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Entry
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- *190182 - TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE II; TGFBR2
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- OMIM
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<p>
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<span class="h4">*190182</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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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="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/190182">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div 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=ENSG00000163513;t=ENST00000295754" 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=7048" 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=190182" 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=ENSG00000163513;t=ENST00000295754" 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_001024847,NM_001407126,NM_001407127,NM_001407128,NM_001407129,NM_001407130,NM_001407132,NM_001407133,NM_001407134,NM_001407135,NM_001407136,NM_001407137,NM_001407138,NM_001407139,NM_003242,XM_047448787" 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_003242" 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=190182" 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=01823&isoform_id=01823_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/TGFBR2" 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/339570,624882,1644350,1655963,50234987,50871738,67782324,67782326,110287585,116242818,119584814,119584815,119584816,189054276,194385726,194390716,270048022,270048024,311461818,311461820,584431903,584431905,584431907,584431909,584431911,957950278,957950281,2006609999,2118777727,2217345690,2245367865,2245367867,2245367888,2245367904,2245367917,2245367925,2245367929,2245367935,2245367963,2245367973,2245367977,2245367979,2245367983,2462592186" 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/P37173" 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=7048" 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=ENSG00000163513;t=ENST00000295754" 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=TGFBR2" 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=TGFBR2" 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+7048" 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/TGFBR2" 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:7048" 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/7048" 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=chr3&hgg_gene=ENST00000295754.10&hgg_start=30606356&hgg_end=30694142&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:11773" 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:11773" 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/tgfbr2" 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=190182[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=190182[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/TGFBR2/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/ENSG00000163513" 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=TGFBR2" 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=TGFBR2" 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=TGFBR2" 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.umd.be/TGFBR2/" 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=TGFBR2&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/PA36486" 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:11773" 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:98729" 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/TGFBR2#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:98729" 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/7048/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=7048" 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=WBGene00000900;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-120404-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7048" 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=TGFBR2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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190182
|
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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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TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE II; TGFBR2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TGFBR2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TGFBR2</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/3/135?start=-3&limit=10&highlight=135">3p24.1</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:30606356-30694142&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'})">3:30,606,356-30,694,142</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>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
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|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=614331,133239,610168" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/3/135?start=-3&limit=10&highlight=135">
|
|
3p24.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Colorectal cancer, hereditary nonpolyposis, type 6
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/614331"> 614331 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
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</td>
|
|
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|
|
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|
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Esophageal cancer, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/133239"> 133239 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Loeys-Dietz syndrome 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/610168"> 610168 </a>
|
|
|
|
</span>
|
|
</td>
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<p>By screening a human hepatoma cell cDNA library with a porcine TGFBR2 cDNA as probe, <a href="#20" class="mim-tip-reference" title="Lin, H. Y., Wang, X.-F., Ng-Eaton, E., Weinberg, R. A., Lodish, H. F. <strong>Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase.</strong> Cell 68: 775-785, 1992. Note: Erratum: Cell 70: 1069 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1310899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1310899</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90152-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1310899">Lin et al. (1992)</a> isolated a TGFBR2 cDNA encoding a deduced 567-amino acid protein. The protein contains a predicted cysteine-rich extracellular domain, a single hydrophobic transmembrane domain, and a cytoplasmic serine/threonine kinase domain. The human and porcine proteins share 88% sequence identity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1310899" 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>Growth factor-induced protein phosphorylation plays a key role in the signal transduction that leads to mitogenic responses. Most growth factor receptors are transmembrane tyrosine kinases or are associated with cytoplasmic tyrosine kinases. However, another class of transmembrane receptors is predicted to function as serine-threonine kinases. The type II activin receptor (<a href="/entry/102581">102581</a>) and the types I (<a href="/entry/190181">190181</a>) and II TGF-beta receptors (<a href="#20" class="mim-tip-reference" title="Lin, H. Y., Wang, X.-F., Ng-Eaton, E., Weinberg, R. A., Lodish, H. F. <strong>Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase.</strong> Cell 68: 775-785, 1992. Note: Erratum: Cell 70: 1069 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1310899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1310899</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90152-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1310899">Lin et al., 1992</a>) belong to the serine-threonine kinase family. The many activities of TGF-beta (TGFB1; <a href="/entry/190180">190180</a>) in regulating cell proliferation and differentiation and extracellular matrix production are mediated through these receptors. With the use of cells overexpressing truncated type II receptors as dominant-negative mutants to block type II receptor signaling selectively, <a href="#4" class="mim-tip-reference" title="Chen, R.-H., Ebner, R., Derynck, R. <strong>Inactivation of the type II receptor reveals two receptor pathways for the diverse TGF-beta activities.</strong> Science 260: 1335-1338, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8388126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8388126</a>] [<a href="https://doi.org/10.1126/science.8388126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8388126">Chen et al. (1993)</a> demonstrated the existence of 2 receptor pathways. The type II receptors, possibly in conjunction with type I receptors, mediate the induction of growth inhibition and hypophosphorylation of the retinoblastoma gene product. The type I receptors are responsible for effects on extracellular matrix, such as the induction of fibronectin and plasminogen activator inhibitor I, and for increased JUNB (<a href="/entry/165161">165161</a>) expression. Selective inactivation of the type II receptors alters the response to TGF-beta in a manner similar to the functional inactivation of the RB protein (<a href="/entry/614041">614041</a>), suggesting a role for RB in the type II, but not the type I, receptor pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8388126+1310899" 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>Expression of the TGFBR2 gene, a putative tumor suppressor gene, is regulated by ETS transcription factors, of which FLI1 (<a href="/entry/193067">193067</a>) is one. <a href="#11" class="mim-tip-reference" title="Hahm, K.-B., Cho, K., Lee, C., Im, Y.-H., Chang, J., Choi, S.-G., Sorensen, P. H. B., Thiele, C. J., Kim, S.-J. <strong>Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein.</strong> Nature Genet. 23: 222-227, 1999. Note: Erratum: Nature Genet. 23: 481 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508522</a>] [<a href="https://doi.org/10.1038/13854" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508522">Hahm et al. (1999)</a> performed experiments to test the hypothesis that TGFBR2 may be a target of the EWS-FLI1 fusion protein found in Ewing sarcoma and related peripheral primitive neuroectodermal tumors (see <a href="/entry/612219">612219</a>). Their experiments led them to conclude that indeed TGFBR2 is a direct target of EWS-FLI1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508522" 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="Ozdamar, B., Bose, R., Barrios-Rodiles, M., Wang, H.-R., Zhang, Y., Wrana, J. L. <strong>Regulation of the polarity protein Par6 by TGF-beta receptors controls epithelial cell plasticity.</strong> Science 307: 1603-1609, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15761148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15761148</a>] [<a href="https://doi.org/10.1126/science.1105718" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15761148">Ozdamar et al. (2005)</a> demonstrated that PAR6 (<a href="/entry/607484">607484</a>), a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGF-beta receptors and is a substrate of TGFBR2. Phosphorylation of PAR6 is required for TGF-beta-dependent epithelial-mesenchymal transition in mammary gland epithelial cells and controls the interaction of PAR6 with the E3 ubiquitin ligase Smurf1 (<a href="/entry/605568">605568</a>). Smurf1, in turn, targets the guanosine triphosphatase RhoA (<a href="/entry/165390">165390</a>) for degradation, leading to a loss of tight junctions. <a href="#30" class="mim-tip-reference" title="Ozdamar, B., Bose, R., Barrios-Rodiles, M., Wang, H.-R., Zhang, Y., Wrana, J. L. <strong>Regulation of the polarity protein Par6 by TGF-beta receptors controls epithelial cell plasticity.</strong> Science 307: 1603-1609, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15761148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15761148</a>] [<a href="https://doi.org/10.1126/science.1105718" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15761148">Ozdamar et al. (2005)</a> concluded that an extracellular cue signals to the polarity machinery to control epithelial cell morphology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15761148" 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="Tesseur, I., Zou, K., Esposito, L., Bard, F., Berber, E., Van Can, J., Lin, A. H., Crews, L., Tremblay, P., Mathews, P., Mucke, L., Masliah, E., Wyss-Coray, T. <strong>Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology.</strong> J. Clin. Invest. 116: 3060-3069, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17080199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17080199</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17080199[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/JCI27341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17080199">Tesseur et al. (2006)</a> found significantly decreased levels of TGFBR2 in human brain extracts from patients with Alzheimer disease (AD; <a href="/entry/104300">104300</a>) brain compared to controls; the decrease was correlated with pathologic hallmarks of the disease. Similar decreases were not seen in brain extracts from patients with other forms of dementia. In a mouse model of AD, reduced neuronal TGFBR2 signaling resulted in accelerated age-dependent neurodegeneration and promoted beta-amyloid accumulation and dendritic loss. Reduced TGFBR2 signaling in neuroblastoma cell cultures resulted in increased levels of secreted beta-amyloid and soluble APP (<a href="/entry/104760">104760</a>). The findings suggested a role for TGFB1 signaling in the pathogenesis of AD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17080199" 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, <a href="#21" class="mim-tip-reference" title="Liu, M., Kuo, F., Capistrano, K. J., Kang, D., Nixon, B. G., Shi, W., Chou, C., Do, M. H., Stamatiades, E. G., Gao, S., Li, S., Chen, Y., Hsieh, J. J., Hakimi, A. A., Taniuchi, I., Chan, T. A.,. <strong>Li, M. O.: TGF-beta suppresses type 2 immunity to cancer.</strong> Nature 587: 115-120, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33087928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33087928</a>] [<a href="https://doi.org/10.1038/s41586-020-2836-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33087928">Liu et al. (2020)</a> showed that depletion of Tgfbr2 in Cd4 (<a href="/entry/186940">186940</a>)-positive T cells, but not Cd8 (see <a href="/entry/186910">186910</a>)-positive T cells, halted cancer progression due to tissue healing and remodeling of blood vasculature, leading to cancer cell hypoxia and death in distant avascular regions. The host-directed protective response depended on the T-helper-2 cytokine interleukin-4 (IL4; <a href="/entry/147780">147780</a>), but not on the T-helper-1 cytokine Ifng (<a href="/entry/147570">147570</a>). <a href="#21" class="mim-tip-reference" title="Liu, M., Kuo, F., Capistrano, K. J., Kang, D., Nixon, B. G., Shi, W., Chou, C., Do, M. H., Stamatiades, E. G., Gao, S., Li, S., Chen, Y., Hsieh, J. J., Hakimi, A. A., Taniuchi, I., Chan, T. A.,. <strong>Li, M. O.: TGF-beta suppresses type 2 immunity to cancer.</strong> Nature 587: 115-120, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33087928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33087928</a>] [<a href="https://doi.org/10.1038/s41586-020-2836-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33087928">Liu et al. (2020)</a> concluded that type-2 immunity can be mobilized as an effective tissue-level defense mechanism against cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33087928" 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 follow-up to the work of <a href="#21" class="mim-tip-reference" title="Liu, M., Kuo, F., Capistrano, K. J., Kang, D., Nixon, B. G., Shi, W., Chou, C., Do, M. H., Stamatiades, E. G., Gao, S., Li, S., Chen, Y., Hsieh, J. J., Hakimi, A. A., Taniuchi, I., Chan, T. A.,. <strong>Li, M. O.: TGF-beta suppresses type 2 immunity to cancer.</strong> Nature 587: 115-120, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33087928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33087928</a>] [<a href="https://doi.org/10.1038/s41586-020-2836-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33087928">Liu et al. (2020)</a>, <a href="#19" class="mim-tip-reference" title="Li, S., Liu, M., Do, M. H., Chou, C., Stamatiades, E. G., Nixon, B. G., Shi, W., Zhang, X., Li, P., Gao, S., Capistrano, K. J., Xu, H., Cheung, K.-K. V., Li, M. O. <strong>Cancer immunotherapy via targeted TGF-beta signalling blockade in T(H) cells.</strong> Nature 587: 121-125, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33087933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33087933</a>] [<a href="https://doi.org/10.1038/s41586-020-2850-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33087933">Li et al. (2020)</a> showed that blocking TGFB signaling in CD4-positive T cells remodeled the tumor microenvironment and restrained cancer progression. In a mouse model of breast cancer resistant to immune-checkpoint or anti-Vegf (see VEGFA, <a href="/entry/192240">192240</a>) therapies, inducible genetic deletion of Tgfbr2 in Cd4-positive T cells suppressed tumor growth. For pharmacologic blockade, the authors engineered a bispecific receptor decoy termed 'CD4-TGFB-Trap' (4T-Trap) by attaching the TGFB-neutralizing extracellular domain of human TGFBR2 to ibalizumab, a nonimmunosuppressive human CD4 antibody. Compared with a nontargeted TGFB-Trap, 4T-Trap selectively inhibited T-helper cell Tgfb signaling in tumor-draining lymph nodes of transgenic mice expressing human CD4, causing reorganization of tumor vasculature and cancer cell death, a process dependent on Il4. The 4T-Trap-induced tumor tissue hypoxia led to increased Vegfa expression. Vegf inhibition enhanced starvation-triggered cancer cell death and amplified the antitumor effect of 4T-Trap. <a href="#19" class="mim-tip-reference" title="Li, S., Liu, M., Do, M. H., Chou, C., Stamatiades, E. G., Nixon, B. G., Shi, W., Zhang, X., Li, P., Gao, S., Capistrano, K. J., Xu, H., Cheung, K.-K. V., Li, M. O. <strong>Cancer immunotherapy via targeted TGF-beta signalling blockade in T(H) cells.</strong> Nature 587: 121-125, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33087933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33087933</a>] [<a href="https://doi.org/10.1038/s41586-020-2850-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33087933">Li et al. (2020)</a> concluded that targeted TGFB signaling blockade in helper T cells elicits an effective tissue-level cancer defense response that can provide a basis for therapies directed towards the cancer environment. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=33087933+33087928" 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="#37" class="mim-tip-reference" title="Takenoshita, S., Hagiwara, K., Nagashima, M., Gemma, A., Bennett, W. P., Harris, C. C. <strong>The genomic structure of the gene encoding the human transforming growth factor beta type II receptor (TGF-beta RII).</strong> Genomics 36: 341-344, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8812462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8812462</a>] [<a href="https://doi.org/10.1006/geno.1996.0471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8812462">Takenoshita et al. (1996)</a> determined that the TGFBR2 gene comprises 7 coding exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8812462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using a full-length cDNA and a genomic probe in Southern blot analysis of a human/rodent somatic cell hybrid panel and by direct fluorescence in situ hybridization to normal metaphase chromosomes, <a href="#26" class="mim-tip-reference" title="Mathew, S., Murty, V. V. V. S., Cheifetz, S., George, D., Massague, J., Chaganti, R. S. K. <strong>Transforming growth factor receptor gene TGFBR2 maps to human chromosome band 3p22.</strong> Genomics 20: 114-115, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8020936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8020936</a>] [<a href="https://doi.org/10.1006/geno.1994.1134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8020936">Mathew et al. (1994)</a> showed that the TGFBR2 gene maps to chromosome 3p22. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8020936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 7/11/2017."None>Gross (2017)</a> mapped the TGFBR2 gene to chromosome 3p24.1 based on an alignment of the TGFBR2 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AH004921" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AH004921</a>) with the genomic sequence (GRCh38).</p><p><a href="#3" class="mim-tip-reference" title="Bonyadi, M., Cui, W., Nagase, H., Akhurst, R. J. <strong>The TGF-beta type II receptor, Tgfbr2, maps to distal mouse chromosome 9.</strong> Genomics 33: 328-329, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8660988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8660988</a>] [<a href="https://doi.org/10.1006/geno.1996.0204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8660988">Bonyadi et al. (1996)</a> mapped the mouse Tgfbr2 gene to distal mouse chromosome 9 within a region of synteny with human chromosome 3p22-p21. The mapping was done by linkage studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8660988" 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>Role in Carcinogenesis</em></strong></p><p>
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Germline (<a href="#0002">190182.0002</a>) and somatic (e.g., <a href="#0001">190182.0001</a>) mutations in the TGFBR2 gene can result in hereditary nonpolyposis colorectal cancer-6 (HNPCC6; <a href="/entry/614331">614331</a>).</p><p><a href="#25" class="mim-tip-reference" title="Markowitz, S., Wang, J., Myeroff, L., Parsons, R., Sun, L., Lutterbaugh, J., Fan, R. S., Zborowska, E., Kinzler, K. W., Vogelstein, B., Brattain, M., Willson, J. K. V. <strong>Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability.</strong> Science 268: 1336-1338, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7761852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7761852</a>] [<a href="https://doi.org/10.1126/science.7761852" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7761852">Markowitz et al. (1995)</a> stated that transforming growth factor-beta (TGFB; <a href="/entry/190180">190180</a>) inhibits the growth of multiple epithelial cell types, and loss of this negative regulation is thought to contribute to tumor development. The TGFB growth inhibitory signal is transduced through 2 receptors, type I (TGFBR1) and type II (TGFBR2), which function as a heteromeric complex. <a href="#25" class="mim-tip-reference" title="Markowitz, S., Wang, J., Myeroff, L., Parsons, R., Sun, L., Lutterbaugh, J., Fan, R. S., Zborowska, E., Kinzler, K. W., Vogelstein, B., Brattain, M., Willson, J. K. V. <strong>Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability.</strong> Science 268: 1336-1338, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7761852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7761852</a>] [<a href="https://doi.org/10.1126/science.7761852" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7761852">Markowitz et al. (1995)</a> investigated whether inactivation of TGF-beta receptors is a mechanism by which human colon cancer cells lose responsiveness to TGF-beta. They found that the TGFBR2 gene was inactivated in a subset of colon cancer cell lines (referred to as RER(+), for 'replication errors') exhibiting microsatellite instability, but not in RER(-) cells. Eight such examples, due to 3 different mutations, were identified. The mutations (e.g., <a href="#0001">190182.0001</a>) were clustered within small repeated sequences in the TGFBR2 gene and were accompanied by the absence of cell surface receptors. <a href="#25" class="mim-tip-reference" title="Markowitz, S., Wang, J., Myeroff, L., Parsons, R., Sun, L., Lutterbaugh, J., Fan, R. S., Zborowska, E., Kinzler, K. W., Vogelstein, B., Brattain, M., Willson, J. K. V. <strong>Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability.</strong> Science 268: 1336-1338, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7761852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7761852</a>] [<a href="https://doi.org/10.1126/science.7761852" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7761852">Markowitz et al. (1995)</a> stated that TGFBR2 mutation, by inducing the escape of cells from TGF-beta-mediated growth control, links DNA repair defects (<a href="/entry/120435">120435</a>) with a specific pathway of tumor progression. The small repeat sequences in the TGFBR2 gene make it a favorable target for RER(+)-associated mutator mechanisms. Once generated, the proliferative advantage of cells with inactivated type II receptor would drive colon tumor progression. This pathway may also be operative in other human malignancies in which the RER(+) phenotype has been detected (reviewed by <a href="#7" class="mim-tip-reference" title="Eshleman, J. R., Markowitz, S. D. <strong>Microsatellite instability in inherited and sporadic neoplasms.</strong> Curr. Opin. Oncol. 7: 83-89, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7696368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7696368</a>]" pmid="7696368">Eshleman and Markowitz, 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7761852+7696368" 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>Whereas TGFB inhibits the growth of many epithelial cell types including nontransformed colon epithelial cells, colon and many other cancer cell lines are resistant to suppression of growth by TGFB. <a href="#32" 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> confirmed the presence of TGFBR2 mutations in 100 of 111 cases of RER+ colon cancers. As in the report of <a href="#25" class="mim-tip-reference" title="Markowitz, S., Wang, J., Myeroff, L., Parsons, R., Sun, L., Lutterbaugh, J., Fan, R. S., Zborowska, E., Kinzler, K. W., Vogelstein, B., Brattain, M., Willson, J. K. V. <strong>Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability.</strong> Science 268: 1336-1338, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7761852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7761852</a>] [<a href="https://doi.org/10.1126/science.7761852" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7761852">Markowitz et al. (1995)</a>, in each of these cases, a frameshift mutation was detected within a small adenine mononucleotide repeat at nucleotides 709-718 of the TGFBR2 cDNA. Insertions or deletions of adenines within this repeat produce -1, -2, or +1 frameshift mutations, resulting in predicted synthesis of truncated receptor proteins of 161, 129, or 130 amino acids, respectively. <a href="#28" class="mim-tip-reference" title="Myeroff, L. L., Parsons, R., Kim, S.-J., Hedrick, L., Cho, K. R., Orth, K., Mathis, M., Kinzler, K. W., Lutterbaugh, J., Park, K., Bang, Y.-J., Lee, H. Y., Park, J.-G., Lynch, H. T., Roberts, A. B., Vogelstein, B., Markowitz, S. D. <strong>A transforming growth factor beta receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability.</strong> Cancer Res. 55: 5545-5547, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7585631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7585631</a>]" pmid="7585631">Myeroff et al. (1995)</a> demonstrated that TGFBR2 gene mutations are also commonly present in RER+ gastric cancers. In contrast, they found that mutations in this gene are distinctly uncommon in RER+ endometrial cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7585632+7761852+7585631" 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="#36" class="mim-tip-reference" title="Souza, R. F., Appel, R., Yin, J., Wang, S., Smolinski, K. N., Abraham, J. M., Zou, T.-T., Shi, Y.-Q., Lei, J., Cottrell, J., Cymes, K., Biden, K., Simms, L., Leggett, B., Lynch, P. M., Frazier, M., Powell, S. M., Harpaz, N., Sugimura, H., Young, J., Meltzer, S. J. <strong>Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours. (Letter)</strong> Nature Genet. 14: 255-257, 1996. Note: Erratum: Nature Genet. 14: 488 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896552</a>] [<a href="https://doi.org/10.1038/ng1196-255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896552">Souza et al. (1996)</a> analyzed microsatellite instability within the coding regions of the TGFBR2 and IGF2R (<a href="/entry/147280">147280</a>) genes. They noted an anticorrespondence of IGF2R and TGFBR2 mutations. Of 31 gastrointestinal lesions studied with IGF2R or TGFBR2 mutations, 90% (28) contained mutations in one or the other, but not both, of these genes. They suggested that IGF2R and TGFBR2 genes comprise serial points in the same tumorigenesis pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896552" 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="#39" class="mim-tip-reference" title="Tannergard, P., Liu, T., Weger, A., Nordenskjold, M., Lindbloom, A. <strong>Tumorigenesis in colorectal tumors from patients with hereditary non-polyposis colorectal cancer.</strong> Hum. Genet. 101: 51-55, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9385369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9385369</a>] [<a href="https://doi.org/10.1007/s004390050585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9385369">Tannergard et al. (1997)</a> studied colorectal tumorigenesis in patients with HNPCC. Tumors from members of 29 HNPCC families known to have germline mutations of the MLH1 gene (<a href="/entry/120436">120436</a>) were studied. By using intragenic markers, inactivation of the wildtype allele of MLH1 was shown to have occurred through loss of heterozygosity and not through a somatic point mutation. Microsatellite instability was very common and occurred early in almost all colorectal tumors from HNPCC patients. Mutations in the TGFBR2 gene occurred at a high frequency in these tumors. Of colorectal cancers from HNPCC families, 63% had frameshift mutations in TGFBR2, compared with 10% of sporadic colorectal cancers. Mutations in APC (<a href="/entry/611731">611731</a>) and KRAS2 (<a href="/entry/190070">190070</a>) appeared to be as frequent in the HNPCC tumors as in the sporadic counterpart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9385369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Lu, S.-L., Kawabata, M., Imamura, T., Akiyama, Y., Nomizu, T., Miyazono, K., Yuasa, Y. <strong>HNPCC associated with germline mutation in the TGF-beta type II receptor gene. (Letter)</strong> Nature Genet. 19: 17-18, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590282</a>] [<a href="https://doi.org/10.1038/ng0598-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590282">Lu et al. (1998)</a> identified a germline mutation in TGFBR2 in an 80-year old patient with colorectal cancer (HNPCC6; <a href="/entry/614331">614331</a>). The patient and her 2 brothers had had colorectal cancers complying with the clinical criteria of HNPCC, except that the onset of cancer was beyond 50 years of age in all cases. Constitutional DNA was heterozygous for a thr315-to-met (T315M; <a href="#0002">190182.0002</a>) mutation, whereas loss of the wildtype allele was observed in tumor DNA. The same mutation was present in 2 of the patient's 6 children, but they had not developed cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590282" 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>Adjuvant chemotherapy improves survival among certain patients with stage III colon cancer. <a href="#42" class="mim-tip-reference" title="Watanabe, T., Wu, T.-T., Catalano, P. J., Ueki, T., Satriano, R., Haller, D. G., Benson, A. B., III, Hamilton, S. R. <strong>Molecular predictors of survival after adjuvant chemotherapy for colon cancer.</strong> New Eng. J. Med. 344: 1196-1206, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309634</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11309634[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/10.1056/NEJM200104193441603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309634">Watanabe et al. (2001)</a> studied molecular predictors of outcome and found that retention of 18q alleles in microsatellite-stable cancers and mutation of the TGFBR2 gene in cancers with high levels of microsatellite instability pointed to a favorable outcome after adjuvant chemotherapy with fluorouracil-based regimens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11309634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Loeys-Dietz Syndrome</em></strong></p><p>
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Identification of a 3p24.1 chromosomal breakpoint disrupting the TGFBR2 gene in a Japanese individual with a diagnosis of Marfan syndrome (<a href="/entry/154700">154700</a>) led <a href="#27" class="mim-tip-reference" title="Mizuguchi, T., Collod-Beroud, G., Akiyama, T., Abifadel, M., Harada, N., Morisaki, T., Allard, D., Varret, M., Claustres, M., Morisaki, H., Ihara, M., Kinoshita, A., and 11 others. <strong>Heterozygous TGFBR2 mutations in Marfan syndrome.</strong> Nature Genet. 36: 855-860, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15235604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15235604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15235604[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/ng1392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15235604">Mizuguchi et al. (2004)</a> to consider TGFBR2 as a gene underlying a phenotype referred to as Marfan syndrome type 2 (see LDS2, <a href="/entry/610168">610168</a>) which mapped to a locus on chromosome 3p. They identified the mutation 1524G-A in TGFBR2 (causing the synonymous amino acid substitution Q508Q and resulting in abnormal splicing; <a href="#0004">190182.0004</a>) to segregate with the phenotype in the French family described by <a href="#2" class="mim-tip-reference" title="Boileau, C., Jondeau, G., Babron, M.-C., Coulon, M., Alexandre, J.-A., Sakai, L., Melki, J., Delorme, G., Dubourg, O., Bonaiti-Pellie, C., Bourdarias, J.-P., Junien, C. <strong>Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomalies not linked to the fibrillin gene.</strong> Am. J. Hum. Genet. 53: 46-54, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8317497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8317497</a>]" pmid="8317497">Boileau et al. (1993)</a>. In 4 unrelated probands, they identified 3 other missense mutations in TGFBR2 that led to loss of function of TGF-beta signaling activity on extracellular matrix formation. These results showed that heterozygous mutations in TGFBR2, a putative tumor suppressor gene implicated in several malignancies, are also associated with inherited connective tissue disorders. Fbn1 (<a href="/entry/134797">134797</a>)-deficient mice have excessive TGF-beta activity that probably underlies their tendency to develop emphysema and could explain other manifestations of Marfan syndrome (<a href="#29" class="mim-tip-reference" title="Neptune, E. R., Frischmeyer, P. A., Arking, D. E., Myers, L., Bunton, T. E., Gayraud, B., Ramirez, F., Sakai, L. Y., Dietz, H. C. <strong>Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome.</strong> Nature Genet. 33: 407-411, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12598898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12598898</a>] [<a href="https://doi.org/10.1038/ng1116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12598898">Neptune et al., 2003</a>). Domain-specific germline mutations of TGFB1 (<a href="/entry/190180">190180</a>) have been described in Camurati-Engelmann syndrome (<a href="/entry/131300">131300</a>) and affected individuals usually have Marfanoid habitus, i.e., long slender limbs and vertebral deformation. The findings of TGFBR2 mutations provides further evidence that perturbation of TGF-beta signaling contributes to the pathogenesis of extracellular matrix disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12598898+15235604+8317497" 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>Among the 10 French probands with a diagnosis of Marfan syndrome examined by <a href="#27" class="mim-tip-reference" title="Mizuguchi, T., Collod-Beroud, G., Akiyama, T., Abifadel, M., Harada, N., Morisaki, T., Allard, D., Varret, M., Claustres, M., Morisaki, H., Ihara, M., Kinoshita, A., and 11 others. <strong>Heterozygous TGFBR2 mutations in Marfan syndrome.</strong> Nature Genet. 36: 855-860, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15235604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15235604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15235604[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/ng1392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15235604">Mizuguchi et al. (2004)</a>, only 4 had mutations in TGFBR2. These 4 individuals shared a common clinical description: prominent aortic, skeletal, and skin/integument anomalies; mild ocular anomalies (except for one individual in the original family who had ectopia lentis); infrequent dural ectasia; and pulmonary abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15235604" 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 10 families with a disorder characterized by widespread perturbations in cardiovascular, craniofacial, neurocognitive, and skeletal development (see LDS1, <a href="/entry/609192">609192</a>), <a href="#22" class="mim-tip-reference" title="Loeys, B. L., Chen, J., Neptune, E. R., Judge, D. P., Podowski, M., Holm, T., Meyers, J., Leitch, C. C., Katsanis, N., Sharifi, N., Xu, F. L., Myers, L. A., and 12 others. <strong>A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.</strong> Nature Genet. 37: 275-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15731757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15731757</a>] [<a href="https://doi.org/10.1038/ng1511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15731757">Loeys et al. (2005)</a> reported heterozygous mutations in the genes encoding either TGFBR1 (<a href="/entry/190181">190181</a>) or TGFBR2. <a href="#22" class="mim-tip-reference" title="Loeys, B. L., Chen, J., Neptune, E. R., Judge, D. P., Podowski, M., Holm, T., Meyers, J., Leitch, C. C., Katsanis, N., Sharifi, N., Xu, F. L., Myers, L. A., and 12 others. <strong>A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.</strong> Nature Genet. 37: 275-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15731757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15731757</a>] [<a href="https://doi.org/10.1038/ng1511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15731757">Loeys et al. (2005)</a> considered TGFBR2 as a candidate gene because TGF-beta signaling has a prominent role in vascular and craniofacial development in mouse models (<a href="#34" class="mim-tip-reference" title="Sanford, L. P., Ormsby, I., Gittenberger-de Groot, A. C., Sariola, H., Friedman, R., Boivin, G. P., Cardell, E. L., Doetschman, T. <strong>TGF-beta-2 knockout mice have multiple developmental defects that are non-overlapping with other TGF-beta knockout phenotypes.</strong> Development 124: 2659-2670, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9217007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9217007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9217007[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/10.1242/dev.124.13.2659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9217007">Sanford et al., 1997</a>; <a href="#1" class="mim-tip-reference" title="Azhar, M., Schultz, J. E. J., Grupp, I., Dorn, G. W., II, Meneton, P., Molin, D. G. M., Gittenberger-de Groot, A. C., Doetschman, T. <strong>Transforming growth factor beta in cardiovascular development and function.</strong> Cytokine Growth Factor Rev. 14: 391-407, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12948523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12948523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12948523[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/s1359-6101(03)00044-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12948523">Azhar et al., 2003</a>) and because conditional knockout of TGFBR2 in neural crest cells causes cleft palate and defects of the calvaria (<a href="#14" class="mim-tip-reference" title="Ito, Y., Yeo, J. Y., Chytil, A., Han, J., Bringas, P., Jr., Nakajima, A., Shuler, C. F., Moses, H. L., Chai, Y. <strong>Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects.</strong> Development 130: 5269-5280, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12975342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12975342</a>] [<a href="https://doi.org/10.1242/dev.00708" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12975342">Ito et al., 2003</a>). <a href="#22" class="mim-tip-reference" title="Loeys, B. L., Chen, J., Neptune, E. R., Judge, D. P., Podowski, M., Holm, T., Meyers, J., Leitch, C. C., Katsanis, N., Sharifi, N., Xu, F. L., Myers, L. A., and 12 others. <strong>A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.</strong> Nature Genet. 37: 275-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15731757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15731757</a>] [<a href="https://doi.org/10.1038/ng1511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15731757">Loeys et al. (2005)</a> sequenced all exons of TGFBR2 and identified heterozygous mutations in 6 of 10 families (LDS2; <a href="/entry/610168">610168</a>). The other 4 families were found to have mutations in the TGFBR1 gene (<a href="/entry/190181">190181</a>). Despite evidence that receptors derived from selected mutated alleles cannot support TGF-beta signal propagation (<a href="#27" class="mim-tip-reference" title="Mizuguchi, T., Collod-Beroud, G., Akiyama, T., Abifadel, M., Harada, N., Morisaki, T., Allard, D., Varret, M., Claustres, M., Morisaki, H., Ihara, M., Kinoshita, A., and 11 others. <strong>Heterozygous TGFBR2 mutations in Marfan syndrome.</strong> Nature Genet. 36: 855-860, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15235604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15235604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15235604[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/ng1392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15235604">Mizuguchi et al., 2004</a>), cells derived from individuals heterozygous with respect to these mutations did not show altered kinetics of the acute phase response to administered ligand. Furthermore, tissues derived from affected individuals showed increased expression of both collagen (see <a href="/entry/120150">120150</a>) and connective tissue growth factor (CTGF; <a href="/entry/121009">121009</a>), as well as nuclear enrichment of phosphorylated SMAD2 (<a href="/entry/601366">601366</a>), indicative of increased TGF-beta signaling. The data were interpreted as indicating that perturbation of TGF-beta signaling is involved in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease, and mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15235604+9217007+12948523+12975342+15731757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Loeys, B. L., Chen, J., Neptune, E. R., Judge, D. P., Podowski, M., Holm, T., Meyers, J., Leitch, C. C., Katsanis, N., Sharifi, N., Xu, F. L., Myers, L. A., and 12 others. <strong>A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.</strong> Nature Genet. 37: 275-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15731757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15731757</a>] [<a href="https://doi.org/10.1038/ng1511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15731757">Loeys et al. (2005)</a> reported that histologic analysis in patients with mutations in TGFBR2 showed loss of elastin (<a href="/entry/130160">130160</a>) content and disarrayed elastic fibers in the aortic media similar to that in patients with classic Marfan syndrome. Structural analysis showed loss of intimate spatial association between elastin deposits and vascular smooth muscle cells. These characteristics were observed in young children and in the absence of inflammation, suggestive of a severe defect in elastogenesis rather than secondary elastic fiber destruction. In addition, they had previously observed a marked excess of aortic wall collagen in individuals with Marfan syndrome compared with age-matched controls; this collagen excess was accentuated in individuals with mutations in TGFBR2. As multiple collagens normally expressed in the aorta are derived from early-induced target genes of TGF-beta (including COL1A1 and COL3A1), these data were considered consistent with increased (rather than decreased) TGF-beta signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15731757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Disabella, E., Grasso, M., Marziliano, N., Ansaldi, S., Lucchelli, C., Porcu, E., Tagliani, M., Pilotto, A., Diegoli, M., Lanzarini, L., Malattia, C., Pelliccia, A., Ficcadenti, A., Gabrielli, O., Arbustini, E. <strong>Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects.</strong> Europ. J. Hum. Genet. 14: 34-38, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16251899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16251899</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16251899">Disabella et al. (2006)</a> identified 3 different mutations in the TGFBR2 gene (e.g., <a href="#0015">190182.0015</a>) in 3 unrelated patients with a phenotype that they identified as Marfan syndrome. None of the patients had major ocular signs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16251899" 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 boy with clinical findings reported as Shprintzen-Goldberg syndrome (SGS; <a href="/entry/182212">182212</a>) but consistent with Loeys-Dietz syndrome, <a href="#16" class="mim-tip-reference" title="Kosaki, K., Takahashi, D., Udaka, T., Kosaki, R., Matsumoto, M., Ibe, S., Isobe, T., Tanaka, Y., Takahashi, T. <strong>Molecular pathology of Shprintzen-Goldberg syndrome. (Letter)</strong> Am. J. Med. Genet. 140A: 104-108, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16333834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16333834</a>] [<a href="https://doi.org/10.1002/ajmg.a.31006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16333834">Kosaki et al. (2006)</a> identified heterozygosity for a splice site mutation in the TGFBR2 gene (<a href="#0016">190182.0016</a>). Because the patient had a bifid uvula and sigmoid configuration of the brachycephalic, left common carotid, and left subclavian arteries, <a href="#33" class="mim-tip-reference" title="Robinson, P. N., Neumann, L. M., Tinschert, S. <strong>Response to Kosaki et al. (Letter)</strong> Am. J. Med. Genet. 140A: 109-110, 2006."None>Robinson et al. (2006)</a> suggested that the diagnosis of Loeys-Dietz syndrome would also be appropriate for this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16333834" 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="Singh, K. K., Rommel, K., Mishra, A., Karck, M., Haverich, A., Schmidtke, J., Arslan-Kirchner, M. <strong>TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome.</strong> Hum. Mutat. 27: 770-777, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16799921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16799921</a>] [<a href="https://doi.org/10.1002/humu.20354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16799921">Singh et al. (2006)</a> searched for TGFBR1 and TGFBR2 mutations in 41 unrelated patients fulfilling the diagnostic criteria for Marfan syndrome of the Ghent nosology (<a href="#5" class="mim-tip-reference" title="De Paepe, A., Devereux, R. B., Dietz, H. C., Hennekam, R. C. M., Pyeritz, R. E. <strong>Revised diagnostic criteria for the Marfan syndrome.</strong> Am. J. Med. Genet. 62: 417-426, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8723076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8723076</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19960424)62:4<417::AID-AJMG15>3.0.CO;2-R" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8723076">De Paepe et al., 1996</a>) or with the tentative diagnosis of Marfan syndrome, in whom mutations in the FBN1 coding region were not identified. In TGFBR1, 2 mutations and 2 polymorphisms were detected. In TGFBR2, 5 mutations and 6 polymorphisms were identified. Reexamination of patients with a TGFBR1 or TGFBR2 mutation revealed extensive clinical overlap between patients diagnosed with Marfan syndrome type 1 (MFS1; <a href="/entry/154700">154700</a>), Marfan syndrome type 2, and Loeys-Dietz syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16799921+8723076" 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 male patients with Loeys-Dietz syndrome who had a significant history of low bone mineral density and multiple low-impact fractures, <a href="#15" class="mim-tip-reference" title="Kirmani, S., Tebben, P. J., Lteif, A. N., Gordon, D., Clarke, B. L., Hefferan, T. E., Yaszemski, M. J., McGrann, P. S., Lindor, N. M., Ellison, J. W. <strong>Germline TGF-beta receptor mutations and skeletal fragility: a report on two patients with Loeys-Dietz syndrome.</strong> Am. J. Med. Genet. 152A: 1016-1019, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20358619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20358619</a>] [<a href="https://doi.org/10.1002/ajmg.a.33356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20358619">Kirmani et al. (2010)</a> identified 2 different heterozygous mutations in the TGFBR2 gene, respectively (see, e.g., <a href="#0005">190182.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20358619" 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>Susceptibility To Abdominal Aortic Aneurysm</em></strong></p><p>
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For a discussion of a possible association between variation in the TGFBR2 gene and susceptibility to abdominal aortic aneurysm, see AAA (<a href="/entry/100070">100070</a>).</p><p><strong><em>Role in Left-Right Patterning</em></strong></p><p>
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By high-resolution genotyping of 262 heterotaxy (see HTX1, <a href="/entry/306955">306955</a>) subjects and 991 controls, <a href="#8" class="mim-tip-reference" title="Fakhro, K. A., Choi, M., Ware, S. M., Belmont, J. W., Towbin, J. A., Lifton, R. P., Khokha, M. K., Brueckner, M. <strong>Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning.</strong> Proc. Nat. Acad. Sci. 108: 2915-2920, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21282601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21282601</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21282601[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.1019645108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21282601">Fakhro et al. (2011)</a> identified a 2-fold excess of subjects with rare genic copy number variations (CNVs) in heterotaxy (14.5% vs 7.4%, p = 1.5 x 10(-4)). Although 7 of 45 heterotaxy CNVs were large chromosomal abnormalities, 38 smaller CNVs altered a total of 61 genes, 22 of which had Xenopus orthologs. In situ hybridization identified 7 of these 22 genes with expression in the ciliated left-right organizer, a marked enrichment compared with 40 of 845 previously studied genes (7-fold enrichment, p less than 10(-6)). Morpholino knockdown in Xenopus of heterotaxy candidate genes demonstrated that 5 genes (NEK2, <a href="/entry/604043">604043</a>; ROCK2, <a href="/entry/604002">604002</a>; TGFBR2; GALNT11, <a href="/entry/615130">615130</a>; and NUP188, <a href="/entry/615587">615587</a>) strongly disrupted both morphologic left-right development and expression of PITX2 (<a href="/entry/601542">601542</a>), a molecular marker of left-right patterning. These effects were specific, because 0 of 13 control genes from rare heterotaxy or control CNVs produced significant left-right abnormalities (p = 0.001). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21282601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#12" class="mim-tip-reference" title="Han, G., Lu, S.-L, Li, A. G., He, W., Corless, C. L., Kulesz-Martin, M., Wang, X.-J. <strong>Distinct mechanisms of TGF-beta-1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis.</strong> J. Clin. Invest. 115: 1714-1723, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937546</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15937546[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/JCI24399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15937546">Han et al. (2005)</a> found that human skin cancers frequently overexpress TGFB1 (<a href="/entry/190180">190180</a>) but exhibit decreased expression of TGFBR2. In transgenic mouse models in which Tgfb1 expression could be induced at specific stages of skin carcinogenesis in tumor epithelia expressing a dominant-negative Tgfbr2, they observed that late-stage Tgfb1 overexpression in chemically induced skin papillomas did not exert a tumor-suppressive effect and that dominant-negative Tgfbr2 expression selectively blocked Tgfb1-mediated epithelial-to-mesenchymal transition but cooperated with Tgfb1 for tumor invasion. <a href="#12" class="mim-tip-reference" title="Han, G., Lu, S.-L, Li, A. G., He, W., Corless, C. L., Kulesz-Martin, M., Wang, X.-J. <strong>Distinct mechanisms of TGF-beta-1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis.</strong> J. Clin. Invest. 115: 1714-1723, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937546</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15937546[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/JCI24399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15937546">Han et al. (2005)</a> concluded that TGFB1 induces epithelial-to-mesenchymal transition and invasion via distinct mechanisms: TGFB1-mediated epithelial-to-mesenchymal transition requires functional TGFBR2, whereas TGFB1-mediated tumor invasion cooperates with reduced TGFBR2 signaling in tumor epithelia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15937546" 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="Li, M. O., Sanjabi, S., Flavell, R. A. <strong>Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms.</strong> Immunity 25: 455-471, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16973386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16973386</a>] [<a href="https://doi.org/10.1016/j.immuni.2006.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16973386">Li et al. (2006)</a> found that mice lacking Tgfbr2 specifically in T cells had lethal inflammation associated with T-cell activation and differentiation. Maturation of Cd8-positive T cells and development of natural killer T cells were inhibited in thymus. Peripheral Foxp3 (<a href="/entry/300292">300292</a>)-positive regulatory T cell numbers were reduced, and Cd4-positive T-cell survival depended on Tgfb signaling. <a href="#18" class="mim-tip-reference" title="Li, M. O., Sanjabi, S., Flavell, R. A. <strong>Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms.</strong> Immunity 25: 455-471, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16973386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16973386</a>] [<a href="https://doi.org/10.1016/j.immuni.2006.07.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16973386">Li et al. (2006)</a> concluded that TGFB has pleiotropic functions in T cells in terms of T-cell development, tolerance, and homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16973386" 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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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>20 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=190182[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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<strong>.0001 COLON CANCER, HEREDITARY NONPOLYPOSIS, TYPE 6, SOMATIC</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">rs587776769 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776769;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=rs587776769" 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=rs587776769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>The mutations identified by <a href="#25" class="mim-tip-reference" title="Markowitz, S., Wang, J., Myeroff, L., Parsons, R., Sun, L., Lutterbaugh, J., Fan, R. S., Zborowska, E., Kinzler, K. W., Vogelstein, B., Brattain, M., Willson, J. K. V. <strong>Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability.</strong> Science 268: 1336-1338, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7761852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7761852</a>] [<a href="https://doi.org/10.1126/science.7761852" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7761852">Markowitz et al. (1995)</a> included (in the VACO481 cell line) a GT insertion into a 6-bp GTGTGT repeat at nucleotides 1931 to 1936. The resulting frameshift was predicted to substitute a highly basic, 29-amino acid C terminus for the slightly acidic 33-amino acid wildtype C terminus. The same frameshift mutation was detected in the primary colon tumor from which the VACO481 cell line was established, but not in normal colon tissue from the same patient, indicating that the mutation was somatic and that it occurred before cell culture. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7761852" 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> rs34833812 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34833812;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/rs34833812?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=rs34833812" 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=rs34833812" 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=RCV000013325 OR RCV000247266 OR RCV000290470 OR RCV000344037 OR RCV000626289 OR RCV001094839 OR RCV001310481 OR RCV002276544 OR RCV004586001" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013325, RCV000247266, RCV000290470, RCV000344037, RCV000626289, RCV001094839, RCV001310481, RCV002276544, RCV004586001" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013325...</a>
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<p><a href="#24" class="mim-tip-reference" title="Lu, S.-L., Kawabata, M., Imamura, T., Akiyama, Y., Nomizu, T., Miyazono, K., Yuasa, Y. <strong>HNPCC associated with germline mutation in the TGF-beta type II receptor gene. (Letter)</strong> Nature Genet. 19: 17-18, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590282</a>] [<a href="https://doi.org/10.1038/ng0598-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590282">Lu et al. (1998)</a> described a heterozygous germline thr315-to-met (T315M) mutation in an 80-year-old patient with colorectal cancer (HNPCC6; <a href="/entry/614331">614331</a>). The other allele was wildtype in the constitutional DNA and showed deletion in tumor tissue. Unlike patients with typical HNPCC, the affected members of this family lacked multiple synchronous, metachronous colorectal cancers and extracolonic cancers. Notably, there was no microsatellite instability in this case. The patient's 2 brothers had developed colon cancer at the ages of 65 and 60. The T315M mutation was found in 2 of the patient's 6 children, neither of whom had developed cancer. Tissue samples could not be obtained from the brothers of the patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590282" 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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TGFBR2, GLU526GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918714 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918714;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=rs121918714" 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=rs121918714" 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=RCV000013326 OR RCV000688883" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013326, RCV000688883" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013326...</a>
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<p><a href="#38" class="mim-tip-reference" title="Tanaka, S., Mori, M., Mafune, K., Ohno, S., Sugimachi, K. <strong>A dominant negative mutation of transforming growth factor-beta receptor type II gene in microsatellite stable oesophageal carcinoma.</strong> Brit. J. Cancer 82: 1557-1560, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10789724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10789724</a>] [<a href="https://doi.org/10.1054/bjoc.1999.1178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10789724">Tanaka et al. (2000)</a> identified a missense mutation, glu526 to gln (E526Q), in the serine/threonine kinase domain of TGF-beta receptor II in an esophageal carcinoma (<a href="/entry/133239">133239</a>) tissue sample. The mutant protein could completely inhibit TGF-beta induction of nuclear translocation of SMAD4 protein (<a href="/entry/600993">600993</a>) in esophageal carcinoma cells. This mutation was not associated with microsatellite instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10789724" 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>.0004 LOEYS-DIETZ SYNDROME 2</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">rs121918715 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918715;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=rs121918715" 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=rs121918715" 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=RCV000013327" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013327" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013327</a>
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<p>In a large French family in which a Marfan syndrome-like phenotype mapped to 3p25-p24.2 (LDS2; <a href="/entry/610168">610168</a>; <a href="#2" class="mim-tip-reference" title="Boileau, C., Jondeau, G., Babron, M.-C., Coulon, M., Alexandre, J.-A., Sakai, L., Melki, J., Delorme, G., Dubourg, O., Bonaiti-Pellie, C., Bourdarias, J.-P., Junien, C. <strong>Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomalies not linked to the fibrillin gene.</strong> Am. J. Hum. Genet. 53: 46-54, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8317497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8317497</a>]" pmid="8317497">Boileau et al., 1993</a>), <a href="#27" class="mim-tip-reference" title="Mizuguchi, T., Collod-Beroud, G., Akiyama, T., Abifadel, M., Harada, N., Morisaki, T., Allard, D., Varret, M., Claustres, M., Morisaki, H., Ihara, M., Kinoshita, A., and 11 others. <strong>Heterozygous TGFBR2 mutations in Marfan syndrome.</strong> Nature Genet. 36: 855-860, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15235604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15235604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15235604[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/ng1392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15235604">Mizuguchi et al. (2004)</a> identified the mutation 1524G-A in TGFBR2 segregating with the phenotype. The mutation caused the synonymous amino acid substitution gln508-to-gln (Q508Q) and resulted in abnormal splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15235604+8317497" 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">rs28934568 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28934568;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=rs28934568" 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=rs28934568" 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=RCV000013329" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013329" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013329</a>
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<p><a href="#27" class="mim-tip-reference" title="Mizuguchi, T., Collod-Beroud, G., Akiyama, T., Abifadel, M., Harada, N., Morisaki, T., Allard, D., Varret, M., Claustres, M., Morisaki, H., Ihara, M., Kinoshita, A., and 11 others. <strong>Heterozygous TGFBR2 mutations in Marfan syndrome.</strong> Nature Genet. 36: 855-860, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15235604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15235604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15235604[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/ng1392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15235604">Mizuguchi et al. (2004)</a> identified the mutation 923T-C in the TGFBR2 gene, resulting in the amino acid substitution leu308-to-pro (L308P), associated with a phenotype identified as Marfan syndrome type 2 (see LDS2, <a href="/entry/610168">610168</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15235604" 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 17-year-old male patient with Loeys-Dietz syndrome with craniofacial involvement who had a significant history of low bone mineral density and multiple low-impact fractures, <a href="#15" class="mim-tip-reference" title="Kirmani, S., Tebben, P. J., Lteif, A. N., Gordon, D., Clarke, B. L., Hefferan, T. E., Yaszemski, M. J., McGrann, P. S., Lindor, N. M., Ellison, J. W. <strong>Germline TGF-beta receptor mutations and skeletal fragility: a report on two patients with Loeys-Dietz syndrome.</strong> Am. J. Med. Genet. 152A: 1016-1019, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20358619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20358619</a>] [<a href="https://doi.org/10.1002/ajmg.a.33356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20358619">Kirmani et al. (2010)</a> identified heterozygosity for the L308P mutation in the TGFBR2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20358619" 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">rs104893807 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893807;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=rs104893807" 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=rs104893807" 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="#27" class="mim-tip-reference" title="Mizuguchi, T., Collod-Beroud, G., Akiyama, T., Abifadel, M., Harada, N., Morisaki, T., Allard, D., Varret, M., Claustres, M., Morisaki, H., Ihara, M., Kinoshita, A., and 11 others. <strong>Heterozygous TGFBR2 mutations in Marfan syndrome.</strong> Nature Genet. 36: 855-860, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15235604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15235604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15235604[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/ng1392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15235604">Mizuguchi et al. (2004)</a> identified the heterozygous mutation 1346C-T in the TGFBR2 gene, resulting in the ser449-to-phe (S449F) amino acid substitution, in association with a phenotype identified as Marfan syndrome type 2 (see LDS2, <a href="/entry/610168">610168</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15235604" 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">rs104893809 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893809;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=rs104893809" 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=rs104893809" 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=RCV000013331 OR RCV000196289 OR RCV000529794" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013331, RCV000196289, RCV000529794" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013331...</a>
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<p><a href="#27" class="mim-tip-reference" title="Mizuguchi, T., Collod-Beroud, G., Akiyama, T., Abifadel, M., Harada, N., Morisaki, T., Allard, D., Varret, M., Claustres, M., Morisaki, H., Ihara, M., Kinoshita, A., and 11 others. <strong>Heterozygous TGFBR2 mutations in Marfan syndrome.</strong> Nature Genet. 36: 855-860, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15235604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15235604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15235604[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/ng1392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15235604">Mizuguchi et al. (2004)</a> found the mutation 1609C-T in the TGFBR2 gene, resulting in the amino acid substitution arg537-to-cys (R537C), in association with a phenotype identified as Marfan syndrome type 2 (see LDS2, <a href="/entry/610168">610168</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15235604" 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">rs104893812 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893812;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=rs104893812" 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=rs104893812" 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=RCV000013332" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013332" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013332</a>
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<p>In their family 6 in which a father and 2 daughters had Loeys-Dietz syndrome (LDS2; <a href="/entry/610168">610168</a>), <a href="#22" class="mim-tip-reference" title="Loeys, B. L., Chen, J., Neptune, E. R., Judge, D. P., Podowski, M., Holm, T., Meyers, J., Leitch, C. C., Katsanis, N., Sharifi, N., Xu, F. L., Myers, L. A., and 12 others. <strong>A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.</strong> Nature Genet. 37: 275-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15731757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15731757</a>] [<a href="https://doi.org/10.1038/ng1511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15731757">Loeys et al. (2005)</a> found a heterozygous mutation in the TGFBR2 gene segregating with the disorder, a 1006T-A transversion in exon 4 that resulted in a tyr336-to-asn (Y336N) substitution in the kinase domain of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15731757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 LOEYS-DIETZ SYNDROME 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104893813 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893813;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/rs104893813?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=rs104893813" 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=rs104893813" 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=RCV000013333 OR RCV001193761 OR RCV001253567 OR RCV001851822" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013333, RCV001193761, RCV001253567, RCV001851822" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013333...</a>
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<p>In a family in which members of 3 generations had the Loeys-Dietz syndrome (LDS2; <a href="/entry/610168">610168</a>), <a href="#22" class="mim-tip-reference" title="Loeys, B. L., Chen, J., Neptune, E. R., Judge, D. P., Podowski, M., Holm, T., Meyers, J., Leitch, C. C., Katsanis, N., Sharifi, N., Xu, F. L., Myers, L. A., and 12 others. <strong>A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.</strong> Nature Genet. 37: 275-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15731757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15731757</a>] [<a href="https://doi.org/10.1038/ng1511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15731757">Loeys et al. (2005)</a> found heterozygosity in affected individuals for a 1063G-C transversion in exon 4 of the TGFBR2 gene, resulting in an ala355-to-pro (A355P) substitution in the kinase domain of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15731757" 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">rs104893814 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893814;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=rs104893814" 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=rs104893814" 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=RCV000013334" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013334" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013334</a>
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<p>In their family 4, <a href="#22" class="mim-tip-reference" title="Loeys, B. L., Chen, J., Neptune, E. R., Judge, D. P., Podowski, M., Holm, T., Meyers, J., Leitch, C. C., Katsanis, N., Sharifi, N., Xu, F. L., Myers, L. A., and 12 others. <strong>A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.</strong> Nature Genet. 37: 275-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15731757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15731757</a>] [<a href="https://doi.org/10.1038/ng1511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15731757">Loeys et al. (2005)</a> found that the single patient with Loeys-Dietz syndrome (LDS2; <a href="/entry/610168">610168</a>) was heterozygous for a 1069G-T transversion in exon 4 of the TGFBR2 gene, resulting in a gly357-to-trp (G357W) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15731757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 LOEYS-DIETZ SYNDROME 2</strong>
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COLON CANCER, HEREDITARY NONPOLYPOSIS, TYPE 6, SOMATIC, INCLUDED
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TGFBR2, ARG528HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893815 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893815;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=rs104893815" 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=rs104893815" 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=RCV000013335 OR RCV000013336 OR RCV000200178 OR RCV000211858 OR RCV000654809" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013335, RCV000013336, RCV000200178, RCV000211858, RCV000654809" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013335...</a>
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<p>In their family 2, <a href="#22" class="mim-tip-reference" title="Loeys, B. L., Chen, J., Neptune, E. R., Judge, D. P., Podowski, M., Holm, T., Meyers, J., Leitch, C. C., Katsanis, N., Sharifi, N., Xu, F. L., Myers, L. A., and 12 others. <strong>A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.</strong> Nature Genet. 37: 275-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15731757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15731757</a>] [<a href="https://doi.org/10.1038/ng1511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15731757">Loeys et al. (2005)</a> demonstrated that the single case of Loeys-Dietz syndrome (LDS2; <a href="/entry/610168">610168</a>) was heterozygous for a 1583G-A transition in exon 7 of the TGFBR2 gene that resulted in an arg528-to-his (R528H) amino acid substitution. R528H had been reported as a somatic event in colon cancer and shown to cause loss of function in a transient transfection assay (<a href="#9" class="mim-tip-reference" title="Grady, W. M., Myeroff, L. L., Swinler, S. E., Rajput, A., Thiagalingam, S., Lutterbaugh, J. D., Neumann, A., Brattain, M. G., Chang, J., Kim, S.-J., Kinzler, K. W., Vogelstein, B., Willson, J. K. V., Markowitz, S. <strong>Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers.</strong> Cancer Res. 59: 320-324, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9927040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9927040</a>]" pmid="9927040">Grady et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9927040+15731757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 LOEYS-DIETZ SYNDROME 2</strong>
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TGFBR2, ARG528CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893810 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893810;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=rs104893810" 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=rs104893810" 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=RCV000013337 OR RCV000197944 OR RCV000691207 OR RCV000825631 OR RCV003904831 OR RCV004668719" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013337, RCV000197944, RCV000691207, RCV000825631, RCV003904831, RCV004668719" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013337...</a>
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<p>In their family 3 with a isolated case of Loeys-Dietz syndrome (LDS2; <a href="/entry/610168">610168</a>), <a href="#22" class="mim-tip-reference" title="Loeys, B. L., Chen, J., Neptune, E. R., Judge, D. P., Podowski, M., Holm, T., Meyers, J., Leitch, C. C., Katsanis, N., Sharifi, N., Xu, F. L., Myers, L. A., and 12 others. <strong>A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.</strong> Nature Genet. 37: 275-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15731757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15731757</a>] [<a href="https://doi.org/10.1038/ng1511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15731757">Loeys et al. (2005)</a> found a 1582C-T transition in exon 7 of the TGFBR2 gene, resulting in an arg528-to-cys (R528C) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15731757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0013" class="mim-anchor"></a>
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<strong>.0013 LOEYS-DIETZ SYNDROME 2</strong>
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TGFBR2, IVS1, A-G, -2
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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> rs779131465 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs779131465;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/rs779131465?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=rs779131465" 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=rs779131465" 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=RCV000013338 OR RCV001183529 OR RCV001374778 OR RCV003221782" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013338, RCV001183529, RCV001374778, RCV003221782" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013338...</a>
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<p>In a single individual with Loeys-Dietz syndrome (LDS2; <a href="/entry/610168">610168</a>) in their family 5, <a href="#22" class="mim-tip-reference" title="Loeys, B. L., Chen, J., Neptune, E. R., Judge, D. P., Podowski, M., Holm, T., Meyers, J., Leitch, C. C., Katsanis, N., Sharifi, N., Xu, F. L., Myers, L. A., and 12 others. <strong>A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.</strong> Nature Genet. 37: 275-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15731757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15731757</a>] [<a href="https://doi.org/10.1038/ng1511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15731757">Loeys et al. (2005)</a> found an A-to-G transition in the splice acceptor sequence, -2 position, in intron 1 of the TGFBR2 gene (95-2A-G). This mutation induced use of a cryptic splice acceptor in exon 2 that resulted in the in-frame skipping of nucleotides 95-112 and deletion of residues 32-37 in the extracellular domain of the TGFBR2 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15731757" 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>.0014 LOEYS-DIETZ SYNDROME 2</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">rs104893811 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893811;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=rs104893811" 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=rs104893811" 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=RCV000013339 OR RCV000199227 OR RCV000252297 OR RCV000654788" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013339, RCV000199227, RCV000252297, RCV000654788" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013339...</a>
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<p>In 2 families with thoracic aortic aneurysm and dissection mapping to chromosome 3p25-p24 (LDS2; <a href="/entry/610168">610168</a>), <a href="#31" class="mim-tip-reference" title="Pannu, H., Fadulu, V. T., Chang, J., Lafont, A., Hasham, S. N., Sparks, E., Giampietro, P. F., Zaleski, C., Estrera, A. L., Safi, H. J., Shete, S., Willing, M. C., Raman, C. S., Milewicz, D. M. <strong>Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections.</strong> Circulation 112: 513-520, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16027248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16027248</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.105.537340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16027248">Pannu et al. (2005)</a> detected a 1378C-T transition in exon 5 of the TGFBR2 gene that resulted in the substitution of cysteine for arginine at amino acid 460 (R460C). The clinical features of one of these families had been reported by <a href="#13" class="mim-tip-reference" title="Hasham, S. N., Willing, M. C., Guo, D., Muilenburg, A., He, R., Tran, V. T., Scherer, S. E., Shete, S. S., Milewicz, D. M. <strong>Mapping a locus for familial thoracic aortic aneurysms and dissections (TAAD2) to 3p24-25.</strong> Circulation 107: 3184-3190, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12821554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12821554</a>] [<a href="https://doi.org/10.1161/01.CIR.0000078634.33124.95" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12821554">Hasham et al. (2003)</a>. The proband of the second family, a 4-generation family with autosomal dominant thoracic aortic aneurysm and dissection, presented at 41 years of age with an aneurysm of the ascending aorta and mitral valve prolapse. Affected members of the family presented primarily with type A dissections. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16027248+12821554" 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> rs104893816 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893816;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/rs104893816?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=rs104893816" 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=rs104893816" 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=RCV000013340 OR RCV000196002 OR RCV000702388" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013340, RCV000196002, RCV000702388" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013340...</a>
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<p>In 2 large kindreds with autosomal dominant thoracic aortic aneurysm and dissection (LDS2; <a href="/entry/610168">610168</a>), <a href="#31" class="mim-tip-reference" title="Pannu, H., Fadulu, V. T., Chang, J., Lafont, A., Hasham, S. N., Sparks, E., Giampietro, P. F., Zaleski, C., Estrera, A. L., Safi, H. J., Shete, S., Willing, M. C., Raman, C. S., Milewicz, D. M. <strong>Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections.</strong> Circulation 112: 513-520, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16027248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16027248</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.105.537340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16027248">Pannu et al. (2005)</a> found a mutation in exon 5 of the TGFBR2 gene, 1379G-A, changing arginine-460 to histidine (R460H). The proband of 1 family presented with type B aortic dissection at the age of 43 years. Some affected individuals in this family also had carotid and cerebral aneurysms and dissections, as well as pulmonary artery enlargement. The proband of the second family presented at age 42 years with a type A aortic dissection that was surgically repaired. In the first family, affected individuals presented with aneurysms of both the ascending and descending thoracic aorta; in the second family, the majority of individuals presented with aneurysm of the ascending thoracic aorta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16027248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Disabella, E., Grasso, M., Marziliano, N., Ansaldi, S., Lucchelli, C., Porcu, E., Tagliani, M., Pilotto, A., Diegoli, M., Lanzarini, L., Malattia, C., Pelliccia, A., Ficcadenti, A., Gabrielli, O., Arbustini, E. <strong>Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects.</strong> Europ. J. Hum. Genet. 14: 34-38, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16251899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16251899</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16251899">Disabella et al. (2006)</a> identified a heterozygous R460H mutation in a 24-year-old woman with a phenotype they identified as Marfan syndrome. An affected father and aunt died of aortic root dissection at age 37 and 45 years, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16251899" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Law, C., Bunyan, D., Castle, B., Day, L., Simpson, I., Westwood, G., Keeton, B. <strong>Clinical features in a family with an R460H mutation in transforming growth factor beta receptor 2 gene.</strong> J. Med. Genet. 43: 908-916, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16885183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16885183</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16885183[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2006.042176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16885183">Law et al. (2006)</a> described the clinical findings and natural history of 22 carriers of the R460H mutation in TGFBR2 gene in a 5-generation kindred ascertained by familial aortic dissection. There had been 8 sudden deaths; the cause of death was aortic dissection in all 6 cases in which a postmortem examination was performed. Three individuals had undergone aortic replacement surgery. Dissection had occurred throughout the aorta, and in 1 case in the absence of aortic root dilatation. Subarachnoid hemorrhage due to a ruptured berry aneurysm had occurred in 2 individuals. Four gene carriers and 1 deceased family member who were investigated had tortuous cerebral blood vessels. One had tortuous vertebral arteries, 2 had tortuous carotid arteries, and 1 had tortuous abdominal aorta. Two individuals were found to have a brachiocephalic artery aneurysm and a subclavian artery aneurysm, respectively. Despite the predisposition to aortic dilatation and dissection, members of the family did not frequently manifest the skeletal features of Marfan syndrome, with the exception of joint hypermobility. None had ocular lens dislocation. Striae and hernias were common. There was some overlap with Ehlers-Danlos syndrome type IV (<a href="/entry/130050">130050</a>), with soft translucent skin that was easily bruised. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16885183" 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">rs587776770 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776770;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=rs587776770" 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=rs587776770" 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=RCV000013341 OR RCV004700224" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013341, RCV004700224" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013341...</a>
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<p>In a Japanese boy with clinical findings reported as Shprintzen-Goldberg syndrome (<a href="/entry/182212">182212</a>) but consistent with Loeys-Dietz syndrome (LDS2; <a href="/entry/610168">610168</a>), <a href="#16" class="mim-tip-reference" title="Kosaki, K., Takahashi, D., Udaka, T., Kosaki, R., Matsumoto, M., Ibe, S., Isobe, T., Tanaka, Y., Takahashi, T. <strong>Molecular pathology of Shprintzen-Goldberg syndrome. (Letter)</strong> Am. J. Med. Genet. 140A: 104-108, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16333834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16333834</a>] [<a href="https://doi.org/10.1002/ajmg.a.31006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16333834">Kosaki et al. (2006)</a> identified heterozygosity for a -2A-G transition at the splice acceptor site in intron 5 of the TGFBR2 gene. Because the patient had a bifid uvula and sigmoid configuration of the brachycephalic, left common carotid and left subclavian arteries, <a href="#33" class="mim-tip-reference" title="Robinson, P. N., Neumann, L. M., Tinschert, S. <strong>Response to Kosaki et al. (Letter)</strong> Am. J. Med. Genet. 140A: 109-110, 2006."None>Robinson et al. (2006)</a> suggested that the diagnosis of Loeys-Dietz syndrome would also be appropriate for this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16333834" 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">rs104893817 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893817;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=rs104893817" 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=rs104893817" 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=RCV000013342 OR RCV001325332" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013342, RCV001325332" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013342...</a>
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<p>In a man with a diagnosis of Marfan syndrome type 2 (LDS2; <a href="/entry/610168">610168</a>), <a href="#6" class="mim-tip-reference" title="Disabella, E., Grasso, M., Marziliano, N., Ansaldi, S., Lucchelli, C., Porcu, E., Tagliani, M., Pilotto, A., Diegoli, M., Lanzarini, L., Malattia, C., Pelliccia, A., Ficcadenti, A., Gabrielli, O., Arbustini, E. <strong>Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects.</strong> Europ. J. Hum. Genet. 14: 34-38, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16251899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16251899</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16251899">Disabella et al. (2006)</a> identified a heterozygous mutation in the TGFBR2 gene, resulting in a met425-to-val (M425V) substitution in the serine/threonine kinase domain of the protein. The mutation was not identified in 192 healthy controls. The patient's affected father died at age 40 years from aortic dissection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16251899" 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">rs104893818 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893818;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=rs104893818" 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=rs104893818" 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=RCV000013343" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013343" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013343</a>
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<p>In a patient with Loeys-Dietz syndrome type 2 (LDS2; <a href="/entry/610168">610168</a>) , <a href="#23" class="mim-tip-reference" title="Loeys, B. L., Schwarze, U., Holm, T., Callewaert, B. L., Thomas, G. H., Pannu, H., De Backer, J. F., Oswald, G. L., Symoens, S., Manouvrier, S., Roberts, A. E., Faravelli, F., and 9 others. <strong>Aneurysm syndromes caused by mutations in the TGF-beta receptor.</strong> New Eng. J. Med. 355: 788-798, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16928994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16928994</a>] [<a href="https://doi.org/10.1056/NEJMoa055695" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16928994">Loeys et al. (2006)</a> detected a missense mutation, pro427 to leu (P427L), in the TGFBR2 gene. The female patient had aortic root aneurysm with dissection and other arterial aneurysms, arterial tortuosity, vascular rapture during pregnancy, uterine rupture, and splenic rupture. Easy bruising, velvety skin, and joint laxity were also present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16928994" 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">rs104893819 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893819;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=rs104893819" 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=rs104893819" 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=RCV000013344 OR RCV000157519 OR RCV000195964 OR RCV000253575 OR RCV000763512" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013344, RCV000157519, RCV000195964, RCV000253575, RCV000763512" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013344...</a>
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<p><a href="#23" class="mim-tip-reference" title="Loeys, B. L., Schwarze, U., Holm, T., Callewaert, B. L., Thomas, G. H., Pannu, H., De Backer, J. F., Oswald, G. L., Symoens, S., Manouvrier, S., Roberts, A. E., Faravelli, F., and 9 others. <strong>Aneurysm syndromes caused by mutations in the TGF-beta receptor.</strong> New Eng. J. Med. 355: 788-798, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16928994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16928994</a>] [<a href="https://doi.org/10.1056/NEJMoa055695" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16928994">Loeys et al. (2006)</a> pictured a patient with Loeys-Dietz syndrome (LDS2; <a href="/entry/610168">610168</a>) who carried a heterozygous nonsense mutation, arg495 to stop (R495X), in the TGFBR2 gene. The man showed hypertelorism and bifid uvula. Immunostaining of aortic tissue revealed increased nuclear accumulation of phosphorylated Smad2 (<a href="/entry/601366">601366</a>) and levels of expression of connective-tissue growth factor (CTGF; <a href="/entry/121009">121009</a>), both indicative of increased TGF-beta signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16928994" 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> rs863223852 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863223852;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/rs863223852?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=rs863223852" 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=rs863223852" 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=RCV000199072 OR RCV000244033 OR RCV000490801 OR RCV000680613 OR RCV001449740" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000199072, RCV000244033, RCV000490801, RCV000680613, RCV001449740" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000199072...</a>
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<p>In a male patient of German origin with Loeys-Dietz syndrome (LDS2; <a href="/entry/610168">610168</a>), <a href="#35" class="mim-tip-reference" title="Singh, K. K., Rommel, K., Mishra, A., Karck, M., Haverich, A., Schmidtke, J., Arslan-Kirchner, M. <strong>TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome.</strong> Hum. Mutat. 27: 770-777, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16799921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16799921</a>] [<a href="https://doi.org/10.1002/humu.20354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16799921">Singh et al. (2006)</a> identified a c.1489C-T transition in exon 6 of the TGFBR2 gene that resulted in premature termination of the protein at arg497 (R497X). Height was 195 cm, while family members were of rather short stature. Dilated ascending aorta without dissection was replaced at a size of 8.0 cm. Involvement of the skeletal system included pectus excavatum, scoliosis, and arachnodactyly with positive thumb and wrist signs. Ocular symptoms were absent. The patient was lost to follow-up. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16799921" 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="#41" class="mim-tip-reference" title="Tooley, M. J., Stuart, G. A., Tometzki, A. J., Oliver, A., Scurr, I. J. <strong>Extreme phenotypes of Loeys Dietz syndrome.</strong> Clin. Dysmorph. 26: 91-94, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28225382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28225382</a>] [<a href="https://doi.org/10.1097/MCD.0000000000000173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28225382">Tooley et al. (2017)</a> reported a 3-generation pedigree with LDS2 segregating the R497X mutation. The proband was a 48-year-old man who had been referred for genetic testing because his maternal cousin had undergone surgery for a dilated aortic root and was found to carry the R497X mutation, prompting cascade testing. The proband had a right inguinal hernia repair at age 14 years, resection of Meckel diverticulum at age 16, and gastric adenocarcinoma at 42 years of age, treated with subtotal gastrectomy and chemotherapy. A dilated aortic root of 43 mm was present at the sinus of Valsalva. His oldest son had hypertelorism, downslanting palpebral fissures, and bifid uvula. Echocardiogram showed a dilated aortic root of 40 mm. The second affected son was diagnosed antenatally with hypoplastic left heart syndrome (HLHS) on ultrasound scan at 20 weeks' gestation. At 12 years of age he had subtle nasal speech but no other features to suggest LDS. At 14 years of age he had developed downslanting palpebral fissures, hypertelorism, and arachnodactyly; these were not appreciated before. The neoascending aorta was found to be 50 mm at that time. The last affected child was 8 months old and had been diagnosed with Loeys-Dietz syndrome, with aortic root measurement at the upper limit of normal. The proband and his 2 older affected sons were being treated with irbesartan. The proband's mother and maternal aunt, ages 73 and 68 years, respectively, were both mutation carriers and were asymptomatic at the time of the proband's diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28225382" 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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Azhar, M., Schultz, J. E. J., Grupp, I., Dorn, G. W., II, Meneton, P., Molin, D. G. M., Gittenberger-de Groot, A. C., Doetschman, T.
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Bonyadi, M., Cui, W., Nagase, H., Akhurst, R. J.
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[<a href="https://doi.org/10.1006/geno.1996.0204" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1096-8628(19960424)62:4<417::AID-AJMG15>3.0.CO;2-R" target="_blank">Full Text</a>]
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Disabella, E., Grasso, M., Marziliano, N., Ansaldi, S., Lucchelli, C., Porcu, E., Tagliani, M., Pilotto, A., Diegoli, M., Lanzarini, L., Malattia, C., Pelliccia, A., Ficcadenti, A., Gabrielli, O., Arbustini, E.
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[<a href="https://doi.org/10.1172/JCI27341" target="_blank">Full Text</a>]
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<a id="41" class="mim-anchor"></a>
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<a id="Tooley2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tooley, M. J., Stuart, G. A., Tometzki, A. J., Oliver, A., Scurr, I. J.
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<strong>Extreme phenotypes of Loeys Dietz syndrome.</strong>
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Clin. Dysmorph. 26: 91-94, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28225382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28225382</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28225382" 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/10.1097/MCD.0000000000000173" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="42" class="mim-anchor"></a>
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<a id="Watanabe2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Watanabe, T., Wu, T.-T., Catalano, P. J., Ueki, T., Satriano, R., Haller, D. G., Benson, A. B., III, Hamilton, S. R.
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<strong>Molecular predictors of survival after adjuvant chemotherapy for colon cancer.</strong>
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New Eng. J. Med. 344: 1196-1206, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309634</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11309634[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=11309634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM200104193441603" target="_blank">Full Text</a>]
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</p>
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</ol>
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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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Ada Hamosh - updated : 01/04/2021
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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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Matthew B. Gross - updated : 07/11/2017<br>Ada Hamosh - updated : 06/12/2017<br>Ada Hamosh - updated : 1/16/2014<br>Marla J. F. O'Neill - updated : 12/1/2010<br>Paul J. Converse - updated : 10/25/2007<br>Victor A. McKusick - updated : 5/31/2007<br>Cassandra L. Kniffin - updated : 12/8/2006<br>Victor A. McKusick - updated : 9/20/2006<br>Victor A. McKusick - updated : 8/24/2006<br>Cassandra L. Kniffin - updated : 3/8/2006<br>Marla J. F. O'Neill - updated : 3/7/2006<br>Victor A. McKusick - updated : 12/13/2005<br>Marla J. F. O'Neill - updated : 7/28/2005<br>Ada Hamosh - updated : 6/1/2005<br>Victor A. McKusick - updated : 2/4/2005<br>Victor A. McKusick - updated : 8/2/2004<br>Victor A. McKusick - updated : 5/10/2001<br>Victor A. McKusick - updated : 12/4/2000<br>Victor A. McKusick - updated : 9/29/1999<br>Victor A. McKusick - updated : 4/27/1998<br>Victor A. McKusick - updated : 10/14/1997<br>Victor A. McKusick - edited : 2/14/1997<br>Moyra Smith - updated : 11/7/1996
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/10/1993
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</span>
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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>
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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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mgross : 01/04/2021
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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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mgross : 01/04/2021<br>mgross : 07/11/2017<br>alopez : 06/12/2017<br>joanna : 08/04/2016<br>alopez : 04/22/2014<br>alopez : 4/7/2014<br>alopez : 1/16/2014<br>terry : 3/14/2013<br>carol : 3/11/2013<br>alopez : 3/11/2013<br>carol : 11/7/2012<br>alopez : 1/11/2012<br>alopez : 11/8/2011<br>alopez : 11/8/2011<br>terry : 6/21/2011<br>wwang : 12/2/2010<br>terry : 12/1/2010<br>carol : 9/2/2010<br>alopez : 4/3/2009<br>carol : 9/11/2008<br>carol : 8/5/2008<br>alopez : 3/31/2008<br>alopez : 3/7/2008<br>ckniffin : 2/5/2008<br>mgross : 10/25/2007<br>terry : 10/25/2007<br>alopez : 6/4/2007<br>terry : 5/31/2007<br>wwang : 12/11/2006<br>ckniffin : 12/8/2006<br>alopez : 10/11/2006<br>terry : 9/20/2006<br>terry : 8/24/2006<br>carol : 4/13/2006<br>wwang : 3/14/2006<br>ckniffin : 3/8/2006<br>wwang : 3/7/2006<br>alopez : 2/24/2006<br>terry : 12/13/2005<br>alopez : 8/10/2005<br>terry : 7/28/2005<br>joanna : 6/16/2005<br>wwang : 6/1/2005<br>terry : 6/1/2005<br>alopez : 4/27/2005<br>mgross : 4/15/2005<br>alopez : 3/2/2005<br>alopez : 2/7/2005<br>alopez : 2/7/2005<br>alopez : 2/7/2005<br>terry : 2/4/2005<br>alopez : 8/4/2004<br>terry : 8/2/2004<br>carol : 3/17/2004<br>carol : 7/11/2001<br>cwells : 5/18/2001<br>terry : 5/10/2001<br>mcapotos : 12/19/2000<br>mcapotos : 12/14/2000<br>terry : 12/4/2000<br>carol : 5/9/2000<br>alopez : 9/30/1999<br>terry : 9/29/1999<br>dkim : 9/11/1998<br>alopez : 4/27/1998<br>alopez : 4/27/1998<br>terry : 4/27/1998<br>jenny : 10/21/1997<br>terry : 10/14/1997<br>mark : 2/14/1997<br>terry : 2/13/1997<br>mark : 11/7/1996<br>terry : 5/7/1996<br>terry : 4/30/1996<br>terry : 4/5/1996<br>mark : 2/19/1996<br>terry : 2/15/1996<br>terry : 7/28/1995<br>mark : 7/11/1995<br>carol : 4/5/1994<br>carol : 7/13/1993<br>carol : 7/9/1993<br>carol : 6/23/1993
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</span>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 190182
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</span>
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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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TRANSFORMING GROWTH FACTOR-BETA RECEPTOR, TYPE II; TGFBR2
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TGFBR2</em></strong>
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</span>
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</p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 3p24.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:30,606,356-30,694,142 </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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</p>
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</div>
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<h4>
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<span class="mim-font">
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<strong>Gene-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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Location
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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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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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<td rowspan="3">
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<span class="mim-font">
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3p24.1
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<td>
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<span class="mim-font">
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Colorectal cancer, hereditary nonpolyposis, type 6
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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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614331
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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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Esophageal 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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133239
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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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</td>
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<tr>
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<td>
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<span class="mim-font">
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Loeys-Dietz syndrome 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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610168
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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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</td>
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</tr>
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</tbody>
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</table>
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<br />
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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>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>By screening a human hepatoma cell cDNA library with a porcine TGFBR2 cDNA as probe, Lin et al. (1992) isolated a TGFBR2 cDNA encoding a deduced 567-amino acid protein. The protein contains a predicted cysteine-rich extracellular domain, a single hydrophobic transmembrane domain, and a cytoplasmic serine/threonine kinase domain. The human and porcine proteins share 88% sequence identity. </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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<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>Growth factor-induced protein phosphorylation plays a key role in the signal transduction that leads to mitogenic responses. Most growth factor receptors are transmembrane tyrosine kinases or are associated with cytoplasmic tyrosine kinases. However, another class of transmembrane receptors is predicted to function as serine-threonine kinases. The type II activin receptor (102581) and the types I (190181) and II TGF-beta receptors (Lin et al., 1992) belong to the serine-threonine kinase family. The many activities of TGF-beta (TGFB1; 190180) in regulating cell proliferation and differentiation and extracellular matrix production are mediated through these receptors. With the use of cells overexpressing truncated type II receptors as dominant-negative mutants to block type II receptor signaling selectively, Chen et al. (1993) demonstrated the existence of 2 receptor pathways. The type II receptors, possibly in conjunction with type I receptors, mediate the induction of growth inhibition and hypophosphorylation of the retinoblastoma gene product. The type I receptors are responsible for effects on extracellular matrix, such as the induction of fibronectin and plasminogen activator inhibitor I, and for increased JUNB (165161) expression. Selective inactivation of the type II receptors alters the response to TGF-beta in a manner similar to the functional inactivation of the RB protein (614041), suggesting a role for RB in the type II, but not the type I, receptor pathway. </p><p>Expression of the TGFBR2 gene, a putative tumor suppressor gene, is regulated by ETS transcription factors, of which FLI1 (193067) is one. Hahm et al. (1999) performed experiments to test the hypothesis that TGFBR2 may be a target of the EWS-FLI1 fusion protein found in Ewing sarcoma and related peripheral primitive neuroectodermal tumors (see 612219). Their experiments led them to conclude that indeed TGFBR2 is a direct target of EWS-FLI1. </p><p>Ozdamar et al. (2005) demonstrated that PAR6 (607484), a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGF-beta receptors and is a substrate of TGFBR2. Phosphorylation of PAR6 is required for TGF-beta-dependent epithelial-mesenchymal transition in mammary gland epithelial cells and controls the interaction of PAR6 with the E3 ubiquitin ligase Smurf1 (605568). Smurf1, in turn, targets the guanosine triphosphatase RhoA (165390) for degradation, leading to a loss of tight junctions. Ozdamar et al. (2005) concluded that an extracellular cue signals to the polarity machinery to control epithelial cell morphology. </p><p>Tesseur et al. (2006) found significantly decreased levels of TGFBR2 in human brain extracts from patients with Alzheimer disease (AD; 104300) brain compared to controls; the decrease was correlated with pathologic hallmarks of the disease. Similar decreases were not seen in brain extracts from patients with other forms of dementia. In a mouse model of AD, reduced neuronal TGFBR2 signaling resulted in accelerated age-dependent neurodegeneration and promoted beta-amyloid accumulation and dendritic loss. Reduced TGFBR2 signaling in neuroblastoma cell cultures resulted in increased levels of secreted beta-amyloid and soluble APP (104760). The findings suggested a role for TGFB1 signaling in the pathogenesis of AD. </p><p>Using mice, Liu et al. (2020) showed that depletion of Tgfbr2 in Cd4 (186940)-positive T cells, but not Cd8 (see 186910)-positive T cells, halted cancer progression due to tissue healing and remodeling of blood vasculature, leading to cancer cell hypoxia and death in distant avascular regions. The host-directed protective response depended on the T-helper-2 cytokine interleukin-4 (IL4; 147780), but not on the T-helper-1 cytokine Ifng (147570). Liu et al. (2020) concluded that type-2 immunity can be mobilized as an effective tissue-level defense mechanism against cancer. </p><p>In a follow-up to the work of Liu et al. (2020), Li et al. (2020) showed that blocking TGFB signaling in CD4-positive T cells remodeled the tumor microenvironment and restrained cancer progression. In a mouse model of breast cancer resistant to immune-checkpoint or anti-Vegf (see VEGFA, 192240) therapies, inducible genetic deletion of Tgfbr2 in Cd4-positive T cells suppressed tumor growth. For pharmacologic blockade, the authors engineered a bispecific receptor decoy termed 'CD4-TGFB-Trap' (4T-Trap) by attaching the TGFB-neutralizing extracellular domain of human TGFBR2 to ibalizumab, a nonimmunosuppressive human CD4 antibody. Compared with a nontargeted TGFB-Trap, 4T-Trap selectively inhibited T-helper cell Tgfb signaling in tumor-draining lymph nodes of transgenic mice expressing human CD4, causing reorganization of tumor vasculature and cancer cell death, a process dependent on Il4. The 4T-Trap-induced tumor tissue hypoxia led to increased Vegfa expression. Vegf inhibition enhanced starvation-triggered cancer cell death and amplified the antitumor effect of 4T-Trap. Li et al. (2020) concluded that targeted TGFB signaling blockade in helper T cells elicits an effective tissue-level cancer defense response that can provide a basis for therapies directed towards the cancer environment. </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>Takenoshita et al. (1996) determined that the TGFBR2 gene comprises 7 coding 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>Using a full-length cDNA and a genomic probe in Southern blot analysis of a human/rodent somatic cell hybrid panel and by direct fluorescence in situ hybridization to normal metaphase chromosomes, Mathew et al. (1994) showed that the TGFBR2 gene maps to chromosome 3p22. </p><p>Gross (2017) mapped the TGFBR2 gene to chromosome 3p24.1 based on an alignment of the TGFBR2 sequence (GenBank AH004921) with the genomic sequence (GRCh38).</p><p>Bonyadi et al. (1996) mapped the mouse Tgfbr2 gene to distal mouse chromosome 9 within a region of synteny with human chromosome 3p22-p21. The mapping was done by linkage studies. </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>Role in Carcinogenesis</em></strong></p><p>
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Germline (190182.0002) and somatic (e.g., 190182.0001) mutations in the TGFBR2 gene can result in hereditary nonpolyposis colorectal cancer-6 (HNPCC6; 614331).</p><p>Markowitz et al. (1995) stated that transforming growth factor-beta (TGFB; 190180) inhibits the growth of multiple epithelial cell types, and loss of this negative regulation is thought to contribute to tumor development. The TGFB growth inhibitory signal is transduced through 2 receptors, type I (TGFBR1) and type II (TGFBR2), which function as a heteromeric complex. Markowitz et al. (1995) investigated whether inactivation of TGF-beta receptors is a mechanism by which human colon cancer cells lose responsiveness to TGF-beta. They found that the TGFBR2 gene was inactivated in a subset of colon cancer cell lines (referred to as RER(+), for 'replication errors') exhibiting microsatellite instability, but not in RER(-) cells. Eight such examples, due to 3 different mutations, were identified. The mutations (e.g., 190182.0001) were clustered within small repeated sequences in the TGFBR2 gene and were accompanied by the absence of cell surface receptors. Markowitz et al. (1995) stated that TGFBR2 mutation, by inducing the escape of cells from TGF-beta-mediated growth control, links DNA repair defects (120435) with a specific pathway of tumor progression. The small repeat sequences in the TGFBR2 gene make it a favorable target for RER(+)-associated mutator mechanisms. Once generated, the proliferative advantage of cells with inactivated type II receptor would drive colon tumor progression. This pathway may also be operative in other human malignancies in which the RER(+) phenotype has been detected (reviewed by Eshleman and Markowitz, 1995). </p><p>Whereas TGFB inhibits the growth of many epithelial cell types including nontransformed colon epithelial cells, colon and many other cancer cell lines are resistant to suppression of growth by TGFB. Parsons et al. (1995) confirmed the presence of TGFBR2 mutations in 100 of 111 cases of RER+ colon cancers. As in the report of Markowitz et al. (1995), in each of these cases, a frameshift mutation was detected within a small adenine mononucleotide repeat at nucleotides 709-718 of the TGFBR2 cDNA. Insertions or deletions of adenines within this repeat produce -1, -2, or +1 frameshift mutations, resulting in predicted synthesis of truncated receptor proteins of 161, 129, or 130 amino acids, respectively. Myeroff et al. (1995) demonstrated that TGFBR2 gene mutations are also commonly present in RER+ gastric cancers. In contrast, they found that mutations in this gene are distinctly uncommon in RER+ endometrial cancers. </p><p>Souza et al. (1996) analyzed microsatellite instability within the coding regions of the TGFBR2 and IGF2R (147280) genes. They noted an anticorrespondence of IGF2R and TGFBR2 mutations. Of 31 gastrointestinal lesions studied with IGF2R or TGFBR2 mutations, 90% (28) contained mutations in one or the other, but not both, of these genes. They suggested that IGF2R and TGFBR2 genes comprise serial points in the same tumorigenesis pathway. </p><p>Tannergard et al. (1997) studied colorectal tumorigenesis in patients with HNPCC. Tumors from members of 29 HNPCC families known to have germline mutations of the MLH1 gene (120436) were studied. By using intragenic markers, inactivation of the wildtype allele of MLH1 was shown to have occurred through loss of heterozygosity and not through a somatic point mutation. Microsatellite instability was very common and occurred early in almost all colorectal tumors from HNPCC patients. Mutations in the TGFBR2 gene occurred at a high frequency in these tumors. Of colorectal cancers from HNPCC families, 63% had frameshift mutations in TGFBR2, compared with 10% of sporadic colorectal cancers. Mutations in APC (611731) and KRAS2 (190070) appeared to be as frequent in the HNPCC tumors as in the sporadic counterpart. </p><p>Lu et al. (1998) identified a germline mutation in TGFBR2 in an 80-year old patient with colorectal cancer (HNPCC6; 614331). The patient and her 2 brothers had had colorectal cancers complying with the clinical criteria of HNPCC, except that the onset of cancer was beyond 50 years of age in all cases. Constitutional DNA was heterozygous for a thr315-to-met (T315M; 190182.0002) mutation, whereas loss of the wildtype allele was observed in tumor DNA. The same mutation was present in 2 of the patient's 6 children, but they had not developed cancer. </p><p>Adjuvant chemotherapy improves survival among certain patients with stage III colon cancer. Watanabe et al. (2001) studied molecular predictors of outcome and found that retention of 18q alleles in microsatellite-stable cancers and mutation of the TGFBR2 gene in cancers with high levels of microsatellite instability pointed to a favorable outcome after adjuvant chemotherapy with fluorouracil-based regimens. </p><p><strong><em>Loeys-Dietz Syndrome</em></strong></p><p>
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Identification of a 3p24.1 chromosomal breakpoint disrupting the TGFBR2 gene in a Japanese individual with a diagnosis of Marfan syndrome (154700) led Mizuguchi et al. (2004) to consider TGFBR2 as a gene underlying a phenotype referred to as Marfan syndrome type 2 (see LDS2, 610168) which mapped to a locus on chromosome 3p. They identified the mutation 1524G-A in TGFBR2 (causing the synonymous amino acid substitution Q508Q and resulting in abnormal splicing; 190182.0004) to segregate with the phenotype in the French family described by Boileau et al. (1993). In 4 unrelated probands, they identified 3 other missense mutations in TGFBR2 that led to loss of function of TGF-beta signaling activity on extracellular matrix formation. These results showed that heterozygous mutations in TGFBR2, a putative tumor suppressor gene implicated in several malignancies, are also associated with inherited connective tissue disorders. Fbn1 (134797)-deficient mice have excessive TGF-beta activity that probably underlies their tendency to develop emphysema and could explain other manifestations of Marfan syndrome (Neptune et al., 2003). Domain-specific germline mutations of TGFB1 (190180) have been described in Camurati-Engelmann syndrome (131300) and affected individuals usually have Marfanoid habitus, i.e., long slender limbs and vertebral deformation. The findings of TGFBR2 mutations provides further evidence that perturbation of TGF-beta signaling contributes to the pathogenesis of extracellular matrix disorders. </p><p>Among the 10 French probands with a diagnosis of Marfan syndrome examined by Mizuguchi et al. (2004), only 4 had mutations in TGFBR2. These 4 individuals shared a common clinical description: prominent aortic, skeletal, and skin/integument anomalies; mild ocular anomalies (except for one individual in the original family who had ectopia lentis); infrequent dural ectasia; and pulmonary abnormalities. </p><p>In 10 families with a disorder characterized by widespread perturbations in cardiovascular, craniofacial, neurocognitive, and skeletal development (see LDS1, 609192), Loeys et al. (2005) reported heterozygous mutations in the genes encoding either TGFBR1 (190181) or TGFBR2. Loeys et al. (2005) considered TGFBR2 as a candidate gene because TGF-beta signaling has a prominent role in vascular and craniofacial development in mouse models (Sanford et al., 1997; Azhar et al., 2003) and because conditional knockout of TGFBR2 in neural crest cells causes cleft palate and defects of the calvaria (Ito et al., 2003). Loeys et al. (2005) sequenced all exons of TGFBR2 and identified heterozygous mutations in 6 of 10 families (LDS2; 610168). The other 4 families were found to have mutations in the TGFBR1 gene (190181). Despite evidence that receptors derived from selected mutated alleles cannot support TGF-beta signal propagation (Mizuguchi et al., 2004), cells derived from individuals heterozygous with respect to these mutations did not show altered kinetics of the acute phase response to administered ligand. Furthermore, tissues derived from affected individuals showed increased expression of both collagen (see 120150) and connective tissue growth factor (CTGF; 121009), as well as nuclear enrichment of phosphorylated SMAD2 (601366), indicative of increased TGF-beta signaling. The data were interpreted as indicating that perturbation of TGF-beta signaling is involved in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease, and mental retardation. </p><p>Loeys et al. (2005) reported that histologic analysis in patients with mutations in TGFBR2 showed loss of elastin (130160) content and disarrayed elastic fibers in the aortic media similar to that in patients with classic Marfan syndrome. Structural analysis showed loss of intimate spatial association between elastin deposits and vascular smooth muscle cells. These characteristics were observed in young children and in the absence of inflammation, suggestive of a severe defect in elastogenesis rather than secondary elastic fiber destruction. In addition, they had previously observed a marked excess of aortic wall collagen in individuals with Marfan syndrome compared with age-matched controls; this collagen excess was accentuated in individuals with mutations in TGFBR2. As multiple collagens normally expressed in the aorta are derived from early-induced target genes of TGF-beta (including COL1A1 and COL3A1), these data were considered consistent with increased (rather than decreased) TGF-beta signaling. </p><p>Disabella et al. (2006) identified 3 different mutations in the TGFBR2 gene (e.g., 190182.0015) in 3 unrelated patients with a phenotype that they identified as Marfan syndrome. None of the patients had major ocular signs. </p><p>In a Japanese boy with clinical findings reported as Shprintzen-Goldberg syndrome (SGS; 182212) but consistent with Loeys-Dietz syndrome, Kosaki et al. (2006) identified heterozygosity for a splice site mutation in the TGFBR2 gene (190182.0016). Because the patient had a bifid uvula and sigmoid configuration of the brachycephalic, left common carotid, and left subclavian arteries, Robinson et al. (2006) suggested that the diagnosis of Loeys-Dietz syndrome would also be appropriate for this patient. </p><p>Singh et al. (2006) searched for TGFBR1 and TGFBR2 mutations in 41 unrelated patients fulfilling the diagnostic criteria for Marfan syndrome of the Ghent nosology (De Paepe et al., 1996) or with the tentative diagnosis of Marfan syndrome, in whom mutations in the FBN1 coding region were not identified. In TGFBR1, 2 mutations and 2 polymorphisms were detected. In TGFBR2, 5 mutations and 6 polymorphisms were identified. Reexamination of patients with a TGFBR1 or TGFBR2 mutation revealed extensive clinical overlap between patients diagnosed with Marfan syndrome type 1 (MFS1; 154700), Marfan syndrome type 2, and Loeys-Dietz syndrome. </p><p>In 2 male patients with Loeys-Dietz syndrome who had a significant history of low bone mineral density and multiple low-impact fractures, Kirmani et al. (2010) identified 2 different heterozygous mutations in the TGFBR2 gene, respectively (see, e.g., 190182.0005). </p><p><strong><em>Susceptibility To Abdominal Aortic Aneurysm</em></strong></p><p>
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For a discussion of a possible association between variation in the TGFBR2 gene and susceptibility to abdominal aortic aneurysm, see AAA (100070).</p><p><strong><em>Role in Left-Right Patterning</em></strong></p><p>
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By high-resolution genotyping of 262 heterotaxy (see HTX1, 306955) subjects and 991 controls, Fakhro et al. (2011) identified a 2-fold excess of subjects with rare genic copy number variations (CNVs) in heterotaxy (14.5% vs 7.4%, p = 1.5 x 10(-4)). Although 7 of 45 heterotaxy CNVs were large chromosomal abnormalities, 38 smaller CNVs altered a total of 61 genes, 22 of which had Xenopus orthologs. In situ hybridization identified 7 of these 22 genes with expression in the ciliated left-right organizer, a marked enrichment compared with 40 of 845 previously studied genes (7-fold enrichment, p less than 10(-6)). Morpholino knockdown in Xenopus of heterotaxy candidate genes demonstrated that 5 genes (NEK2, 604043; ROCK2, 604002; TGFBR2; GALNT11, 615130; and NUP188, 615587) strongly disrupted both morphologic left-right development and expression of PITX2 (601542), a molecular marker of left-right patterning. These effects were specific, because 0 of 13 control genes from rare heterotaxy or control CNVs produced significant left-right abnormalities (p = 0.001). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Han et al. (2005) found that human skin cancers frequently overexpress TGFB1 (190180) but exhibit decreased expression of TGFBR2. In transgenic mouse models in which Tgfb1 expression could be induced at specific stages of skin carcinogenesis in tumor epithelia expressing a dominant-negative Tgfbr2, they observed that late-stage Tgfb1 overexpression in chemically induced skin papillomas did not exert a tumor-suppressive effect and that dominant-negative Tgfbr2 expression selectively blocked Tgfb1-mediated epithelial-to-mesenchymal transition but cooperated with Tgfb1 for tumor invasion. Han et al. (2005) concluded that TGFB1 induces epithelial-to-mesenchymal transition and invasion via distinct mechanisms: TGFB1-mediated epithelial-to-mesenchymal transition requires functional TGFBR2, whereas TGFB1-mediated tumor invasion cooperates with reduced TGFBR2 signaling in tumor epithelia. </p><p>Li et al. (2006) found that mice lacking Tgfbr2 specifically in T cells had lethal inflammation associated with T-cell activation and differentiation. Maturation of Cd8-positive T cells and development of natural killer T cells were inhibited in thymus. Peripheral Foxp3 (300292)-positive regulatory T cell numbers were reduced, and Cd4-positive T-cell survival depended on Tgfb signaling. Li et al. (2006) concluded that TGFB has pleiotropic functions in T cells in terms of T-cell development, tolerance, and homeostasis. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>20 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 COLON CANCER, HEREDITARY NONPOLYPOSIS, TYPE 6, 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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TGFBR2, 2-BP INS, 1931GT
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<br />
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SNP: rs587776769,
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ClinVar: RCV000013324
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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>The mutations identified by Markowitz et al. (1995) included (in the VACO481 cell line) a GT insertion into a 6-bp GTGTGT repeat at nucleotides 1931 to 1936. The resulting frameshift was predicted to substitute a highly basic, 29-amino acid C terminus for the slightly acidic 33-amino acid wildtype C terminus. The same frameshift mutation was detected in the primary colon tumor from which the VACO481 cell line was established, but not in normal colon tissue from the same patient, indicating that the mutation was somatic and that it occurred before cell culture. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 6</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TGFBR2, THR315MET
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<br />
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SNP: rs34833812,
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gnomAD: rs34833812,
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ClinVar: RCV000013325, RCV000247266, RCV000290470, RCV000344037, RCV000626289, RCV001094839, RCV001310481, RCV002276544, RCV004586001
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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>Lu et al. (1998) described a heterozygous germline thr315-to-met (T315M) mutation in an 80-year-old patient with colorectal cancer (HNPCC6; 614331). The other allele was wildtype in the constitutional DNA and showed deletion in tumor tissue. Unlike patients with typical HNPCC, the affected members of this family lacked multiple synchronous, metachronous colorectal cancers and extracolonic cancers. Notably, there was no microsatellite instability in this case. The patient's 2 brothers had developed colon cancer at the ages of 65 and 60. The T315M mutation was found in 2 of the patient's 6 children, neither of whom had developed cancer. Tissue samples could not be obtained from the brothers of the patient. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 ESOPHAGEAL CANCER, 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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TGFBR2, GLU526GLN
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<br />
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SNP: rs121918714,
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ClinVar: RCV000013326, RCV000688883
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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>Tanaka et al. (2000) identified a missense mutation, glu526 to gln (E526Q), in the serine/threonine kinase domain of TGF-beta receptor II in an esophageal carcinoma (133239) tissue sample. The mutant protein could completely inhibit TGF-beta induction of nuclear translocation of SMAD4 protein (600993) in esophageal carcinoma cells. This mutation was not associated with microsatellite instability. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 LOEYS-DIETZ SYNDROME 2</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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TGFBR2, GLN508GLN
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<br />
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SNP: rs121918715,
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ClinVar: RCV000013327
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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 large French family in which a Marfan syndrome-like phenotype mapped to 3p25-p24.2 (LDS2; 610168; Boileau et al., 1993), Mizuguchi et al. (2004) identified the mutation 1524G-A in TGFBR2 segregating with the phenotype. The mutation caused the synonymous amino acid substitution gln508-to-gln (Q508Q) and resulted in abnormal splicing. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 LOEYS-DIETZ SYNDROME 2</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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TGFBR2, LEU308PRO
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<br />
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SNP: rs28934568,
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ClinVar: RCV000013329
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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>Mizuguchi et al. (2004) identified the mutation 923T-C in the TGFBR2 gene, resulting in the amino acid substitution leu308-to-pro (L308P), associated with a phenotype identified as Marfan syndrome type 2 (see LDS2, 610168). </p><p>In a 17-year-old male patient with Loeys-Dietz syndrome with craniofacial involvement who had a significant history of low bone mineral density and multiple low-impact fractures, Kirmani et al. (2010) identified heterozygosity for the L308P mutation in the TGFBR2 gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 LOEYS-DIETZ SYNDROME 2</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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TGFBR2, SER449PHE
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<br />
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SNP: rs104893807,
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ClinVar: RCV000013330
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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>Mizuguchi et al. (2004) identified the heterozygous mutation 1346C-T in the TGFBR2 gene, resulting in the ser449-to-phe (S449F) amino acid substitution, in association with a phenotype identified as Marfan syndrome type 2 (see LDS2, 610168). </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 LOEYS-DIETZ SYNDROME 2</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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TGFBR2, ARG537CYS
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<br />
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SNP: rs104893809,
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ClinVar: RCV000013331, RCV000196289, RCV000529794
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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>Mizuguchi et al. (2004) found the mutation 1609C-T in the TGFBR2 gene, resulting in the amino acid substitution arg537-to-cys (R537C), in association with a phenotype identified as Marfan syndrome type 2 (see LDS2, 610168). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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|
|
<div>
|
|
|
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<div>
|
|
<h4>
|
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<span class="mim-font">
|
|
<strong>.0008 LOEYS-DIETZ SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
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<div>
|
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<span class="mim-text-font">
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|
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|
TGFBR2, TYR336ASN
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|
|
<br />
|
|
|
|
SNP: rs104893812,
|
|
|
|
|
|
|
|
ClinVar: RCV000013332
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
<div>
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<span class="mim-text-font">
|
|
<p>In their family 6 in which a father and 2 daughters had Loeys-Dietz syndrome (LDS2; 610168), Loeys et al. (2005) found a heterozygous mutation in the TGFBR2 gene segregating with the disorder, a 1006T-A transversion in exon 4 that resulted in a tyr336-to-asn (Y336N) substitution in the kinase domain of the protein. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0009 LOEYS-DIETZ SYNDROME 2</strong>
|
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</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
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TGFBR2, ALA355PRO
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<br />
|
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|
|
SNP: rs104893813,
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|
|
gnomAD: rs104893813,
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|
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|
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ClinVar: RCV000013333, RCV001193761, RCV001253567, RCV001851822
|
|
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|
|
|
</span>
|
|
</div>
|
|
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<div>
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<span class="mim-text-font">
|
|
<p>In a family in which members of 3 generations had the Loeys-Dietz syndrome (LDS2; 610168), Loeys et al. (2005) found heterozygosity in affected individuals for a 1063G-C transversion in exon 4 of the TGFBR2 gene, resulting in an ala355-to-pro (A355P) substitution in the kinase domain of the protein. </p>
|
|
</span>
|
|
</div>
|
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|
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|
<div>
|
|
<br />
|
|
</div>
|
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</div>
|
|
|
|
|
|
<div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 LOEYS-DIETZ SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
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|
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|
TGFBR2, GLY357TRP
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|
<br />
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|
|
SNP: rs104893814,
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|
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|
|
ClinVar: RCV000013334
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In their family 4, Loeys et al. (2005) found that the single patient with Loeys-Dietz syndrome (LDS2; 610168) was heterozygous for a 1069G-T transversion in exon 4 of the TGFBR2 gene, resulting in a gly357-to-trp (G357W) amino acid substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 LOEYS-DIETZ SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
COLON CANCER, HEREDITARY NONPOLYPOSIS, TYPE 6, SOMATIC, INCLUDED
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TGFBR2, ARG528HIS
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|
|
<br />
|
|
|
|
SNP: rs104893815,
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|
|
|
|
|
|
|
ClinVar: RCV000013335, RCV000013336, RCV000200178, RCV000211858, RCV000654809
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In their family 2, Loeys et al. (2005) demonstrated that the single case of Loeys-Dietz syndrome (LDS2; 610168) was heterozygous for a 1583G-A transition in exon 7 of the TGFBR2 gene that resulted in an arg528-to-his (R528H) amino acid substitution. R528H had been reported as a somatic event in colon cancer and shown to cause loss of function in a transient transfection assay (Grady et al., 1999). </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 LOEYS-DIETZ SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TGFBR2, ARG528CYS
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs104893810,
|
|
|
|
|
|
|
|
ClinVar: RCV000013337, RCV000197944, RCV000691207, RCV000825631, RCV003904831, RCV004668719
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In their family 3 with a isolated case of Loeys-Dietz syndrome (LDS2; 610168), Loeys et al. (2005) found a 1582C-T transition in exon 7 of the TGFBR2 gene, resulting in an arg528-to-cys (R528C) amino acid substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 LOEYS-DIETZ SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TGFBR2, IVS1, A-G, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs779131465,
|
|
|
|
|
|
gnomAD: rs779131465,
|
|
|
|
|
|
ClinVar: RCV000013338, RCV001183529, RCV001374778, RCV003221782
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a single individual with Loeys-Dietz syndrome (LDS2; 610168) in their family 5, Loeys et al. (2005) found an A-to-G transition in the splice acceptor sequence, -2 position, in intron 1 of the TGFBR2 gene (95-2A-G). This mutation induced use of a cryptic splice acceptor in exon 2 that resulted in the in-frame skipping of nucleotides 95-112 and deletion of residues 32-37 in the extracellular domain of the TGFBR2 protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 LOEYS-DIETZ SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TGFBR2, ARG460CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104893811,
|
|
|
|
|
|
|
|
ClinVar: RCV000013339, RCV000199227, RCV000252297, RCV000654788
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 families with thoracic aortic aneurysm and dissection mapping to chromosome 3p25-p24 (LDS2; 610168), Pannu et al. (2005) detected a 1378C-T transition in exon 5 of the TGFBR2 gene that resulted in the substitution of cysteine for arginine at amino acid 460 (R460C). The clinical features of one of these families had been reported by Hasham et al. (2003). The proband of the second family, a 4-generation family with autosomal dominant thoracic aortic aneurysm and dissection, presented at 41 years of age with an aneurysm of the ascending aorta and mitral valve prolapse. Affected members of the family presented primarily with type A dissections. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 LOEYS-DIETZ SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TGFBR2, ARG460HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104893816,
|
|
|
|
|
|
gnomAD: rs104893816,
|
|
|
|
|
|
ClinVar: RCV000013340, RCV000196002, RCV000702388
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 large kindreds with autosomal dominant thoracic aortic aneurysm and dissection (LDS2; 610168), Pannu et al. (2005) found a mutation in exon 5 of the TGFBR2 gene, 1379G-A, changing arginine-460 to histidine (R460H). The proband of 1 family presented with type B aortic dissection at the age of 43 years. Some affected individuals in this family also had carotid and cerebral aneurysms and dissections, as well as pulmonary artery enlargement. The proband of the second family presented at age 42 years with a type A aortic dissection that was surgically repaired. In the first family, affected individuals presented with aneurysms of both the ascending and descending thoracic aorta; in the second family, the majority of individuals presented with aneurysm of the ascending thoracic aorta. </p><p>Disabella et al. (2006) identified a heterozygous R460H mutation in a 24-year-old woman with a phenotype they identified as Marfan syndrome. An affected father and aunt died of aortic root dissection at age 37 and 45 years, respectively. </p><p>Law et al. (2006) described the clinical findings and natural history of 22 carriers of the R460H mutation in TGFBR2 gene in a 5-generation kindred ascertained by familial aortic dissection. There had been 8 sudden deaths; the cause of death was aortic dissection in all 6 cases in which a postmortem examination was performed. Three individuals had undergone aortic replacement surgery. Dissection had occurred throughout the aorta, and in 1 case in the absence of aortic root dilatation. Subarachnoid hemorrhage due to a ruptured berry aneurysm had occurred in 2 individuals. Four gene carriers and 1 deceased family member who were investigated had tortuous cerebral blood vessels. One had tortuous vertebral arteries, 2 had tortuous carotid arteries, and 1 had tortuous abdominal aorta. Two individuals were found to have a brachiocephalic artery aneurysm and a subclavian artery aneurysm, respectively. Despite the predisposition to aortic dilatation and dissection, members of the family did not frequently manifest the skeletal features of Marfan syndrome, with the exception of joint hypermobility. None had ocular lens dislocation. Striae and hernias were common. There was some overlap with Ehlers-Danlos syndrome type IV (130050), with soft translucent skin that was easily bruised. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 LOEYS-DIETZ SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TGFBR2, IVS5AS, -2A-G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776770,
|
|
|
|
|
|
|
|
ClinVar: RCV000013341, RCV004700224
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese boy with clinical findings reported as Shprintzen-Goldberg syndrome (182212) but consistent with Loeys-Dietz syndrome (LDS2; 610168), Kosaki et al. (2006) identified heterozygosity for a -2A-G transition at the splice acceptor site in intron 5 of the TGFBR2 gene. Because the patient had a bifid uvula and sigmoid configuration of the brachycephalic, left common carotid and left subclavian arteries, Robinson et al. (2006) suggested that the diagnosis of Loeys-Dietz syndrome would also be appropriate for this patient. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 LOEYS-DIETZ SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TGFBR2, MET425VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104893817,
|
|
|
|
|
|
|
|
ClinVar: RCV000013342, RCV001325332
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a man with a diagnosis of Marfan syndrome type 2 (LDS2; 610168), Disabella et al. (2006) identified a heterozygous mutation in the TGFBR2 gene, resulting in a met425-to-val (M425V) substitution in the serine/threonine kinase domain of the protein. The mutation was not identified in 192 healthy controls. The patient's affected father died at age 40 years from aortic dissection. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 LOEYS-DIETZ SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TGFBR2, PRO427LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104893818,
|
|
|
|
|
|
|
|
ClinVar: RCV000013343
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Loeys-Dietz syndrome type 2 (LDS2; 610168) , Loeys et al. (2006) detected a missense mutation, pro427 to leu (P427L), in the TGFBR2 gene. The female patient had aortic root aneurysm with dissection and other arterial aneurysms, arterial tortuosity, vascular rapture during pregnancy, uterine rupture, and splenic rupture. Easy bruising, velvety skin, and joint laxity were also present. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 LOEYS-DIETZ SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TGFBR2, ARG495TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104893819,
|
|
|
|
|
|
|
|
ClinVar: RCV000013344, RCV000157519, RCV000195964, RCV000253575, RCV000763512
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Loeys et al. (2006) pictured a patient with Loeys-Dietz syndrome (LDS2; 610168) who carried a heterozygous nonsense mutation, arg495 to stop (R495X), in the TGFBR2 gene. The man showed hypertelorism and bifid uvula. Immunostaining of aortic tissue revealed increased nuclear accumulation of phosphorylated Smad2 (601366) and levels of expression of connective-tissue growth factor (CTGF; 121009), both indicative of increased TGF-beta signaling. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 LOEYS-DIETZ SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TGFBR2, ARG497TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs863223852,
|
|
|
|
|
|
gnomAD: rs863223852,
|
|
|
|
|
|
ClinVar: RCV000199072, RCV000244033, RCV000490801, RCV000680613, RCV001449740
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male patient of German origin with Loeys-Dietz syndrome (LDS2; 610168), Singh et al. (2006) identified a c.1489C-T transition in exon 6 of the TGFBR2 gene that resulted in premature termination of the protein at arg497 (R497X). Height was 195 cm, while family members were of rather short stature. Dilated ascending aorta without dissection was replaced at a size of 8.0 cm. Involvement of the skeletal system included pectus excavatum, scoliosis, and arachnodactyly with positive thumb and wrist signs. Ocular symptoms were absent. The patient was lost to follow-up. </p><p>Tooley et al. (2017) reported a 3-generation pedigree with LDS2 segregating the R497X mutation. The proband was a 48-year-old man who had been referred for genetic testing because his maternal cousin had undergone surgery for a dilated aortic root and was found to carry the R497X mutation, prompting cascade testing. The proband had a right inguinal hernia repair at age 14 years, resection of Meckel diverticulum at age 16, and gastric adenocarcinoma at 42 years of age, treated with subtotal gastrectomy and chemotherapy. A dilated aortic root of 43 mm was present at the sinus of Valsalva. His oldest son had hypertelorism, downslanting palpebral fissures, and bifid uvula. Echocardiogram showed a dilated aortic root of 40 mm. The second affected son was diagnosed antenatally with hypoplastic left heart syndrome (HLHS) on ultrasound scan at 20 weeks' gestation. At 12 years of age he had subtle nasal speech but no other features to suggest LDS. At 14 years of age he had developed downslanting palpebral fissures, hypertelorism, and arachnodactyly; these were not appreciated before. The neoascending aorta was found to be 50 mm at that time. The last affected child was 8 months old and had been diagnosed with Loeys-Dietz syndrome, with aortic root measurement at the upper limit of normal. The proband and his 2 older affected sons were being treated with irbesartan. The proband's mother and maternal aunt, ages 73 and 68 years, respectively, were both mutation carriers and were asymptomatic at the time of the proband's diagnosis. </p>
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