified a heterozygous 1-bp insertion in exon 5 of the SMAD4 gene that was previously reported by <a href="#21" class="mim-tip-reference" title="Howe, J. R., Roth, S., Ringold, J. C., Summers, R. W., Jarvinen, H. J., Sistonen, P., Tomlinson, I. P. M., Houlston, R. S., Bevan, S., Mitros, F. A., Stone, E. M., Aaltonen, L. A. <strong>Mutations in the SMAD4/DPC4 gene in juvenile polyposis.</strong> Science 280: 1086-1088, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9582123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9582123</a>] [<a href="https://doi.org/10.1126/science.280.5366.1086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9582123">Howe et al. (1998)</a>. In the patient of <a href="#41" class="mim-tip-reference" title="Shikata, K., Kukita, Y., Matsumoto, T., Esaki, M., Yao, T., Mochizuki, Y., Hayashi, K., Iida, M. <strong>Gastric juvenile polyposis associated with germline SMAD4 mutation.</strong> Am. J. Med. Genet. 134A: 326-329, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15754356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15754356</a>] [<a href="https://doi.org/10.1002/ajmg.a.30482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15754356">Shikata et al. (2005)</a>, the polyps were restricted to the stomach, and no polyps were detected in the intestine, a phenotype distinct from that seen by <a href="#21" class="mim-tip-reference" title="Howe, J. R., Roth, S., Ringold, J. C., Summers, R. W., Jarvinen, H. J., Sistonen, P., Tomlinson, I. P. M., Houlston, R. S., Bevan, S., Mitros, F. A., Stone, E. M., Aaltonen, L. A. <strong>Mutations in the SMAD4/DPC4 gene in juvenile polyposis.</strong> Science 280: 1086-1088, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9582123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9582123</a>] [<a href="https://doi.org/10.1126/science.280.5366.1086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9582123">Howe et al. (1998)</a>. Histologic examination of the stomach after gastrectomy revealed areas of epithelial atypia consistent with adenocarcinoma confined to the mucosa. The patient also had a pulmonary arteriovenous malformation, suggesting JPS/HHT (JPHT; <a href="/entry/175050">175050</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15754356+9582123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80338963 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338963;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80338963?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80338963" 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=rs80338963" 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=RCV000009071 OR RCV000009072 OR RCV000059732 OR RCV001376609 OR RCV002311508 OR RCV003924819" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009071, RCV000009072, RCV000059732, RCV001376609, RCV002311508, RCV003924819" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009071...</a>
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<p>In a patient with familial juvenile polyposis syndrome (JPS; <a href="/entry/174900">174900</a>), <a href="#19" class="mim-tip-reference" title="Houlston, R., Bevan, S., Williams, A., Young, J., Dunlop, M., Rozen, P., Eng, C., Markie, D., Woodford-Richens, K., Rodriguez-Bigas, M. A., Leggett, B., Neale, K., Phillips, R., Sheridan, E., Hodgson, S., Iwama, T., Eccles, D., Bodmer, W., Tomlinson, I. <strong>Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases.</strong> Hum. Molec. Genet. 7: 1907-1912, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9811934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9811934</a>] [<a href="https://doi.org/10.1093/hmg/7.12.1907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9811934">Houlston et al. (1998)</a> found a germline mutation of the MADH4 gene. Like the 3 germline mutations reported by <a href="#21" class="mim-tip-reference" title="Howe, J. R., Roth, S., Ringold, J. C., Summers, R. W., Jarvinen, H. J., Sistonen, P., Tomlinson, I. P. M., Houlston, R. S., Bevan, S., Mitros, F. A., Stone, E. M., Aaltonen, L. A. <strong>Mutations in the SMAD4/DPC4 gene in juvenile polyposis.</strong> Science 280: 1086-1088, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9582123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9582123</a>] [<a href="https://doi.org/10.1126/science.280.5366.1086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9582123">Howe et al. (1998)</a>, this variant occurred toward the C terminus of the DPC4 protein. However, whereas the 3 earlier mutations were small insertions or deletions, the mutation reported by <a href="#19" class="mim-tip-reference" title="Houlston, R., Bevan, S., Williams, A., Young, J., Dunlop, M., Rozen, P., Eng, C., Markie, D., Woodford-Richens, K., Rodriguez-Bigas, M. A., Leggett, B., Neale, K., Phillips, R., Sheridan, E., Hodgson, S., Iwama, T., Eccles, D., Bodmer, W., Tomlinson, I. <strong>Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases.</strong> Hum. Molec. Genet. 7: 1907-1912, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9811934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9811934</a>] [<a href="https://doi.org/10.1093/hmg/7.12.1907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9811934">Houlston et al. (1998)</a> was a missense change (arg361 to cys; R361C). Somatic missense mutations in DPC4 had previously been reported in colorectal cancers (<a href="#44" class="mim-tip-reference" title="Takagi, Y., Kohmura, H., Futamura, M., Kida, H., Tanemura, H., Shimokawa, K., Saji, S. <strong>Somatic alterations of the DPC4 gene in human colorectal cancers in vivo.</strong> Gastroenterology 111: 1369-1372, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898652</a>] [<a href="https://doi.org/10.1053/gast.1996.v111.pm8898652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898652">Takagi et al., 1996</a>; <a href="#34" class="mim-tip-reference" title="MacGrogan, D., Pegram, M., Slamon, D., Bookstein, R. <strong>Comparative mutational analysis of DPC4 (Smad4) in prostatic and colorectal carcinomas.</strong> Oncogene 15: 1111-1114, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9285566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9285566</a>] [<a href="https://doi.org/10.1038/sj.onc.1201232" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9285566">MacGrogan et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9285566+9811934+9582123+8898652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with hereditary hemorrhagic telangiectasia but no prior diagnosis of juvenile polyposis (JPHT; see <a href="/entry/175050">175050</a>), <a href="#16" class="mim-tip-reference" title="Gallione, C. J., Richards, J. A., Letteboer, T. G. W., Rushlow, D., Prigoda, N. L., Leedom, T. P., Ganguly, A., Castells, A., Ploos van Amstel, J. K., Westermann, C. J. J., Pyeritz, R. E., Marchuk, D. A. <strong>SMAD4 mutations found in unselected HHT patients.</strong> J. Med. Genet. 43: 793-797, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16613914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16613914</a>] [<a href="https://doi.org/10.1136/jmg.2006.041517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16613914">Gallione et al. (2006)</a> identified the R361C mutation in exon 8 of the SMAD4 gene. One patient had a history of colorectal cancer and was found to have 7 polyps in the ascending colon and 3 in the duodenum; the other was found to have colonic polyps. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16613914" 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">rs377767336 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs377767336;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=rs377767336" 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=rs377767336" 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=RCV001797981" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001797981" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001797981</a>
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<p>In a patient with familial juvenile polyposis syndrome (JPS; <a href="/entry/174900">174900</a>), <a href="#12" class="mim-tip-reference" title="Friedl, W., Kruse, R., Uhlhaas, S., Stolte, M., Schartmann, B., Keller, K. M., Jungck, M., Stern, M., Loff, S., Back, W., Propping, P., Jenne, D. E. <strong>Frequent 4-bp deletion in exon 9 of the SMAD4/MADH4 gene in familial juvenile polyposis patients.</strong> Genes Chromosomes Cancer 25: 403-406, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10398437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10398437</a>]" pmid="10398437">Friedl et al. (1999)</a> identified a 2-bp deletion (959_960delAC) in exon 6 of the MADH4 gene. In addition to colonic polyposis diagnosed at the age of 12 years, the patient developed a severe gastric polyposis at the age of 28 years. The mutation was also detected in her asymptomatic 5-year-old son. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10398437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121912580 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912580;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=rs121912580" 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=rs121912580" 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=RCV000009074" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009074" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009074</a>
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<p><a href="#6" class="mim-tip-reference" title="Burger, B., Uhlhaas, S., Mangold, E., Propping, P., Friedl, W., Jenne, D., Dockter, G., Back, W. <strong>Novel de novo mutation of MADH4/SMAD4 in a patient with juvenile polyposis. (Letter)</strong> Am. J. Med. Genet. 110: 289-291, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12116240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12116240</a>] [<a href="https://doi.org/10.1002/ajmg.10411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12116240">Burger et al. (2002)</a> described an 11-year-old girl with juvenile polyposis and a de novo mutation in the MADH4 gene. The patient had developed more than 70 juvenile colonic polyps which were removed from the cecum, ascending colon, and transverse colon. The patient also had pulmonary arteriovenous fistulae of the left lung, clubbing of fingers, skeletal anomalies of the thorax, and additional dental germs. Neither parent had polyposis. Direct genomic sequencing of all 11 exons of the MADH4 gene revealed a heterozygous base exchange (1157G-A) in exon 9. This change, replacing the triplet GGT (gly) by GAT (asp), was predicted to result in an amino acid exchange at codon 386. Neither parent carried the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12116240" 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="Gallione, C. J., Repetto, G. M., Legius, E., Rustgi, A. K., Schelley, S. L., Tejpar, S., Mitchell, G., Drouin, E., Westermann, C. J. J., Marchuk, D. A. <strong>A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).</strong> Lancet 363: 852-859, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15031030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15031030</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)15732-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15031030">Gallione et al. (2004)</a> demonstrated that the same mutation occurred de novo in the patient of <a href="#2" class="mim-tip-reference" title="Baert, A. L., Casteels-Van Daele, M., Broeckx, J., Wijndaele, L., Wilms, G., Eggermont, E. <strong>Generalized juvenile polyposis with pulmonary arteriovenous malformations and hypertrophic osteoarthropathy.</strong> Am. J. Roentgen. 141: 661-662, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6604412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6604412</a>] [<a href="https://doi.org/10.2214/ajr.141.4.661" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6604412">Baert et al. (1983)</a>. Juvenile polyps had been diagnosed in the colon. Arteriovenous malformations were found in the lung at the age of 15 years. <a href="#15" class="mim-tip-reference" title="Gallione, C. J., Repetto, G. M., Legius, E., Rustgi, A. K., Schelley, S. L., Tejpar, S., Mitchell, G., Drouin, E., Westermann, C. J. J., Marchuk, D. A. <strong>A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).</strong> Lancet 363: 852-859, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15031030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15031030</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)15732-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15031030">Gallione et al. (2004)</a> classified the patient of <a href="#6" class="mim-tip-reference" title="Burger, B., Uhlhaas, S., Mangold, E., Propping, P., Friedl, W., Jenne, D., Dockter, G., Back, W. <strong>Novel de novo mutation of MADH4/SMAD4 in a patient with juvenile polyposis. (Letter)</strong> Am. J. Med. Genet. 110: 289-291, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12116240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12116240</a>] [<a href="https://doi.org/10.1002/ajmg.10411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12116240">Burger et al. (2002)</a> as having juvenile polyposis with hereditary hemorrhagic telangiectasia (see JPHT, <a href="/entry/175050">175050</a>), noting the presence of an arteriovenous malformation in the lung and digital clubbing. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6604412+15031030+12116240" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a family in which members of 3 successive generations had the JP/HHT syndrome (JPHT; <a href="/entry/175050">175050</a>), <a href="#15" class="mim-tip-reference" title="Gallione, C. J., Repetto, G. M., Legius, E., Rustgi, A. K., Schelley, S. L., Tejpar, S., Mitchell, G., Drouin, E., Westermann, C. J. J., Marchuk, D. A. <strong>A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).</strong> Lancet 363: 852-859, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15031030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15031030</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)15732-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15031030">Gallione et al. (2004)</a> found a 1054G-A transition in the MADH4 gene predicted to result in a gly352-to-arg change (G352R). Juvenile polyps were present in the colon in 1 member of each of 3 successive generations with a diagnosis at 9 years, 5 years, and 3 years. Arteriovenous malformations were present in the lung and in the liver. Cerebral capillary telangiectases and pancytopenia occurred in the first generation, and an episode of intracranial bleeding in the second. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15031030" 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">rs377767385 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs377767385;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=rs377767385" 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=rs377767385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#15" class="mim-tip-reference" title="Gallione, C. J., Repetto, G. M., Legius, E., Rustgi, A. K., Schelley, S. L., Tejpar, S., Mitchell, G., Drouin, E., Westermann, C. J. J., Marchuk, D. A. <strong>A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).</strong> Lancet 363: 852-859, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15031030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15031030</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)15732-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15031030">Gallione et al. (2004)</a> described a parent and child with juvenile polyps of the cecum and colon, respectively, diagnosed at ages 41 and 8 years. Both also had telangiectases and epistaxis (JPHT; <a href="/entry/175050">175050</a>). The parent had arteriovenous malformations of the lung and liver together with cerebellar cavernous hemangioma diagnosed at the age of 32 years. The parent and child had deletion of MADH4 nucleotides 1612-25. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15031030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs377767379 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs377767379;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs377767379?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs377767379" 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=rs377767379" 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 hereditary hemorrhagic telangiectasia but no prior diagnosis of juvenile polyposis (see <a href="/entry/175050">175050</a>), <a href="#16" class="mim-tip-reference" title="Gallione, C. J., Richards, J. A., Letteboer, T. G. W., Rushlow, D., Prigoda, N. L., Leedom, T. P., Ganguly, A., Castells, A., Ploos van Amstel, J. K., Westermann, C. J. J., Pyeritz, R. E., Marchuk, D. A. <strong>SMAD4 mutations found in unselected HHT patients.</strong> J. Med. Genet. 43: 793-797, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16613914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16613914</a>] [<a href="https://doi.org/10.1136/jmg.2006.041517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16613914">Gallione et al. (2006)</a> identified a 2-bp deletion and 1-bp insertion (1596delCCinsT) in exon 11 of the SMAD4 gene. The patient was later found to have colonic polyps on endoscopy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16613914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs377767360 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs377767360;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs377767360?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs377767360" 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=rs377767360" 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=RCV000023059 OR RCV000493396 OR RCV001374448 OR RCV001376567 OR RCV002310634 OR RCV004668739" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023059, RCV000493396, RCV001374448, RCV001376567, RCV002310634, RCV004668739" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023059...</a>
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<p>In 3 affected members of a family with a clinical variant of JPHT (<a href="/entry/175050">175050</a>), <a href="#1" class="mim-tip-reference" title="Andrabi, S., Bekheirnia, M. R., Robbins-Furman, P., Lewis, R. A., Prior, T. W., Potocki, L. <strong>SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction.</strong> Am. J. Med. Genet. 155A: 1165-1169, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21465659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21465659</a>] [<a href="https://doi.org/10.1002/ajmg.a.33968" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21465659">Andrabi et al. (2011)</a> identified a heterozygous mutation in exon 10 of the SMAD4 gene, resulting in an arg445-to-ter (R445X) substitution. The clinical features in this family were unusual in that affected members had mitral valve prolapse, mitral valve regurgitation, and aortic dilatation in addition to gastrointestinal hamartomatous polyps; telangiectases were not reported. <a href="#1" class="mim-tip-reference" title="Andrabi, S., Bekheirnia, M. R., Robbins-Furman, P., Lewis, R. A., Prior, T. W., Potocki, L. <strong>SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction.</strong> Am. J. Med. Genet. 155A: 1165-1169, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21465659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21465659</a>] [<a href="https://doi.org/10.1002/ajmg.a.33968" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21465659">Andrabi et al. (2011)</a> noted the role of SMAD4 in the TGF-beta-1 signaling pathway, suggesting overlap with other connective tissue disorders such as Marfan syndrome (<a href="/entry/154700">154700</a>) and Loeys-Dietz syndrome (see, e.g., <a href="/entry/609192">609192</a>). The findings indicated that haploinsufficiency of SMAD4 may cause an aortopathy and mitral valve dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21465659" 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">rs281875321 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281875321;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=rs281875321" 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=rs281875321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 5 unrelated patients with sporadic occurrence of Myhre syndrome (MYHRS; <a href="/entry/139210">139210</a>), <a href="#29" class="mim-tip-reference" title="Le Goff, C., Mahaut, C., Abhyankar, A., Le Goff, W., Serre, V., Afenjar, A., Destree, A., di Rocco, M., Heron, D., Jacquemont, S., Marlin, S., Simon, M., Tolmie, J., Verloes, A., Casanova, J.-L., Munnich, A., Cormier-Daire, V. <strong>Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.</strong> Nature Genet. 44: 85-88, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22158539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22158539</a>] [<a href="https://doi.org/10.1038/ng.1016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22158539">Le Goff et al. (2012)</a> identified a de novo heterozygous 1499T-C transition in the SMAD4 gene, resulting in an ile500-to-thr (I500T) substitution in a highly conserved residue in the MH2 domain involved in transcriptional activation. The mutation was not found in 200 controls. The same residue was mutated in other patients with the disorder (I500V, <a href="#0016">600993.0016</a> and I500M, <a href="#0017">600993.0017</a>). Studies of fibroblasts from 2 patients with the I500T mutation showed enhanced levels of SMAD4 protein with lower levels of ubiquitinated SMAD4 fibroblasts compared to controls, suggesting stabilization of the mutant protein. Since SMAD4 has a pivotal role in TGF-beta and BMP signaling, <a href="#29" class="mim-tip-reference" title="Le Goff, C., Mahaut, C., Abhyankar, A., Le Goff, W., Serre, V., Afenjar, A., Destree, A., di Rocco, M., Heron, D., Jacquemont, S., Marlin, S., Simon, M., Tolmie, J., Verloes, A., Casanova, J.-L., Munnich, A., Cormier-Daire, V. <strong>Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.</strong> Nature Genet. 44: 85-88, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22158539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22158539</a>] [<a href="https://doi.org/10.1038/ng.1016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22158539">Le Goff et al. (2012)</a> analyzed the level of phosphorylation of other SMAD proteins. There was an 8-fold increase in phosphorylated SMAD2 (<a href="/entry/601366">601366</a>) and SMAD3 (<a href="/entry/603109">603109</a>), and an 11-fold increase in phosphorylated SMAD1 (<a href="/entry/601595">601595</a>), SMAD5 (<a href="/entry/603110">603110</a>), and SMAD8 (<a href="/entry/603295">603295</a>) in cell nuclei compared to controls. The mutant SMAD4-containing complexes were associated with decreased mRNA levels of downstream TGF-beta and variable effects on BMP targets. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22158539" 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="Caputo, V., Cianetti, L., Niceta, M., Carta, C., Ciolfi, A., Bocchinfuso, G., Carrani, E., Dentici, M. L., Biamino, E., Belligni, E., Garavelli, L., Boccone, L., Melis, D., Andria, G., Gelb, B. D., Stella, L., Silengo, M., Dallapiccola, B., Tartaglia, M. <strong>A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome.</strong> Am. J. Hum. Genet. 90: 161-169, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22243968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22243968</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22243968[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.12.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22243968">Caputo et al. (2012)</a> identified a heterozygous de novo I500T mutation in 3 unrelated patients with Myhre syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22243968" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a woman with laryngotracheal stenosis, arthropathy, prognathism, and short stature, originally described by <a href="#32" class="mim-tip-reference" title="Lindor, N. M., Kasperbauer, J. L., Hoffman, A. D., Parisi, J. E., Wang, H., Warman, M. <strong>Confirmation of existence of a new syndrome: LAPS syndrome.</strong> Am. J. Med. Genet. 109: 93-99, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11977156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11977156</a>] [<a href="https://doi.org/10.1002/ajmg.10316" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11977156">Lindor et al. (2002)</a>, <a href="#31" class="mim-tip-reference" title="Lindor, N. M., Gunawardena, S. R., Thibodeau, S. N. <strong>Mutations of SMAD4 account for both LAPS and Myhre syndromes.</strong> Am. J. Med. Genet. 158A: 1520-1521, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22585601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22585601</a>] [<a href="https://doi.org/10.1002/ajmg.a.35374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22585601">Lindor et al. (2012)</a> identified heterozygosity for the I500T mutation in the SMAD4 gene. The patient had chronically restrictive indices on echocardiography despite having undergone pericardiectomy, and required repeated procedures to address recurrent laryngotracheal stenoses. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22585601+11977156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs281875322 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281875322;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs281875322?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs281875322" 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=rs281875322" 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=RCV000023061 OR RCV000059733 OR RCV000635427 OR RCV000763031 OR RCV001249691 OR RCV001260808 OR RCV001375955 OR RCV001376590 OR RCV004558272 OR RCV004745165 OR RCV004820822" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023061, RCV000059733, RCV000635427, RCV000763031, RCV001249691, RCV001260808, RCV001375955, RCV001376590, RCV004558272, RCV004745165, RCV004820822" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023061...</a>
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<p>In 5 unrelated patients with sporadic occurrence of Myhre syndrome (MYHRS; <a href="/entry/139210">139210</a>), <a href="#29" class="mim-tip-reference" title="Le Goff, C., Mahaut, C., Abhyankar, A., Le Goff, W., Serre, V., Afenjar, A., Destree, A., di Rocco, M., Heron, D., Jacquemont, S., Marlin, S., Simon, M., Tolmie, J., Verloes, A., Casanova, J.-L., Munnich, A., Cormier-Daire, V. <strong>Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.</strong> Nature Genet. 44: 85-88, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22158539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22158539</a>] [<a href="https://doi.org/10.1038/ng.1016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22158539">Le Goff et al. (2012)</a> identified a de novo heterozygous 1498A-G transition in the SMAD4 gene, resulting in an ile500-to-val (I500V) substitution in a highly conserved residue in the MH2 domain involved in transcriptional activation. The mutation was not found in 200 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22158539" 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="Caputo, V., Cianetti, L., Niceta, M., Carta, C., Ciolfi, A., Bocchinfuso, G., Carrani, E., Dentici, M. L., Biamino, E., Belligni, E., Garavelli, L., Boccone, L., Melis, D., Andria, G., Gelb, B. D., Stella, L., Silengo, M., Dallapiccola, B., Tartaglia, M. <strong>A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome.</strong> Am. J. Hum. Genet. 90: 161-169, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22243968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22243968</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22243968[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.12.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22243968">Caputo et al. (2012)</a> identified a heterozygous de novo I500V mutation in 5 unrelated patients with Myhre syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22243968" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a woman with laryngotracheal stenosis, arthropathy, prognathism, and short stature, originally described by <a href="#32" class="mim-tip-reference" title="Lindor, N. M., Kasperbauer, J. L., Hoffman, A. D., Parisi, J. E., Wang, H., Warman, M. <strong>Confirmation of existence of a new syndrome: LAPS syndrome.</strong> Am. J. Med. Genet. 109: 93-99, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11977156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11977156</a>] [<a href="https://doi.org/10.1002/ajmg.10316" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11977156">Lindor et al. (2002)</a>, <a href="#31" class="mim-tip-reference" title="Lindor, N. M., Gunawardena, S. R., Thibodeau, S. N. <strong>Mutations of SMAD4 account for both LAPS and Myhre syndromes.</strong> Am. J. Med. Genet. 158A: 1520-1521, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22585601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22585601</a>] [<a href="https://doi.org/10.1002/ajmg.a.35374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22585601">Lindor et al. (2012)</a> identified heterozygosity for the I500V mutation in the SMAD4 gene. The patient developed a restrictive pericardium requiring pericardiectomy, required repeated procedures to address recurrent laryngotracheal stenoses, and died at 40 years of age due to progressive respiratory failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22585601+11977156" 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">rs281875320 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281875320;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=rs281875320" 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=rs281875320" 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=RCV000023062 OR RCV000059735 OR RCV005089303" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023062, RCV000059735, RCV005089303" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023062...</a>
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<p>In a patient with sporadic occurrence of Myhre syndrome (MYHRS; <a href="/entry/139210">139210</a>), <a href="#29" class="mim-tip-reference" title="Le Goff, C., Mahaut, C., Abhyankar, A., Le Goff, W., Serre, V., Afenjar, A., Destree, A., di Rocco, M., Heron, D., Jacquemont, S., Marlin, S., Simon, M., Tolmie, J., Verloes, A., Casanova, J.-L., Munnich, A., Cormier-Daire, V. <strong>Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.</strong> Nature Genet. 44: 85-88, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22158539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22158539</a>] [<a href="https://doi.org/10.1038/ng.1016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22158539">Le Goff et al. (2012)</a> identified a de novo heterozygous 1500A-G transition in the SMAD4 gene, resulting in an ile500-to-met (I500M) substitution in a highly conserved residue in the MH2 domain involved in transcriptional activation. The mutation was not found in 200 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22158539" 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>Among 47 patients with Myhre syndrome (MYHRS; <a href="/entry/139210">139210</a>), including 4 previously reported, seen at their clinic, <a href="#30" class="mim-tip-reference" title="Lin, A. E., Scimone, E. R., Thom, R. P., Balaguru, D., Kinane, T. B., Moschovis, P. P., Cohen, M. S., Tan, W., Hague, C. D., Dannheim, K., Levitsky, L. L., Lilly, E., and 28 others. <strong>Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).</strong> Am. J. Med. Genet. 194: e63638, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38779990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38779990</a>] [<a href="https://doi.org/10.1002/ajmg.a.63638" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38779990">Lin et al. (2024)</a> found that 18 (38%) had a c.1486C-T transition in the SMAD4 gene, resulting in an arg496-to-cys (R496C) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38779990" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1038/ncb753" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17114584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17114584</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17114584[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=17114584" 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/10.1101/gad.1478706" target="_blank">Full Text</a>]
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Bornstein, S., White, R., Malkoski, S., Oka, M., Han, G., Cleaver, T., Reh, D., Andersen, P., Gross, N., Olson, S., Deng, C., Lu, S.-L., Wang, X.-J.
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[<a href="https://doi.org/10.1172/JCI38854" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.10411" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22243968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22243968</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22243968[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=22243968" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2011.12.011" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(02)00801-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature07086" target="_blank">Full Text</a>]
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Derynck, R., Gelbart, W. M., Harland, R. M., Heldin, C.-H., Kern, S. E., Massague, J., Melton, D. A., Mlodzik, M., Padgett, R. W., Roberts, A. B., Smith, J., Thomsen, G. H., Vogelstein, B., Wang, X.-F.
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[<a href="https://doi.org/10.1016/s0092-8674(00)81335-5" target="_blank">Full Text</a>]
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Ding, Z., Wu, C.-J., Chu, G. C., Xiao, Y., Ho, D., Zhang, J., Perry, S. R., Labrot, E. S., Wu, X., Lis, R., Hoshida, Y., Hiller, D., and 16 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21289624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21289624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21289624[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=21289624" 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/nature09677" target="_blank">Full Text</a>]
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<a id="Friedl1999" class="mim-anchor"></a>
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Friedl, W., Kruse, R., Uhlhaas, S., Stolte, M., Schartmann, B., Keller, K. M., Jungck, M., Stern, M., Loff, S., Back, W., Propping, P., Jenne, D. E.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10398437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10398437</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10398437" 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="Friedl2002" class="mim-anchor"></a>
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<div class="">
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Friedl, W., Uhlhaas, S., Schulmann, K., Stolte, M., Loff, S., Back, W., Mangold, E., Stern, M., Knaebel, H. P., Sutter, C., Weber, R. G., Pistorius, S., Burger, B., Propping, P.
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<strong>Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12136244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12136244</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12136244" 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/10.1007/s00439-002-0748-9" target="_blank">Full Text</a>]
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Gallione, C., Aylsworth, A. S., Beis, J., Berk, T., Bernhardt, B., Clark, R. D., Clericuzio, C., Danesino, C., Drautz, J., Fahl, J., Fan, Z., Faughnan, M. E., and 19 others.
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<strong>Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20101697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20101697</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20101697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.</strong>
|
|
Am. J. Hum. Genet. 111: 1953-1969, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39116879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39116879</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39116879[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=39116879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2024.07.006" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="48" class="mim-anchor"></a>
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<a id="Wu2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, J.-W., Krawitz, A. R., Chai, J., Li, W., Zhang, F., Luo, K., Shi, Y.
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|
<strong>Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: insights on Ski-mediated repression of TFG-beta signaling.</strong>
|
|
Cell 111: 357-367, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12419246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12419246</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12419246" 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(02)01006-1" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="49" class="mim-anchor"></a>
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<a id="Yan2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yan, J., Li, J., Hu, J., Zhang, L., Wei, C., Sultana, N., Cai, X., Zhang, W., Cai, C.-L.
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<strong>Smad4 deficiency impairs chondrocyte hypertrophy via the Runx2 transcription factor in mouse skeletal development.</strong>
|
|
J. Biol. Chem. 293: 9162-9175, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29735531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29735531</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29735531[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=29735531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.RA118.001825" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="50" class="mim-anchor"></a>
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<a id="Zawel1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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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>
|
|
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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</p>
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</div>
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</li>
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<li>
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<a id="51" class="mim-anchor"></a>
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<a id="Zhang2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, P., Hou, S., Chen, J., Zhang, J., Lin, F., Ju, R., Cheng, X., Ma, X., Song, Y., Zhang, Y., Zhu, M., Du, J., Lan, Y., Yang, X.
|
|
<strong>Smad4 deficiency in smooth muscle cells initiates the formation of aortic aneurysm.</strong>
|
|
Circ. Res. 118: 388-399, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26699655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26699655</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26699655" 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/10.1161/CIRCRESAHA.115.308040" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="52" class="mim-anchor"></a>
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<a id="Zhang2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, S., Takaku, M., Zou, L., Gu, A., Chou, W., Zhang, G., Wu, B., Kong, Q., Thomas, S. Y., Serody, J. S., Chen, X., Xu, X., Wade, P. A., Cook, D. N., Ting, J. P. Y., Wan, Y. Y.
|
|
<strong>Reversing SKI-SMAD4-mediated suppression is essential for T(H)17 cell differentiation.</strong>
|
|
Nature 551: 105-109, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29072299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29072299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29072299[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=29072299" 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/nature24283" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="53" class="mim-anchor"></a>
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<a id="Zhou1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhou, S., Buckhaults, P., Zawel, L., Bunz, F., Riggins, G., Le Dai, J., Kern, S. E., Kinzler, K. W., Vogelstein, B.
|
|
<strong>Targeted deletion of Smad4 shows it is required for transforming growth factor beta and activin signaling in colorectal cancer cells.</strong>
|
|
Proc. Nat. Acad. Sci. 95: 2412-2416, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9482899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9482899</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9482899[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=9482899" 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/10.1073/pnas.95.5.2412" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<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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Hilary J. Vernon - updated : 10/30/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 09/24/2024<br>Bao Lige - updated : 10/03/2019<br>Bao Lige - updated : 07/09/2019<br>Bao Lige - updated : 06/28/2019<br>Ada Hamosh - updated : 02/05/2018<br>Patricia A. Hartz - updated : 12/18/2013<br>Ada Hamosh - updated : 5/20/2013<br>Marla J. F. O'Neill - updated : 7/26/2012<br>Cassandra L. Kniffin - updated : 1/30/2012<br>Cassandra L. Kniffin - updated : 9/21/2011<br>Cassandra L. Kniffin - updated : 6/30/2011<br>Ada Hamosh - updated : 3/25/2011<br>Patricia A. Hartz - updated : 12/28/2010<br>Matthew B. Gross - updated : 4/12/2010<br>Ada Hamosh - updated : 9/11/2008<br>Victor A. McKusick - updated : 6/8/2007<br>Marla J. F. O'Neill - updated : 1/12/2007<br>Patricia A. Hartz - updated : 1/5/2007<br>Cassandra L. Kniffin - updated : 10/2/2006<br>Ada Hamosh - updated : 8/1/2006<br>Marla J. F. O'Neill - updated : 8/27/2004<br>Matthew B. Gross - updated : 6/11/2004<br>Victor A. McKusick - updated : 5/4/2004<br>Stylianos E. Antonarakis - updated : 11/26/2002<br>Stylianos E. Antonarakis - updated : 9/11/2002<br>Victor A. McKusick - updated : 9/10/2002<br>Victor A. McKusick - updated : 7/2/2002<br>Patricia A. Hartz - updated : 6/5/2002<br>Victor A. McKusick - updated : 5/20/2002<br>Michael J. Wright - updated : 1/8/2001<br>Victor A. McKusick - updated : 9/30/1999<br>Stylianos E. Antonarakis - updated : 1/31/1999<br>Victor A. McKusick - updated : 11/9/1998<br>Stylianos E. Antonarakis - updated : 5/29/1998<br>Victor A. McKusick - updated : 5/13/1998<br>Victor A. McKusick - updated : 1/27/1998<br>Moyra Smith - updated : 7/4/1996
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<div 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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Alan F. Scott : 1/18/1996
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 10/30/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 10/30/2024<br>carol : 09/24/2024<br>carol : 01/09/2020<br>mgross : 10/03/2019<br>mgross : 07/10/2019<br>mgross : 07/09/2019<br>mgross : 06/28/2019<br>alopez : 02/05/2018<br>carol : 12/06/2017<br>carol : 11/20/2017<br>carol : 11/20/2017<br>carol : 06/24/2016<br>mgross : 12/18/2013<br>mcolton : 12/13/2013<br>alopez : 5/20/2013<br>terry : 7/27/2012<br>carol : 7/27/2012<br>terry : 7/26/2012<br>carol : 1/30/2012<br>ckniffin : 1/30/2012<br>terry : 1/25/2012<br>carol : 9/22/2011<br>ckniffin : 9/21/2011<br>wwang : 7/14/2011<br>ckniffin : 6/30/2011<br>carol : 6/17/2011<br>terry : 4/26/2011<br>alopez : 3/28/2011<br>terry : 3/25/2011<br>mgross : 1/10/2011<br>terry : 12/28/2010<br>wwang : 4/28/2010<br>mgross : 4/12/2010<br>ckniffin : 3/23/2009<br>alopez : 9/11/2008<br>ckniffin : 2/5/2008<br>carol : 7/2/2007<br>alopez : 6/13/2007<br>terry : 6/8/2007<br>wwang : 3/30/2007<br>carol : 1/18/2007<br>terry : 1/12/2007<br>mgross : 1/5/2007<br>carol : 12/22/2006<br>wwang : 10/9/2006<br>ckniffin : 10/2/2006<br>alopez : 8/3/2006<br>terry : 8/1/2006<br>terry : 8/3/2005<br>carol : 4/28/2005<br>mgross : 4/14/2005<br>mgross : 4/13/2005<br>tkritzer : 10/1/2004<br>carol : 8/27/2004<br>terry : 8/27/2004<br>mgross : 6/11/2004<br>alopez : 5/6/2004<br>alopez : 5/6/2004<br>alopez : 5/6/2004<br>terry : 5/4/2004<br>ckniffin : 3/23/2004<br>ckniffin : 3/11/2003<br>mgross : 11/26/2002<br>mgross : 9/11/2002<br>alopez : 9/10/2002<br>mgross : 7/26/2002<br>cwells : 7/15/2002<br>terry : 7/2/2002<br>carol : 6/5/2002<br>carol : 6/5/2002<br>alopez : 5/24/2002<br>terry : 5/20/2002<br>alopez : 1/8/2001<br>alopez : 10/5/1999<br>terry : 9/30/1999<br>carol : 2/2/1999<br>carol : 1/31/1999<br>carol : 11/13/1998<br>terry : 11/9/1998<br>carol : 10/20/1998<br>carol : 10/13/1998<br>terry : 10/8/1998<br>dkim : 9/30/1998<br>dkim : 9/30/1998<br>alopez : 9/1/1998<br>carol : 5/30/1998<br>terry : 5/29/1998<br>alopez : 5/15/1998<br>alopez : 5/14/1998<br>alopez : 5/14/1998<br>terry : 5/13/1998<br>carol : 4/7/1998<br>terry : 3/28/1998<br>mark : 1/28/1998<br>terry : 1/27/1998<br>mark : 12/20/1996<br>mark : 12/20/1996<br>mark : 12/20/1996<br>terry : 12/9/1996<br>mark : 8/27/1996<br>marlene : 8/15/1996<br>mark : 7/4/1996<br>terry : 4/17/1996<br>mark : 2/5/1996<br>terry : 2/1/1996<br>mark : 1/18/1996
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600993
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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SMAD FAMILY MEMBER 4; SMAD4
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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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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MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 4; MADH4<br />
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SMA- AND MAD-RELATED PROTEIN 4<br />
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DELETED IN PANCREATIC CARCINOMA 4; DPC4
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</span>
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</h4>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SMAD4</em></strong>
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</span>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1149069001, 699316006, 9273005;
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<strong>
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<em>
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Cytogenetic location: 18q21.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 18:51,030,213-51,085,042 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="4">
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<span class="mim-font">
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18q21.2
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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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Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
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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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175050
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Myhre syndrome
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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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139210
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Pancreatic cancer, somatic
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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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260350
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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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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Polyposis, juvenile intestinal
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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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174900
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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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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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The SMAD4 gene encodes a protein involved in signal transduction of the transforming growth factor-beta (see, e.g., TGFB1, 190180) superfamily and bone morphogenic proteins (see, e.g., BMP1, 112264) by mediating transcriptional activation of target genes. SMAD4 is the common SMAD protein required for most transcriptional responses to TGFB and BMP signaling (summary by Shioda et al., 1998 and Davis et al., 2008). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>About 90% of human pancreatic carcinomas show allelic loss at 18q. Hahn et al. (1996) reported the identification of a putative tumor suppressor gene on chromosome 18q21.1 that may be a candidate for pancreatic carcinoma. The gene was homozygously deleted in 25 of 84 tumors and mutations were identified as somatic mutations in 6 of 27 carcinomas that lacked deletions. The gene was localized by deletion analysis of xenograft DNA. Markers absent in these samples were used to screen the CEPH mega-YAC library. YACs spanning the minimal deletion region were subcloned as cosmids for sequencing and recovery of cDNAs. A 2,680-bp cDNA was found and shown to code for a predicted 552-amino acid protein. The predicted protein shares blocks of as much as 85% similarity to the Drosophila Mad protein and the Caenorhabditis elegans sma-2,-3 and -4 proteins. In Drosophila, homozygous Mad mutants exhibit a variety of developmental defects. Hahn et al. (1996) designated the gene DPC4 (for homozygously deleted in pancreatic carcinoma, locus 4). This region of chromosome 18q also contains a gene (DCC; 120470) found to be deleted in colorectal cancers. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hahn et al. (1996) demonstrated that the SMAD4 gene contains 11 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hahn et al. (1996) identified the SMAD4 gene on chromosome 18q21.1. Howe et al. (1998) identified the SMAD4 gene within a region on 18q21.1 defined by linkage analysis in a kindred with juvenile polyposis syndrome (174900). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To test directly the hypothesis that the SMAD4 gene is a tumor suppressor that is critical for transmitting signals from transforming growth factor-beta (TGFB1; 190180) and related ligands, Zhou et al. (1998) deleted the SMAD4 gene through homologous recombination in human colorectal cancer cells. This deletion abrogated signaling from TGF-beta, as well as from the TGF-beta family member activin (147290). These results provided unequivocal evidence that mutational inactivation of SMAD4 causes TGF-beta unresponsiveness and gave a basis for understanding the physiologic role of this gene in tumorigenesis. </p><p>SMAD4 plays a pivotal role in signal transduction of the transforming growth factor beta superfamily cytokines by mediating transcriptional activation of target genes. Shioda et al. (1998) presented results demonstrating additional roles of SMAD heterooligomerization in SMAD4-mediated transcriptional activation. The results also suggested that the transcriptional-activating activity observed in the presence of SMAD4 in mammalian cells may be derived, at least in part, from endogenously expressed separate transcriptional activators, such as MSG1 (300149). </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>Bai et al. (2002) found that SMAD4 interacts directly with SMIF (607010). They found no interaction between other SMAD proteins and SMIF. By deletion analysis, they determined that tyr/phe301 and trp302 of SMAD4 and the N-terminal 100 amino acids of SMIF are required for this interaction. Cotransfection experiments demonstrated that treatment with TGF-beta or bone morphogenic protein-4 (BMP4; 112262) resulted in SMAD4/SMIF interaction, followed by their nuclear translocation and accumulation. With use of several transient reporter assays to monitor TGF-beta-dependent transcriptional activity, Bai et al. (2002) determined that the SMAD4/SMIF complex was the transcriptional unit, since neither protein alone was active. </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 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>He et al. (2006) found that TIF1-gamma (TRIM33; 605769) competed with SMAD4 for selective binding of receptor-phosphorylated SMAD2 and SMAD3 in human cells. TGF-beta induced formation of endogenous SMAD2/3-TIF1-gamma and SMAD2/3-SMAD4 complexes in human and other mammalian hematopoietic, mesenchymal, and epithelial cells. In human CD34-positive hematopoietic stem/progenitor cells, where TGF-beta inhibits proliferation and stimulates erythroid differentiation, TIF1-gamma mediated the differentiation response, whereas SMAD4 mediated the antiproliferative response, with SMAD2 and SMAD3 participating in both responses. He et al. (2006) concluded that SMAD2/3-TIF1-gamma and SMAD2/3-SMAD4 function as complementary effector arms in the control of hematopoietic cell fate by the TGF-beta/SMAD pathway. </p><p>Kim et al. (2006) showed that selective loss of Smad4-dependent signaling in T cells leads to spontaneous epithelial cancers throughout the gastrointestinal tract in mice, whereas epithelial-specific deletion of the Smad4 gene does not. Tumors arising within the colon, rectum, duodenum, stomach, and oral cavity are stroma-rich with dense plasma cell infiltrates. Smad4-null T cells produce abundant TH2-type cytokines including IL5 (147850), IL6 (147620), and IL13 (147683), known mediators of plasma cell and stromal expression. Kim et al. (2006) concluded that their results support the concept that cancer, as an outcome, reflects the loss of normal communication between the cellular constituents of a given organ, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbors. </p><p>Davis et al. (2008) found that SMAD4, the common SMAD required for most transcriptional responses to BMP and TGFB signaling, is not required for processing of miR21 (611020) by BMP4 (112262) in primary pulmonary artery smooth muscle cells (PASMCs). </p><p>Bornstein et al. (2009) found that expression of SMAD4 was downregulated in both malignant human head and neck squamous cell carcinomas (see 275355) and in grossly normal adjacent buccal mucosa. Deletion of Smad4 specifically in mouse head and neck epithelia resulted in spontaneous head and neck squamous cell carcinomas with evidence of increased genomic instability and inflammation. </p><p>Ding et al. (2011) exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten (601728)-null mouse prostate tumors and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonic pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFB/BMP-SMAD4 signaling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic, and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathologic and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumors identified cell proliferation and invasion as 2 cardinal tumor biologic features in the metastatic Smad4/Pten-null prostate cancer model. Follow-on pathologic and functional assessment confirmed cyclin D1 (168461) and SPP1 (166490) as key mediators of these biologic processes, which together with PTEN and SMAD4 form a 4-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human prostate cancer. Ding et al. (2011) concluded that this model-informed progression analysis, together with genetic, functional, and translational studies, established SMAD4 as a key regulator of prostate cancer progression in mice and humans. </p><p>Qin et al. (2013) demonstrated that COUP transcription factor-2, or COUP-TFII (NR2F2; 107773), a member of the nuclear receptor superfamily, serves as a key regulator to inhibit SMAD4-dependent transcription, and consequently overrides the TGF-beta-dependent checkpoint for PTEN-null indolent tumors. Overexpression of COUP-TFII in the mouse prostate epithelium cooperates with PTEN deletion to augment malignant progression and produce an aggressive metastasis-prone tumor. The functional counteraction between COUP-TFII and SMAD4 is reinforced by genetically engineered mouse models in which conditional loss of SMAD4 diminishes the inhibitory effects elicited by COUP-TFII ablation. The biologic significance of COUP-TFII in prostate carcinogenesis is substantiated by patient sample analysis, in which COUP-TFII expression or activity is tightly correlated with tumor recurrence and disease progression, whereas it is inversely associated with TGF-beta signaling. Qin et al. (2013) concluded that the destruction of the TGF-beta-dependent barrier by COUP-TFII is crucial for the progression of PTEN-mutant prostate cancer into a life-threatening disease. </p><p>Zhang et al. (2017) demonstrated that TGF-beta (190180) enables TH17 cell differentiation by reversing SKI (164780)-SMAD4-mediated suppression of the retinoic acid receptor (RAR)-related orphan receptor ROR-gamma-t (RORC; 602943). Zhang et al. (2017) found that, unlike wildtype T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGF-beta signaling in a RORC-dependent manner. Ectopic SMAD4 expression suppresses RORC expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGF-beta neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the RORC locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGF-beta stimulation. SKI controls histone acetylation and deacetylation of the RORC locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the RORC locus, RORC expression, and TH17 cell differentiation in a SMAD4-dependent manner. Therefore, Zhang et al. (2017) concluded that TGF-beta-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of ROR-gamma-t to enable TH17 cell differentiation. </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 (116899), 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>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Wu et al. (2002) determined the crystal structure of the SMAD4-binding domain of SKI (164780) in complex with the MH2 domain of SMAD4 at 2.85-angstrom resolution. The structure revealed specific recognition of the SMAD4 L3 loop region by a highly conserved interaction loop (I loop) from SKI. The SKI-binding surface on SMAD4 was found to significantly overlap with that required for binding of the receptor-mediated SMADs (R-SMADs). Indeed, SKI disrupted the formation of a functional complex between the comediator SMADs (Co-SMADs) and R-SMADs, explaining how it could lead to repression of TGF-beta, activin, and BMP responses. The structure of the SKI fragment, stabilized by a bound zinc atom, resembled the SAND domain found in transcription factors and other nuclear proteins, in which the corresponding I loop is responsible for DNA binding. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Juvenile Polyposis Syndrome</em></strong></p><p>
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In a large Iowa kindred with generalized juvenile polyposis and gastrointestinal cancer (JPS; 174900), Howe et al. (1998) mapped a gene predisposing to JPS to chromosome 18q21.1, between markers D18S1118 and D18S487. This interval contains 2 putative tumor suppressor genes, DCC and SMAD4. The high incidence of colorectal cancer (as well as 1 case of pancreatic cancer) in affected members of the Iowa juvenile polyposis kindred displaying 18q21 linkage led Howe et al. (1998) to propose that one of these tumor suppressor genes predisposes to JPS. After sequencing 14 DCC exons and all 11 SMAD4 exons, they detected a 4-basepair deletion in exon 9 of SMAD4. Eight additional unrelated JPS patients were subsequently analyzed for mutations of all exons of SMAD4 by SSCP and genomic sequencing. In 2 JPS kindreds, a similar 4-bp deletion in exon 9 was segregating (600993.0005). Because of the nature of the sequence in this region, these deletions can begin at any of 4 consecutive nucleotides and result in the same mutant sequence and new stop codon. The 3 kindreds segregating these deletions were all Caucasian and originated from Iowa, Mississippi, and Finland. There was no common ancestral haplotype, as assessed by analysis of microsatellite markers close to SMAD4. A patient with colonic and gastric JPS was found to have a 2-basepair deletion in exon 8 of SMAD4, at nucleotides 1170 to 1171 (codon 348) (600993.0006). This deletion caused a frameshift that created a stop codon at nucleotides 1178 to 1180 (codon 350). Another patient with 30 to 40 colonic juvenile polyps at age 6 but with no family history of JPS was found to have a 1-bp insertion between nucleotides 815 and 820 of exon 5 (600993.0007); this change added a guanine to a stretch of 6 sequential guanines in the wildtype sequence and created a frameshift and a new stop codon at nucleotides 830 to 832 (codon 235). No SMAD4 mutations were found in 4 other unrelated JPS patients. The mutant SMAD4 proteins were predicted to be truncated at the carboxy terminus and to lack sequences required for normal function. </p><p>Kinzler and Vogelstein (1998) referred to colorectal cancers developing on the basis of juvenile polyposis as 'landscaper defects.' This is following the designation 'gatekeeper defects' for the mutations in tumor suppressor genes that are known to prevent cancer through direct control of cell growth, including p53 (191170), RB1 (614041), VHL (608537), and APC (611731). Inactivation of these genes contributes directly to the neoplastic growth of the tumor; thus, they normally function as 'gatekeepers.' Kinzler and Vogelstein (1998) used the designation 'caretaker defects' for the susceptibility genes that indirectly suppress neoplasia (for example, XPB (133510), ATM (607585), MSH2 (609309), and MLH1 (120436)). A second class of indirectly acting cancer susceptibility genes was suggested by findings in juvenile polyposis, which carries an increased risk of colorectal cancer. The polyps in this situation are markedly different from the epithelium-rich adenomatous polyps that give rise to most cases of colorectal cancer. Polyps from JPS patients have a low potential to become malignant and are composed largely of stromal cells, comprising a mixture of mesenchymal and inflammatory elements in which epithelium is entrapped, often forming dilated cysts. The epithelial cells within and surrounding the polyp are initially devoid of neoplastic features but nonetheless are at increased risk of becoming malignant. Kinzler and Vogelstein (1998) proposed that the increased cancer susceptibility due to inherited mutations in juvenile polyposis is the product of an abnormal stromal environment. That an abnormal stroma can affect the development of adjacent epithelial cells is suggested by the experience with ulcerative colitis, which also leads to inflammation and cystic epithelium in the mucosa of the colon. Initially, the embedded epithelium shows no neoplastic changes, but foci of epithelial neoplasia and progression to cancer eventually develop in many cases. The regeneration that occurs to replace damaged epithelium may increase the probability of somatic mutations in this abnormal microenvironment. The increased risk of cancer in JPS and ulcerative colitis patients seems, therefore, primarily the result of an altered terrain for epithelial cell growth and thus can be thought of as a 'landscaper' defect. Kinzler and Vogelstein (1998) found it intriguing that the stromal cells, but not the epithelial cells, of most hamartomas from JPS patients contain a clonal genetic alteration. Similarly, clonal genetic changes have been demonstrated in the stroma, but not the epithelial cells, of endometrial polyps. In contrast, clonal genetic alterations have been demonstrated in epithelial cells, but not stromal cells, of polyps arising in patients with familial adenomatous polyposis (due to mutations in the APC gene) or Peutz-Jeghers syndrome (175200)--which are morphologically distinct from those of JPS patients. These results add to the emerging realization that solid tumors are not simply composed of neoplastic epithelial cells. Historically, the search for drugs that can modulate neoplasia has focused on such epithelial cells. Targeting specific stromal cells (such as those found in blood vessels) may be more valuable for therapeutic purposes. Kinzler and Vogelstein (1998) raised the question: 'Could drug targeting of the paracrine factors and other features of the stromal-epithelial interaction be similarly useful?' </p><p>Friedl et al. (2002) examined 29 patients with the clinical diagnosis of JPS for germline mutations in the MADH4 or BMPR1A (601299) genes and identified MADH4 mutations in 7 (24%) and BMPR1A mutations in 5 patients (17%). A remarkable prevalence of massive gastric polyposis was observed in patients with MADH4 mutations when compared with patients with BMPR1A mutations or without identified mutations. See, for example, 600993.0009. This was claimed to be the first genotype-phenotype correlation observed in JPS. </p><p>In 77 different familial and sporadic cases of juvenile polyposis, Howe et al. (2004) identified germline SMAD4 mutations in 14 cases (18.2%) and BMPR1A mutations in 16 cases (20.8%). The authors noted that because mutations were not found in more than half of the patients with juvenile polyposis, either additional predisposing genes remain to be discovered or alternative means of inactivation of the 2 known genes account for these cases. </p><p>Miyaki and Kuroki (2003) reviewed the role of SMAD4 inactivation in human cancer. </p><p><strong><em>Juvenile Polyposis/Hereditary Hemorrhagic Telangiectasia Syndrome</em></strong></p><p>
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Juvenile polyposis (174900) and hereditary hemorrhagic telangiectasia (187300) are autosomal dominant disorders with distinct nonoverlapping clinical features. The former, an inherited predisposition to gastrointestinal malignancy, is caused by mutations in SMAD4 or BMPR1A (601299), and the latter is a vascular malformation disorder caused by mutations in ENG (131195) or ALK1 (601284). All 4 genes encode proteins involved in the transforming growth factor-beta signaling pathway (see 190180). Although both of these disorders are uncommon, there are many reports of patients and families with both disorders or of patients with juvenile polyposis who show some symptoms of hereditary hemorrhagic telangiectasia; see JPHT, 175050. Gallione et al. (2004) studied DNA from 6 unrelated families segregating both phenotypes and from an individual patient. No patient had mutations in the ENG or ALK1 genes; all had SMAD4 mutations. Three cases of de novo SMAD4 mutations were found. In 1, the mutation was passed on to a similarly affected child. Each mutation cosegregated with the syndromic phenotype in other affected family members. Gallione et al. (2004) concluded that patients with juvenile polyposis who had a SMAD4 mutation should be screened for the vascular lesions associated with hereditary hemorrhagic telangiectasia, especially occult arteriovenous malformations in visceral organs that may otherwise present suddenly with serious medical consequences. </p><p>Gallione et al. (2006) screened the SMAD4 gene in 30 unrelated patients diagnosed with HHT who were negative for mutations in the ENG and ALK1 genes, and identified 3 who had mutations in SMAD4 (see 600993.0008 and 600993.0013, respectively). None of the patients had a prior diagnosis of juvenile polyposis, but all 3 mutation-positive patients had colonic polyps, and 1 of the 3 had colorectal cancer. Gallione et al. (2006) proposed that the SMAD4 gene should routinely be screened in HHT patients in whom mutations in neither ENG nor ALK1 are identified, and that HHT patients with SMAD4 mutations should be screened for colonic and gastric polyps. </p><p>Gallione et al. (2010) identified heterozygous mutations in the SMAD4 gene in 15 of 19 patients with JP/HHT. Thirteen patients had mutations affecting the MH2 domain of the protein, but 2 others had mutations in the linker and MH1 domains, respectively. At least 1 mutation (R361C; 600933.0008) had also been found in patients with isolated JPS. Combined with a review of the literature, the findings indicated that there are no clear genotype/phenotype correlations when comparing JP/HHT to JPS alone. In addition, the mechanism for both disorders is consistent with a loss of function of SMAD4. Gallione et al. (2010) emphasized that any JPS patient with a SMAD4 mutation is at risk for the visceral manifestations of HHT, and any HHT patient with SMAD4 mutation is at risk for early-onset gastrointestinal cancer. </p><p><strong><em>Myhre Syndrome</em></strong></p><p>
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In each of 11 unrelated patients with Myhre syndrome (MYHRS; 139210) tested, Le Goff et al. (2012) identified a heterozygous de novo mutation involving the same codon, ile500, of the SMAD4 gene (I500T, 600993.0015; I500V, 600993.0016; and I500M, 600993.0017). The mutations were identified by exome sequencing of 2 index patients and candidate gene analysis of SMAD4 because of its role in TFGB and BMP signaling. Fibroblast studies from 2 patients showed a defect in SMAD4 ubiquitination, resulting in stabilization of the mutant protein, as well as altered expression of downstream TGFB and BMP target genes associated with increased phosphorylation of multiple SMAD partners. Myhre syndrome is a developmental disorder characterized by pre- and postnatal short stature, brachydactyly, facial dysmorphism, thick skin, muscle hypertrophy, deafness, and developmental delay. The findings of Le Goff et al. (2012) indicated that defective transcriptional regulation during development plays a significant role in the disorder. </p><p>Simultaneously and independently, Caputo et al. (2012) identified 2 different heterozygous de novo mutations affecting residue ile500 in the SMAD4 gene in 8 unrelated patients with Myhre syndrome (I500T, 600993.0015 and I500V, 600993.0016). Caputo et al. (2012) specifically examined genes involved in the TGFB signaling network to identify SMAD4 as the causative gene, because the disorder GPHYSD (see 231050) shows overlapping features. Both mutations occurred in the MH2 domain, which is necessary for SMAD oligomerization and TGFB/BMP signal transduction. Based on the role of SMAD4 in developmental processes, dysregulation of SMAD4 function was expected to have pleiotropic effects, as seen in Myhre syndrome. Affected individuals studied by Caputo et al. (2012) presented with a homogeneous phenotype including short stature, a recognizable facial appearance, generalized muscular hypertrophy, hearing loss, short hands, distinctive skeletal anomalies, and joint stiffness. All subjects presented with low birth weight, but 5 became obese with age. Delayed psychomotor and/or language development and variable intellectual disability was documented in all but 1 individual. There was also a wide spectrum of congenital heart defects. None of the patients had any gross vascular anomaly or skin, pancreatic, or gastrointestinal malignancies. Caputo et al. (2012) noted that the restrictive pattern of SMAD4 mutations suggested genetic homogeneity of Myhre syndrome, which was reflected in the clinically homogeneous presentation. </p><p>In 2 female patients with laryngotracheal stenosis, arthropathy, prognathism, and short stature, originally described by Lindor et al. (2002) and believed to represent a distinct syndrome, Lindor et al. (2012) noted similarities to the Myhre syndrome phenotype and analyzed the SMAD4 gene. Both women were heterozygous for previously identified missense mutations in patients with Myhre syndrome (I500T, 600993.0015; I500V, 600993.0016). </p><p>Lin et al. (2024) reported the SMAD4 mutations identified in 47 patients with Myhre syndrome (including 4 who had previously been reported) from their clinic: 23 (49%) had an ile500-to-val (I500V) substitution (600993.0016), 18 (38%) had an arg496-to-cys (R496C) substitution (600993.0018), 5 (11%) had an ile500-to-thr substitution (600993.0015), and 1 (2%) had an ile500-to-leu (I500L) substitution. </p><p>In 16 trios in which a proband with Myhre syndrome had unaffected parents, Wood et al. (2024) found that the SMAD4 mutation arose on the paternally derived allele. On average, these fathers were 6.3 years older than an age-matched population average, which suggested a paternal age effect for fathers of patients with Myhre syndrome. Deep sequencing analysis of sperm from men of different ages demonstrated that mutations affecting the Ile500 residue of SMAD4, including c.1498A-G (I500V), c.1499T-C (I500T), c.1498A-T (I500L), and c.1498A-C (I500L), were present in the sperm population. These mutations were not present in the donors' blood and were positively correlated with donor age. Wood et al. (2024) concluded that this was consistent with clonal selection for the mutations, as opposed to hypermutability. Dual luciferase assays with SMAD4 with the I500V, I500T, and I500L mutations demonstrated that each mutation increased luciferase activity, and protein stability assays demonstrated that SMAD4 with each mutation had increased stability compared to wildtype. SMAD4 with the I500V and I500T mutations were expressed in HEK293 cells and resulted in increased ERK phosphorylation, indicating a gain-of-function mechanism. </p><p><strong><em>Somatic Mutations in Cancer</em></strong></p><p>
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Thiagalingam et al. (1996) evaluated sporadic colon cancer tumors for allelic deletions. They defined a minimally lost region (MLR) on chromosome 18q21 which extended between markers D18S535 and D18S858. It encompassed 16 cM between D18S535 and 20CO3 and included 2 candidate tumor suppressor genes: DPC4 and DCC. DPC4 was deleted in up to one-third of cases and DCC or a neighboring gene was deleted in the remaining tumors. </p><p>Kim et al. (1996) concluded that DPC4 is altered only infrequently in head and neck squamous cell carcinomas (HNSCCs), but may play some role in the tumorigenesis of a small set of HNSCC, because a nonsense gln526-to-ter mutation (Q526X) was found in the primary tumor and a lymph node metastasis from 1 of 11 patients. </p><p>Schutte et al. (1996) analyzed 338 tumors, originating from 12 distinct anatomic sites, for alterations in the DPC4 gene. DPC4 sequence alterations were sought in 64 specimens selected for the presence of allelic loss of 18q. An alteration of the DPC4 gene sequence was identified in 1 of 8 breast carcinomas and 1 of 8 ovarian carcinomas. These results indicated to them that whereas DPC4 inactivation is prevalent in pancreatic carcinoma (48%), it is distinctly uncommon (less than 10%) in other tumor types. </p><p>Using cDNA, Roth et al. (2000) conducted mutation analysis of the SMAD2, SMAD3 (603109), and SMAD4 genes in 14 Finnish kindreds with hereditary nonpolyposis colon cancer (see 120435). They found no mutations. </p>
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<h4>
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<span class="mim-font">
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<strong>Nomenclature</strong>
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</span>
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<span class="mim-text-font">
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<p>The Mad (for 'mothers against decapentaplegic') gene in Drosophila and the related Sma genes in C. elegans are implicated in signal transduction by members of the IGF-beta family in these organisms and also in vertebrates. Derynck et al. (1996) proposed a revised nomenclature for the Mad-related products in vertebrates. Their proposed root symbol was SMAD, a merger of Sma and Mad, which serves to differentiate these proteins from unrelated gene products previously called Mad (see 600021). DPC4 was to be designated SMAD4. </p>
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<strong>Animal Model</strong>
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<p>Takaku et al. (1998) inactivated the mouse Dpc4 (Smad4) homolog. The homozygous mutants were embryonic lethal, whereas the heterozygotes showed no abnormality. The investigators then introduced the Dpc4 mutation into the knockout mice for the mouse homolog of the human APC (611731) gene, Apc-delta716, a model for human familial adenomatous polyposis. Because both Apc and Dpc4 are located on mouse chromosome 18, they constructed compound heterozygotes carrying both mutations on the same chromosome by meiotic recombination. In such mice, intestinal polyps developed into more malignant tumors than those in the simple Apc-delta716 heterozygotes, showing an extensive stromal cell proliferation, submucosal invasion, cell type heterogeneity, and in vivo transplantability. Takaku et al. (1998) suggested that mutations in DPC4 play a significant role in the malignant progression of colorectal tumors. </p><p>Sirard et al. (1998) demonstrated that homozygous Smad4 mutant mice died before embryonic day 7.5. Mutant embryos have reduced size, fail to gastrulate or express a mesodermal marker, and show abnormal visceral endoderm development. Growth retardation of the Smad4-deficient embryos results from reduced cell proliferation rather than increased apoptosis. Aggregation of mutant Smad4 embryonic stem cells with wildtype tetraploid morulae rescued the gastrulation defect. The results of Sirard et al. (1998) indicated that Smad4 is initially required for the differentiation of the visceral endoderm and that the gastrulation defect in the epiblast is secondary and non-cell autonomous. Rescued embryos showed severe anterior truncations, indicating a second important role for Smad4 in anterior patterning during embryogenesis. </p><p>Bardeesy et al. (2006) found that Smad4 deletion in mouse pancreatic epithelium had no impact on pancreatic development or physiology. However, when combined with an activated Kras (190070) allele, Smad4 deficiency enabled rapid progression to activated Kras-initiated neoplasm. Smad4 deficiency also altered the tumor phenotypes of mice with combined Kras activation and Ink4a/Arf (600160) deletion. </p><p>In colon cancer, 38% of sporadic cases show loss of SMAD4 protein (Parsons et al., 1995). To investigate the role of impaired TGF-beta family signaling in colon cancer progression, Takaku et al. (1998) constructed a compound mutant mouse strain that carries a knockout allele of Smad4 on the same chromatid as that of Apc. In the compound mutant, loss of Smad4-dependent TGF-beta family signaling caused intestinal adenomas to develop into adenocarcinomas, although Smad4-independent signaling remained unaffected. Kitamura et al. (2007) showed that a new type of immature myeloid cell is recruited from the bone marrow to the tumor invasion front. These Cd34+ immature myeloid cells express the matrix metalloproteinases Mmp9 (120361) and Mmp2 (120360) and CC-chemokinin receptor-1 (CCR1; 601159) and migrate toward the Ccr1 ligand Ccl9. In adenocarcinomas, expression of Ccl9 is increased in the tumor epithelium. By deleting Ccr1 in the background of the doubly mutant cis-Apc/Smad4, Kitamura et al. (2007) showed that lack of Ccr1 prevents accumulation of Cd34+ immature myeloid cells at the tumor invasion front and suppresses tumor invasion. These results indicated that loss of TGF-beta family signaling in tumor epithelium causes accumulation of immature myeloid cells that promote tumor invasion. </p><p>Using mice with skeletal muscle-specific knockout or knockdown of BMP signaling molecules, Sartori et al. (2013) found that BMP signaling, acting via Smad1 (601595), Smad5 (603110), and Smad8 (SMAD9; 603295) (Smad1/5/8) and Smad4, regulated muscle mass. Inhibition of BMP signaling caused muscle atrophy, abolished the hypertrophic phenotype of myostatin (MSTN; 601788)-deficient mice, and exacerbated the muscle-wasting effects of denervation and fasting. Bmp14 (GDF5; 601146) was required to prevent excessive muscle loss following denervation. The BMP-Smad1/5/8-Smad4 pathway negatively regulated Fbxo30 (609101), a ubiquitin ligase required for muscle loss. Inhibition of Fbxo30 protected denervated muscle from atrophy and blunted atrophy in Smad4-deficient muscle. Sartori et al. (2013) concluded that BMP signaling is the dominant pathway controlling muscle mass and that the hypertrophic phenotype caused by myostatin inhibition results from unrestrained BMP signaling. </p><p>Zhang et al. (2016) found that mice with Smad4 deleted specifically in smooth muscle cells (SMCs) developed aortic aneurysm and died of dissection at 3 to 10 weeks of age. Smad4 mutant mice showed compromised TGF-beta superfamily signaling in aorta and upregulation of Ctss (116845) and Mmp12 (601046), proteases essential for elastin (ELN; 130160) degradation. Deletion of Tgfbr2 (190182) in SMCs of mice led to aortic aneurysms similar to those observed in Smad4 mutant mice, accompanied by increased expression of Ctss and Mmp12. Immunohistochemical analysis revealed that macrophage infiltration contributed to progression of aortic aneurysms in Smad4 mutant mice, likely due to damage to elastic fibers by increased protease secretion. Microarray analysis showed excessive chemokine production and secretion, causing increased macrophage chemotaxis, in Smad4 mutants. Blocking chemokine signaling partially attenuated progression of aortic aneurysm in Smad4 mutant mice. </p><p>Yan et al. (2018) found that mice with Smad4 conditional knockout (CKO) in chondrocytes died shortly after birth with impaired skeletal development. Quantitative RT-PCR of younger stage mouse embryos showed that Smad4 was essential for chondrocyte differentiation and that loss of Smad4 caused chondrodysplasia in limb development. Humerus of Smad4-CKO mice lacked chondrocyte hypertrophy, as primary chondrocytes failed to undergo hypertrophic differentiation during limb formation. Moreover, the proliferation rate of chondrocyte cells in humerus was decreased. In situ hybridization analysis revealed that Runx2 (600211) expression was dramatically downregulated in Smad4-deficient humerus, and chromatin immunoprecipitation-sequencing analysis demonstrated that Smad4 bound directly to Runx2 regulatory elements to control chondrocyte hypertrophy during mouse limb development. </p>
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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>18 Selected Examples):</strong>
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</span>
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</h4>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 PANCREATIC CARCINOMA, SOMATIC</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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SMAD4, GLY358TER
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<br />
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SNP: rs121912576,
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ClinVar: RCV000009062
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<span class="mim-text-font">
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<p>Schutte et al. (1996) analyzed 11 DPC4 exons for 27 pancreatic tumors that did not have a homozygous deletion of the gene. Six mutations were identified. One of these was a GGA-to-TGA transversion in codon 358 changing gly to stop. </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>.0002 PANCREATIC CARCINOMA, SOMATIC</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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SMAD4, TYR412TER
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<br />
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SNP: rs121912577,
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gnomAD: rs121912577,
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ClinVar: RCV000009063
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</span>
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<div>
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<span class="mim-text-font">
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<p>In tissue tumor derived from pancreatic cancer (260350), Schutte et al. (1996) identified a TAC-to-TAG transversion in codon 412 of the DPC4 gene, changing tyr to stop. </p>
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</span>
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<div>
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<br />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 PANCREATIC CARCINOMA, SOMATIC</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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SMAD4, ASP493HIS
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<br />
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SNP: rs121912578,
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ClinVar: RCV000009064
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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 pancreatic cancer (260350) tumor DNA, Schutte et al. (1996) detected a somatic mutation, a transversion of codon 493 from GAT to CAT, resulting in substitution of his for asp. </p>
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<br />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 PANCREATIC CARCINOMA, SOMATIC</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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SMAD4, ARG515TER
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<br />
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SNP: rs121912579,
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ClinVar: RCV000009065
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<span class="mim-text-font">
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<p>In pancreatic cancer (260350) tumor DNA, Schutte et al. (1996) detected a change of codon 515 from AGA to TGA, resulting in change of arg to stop. </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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<strong>.0005 JUVENILE POLYPOSIS SYNDROME</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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SMAD4, 4-BP DEL, NT1372
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<br />
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SNP: rs80338965,
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ClinVar: RCV000131266, RCV000205495, RCV000254690, RCV000768095, RCV001357425, RCV001376606, RCV002311019, RCV003227672, RCV003485541, RCV004745209
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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 unrelated cases of familial juvenile polyposis (JPS; 174900), Howe et al. (1998) identified a 4-bp deletion involving codons 414 to 416 in exon 9 of the MADH4 gene and resulting in a frameshift with a premature stop at codon 434. </p><p>Friedl et al. (1999) examined 11 unrelated patients with juvenile polyposis for MADH4 germline mutations by direct sequencing of genomic DNA encompassing all 11 exons of the gene. They observed a 4-bp deletion of nucleotides 1372-1375, ACAG, in exon 9 in 2 unrelated patients. Examination with microsatellite markers flanking MADH4 supported an independent origin of the mutation in these 2 families. Combined with previous data (Howe et al., 1998), the results of Friedl et al. (1999) indicated that the 4-bp deletion accounts for about one-fourth of all juvenile polyposis cases and that other MADH4 mutations occur in an additional 15% of patients. </p><p>Howe et al. (2002) did a haplotype analysis on 4 families with juvenile polyposis that had been described as having the same SMAD4 deletion (1244-1247delAGAC). The families came from Iowa, Mississippi, Texas, and Finland. No common haplotype was observed in these families. A 14-bp region containing the deletion had 4 direct repeats and 1 inverted repeat. Because no common ancestor was suggested by haplotype analysis and the sequence flanking the deletion contains repeats frequently associated with microdeletions, this common SMAD4 deletion most probably represents a mutation hotspot. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 JUVENILE POLYPOSIS SYNDROME</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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SMAD4, 2-BP DEL
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<br />
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SNP: rs377767344,
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ClinVar: RCV001797982
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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 sporadic case of juvenile polyposis (JPS; 174900), Howe et al. (1998) identified a 2-bp deletion in codon 348 of exon 8, resulting in frameshift and a premature stop at codon 350. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 JUVENILE POLYPOSIS SYNDROME</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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JUVENILE POLYPOSIS OF STOMACH, INCLUDED<br />
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JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME, INCLUDED
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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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SMAD4, 1-BP INS
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<br />
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SNP: rs377767334,
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ClinVar: RCV000009069, RCV000021692, RCV000214505, RCV001386505, RCV002054467, RCV002310633
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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 sporadic case of juvenile polyposis (JPS; 174900), Howe et al. (1998) described a 1-bp insertion between nucleotides 815 and 820 of exon 5; this change added a guanine to a stretch of 6 sequential guanines in the wildtype sequence and created a frameshift and new stop at codon 235. The patient had been found to have 30 to 40 colonic juvenile polyps at age 6 years. Four sibs and both parents were unaffected. </p><p>In a Japanese woman with gastric juvenile polyposis (see 174900), Shikata et al. (2005) identified a heterozygous 1-bp insertion in exon 5 of the SMAD4 gene that was previously reported by Howe et al. (1998). In the patient of Shikata et al. (2005), the polyps were restricted to the stomach, and no polyps were detected in the intestine, a phenotype distinct from that seen by Howe et al. (1998). Histologic examination of the stomach after gastrectomy revealed areas of epithelial atypia consistent with adenocarcinoma confined to the mucosa. The patient also had a pulmonary arteriovenous malformation, suggesting JPS/HHT (JPHT; 175050). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 JUVENILE POLYPOSIS SYNDROME</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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JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME, INCLUDED
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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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SMAD4, ARG361CYS
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<br />
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SNP: rs80338963,
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gnomAD: rs80338963,
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ClinVar: RCV000009071, RCV000009072, RCV000059732, RCV001376609, RCV002311508, RCV003924819
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a patient with familial juvenile polyposis syndrome (JPS; 174900), Houlston et al. (1998) found a germline mutation of the MADH4 gene. Like the 3 germline mutations reported by Howe et al. (1998), this variant occurred toward the C terminus of the DPC4 protein. However, whereas the 3 earlier mutations were small insertions or deletions, the mutation reported by Houlston et al. (1998) was a missense change (arg361 to cys; R361C). Somatic missense mutations in DPC4 had previously been reported in colorectal cancers (Takagi et al., 1996; MacGrogan et al., 1997). </p><p>In 2 patients with hereditary hemorrhagic telangiectasia but no prior diagnosis of juvenile polyposis (JPHT; see 175050), Gallione et al. (2006) identified the R361C mutation in exon 8 of the SMAD4 gene. One patient had a history of colorectal cancer and was found to have 7 polyps in the ascending colon and 3 in the duodenum; the other was found to have colonic polyps. </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>.0009 JUVENILE POLYPOSIS SYNDROME</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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SMAD4, 2-BP DEL, 959AC
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<br />
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SNP: rs377767336,
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ClinVar: RCV001797981
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with familial juvenile polyposis syndrome (JPS; 174900), Friedl et al. (1999) identified a 2-bp deletion (959_960delAC) in exon 6 of the MADH4 gene. In addition to colonic polyposis diagnosed at the age of 12 years, the patient developed a severe gastric polyposis at the age of 28 years. The mutation was also detected in her asymptomatic 5-year-old son. </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>.0010 JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME</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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SMAD4, GLY386ASP
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<br />
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SNP: rs121912580,
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ClinVar: RCV000009074
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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>Burger et al. (2002) described an 11-year-old girl with juvenile polyposis and a de novo mutation in the MADH4 gene. The patient had developed more than 70 juvenile colonic polyps which were removed from the cecum, ascending colon, and transverse colon. The patient also had pulmonary arteriovenous fistulae of the left lung, clubbing of fingers, skeletal anomalies of the thorax, and additional dental germs. Neither parent had polyposis. Direct genomic sequencing of all 11 exons of the MADH4 gene revealed a heterozygous base exchange (1157G-A) in exon 9. This change, replacing the triplet GGT (gly) by GAT (asp), was predicted to result in an amino acid exchange at codon 386. Neither parent carried the mutation. </p><p>Gallione et al. (2004) demonstrated that the same mutation occurred de novo in the patient of Baert et al. (1983). Juvenile polyps had been diagnosed in the colon. Arteriovenous malformations were found in the lung at the age of 15 years. Gallione et al. (2004) classified the patient of Burger et al. (2002) as having juvenile polyposis with hereditary hemorrhagic telangiectasia (see JPHT, 175050), noting the presence of an arteriovenous malformation in the lung and digital clubbing. </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>.0011 JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMAD4, GLY352ARG
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<br />
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SNP: rs121912581,
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ClinVar: RCV000009075, RCV000059731, RCV001731312
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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 family in which members of 3 successive generations had the JP/HHT syndrome (JPHT; 175050), Gallione et al. (2004) found a 1054G-A transition in the MADH4 gene predicted to result in a gly352-to-arg change (G352R). Juvenile polyps were present in the colon in 1 member of each of 3 successive generations with a diagnosis at 9 years, 5 years, and 3 years. Arteriovenous malformations were present in the lung and in the liver. Cerebral capillary telangiectases and pancytopenia occurred in the first generation, and an episode of intracranial bleeding in the second. </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>.0012 JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME</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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SMAD4, 14-BP DEL, NT1612
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<br />
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SNP: rs377767385,
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ClinVar: RCV000021759
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|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>Gallione et al. (2004) described a parent and child with juvenile polyps of the cecum and colon, respectively, diagnosed at ages 41 and 8 years. Both also had telangiectases and epistaxis (JPHT; 175050). The parent had arteriovenous malformations of the lung and liver together with cerebellar cavernous hemangioma diagnosed at the age of 32 years. The parent and child had deletion of MADH4 nucleotides 1612-25. </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>.0013 JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
SMAD4, 2-BP DEL/1-BP INS, 1596CC/T
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<br />
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|
|
SNP: rs377767379,
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|
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gnomAD: rs377767379,
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|
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|
|
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ClinVar: RCV000021752
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with hereditary hemorrhagic telangiectasia but no prior diagnosis of juvenile polyposis (see 175050), Gallione et al. (2006) identified a 2-bp deletion and 1-bp insertion (1596delCCinsT) in exon 11 of the SMAD4 gene. The patient was later found to have colonic polyps on endoscopy. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMAD4, ARG445TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs377767360,
|
|
|
|
|
|
gnomAD: rs377767360,
|
|
|
|
|
|
ClinVar: RCV000023059, RCV000493396, RCV001374448, RCV001376567, RCV002310634, RCV004668739
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 affected members of a family with a clinical variant of JPHT (175050), Andrabi et al. (2011) identified a heterozygous mutation in exon 10 of the SMAD4 gene, resulting in an arg445-to-ter (R445X) substitution. The clinical features in this family were unusual in that affected members had mitral valve prolapse, mitral valve regurgitation, and aortic dilatation in addition to gastrointestinal hamartomatous polyps; telangiectases were not reported. Andrabi et al. (2011) noted the role of SMAD4 in the TGF-beta-1 signaling pathway, suggesting overlap with other connective tissue disorders such as Marfan syndrome (154700) and Loeys-Dietz syndrome (see, e.g., 609192). The findings indicated that haploinsufficiency of SMAD4 may cause an aortopathy and mitral valve dysfunction. </p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
|
|
</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>.0015 MYHRE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMAD4, ILE500THR
|
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|
|
<br />
|
|
|
|
SNP: rs281875321,
|
|
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|
|
ClinVar: RCV000023060, RCV000059734, RCV001852006
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 unrelated patients with sporadic occurrence of Myhre syndrome (MYHRS; 139210), Le Goff et al. (2012) identified a de novo heterozygous 1499T-C transition in the SMAD4 gene, resulting in an ile500-to-thr (I500T) substitution in a highly conserved residue in the MH2 domain involved in transcriptional activation. The mutation was not found in 200 controls. The same residue was mutated in other patients with the disorder (I500V, 600993.0016 and I500M, 600993.0017). Studies of fibroblasts from 2 patients with the I500T mutation showed enhanced levels of SMAD4 protein with lower levels of ubiquitinated SMAD4 fibroblasts compared to controls, suggesting stabilization of the mutant protein. Since SMAD4 has a pivotal role in TGF-beta and BMP signaling, Le Goff et al. (2012) analyzed the level of phosphorylation of other SMAD proteins. There was an 8-fold increase in phosphorylated SMAD2 (601366) and SMAD3 (603109), and an 11-fold increase in phosphorylated SMAD1 (601595), SMAD5 (603110), and SMAD8 (603295) in cell nuclei compared to controls. The mutant SMAD4-containing complexes were associated with decreased mRNA levels of downstream TGF-beta and variable effects on BMP targets. </p><p>Caputo et al. (2012) identified a heterozygous de novo I500T mutation in 3 unrelated patients with Myhre syndrome. </p><p>In a woman with laryngotracheal stenosis, arthropathy, prognathism, and short stature, originally described by Lindor et al. (2002), Lindor et al. (2012) identified heterozygosity for the I500T mutation in the SMAD4 gene. The patient had chronically restrictive indices on echocardiography despite having undergone pericardiectomy, and required repeated procedures to address recurrent laryngotracheal stenoses. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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<div>
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 MYHRE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMAD4, ILE500VAL
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs281875322,
|
|
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|
|
|
gnomAD: rs281875322,
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|
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|
|
ClinVar: RCV000023061, RCV000059733, RCV000635427, RCV000763031, RCV001249691, RCV001260808, RCV001375955, RCV001376590, RCV004558272, RCV004745165, RCV004820822
|
|
|
|
|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 unrelated patients with sporadic occurrence of Myhre syndrome (MYHRS; 139210), Le Goff et al. (2012) identified a de novo heterozygous 1498A-G transition in the SMAD4 gene, resulting in an ile500-to-val (I500V) substitution in a highly conserved residue in the MH2 domain involved in transcriptional activation. The mutation was not found in 200 controls. </p><p>Caputo et al. (2012) identified a heterozygous de novo I500V mutation in 5 unrelated patients with Myhre syndrome. </p><p>In a woman with laryngotracheal stenosis, arthropathy, prognathism, and short stature, originally described by Lindor et al. (2002), Lindor et al. (2012) identified heterozygosity for the I500V mutation in the SMAD4 gene. The patient developed a restrictive pericardium requiring pericardiectomy, required repeated procedures to address recurrent laryngotracheal stenoses, and died at 40 years of age due to progressive respiratory failure. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 MYHRE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMAD4, ILE500MET
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|
|
<br />
|
|
|
|
SNP: rs281875320,
|
|
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|
|
|
|
|
ClinVar: RCV000023062, RCV000059735, RCV005089303
|
|
|
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|
|
</span>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a patient with sporadic occurrence of Myhre syndrome (MYHRS; 139210), Le Goff et al. (2012) identified a de novo heterozygous 1500A-G transition in the SMAD4 gene, resulting in an ile500-to-met (I500M) substitution in a highly conserved residue in the MH2 domain involved in transcriptional activation. The mutation was not found in 200 controls. </p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 MYHRE SYNDROME</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
SMAD4, ARG496CYS
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<br />
|
|
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|
ClinVar: RCV004720591
|
|
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</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Among 47 patients with Myhre syndrome (MYHRS; 139210), including 4 previously reported, seen at their clinic, Lin et al. (2024) found that 18 (38%) had a c.1486C-T transition in the SMAD4 gene, resulting in an arg496-to-cys (R496C) substitution. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
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Hilary J. Vernon - updated : 10/30/2024<br>Sonja A. Rasmussen - updated : 09/24/2024<br>Bao Lige - updated : 10/03/2019<br>Bao Lige - updated : 07/09/2019<br>Bao Lige - updated : 06/28/2019<br>Ada Hamosh - updated : 02/05/2018<br>Patricia A. Hartz - updated : 12/18/2013<br>Ada Hamosh - updated : 5/20/2013<br>Marla J. F. O'Neill - updated : 7/26/2012<br>Cassandra L. Kniffin - updated : 1/30/2012<br>Cassandra L. Kniffin - updated : 9/21/2011<br>Cassandra L. Kniffin - updated : 6/30/2011<br>Ada Hamosh - updated : 3/25/2011<br>Patricia A. Hartz - updated : 12/28/2010<br>Matthew B. Gross - updated : 4/12/2010<br>Ada Hamosh - updated : 9/11/2008<br>Victor A. McKusick - updated : 6/8/2007<br>Marla J. F. O'Neill - updated : 1/12/2007<br>Patricia A. Hartz - updated : 1/5/2007<br>Cassandra L. Kniffin - updated : 10/2/2006<br>Ada Hamosh - updated : 8/1/2006<br>Marla J. F. O'Neill - updated : 8/27/2004<br>Matthew B. Gross - updated : 6/11/2004<br>Victor A. McKusick - updated : 5/4/2004<br>Stylianos E. Antonarakis - updated : 11/26/2002<br>Stylianos E. Antonarakis - updated : 9/11/2002<br>Victor A. McKusick - updated : 9/10/2002<br>Victor A. McKusick - updated : 7/2/2002<br>Patricia A. Hartz - updated : 6/5/2002<br>Victor A. McKusick - updated : 5/20/2002<br>Michael J. Wright - updated : 1/8/2001<br>Victor A. McKusick - updated : 9/30/1999<br>Stylianos E. Antonarakis - updated : 1/31/1999<br>Victor A. McKusick - updated : 11/9/1998<br>Stylianos E. Antonarakis - updated : 5/29/1998<br>Victor A. McKusick - updated : 5/13/1998<br>Victor A. McKusick - updated : 1/27/1998<br>Moyra Smith - updated : 7/4/1996
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Alan F. Scott : 1/18/1996
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alopez : 10/30/2024<br>carol : 10/30/2024<br>carol : 09/24/2024<br>carol : 01/09/2020<br>mgross : 10/03/2019<br>mgross : 07/10/2019<br>mgross : 07/09/2019<br>mgross : 06/28/2019<br>alopez : 02/05/2018<br>carol : 12/06/2017<br>carol : 11/20/2017<br>carol : 11/20/2017<br>carol : 06/24/2016<br>mgross : 12/18/2013<br>mcolton : 12/13/2013<br>alopez : 5/20/2013<br>terry : 7/27/2012<br>carol : 7/27/2012<br>terry : 7/26/2012<br>carol : 1/30/2012<br>ckniffin : 1/30/2012<br>terry : 1/25/2012<br>carol : 9/22/2011<br>ckniffin : 9/21/2011<br>wwang : 7/14/2011<br>ckniffin : 6/30/2011<br>carol : 6/17/2011<br>terry : 4/26/2011<br>alopez : 3/28/2011<br>terry : 3/25/2011<br>mgross : 1/10/2011<br>terry : 12/28/2010<br>wwang : 4/28/2010<br>mgross : 4/12/2010<br>ckniffin : 3/23/2009<br>alopez : 9/11/2008<br>ckniffin : 2/5/2008<br>carol : 7/2/2007<br>alopez : 6/13/2007<br>terry : 6/8/2007<br>wwang : 3/30/2007<br>carol : 1/18/2007<br>terry : 1/12/2007<br>mgross : 1/5/2007<br>carol : 12/22/2006<br>wwang : 10/9/2006<br>ckniffin : 10/2/2006<br>alopez : 8/3/2006<br>terry : 8/1/2006<br>terry : 8/3/2005<br>carol : 4/28/2005<br>mgross : 4/14/2005<br>mgross : 4/13/2005<br>tkritzer : 10/1/2004<br>carol : 8/27/2004<br>terry : 8/27/2004<br>mgross : 6/11/2004<br>alopez : 5/6/2004<br>alopez : 5/6/2004<br>alopez : 5/6/2004<br>terry : 5/4/2004<br>ckniffin : 3/23/2004<br>ckniffin : 3/11/2003<br>mgross : 11/26/2002<br>mgross : 9/11/2002<br>alopez : 9/10/2002<br>mgross : 7/26/2002<br>cwells : 7/15/2002<br>terry : 7/2/2002<br>carol : 6/5/2002<br>carol : 6/5/2002<br>alopez : 5/24/2002<br>terry : 5/20/2002<br>alopez : 1/8/2001<br>alopez : 10/5/1999<br>terry : 9/30/1999<br>carol : 2/2/1999<br>carol : 1/31/1999<br>carol : 11/13/1998<br>terry : 11/9/1998<br>carol : 10/20/1998<br>carol : 10/13/1998<br>terry : 10/8/1998<br>dkim : 9/30/1998<br>dkim : 9/30/1998<br>alopez : 9/1/1998<br>carol : 5/30/1998<br>terry : 5/29/1998<br>alopez : 5/15/1998<br>alopez : 5/14/1998<br>alopez : 5/14/1998<br>terry : 5/13/1998<br>carol : 4/7/1998<br>terry : 3/28/1998<br>mark : 1/28/1998<br>terry : 1/27/1998<br>mark : 12/20/1996<br>mark : 12/20/1996<br>mark : 12/20/1996<br>terry : 12/9/1996<br>mark : 8/27/1996<br>marlene : 8/15/1996<br>mark : 7/4/1996<br>terry : 4/17/1996<br>mark : 2/5/1996<br>terry : 2/1/1996<br>mark : 1/18/1996
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