3729 lines
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Entry
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- *190230 - TRANSFORMING GROWTH FACTOR, BETA-3; TGFB3
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*190230</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/190230">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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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=ENSG00000119699;t=ENST00000238682" 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=7043" 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=190230" 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=ENSG00000119699;t=ENST00000238682" 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_001329938,NM_001329939,NM_003239" 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_003239" 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=190230" 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=01829&isoform_id=01829_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/TGFB3" 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/37096,135684,339552,553517,1200236,3928927,4507465,17391184,18641277,22531294,27501940,30583413,37683094,37683095,119601655,147836719,148342461,189069306,193783809,1050108310,1050112780" 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/P10600" 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=7043" 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=ENSG00000119699;t=ENST00000238682" 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=TGFB3" 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=TGFB3" 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+7043" 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/TGFB3" 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:7043" 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/7043" 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=chr14&hgg_gene=ENST00000238682.8&hgg_start=75958097&hgg_end=75983011&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11769" 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/tgfb3" 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=190230[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=190230[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/TGFB3/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/ENSG00000119699" 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=TGFB3" 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=TGFB3" 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=TGFB3" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://grenada.lumc.nl/LOVD2/ARVC/home.php?select_db=TGFB3" title="ARVD/C Genetic Variants Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">ARVD/C Genetic Variants Da…</a></div><div style="margin-left: 0.5em;"><a href="http://www.arvcdatabase.info" title="ARVD/C Genes Variants Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">ARVD/C Genes Variants Data…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TGFB3&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/PA36483" 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:11769" 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:98727" 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/TGFB3#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:98727" 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/7043/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=7043" 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://zfin.org/ZDB-GENE-030723-4" 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:7043" 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=TGFB3&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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190230
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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-3; TGFB3
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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=TGFB3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TGFB3</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/14/405?start=-3&limit=10&highlight=405">14q24.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr14:75958097-75983011&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'})">14:75,958,097-75,983,011</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
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<a href="/clinicalSynopsis/table?mimNumber=107970,615582" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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View Clinical Synopses
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</a>
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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<a href="/geneMap/14/405?start=-3&limit=10&highlight=405">
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14q24.3
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Arrhythmogenic right ventricular dysplasia 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/107970"> 107970 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Loeys-Dietz syndrome 5
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/615582"> 615582 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/190230" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/190230" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
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</div>
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<p>Beta-type transforming growth factors are polypeptides that act hormonally to control the proliferation and differentiation of multiple cell types. A cDNA clone for a third form of TGFB was isolated by <a href="#15" class="mim-tip-reference" title="ten Dijke, P., Geurts van Kessel, A. H. M., Foulkes, J. G., Le Beau, M. M. <strong>Transforming growth factor type beta-3 maps to human chromosome 14, region q23-q24.</strong> Oncogene 3: 721-724, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2577876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2577876</a>]" pmid="2577876">ten Dijke et al. (1988)</a>. The C-terminal 112 amino acids of TGF-beta-3 share approximately 80% sequence identity with beta-1 (<a href="/entry/190180">190180</a>) and beta-2 (<a href="/entry/190220">190220</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2577876" 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="Moren, A., Ichijo, H., Miyazono, K. <strong>Molecular cloning and characterization of the human and porcine transforming growth factor-beta type III receptors.</strong> Biochem. Biophys. Res. Commun. 189: 356-362, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1333192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1333192</a>] [<a href="https://doi.org/10.1016/0006-291x(92)91566-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1333192">Moren et al. (1992)</a> isolated full-length cDNAs for TGFB3 from a human placenta cDNA library. The coding region encoded a protein of 849 amino acids with a single transmembrane domain and a short stretch of the intracellular domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1333192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By Southern analysis of DNA prepared from somatic cell hybrids and by in situ hybridization, <a href="#16" class="mim-tip-reference" title="ten Dijke, P., Hansen, P., Iwata, K. K., Pieler, C., Foulkes, J. G. <strong>Identification of another member of the transforming growth factor type beta gene family.</strong> Proc. Nat. Acad. Sci. 85: 4715-4719, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3164476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3164476</a>] [<a href="https://doi.org/10.1073/pnas.85.13.4715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3164476">ten Dijke et al. (1988)</a> assigned the TGFB3 gene to chromosome 14q23-q24. <a href="#1" class="mim-tip-reference" title="Barton, D. E., Foellmer, B. E., Du, J., Tamm, J., Derynck, R., Francke, U. <strong>Chromosomal mapping of genes for transforming growth factors beta-2 and beta-3 in man and mouse: dispersion of TGF-beta gene family.</strong> Oncogene Res. 3: 323-331, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3226728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3226728</a>]" pmid="3226728">Barton et al. (1988)</a> likewise assigned the TGFB3 gene to chromosome 14 and regionalized it to 14q24 by Southern blot analysis of hybrid cell DNAs and by in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3226728+3164476" 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>The mouse Tgfb3 gene was mapped to chromosome 12 (<a href="#1" class="mim-tip-reference" title="Barton, D. E., Foellmer, B. E., Du, J., Tamm, J., Derynck, R., Francke, U. <strong>Chromosomal mapping of genes for transforming growth factors beta-2 and beta-3 in man and mouse: dispersion of TGF-beta gene family.</strong> Oncogene Res. 3: 323-331, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3226728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3226728</a>]" pmid="3226728">Barton et al., 1988</a>; <a href="#4" class="mim-tip-reference" title="Dickinson, M. E., Kobrin, M. S., Silan, C. M., Kingsley, D. M., Justice, M. J., Miller, D. A., Ceci, J. D., Lock, L. F., Lee, A., Buchberg, A. M., Siracusa, L. D., Lyons, K. M., Derynck, R., Hogan, B. L. M., Copeland, N. G., Jenkins, N. A. <strong>Chromosomal localization of seven members of the murine TGF-beta superfamily suggests close linkage to several morphogenetic mutant loci.</strong> Genomics 6: 505-520, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1970330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1970330</a>] [<a href="https://doi.org/10.1016/0888-7543(90)90480-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1970330">Dickinson et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3226728+1970330" 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="#5" class="mim-tip-reference" title="Graycar, J. L., Miller, D. A., Arrick, B. A., Lyons, R. M., Moses, H. L., Derynck, R. <strong>Human transforming growth factor-beta-3: recombinant expression, purification, and biological activities in comparison with transforming growth factors-beta-1 and beta-2.</strong> Molec. Endocr. 3: 1977-1986, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2628733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2628733</a>] [<a href="https://doi.org/10.1210/mend-3-12-1977" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2628733">Graycar et al. (1989)</a> purified to apparent homogeneity human TGFB3 and evaluated its activities in comparison to TGFB1 and TGFB2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2628733" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Lee, B.-S., Nowak, R. A. <strong>Human leiomyoma smooth muscle cells show increased expression of transforming growth factor-beta-3 (TGF-beta-3) and altered responses to the antiproliferative effects of TGF-beta.</strong> J. Clin. Endocr. Metab. 86: 913-920, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11158066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11158066</a>] [<a href="https://doi.org/10.1210/jcem.86.2.7237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11158066">Lee and Nowak (2001)</a> compared expression of the TGFB isoforms in normal myometrium and benign leiomyoma tumors of the uterus (<a href="/entry/150699">150699</a>) and examined the effects of TGFBs on cell proliferation and collagen production by these cells in vitro. Northern blot analysis showed that the levels of TGFB1 mRNA were similar between leiomyoma and myometrium, whereas leiomyoma showed 5-fold higher levels of expression of TGFB3 mRNA than autologous myometrium. Expression of TGFB3 protein detected by immunohistochemistry was much more intense in leiomyoma tissues than in corresponding myometrium. The authors concluded that their results support the hypothesis that alterations in the TGFB system produce loss of sensitivity to the antiproliferative effects of TGFB, and increased expression of TGFB3 may contribute to the growth of these tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11158066" 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>Epithelial mesenchymal transformation (EMT) of the medial edge epithelial seam creates palatal confluence. <a href="#11" class="mim-tip-reference" title="Nawshad, A., Hay, E. D. <strong>TGF-beta-3 signaling activates transcription of the LEF1 gene to induce epithelial mesenchymal transformation during mouse palate development.</strong> J. Cell Biol. 163: 1291-1301, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14691138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14691138</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14691138[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.200306024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14691138">Nawshad and Hay (2003)</a> showed that Tgfb3 brought about palatal seam EMT in mice by stimulating expression of Lef1 (<a href="/entry/153245">153245</a>) in medial edge epithelial cells. Tgfb3 activated Lef1 in the absence of beta-catenin (CTNNB1; <a href="/entry/116806">116806</a>) via nuclear phospho-Smad2 (<a href="/entry/601366">601366</a>) and Smad4 (<a href="/entry/600993">600993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14691138" 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 transfected 293 EBNA cells, <a href="#17" class="mim-tip-reference" title="Venza, I., Visalli, M., Parrillo, L., De Felice, M., Teti, D., Venza, M. <strong>MSX1 and TGF-beta-3 are novel target genes functionally regulated by FOXE1.</strong> Hum. Molec. Genet. 20: 1016-1025, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21177256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21177256</a>] [<a href="https://doi.org/10.1093/hmg/ddq547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21177256">Venza et al. (2011)</a> showed that MSX1 (<a href="/entry/142983">142983</a>) and TGFB3 are direct targets of the forkhead transcription factor FOXE1 (<a href="/entry/602617">602617</a>). They found that mutations in the FOXE1 forkhead domain, which are linked to Bamforth-Lazarus syndrome (<a href="/entry/241850">241850</a>), reduced or eliminated FOXE1-dependent MSX1 and TGFB3 upregulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21177256" 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>Arrhythmogenic Right Ventricular Dysplasia 1</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Beffagna, G., Occhi, G., Nava, A., Vitiello, L., Ditadi, A., Basso, C., Bauce, B., Carraro, G., Thiene, G., Towbin, J. A., Danieli, G. A., Rampazzo, A. <strong>Regulatory mutations in transforming growth factor-beta-3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1.</strong> Cardiovasc. Res. 65: 366-373, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15639475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15639475</a>] [<a href="https://doi.org/10.1016/j.cardiores.2004.10.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15639475">Beffagna et al. (2005)</a> screened 38 members of a 4-generation Italian family with arrhythmogenic right ventricular dysplasia-1 (ARVD1; <a href="/entry/107970">107970</a>), previously reported by <a href="#13" class="mim-tip-reference" title="Rampazzo, A., Beffagna, G., Nava, A., Occhi, G., Bauce, B., Noiato, M., Basso, C., Frigo, G., Thiene, G., Towbin, J., Danieli, G. A. <strong>Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1): confirmation of locus assignment and mutation screening of four candidate genes.</strong> Europ. J. Hum. Genet. 11: 69-76, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529708</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529708">Rampazzo et al. (2003)</a>, and identified a mutation (<a href="#0001">190230.0001</a>) in the 5-prime UTR of the TGFB3 gene. Subsequent screening of 30 unrelated individuals with ARVD1 led to the identification of an additional mutation (<a href="#0002">190230.0002</a>) in the 3-prime UTR of the TGFB3 gene in 1 patient. In transfection studies, both mutations showed significantly higher luciferase reporter activity (about 2.5-fold, p less than 0.01) compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15639475+12529708" 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 case-control study of 711 Japanese individuals with ossification of the posterior longitudinal ligament of the spine (OPLL; <a href="/entry/602475">602475</a>) and 896 controls, <a href="#6" class="mim-tip-reference" title="Horikoshi, T., Maeda, K., Kawaguchi, Y., Chiba, K., Mori, K., Koshizuka, Y., Hirabayashi, S., Sugimori, K., Matsumoto, M., Kawaguchi, H., Takahashi, M., Inoue, H., Kimura, T., Matsusue, Y., Inoue, I., Baba, H., Nakamura, K., Ikegawa, S. <strong>A large-scale genetic association study of ossification of the posterior longitudinal ligament of the spine.</strong> Hum. Genet. 119: 611-616, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16609882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16609882</a>] [<a href="https://doi.org/10.1007/s00439-006-0170-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16609882">Horikoshi et al. (2006)</a> found an association between an intronic SNP in the TGFB3 gene (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2268624;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2268624</a>) and OPLL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16609882" 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 5</em></strong></p><p>
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In a 9-year-old girl with low muscle mass, growth retardation, and distal arthrogryposis, who also exhibited features of Loeys-Dietz syndrome (LDS5; <a href="/entry/615582">615582</a>) as well as Marfan (<a href="/entry/154700">154700</a>) and Beals (<a href="/entry/121050">121050</a>) syndromes, but who did not meet the diagnostic criteria for those syndromes, <a href="#14" class="mim-tip-reference" title="Rienhoff, H. Y., Jr., Yeo, C.-Y., Morissette, R., Khrebtukova, I., Melnick, J., Luo, S., Leng, N., Kim, Y.-J., Schroth, G. Westwick, J., Vogel, H., McDonnell, N., Hall, J. G., Whitman, M. <strong>A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome.</strong> Am. J. Med. Genet. 161A: 2040-2046, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23824657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23824657</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23824657[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/10.1002/ajmg.a.36056" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23824657">Rienhoff et al. (2013)</a> analyzed 6 genes known to be associated with those disorders, including TGFB2 (<a href="/entry/190220">190220</a>), TGFBR1 (<a href="/entry/190181">190181</a>), TGFBR2 (<a href="/entry/190182">190182</a>), SMAD3 (<a href="/entry/603109">603109</a>), FBN1 (<a href="/entry/134797">134797</a>), and FBN2 (<a href="/entry/612570">612570</a>), but found no mutations. Exome sequencing revealed a de novo missense mutation in the TGFB3 gene (C409Y; <a href="#0003">190230.0003</a>), encoding a nonfunctional TGFB3 ligand. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23824657" 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 10.5-year-old girl with low muscle mass, marfanoid features, and bifid uvula, who was negative for mutation in FBN1, TGFBR1, TGFBR2, TGFB2, and SMAD3, <a href="#9" class="mim-tip-reference" title="Matyas, G., Naef, P., Tollens, M., Oexle, K. <strong>De novo mutation of the latency-associated peptide domain of TGFB3 in a patient with overgrowth and Loeys-Dietz syndrome features. (Letter)</strong> Am. J. Med. Genet. 164A: 2141-2143, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24798638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24798638</a>] [<a href="https://doi.org/10.1002/ajmg.a.36593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24798638">Matyas et al. (2014)</a> identified heterozygosity for a de novo missense mutation in the TGFB3 gene (R300Q; <a href="#0004">190230.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24798638" 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 large Dutch pedigree with syndromic aortic aneurysm, negative for mutation in 15 known thoracic aortic aneurysm/dissection (TAAD)-associated genes, <a href="#3" class="mim-tip-reference" title="Bertoli-Avella, A. M., Gillis, E., Morisaki, H., Verhagen, J. M. A., de Graaf, B. M., van de Beek, G., Gallo, E., Kruithof, B. P. T., Venselaar, H., Myers, L. A., Laga, S., Doyle, A. J., and 33 others. <strong>Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections.</strong> J. Am. Coll. Cardiol. 65: 1324-1336, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25835445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25835445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25835445[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jacc.2015.01.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25835445">Bertoli-Avella et al. (2015)</a> identified heterozygosity for a splice site mutation in the TGFB3 gene (<a href="#0005">190230.0005</a>). The mutation, which segregated with disease in the family, was not found in variant databases. Analysis of TGFB3 in an additional 470 probands with syndromic or nonsyndromic TAAD, the majority of whom had been screened for mutation in all known TAAD genes, revealed TGFB3 mutations in 10 probands, including 4 different missense mutations, 2 single-base deletions, and 1 nonsense mutation (see, e.g., <a href="#0006">190230.0006</a>-<a href="#0008">190230.0008</a>). The authors noted that although studies in a Xenopus model led <a href="#14" class="mim-tip-reference" title="Rienhoff, H. Y., Jr., Yeo, C.-Y., Morissette, R., Khrebtukova, I., Melnick, J., Luo, S., Leng, N., Kim, Y.-J., Schroth, G. Westwick, J., Vogel, H., McDonnell, N., Hall, J. G., Whitman, M. <strong>A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome.</strong> Am. J. Med. Genet. 161A: 2040-2046, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23824657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23824657</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23824657[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/10.1002/ajmg.a.36056" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23824657">Rienhoff et al. (2013)</a> to hypothesize that the mutated C409Y allele results in a nonfunctional protein, <a href="#3" class="mim-tip-reference" title="Bertoli-Avella, A. M., Gillis, E., Morisaki, H., Verhagen, J. M. A., de Graaf, B. M., van de Beek, G., Gallo, E., Kruithof, B. P. T., Venselaar, H., Myers, L. A., Laga, S., Doyle, A. J., and 33 others. <strong>Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections.</strong> J. Am. Coll. Cardiol. 65: 1324-1336, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25835445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25835445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25835445[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jacc.2015.01.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25835445">Bertoli-Avella et al. (2015)</a> observed increased TGFB signaling in aortic tissue from a patient with a different missense mutation (D263H; <a href="#0008">190230.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25835445+23824657" 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="Proetzel, G., Pawlowski, S. A., Wiles, M. V., Yin, M., Boivin, G. P., Howles, P. N., Ding, J., Ferguson, M. W. J., Doetschman, T. <strong>Transforming growth factor-beta-3 is required for secondary palate fusion.</strong> Nature Genet. 11: 409-414, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7493021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7493021</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=7493021[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/ng1295-409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7493021">Proetzel et al. (1995)</a> produced Tgfb3-null mice in which exon 6 of the Tgfb3 gene was replaced by the neomycin-resistance gene. Whereas heterozygotes had no apparent phenotypic change, homozygotes had an incompletely penetrant failure of the palatal shelves to fuse, leading to cleft palate. The defect appeared to result from impaired adhesion of the apposing medial edge epithelial of the palatal shelves and subsequent elimination of the midline epithelial seam. No craniofacial abnormalities were observed. Defective palatogenesis was also found in homozygous Tgfb3-null mutant mice by <a href="#7" class="mim-tip-reference" title="Kaartinen, V., Voncken, J. W., Shuler, C., Warburton, D., Bu, D., Heisterkamp, N., Groffen, J. <strong>Abnormal lung development and cleft palate in mice lacking TGF-beta-3 indicates defects of epithelial-mesenchymal interaction.</strong> Nature Genet. 11: 415-421, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7493022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7493022</a>] [<a href="https://doi.org/10.1038/ng1295-415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7493022">Kaartinen et al. (1995)</a> who also found a consistent delay in pulmonary development. They suggested that the study demonstrates an essential function for TGF-beta-3 in normal palate and lung morphogenesis and implicates this cytokine in epithelial-mesenchymal interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7493022+7493021" 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> rs770828281 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs770828281;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/rs770828281?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=rs770828281" 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=rs770828281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 9 affected and 3 unaffected members of a 4-generation Italian family with arrhythmogenic right ventricular dysplasia-1 (ARVD1; <a href="/entry/107970">107970</a>) previously reported by <a href="#13" class="mim-tip-reference" title="Rampazzo, A., Beffagna, G., Nava, A., Occhi, G., Bauce, B., Noiato, M., Basso, C., Frigo, G., Thiene, G., Towbin, J., Danieli, G. A. <strong>Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1): confirmation of locus assignment and mutation screening of four candidate genes.</strong> Europ. J. Hum. Genet. 11: 69-76, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529708</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529708">Rampazzo et al. (2003)</a>, <a href="#2" class="mim-tip-reference" title="Beffagna, G., Occhi, G., Nava, A., Vitiello, L., Ditadi, A., Basso, C., Bauce, B., Carraro, G., Thiene, G., Towbin, J. A., Danieli, G. A., Rampazzo, A. <strong>Regulatory mutations in transforming growth factor-beta-3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1.</strong> Cardiovasc. Res. 65: 366-373, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15639475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15639475</a>] [<a href="https://doi.org/10.1016/j.cardiores.2004.10.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15639475">Beffagna et al. (2005)</a> identified a G-to-A transition at cDNA position -36 in the 5-prime UTR of the TGFB3 gene (c.-36G-A, NM_003239). In transfection studies, the mutant construct showed significantly higher luciferase reporter activity (about 2.5-fold, p less than 0.01) compared to wildtype constructs. All clinically affected members of the family had the mutation; <a href="#2" class="mim-tip-reference" title="Beffagna, G., Occhi, G., Nava, A., Vitiello, L., Ditadi, A., Basso, C., Bauce, B., Carraro, G., Thiene, G., Towbin, J. A., Danieli, G. A., Rampazzo, A. <strong>Regulatory mutations in transforming growth factor-beta-3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1.</strong> Cardiovasc. Res. 65: 366-373, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15639475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15639475</a>] [<a href="https://doi.org/10.1016/j.cardiores.2004.10.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15639475">Beffagna et al. (2005)</a> stated that detection of the mutation in 3 apparently healthy individuals was consistent with reduced penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15639475+12529708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a young man with arrhythmogenic right ventricular dysplasia-1 (ARVD1; <a href="/entry/107970">107970</a>), <a href="#2" class="mim-tip-reference" title="Beffagna, G., Occhi, G., Nava, A., Vitiello, L., Ditadi, A., Basso, C., Bauce, B., Carraro, G., Thiene, G., Towbin, J. A., Danieli, G. A., Rampazzo, A. <strong>Regulatory mutations in transforming growth factor-beta-3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1.</strong> Cardiovasc. Res. 65: 366-373, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15639475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15639475</a>] [<a href="https://doi.org/10.1016/j.cardiores.2004.10.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15639475">Beffagna et al. (2005)</a> identified a C-to-T transition at cDNA position 1723 in the 3-prime UTR of the TGFB3 gene (c.1723C-T, NM_003239). In transfection studies, the mutant construct showed significantly higher luciferase reporter activity (about 2.5-fold, p less than 0.01) compared to wildtype constructs. The patient had a brother who died suddenly at the age of 16 and was found to have ARVD at autopsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15639475" 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">rs398122984 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122984;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=rs398122984" 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=rs398122984" 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=RCV000077765" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000077765" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000077765</a>
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<p>In a 9-year-old girl with low muscle mass, growth retardation, and distal arthrogryposis, who also exhibited blue sclerae, bifid uvula, and hyperextensibility of the large joints (LDS5; <a href="/entry/615582">615582</a>), <a href="#14" class="mim-tip-reference" title="Rienhoff, H. Y., Jr., Yeo, C.-Y., Morissette, R., Khrebtukova, I., Melnick, J., Luo, S., Leng, N., Kim, Y.-J., Schroth, G. Westwick, J., Vogel, H., McDonnell, N., Hall, J. G., Whitman, M. <strong>A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome.</strong> Am. J. Med. Genet. 161A: 2040-2046, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23824657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23824657</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23824657[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/10.1002/ajmg.a.36056" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23824657">Rienhoff et al. (2013)</a> identified heterozygosity for a de novo c.1226G-A transition in the TGFB3 gene, resulting in a cys409-to-tyr (C409Y) substitution. The mutation was not found in the dbSNP (build 130), Exome Variant Server, or 1000 Genomes Project databases. Functional analysis in transfected HEK293T cells showed that wildtype TGFB3 generated a transcriptional signal whereas the C409Y mutant did not. In Xenopus embryos, a 1:1 ratio of mutant to wildtype TGFB3 RNA diminished the SMAD2 (<a href="/entry/601366">601366</a>) and ERK1 (<a href="/entry/601795">601795</a>)/2 (<a href="/entry/176948">176948</a>) signals to approximately 40% and 60% of that generated by wildtype TGFB3 RNA alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23824657" 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 5</strong>
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TGFB3, ARG300GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777617 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777617;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=rs587777617" 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=rs587777617" 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=RCV000133467 OR RCV000417684" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000133467, RCV000417684" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000133467...</a>
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<p>In a 10.5-year-old girl with Loeys-Dietz syndrome-5 (LDS5; <a href="/entry/615582">615582</a>), <a href="#9" class="mim-tip-reference" title="Matyas, G., Naef, P., Tollens, M., Oexle, K. <strong>De novo mutation of the latency-associated peptide domain of TGFB3 in a patient with overgrowth and Loeys-Dietz syndrome features. (Letter)</strong> Am. J. Med. Genet. 164A: 2141-2143, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24798638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24798638</a>] [<a href="https://doi.org/10.1002/ajmg.a.36593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24798638">Matyas et al. (2014)</a> identified heterozygosity for a de novo c.899G-A transition in the TGFB3 gene, resulting in an arg300-to-gln (R300Q) substitution at the last residue of the potential furin (<a href="/entry/136950">136950</a>) cleavage site in the C-terminal end of the LAP domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24798638" 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="0005" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0005 LOEYS-DIETZ SYNDROME 5</strong>
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TGFB3, IVS4DS, T-C, +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">rs875989816 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs875989816;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=rs875989816" 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=rs875989816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000185629" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000185629" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000185629</a>
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<p>In 4 affected individuals over 3 generations of a large Dutch family with Loeys-Dietz syndrome-5 (LDS5; <a href="/entry/615582">615582</a>), <a href="#3" class="mim-tip-reference" title="Bertoli-Avella, A. M., Gillis, E., Morisaki, H., Verhagen, J. M. A., de Graaf, B. M., van de Beek, G., Gallo, E., Kruithof, B. P. T., Venselaar, H., Myers, L. A., Laga, S., Doyle, A. J., and 33 others. <strong>Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections.</strong> J. Am. Coll. Cardiol. 65: 1324-1336, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25835445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25835445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25835445[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jacc.2015.01.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25835445">Bertoli-Avella et al. (2015)</a> identified heterozygosity for a c.754+2T-C transition (c.754+2T-C, NM_003239.2) in intron 4 of the TGFB3 gene. The mutation, which segregated with disease in the family, was not found in the Exome Variant Server, Genome of the Netherlands, or 1000 Genomes Project databases. Analysis of cDNA from 2 affected individuals confirmed that the mutation causes skipping of exon 4, resulting in an in-frame deletion of 36 amino acids (Glu216_Lys251del) involving a central beta strand and subsequent surface loop in the LAP domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25835445" 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="0006" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0006 LOEYS-DIETZ SYNDROME 5</strong>
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TGFB3, ARG300TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs796051885 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796051885;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=rs796051885" 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=rs796051885" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000185630 OR RCV000332014 OR RCV001171230" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000185630, RCV000332014, RCV001171230" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000185630...</a>
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<p>In affected members of 4 unrelated families with Loeys-Dietz syndrome-5 (LDS5; <a href="/entry/615582">615582</a>), <a href="#3" class="mim-tip-reference" title="Bertoli-Avella, A. M., Gillis, E., Morisaki, H., Verhagen, J. M. A., de Graaf, B. M., van de Beek, G., Gallo, E., Kruithof, B. P. T., Venselaar, H., Myers, L. A., Laga, S., Doyle, A. J., and 33 others. <strong>Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections.</strong> J. Am. Coll. Cardiol. 65: 1324-1336, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25835445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25835445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25835445[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jacc.2015.01.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25835445">Bertoli-Avella et al. (2015)</a> identified heterozygosity for a c.898C-T transition (c.898C-T, NM_003239.2) in exon 5 of the TGFB3 gene, resulting in an arg300-to-trp (R300W) substitution at the highly conserved last residue of the RKKR minimal recognition motif of the furin (<a href="/entry/136950">136950</a>) or related protease cleavage site. The mutation, which segregated with disease in each of the families, was not found in the Exome Variant Server, 1000 Genomes Project, or Genome of the Netherlands databases. The youngest patient to carry this mutation was a 3-year-old Japanese girl who had a 19.5-mm aortic root aneurysm and atrial and ventricular septal defects, as well as other features of LDS, including hypertelorism, bifid uvula, and osteoarthritis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25835445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<strong>.0007 LOEYS-DIETZ SYNDROME 5</strong>
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TGFB3, 1-BP DEL, 704A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs875989817 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs875989817;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=rs875989817" 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=rs875989817" 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=RCV000185631" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000185631" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000185631</a>
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<p>In a Japanese mother and son with Loeys-Dietz syndrome-5 (LDS5; <a href="/entry/615582">615582</a>), <a href="#3" class="mim-tip-reference" title="Bertoli-Avella, A. M., Gillis, E., Morisaki, H., Verhagen, J. M. A., de Graaf, B. M., van de Beek, G., Gallo, E., Kruithof, B. P. T., Venselaar, H., Myers, L. A., Laga, S., Doyle, A. J., and 33 others. <strong>Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections.</strong> J. Am. Coll. Cardiol. 65: 1324-1336, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25835445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25835445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25835445[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jacc.2015.01.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25835445">Bertoli-Avella et al. (2015)</a> identified heterozygosity for a 1-bp deletion (c.704delA, NM_003239.2) in exon 4 of the TGFB3 gene, causing a frameshift predicted to result in a premature termination codon (Asn235MetfsTer11). The mutation was not found in an unaffected daughter or in the Exome Variant Server, 1000 Genomes Project, or Genome of the Netherlands databases. The 67-year-old mother and 43-year-old son were both diagnosed with thoracic aortic aneurysm with type A dissections at age 59 and 40 years of age, respectively, and both were tall; in addition, the mother had arachnodactyly, inguinal hernia, and myopia, whereas the son exhibited kyphoscoliosis and pectus deformity, retrognathia, and flat occiput. The maternal grandfather had died of thoracic aortic aneurysm dissection at age 80 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25835445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 LOEYS-DIETZ SYNDROME 5</strong>
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TGFB3, ASP263HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs796051886 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796051886;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=rs796051886" 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=rs796051886" 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=RCV000185632 OR RCV000498355" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000185632, RCV000498355" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000185632...</a>
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<p>In a 31-year-old man who had thoracic aortic aneurysm dissection (TAAD) at age 30 with a 70-mm aortic root and who also exhibited dolichocephaly, high-arched palate, severe retrognathia, delayed puberty, and short stature (LDS5; <a href="/entry/615582">615582</a>), <a href="#3" class="mim-tip-reference" title="Bertoli-Avella, A. M., Gillis, E., Morisaki, H., Verhagen, J. M. A., de Graaf, B. M., van de Beek, G., Gallo, E., Kruithof, B. P. T., Venselaar, H., Myers, L. A., Laga, S., Doyle, A. J., and 33 others. <strong>Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections.</strong> J. Am. Coll. Cardiol. 65: 1324-1336, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25835445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25835445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25835445[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jacc.2015.01.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25835445">Bertoli-Avella et al. (2015)</a> identified heterozygosity for a c.787G-C transversion (c.787G-C, NM_003239.2) in exon 5 of the TGFB3 gene, resulting in an asp263-to-his (D263H) substitution at a highly conserved residue in the RGD motif of the LAP domain. The mutation was present in his 70-year-old maternal aunt, who had a 38-mm aortic sinus diameter and mild mitral insufficiency; it was also found in his 64-year-old mother, who had mild mitral insufficiency but an aortic sinus diameter of only 34 mm, and in his asymptomatic 34-year-old brother, who had an aortic sinus diameter of 32 mm. Microscopic examination of the proband's dissected aortic wall showed elastic fiber fragmentation with higher collagen and proteoglycan deposition. Immunohistochemical analysis of aortic tissue showed paradoxically enhanced TGF-beta (TGFB1; <a href="/entry/190180">190180</a>) signaling, as shown by increased levels of SMAD2 (<a href="/entry/601366">601366</a>) and ERK (see <a href="/entry/601795">601795</a>) as well as elevated TGFB1 mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25835445" 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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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Barton1988" class="mim-anchor"></a>
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<strong>Chromosomal mapping of genes for transforming growth factors beta-2 and beta-3 in man and mouse: dispersion of TGF-beta gene family.</strong>
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<a id="Beffagna2005" class="mim-anchor"></a>
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<strong>Regulatory mutations in transforming growth factor-beta-3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15639475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15639475</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15639475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cardiores.2004.10.005" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Bertoli-Avella2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Bertoli-Avella, A. M., Gillis, E., Morisaki, H., Verhagen, J. M. A., de Graaf, B. M., van de Beek, G., Gallo, E., Kruithof, B. P. T., Venselaar, H., Myers, L. A., Laga, S., Doyle, A. J., and 33 others.
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<strong>Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections.</strong>
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J. Am. Coll. Cardiol. 65: 1324-1336, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25835445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25835445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25835445[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=25835445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jacc.2015.01.040" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Dickinson1990" class="mim-anchor"></a>
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Dickinson, M. E., Kobrin, M. S., Silan, C. M., Kingsley, D. M., Justice, M. J., Miller, D. A., Ceci, J. D., Lock, L. F., Lee, A., Buchberg, A. M., Siracusa, L. D., Lyons, K. M., Derynck, R., Hogan, B. L. M., Copeland, N. G., Jenkins, N. A.
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<strong>Chromosomal localization of seven members of the murine TGF-beta superfamily suggests close linkage to several morphogenetic mutant loci.</strong>
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Genomics 6: 505-520, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1970330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1970330</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1970330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(90)90480-i" target="_blank">Full Text</a>]
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<a id="Graycar1989" class="mim-anchor"></a>
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Graycar, J. L., Miller, D. A., Arrick, B. A., Lyons, R. M., Moses, H. L., Derynck, R.
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[<a href="https://doi.org/10.1210/mend-3-12-1977" target="_blank">Full Text</a>]
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Horikoshi, T., Maeda, K., Kawaguchi, Y., Chiba, K., Mori, K., Koshizuka, Y., Hirabayashi, S., Sugimori, K., Matsumoto, M., Kawaguchi, H., Takahashi, M., Inoue, H., Kimura, T., Matsusue, Y., Inoue, I., Baba, H., Nakamura, K., Ikegawa, S.
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[<a href="https://doi.org/10.1007/s00439-006-0170-9" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7493022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7493022</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7493022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1295-415" target="_blank">Full Text</a>]
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<strong>Human leiomyoma smooth muscle cells show increased expression of transforming growth factor-beta-3 (TGF-beta-3) and altered responses to the antiproliferative effects of TGF-beta.</strong>
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[<a href="https://doi.org/10.1210/jcem.86.2.7237" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.36593" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0006-291x(92)91566-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1083/jcb.200306024" target="_blank">Full Text</a>]
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Proetzel, G., Pawlowski, S. A., Wiles, M. V., Yin, M., Boivin, G. P., Howles, P. N., Ding, J., Ferguson, M. W. J., Doetschman, T.
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<strong>Transforming growth factor-beta-3 is required for secondary palate fusion.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7493021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7493021</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=7493021[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=7493021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1295-409" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Rampazzo2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rampazzo, A., Beffagna, G., Nava, A., Occhi, G., Bauce, B., Noiato, M., Basso, C., Frigo, G., Thiene, G., Towbin, J., Danieli, G. A.
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<strong>Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1): confirmation of locus assignment and mutation screening of four candidate genes.</strong>
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Europ. J. Hum. Genet. 11: 69-76, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529708</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200914" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Rienhoff2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rienhoff, H. Y., Jr., Yeo, C.-Y., Morissette, R., Khrebtukova, I., Melnick, J., Luo, S., Leng, N., Kim, Y.-J., Schroth, G. Westwick, J., Vogel, H., McDonnell, N., Hall, J. G., Whitman, M.
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<strong>A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome.</strong>
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Am. J. Med. Genet. 161A: 2040-2046, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23824657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23824657</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23824657[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=23824657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.36056" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="ten Dijke1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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ten Dijke, P., Geurts van Kessel, A. H. M., Foulkes, J. G., Le Beau, M. M.
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|
<strong>Transforming growth factor type beta-3 maps to human chromosome 14, region q23-q24.</strong>
|
|
Oncogene 3: 721-724, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2577876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2577876</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2577876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="ten Dijke1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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ten Dijke, P., Hansen, P., Iwata, K. K., Pieler, C., Foulkes, J. G.
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<strong>Identification of another member of the transforming growth factor type beta gene family.</strong>
|
|
Proc. Nat. Acad. Sci. 85: 4715-4719, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3164476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3164476</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3164476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.85.13.4715" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Venza2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Venza, I., Visalli, M., Parrillo, L., De Felice, M., Teti, D., Venza, M.
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<strong>MSX1 and TGF-beta-3 are novel target genes functionally regulated by FOXE1.</strong>
|
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Hum. Molec. Genet. 20: 1016-1025, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21177256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21177256</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21177256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddq547" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 07/16/2015
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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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Marla J. F. O'Neill - updated : 7/10/2015<br>Marla J. F. O'Neill - updated : 8/15/2014<br>Patricia A. Hartz - updated : 3/25/2014<br>Marla J. F. O'Neill - updated : 12/23/2013<br>Patricia A. Hartz - updated : 11/14/2008<br>Cassandra L. Kniffin - updated : 8/28/2006<br>Marla J. F. O'Neill - updated : 12/28/2005<br>John A. Phillips, III - updated : 7/13/2001
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 3/21/1989
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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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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carol : 04/14/2017
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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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alopez : 07/16/2015<br>alopez : 7/13/2015<br>mcolton : 7/10/2015<br>alopez : 5/7/2015<br>carol : 8/18/2014<br>mcolton : 8/15/2014<br>mgross : 3/26/2014<br>mcolton : 3/25/2014<br>carol : 12/23/2013<br>carol : 12/23/2013<br>alopez : 8/26/2011<br>terry : 8/24/2011<br>terry : 6/8/2010<br>mgross : 11/14/2008<br>mgross : 11/14/2008<br>mgross : 3/10/2008<br>wwang : 9/5/2006<br>ckniffin : 8/28/2006<br>wwang : 12/29/2005<br>terry : 12/28/2005<br>mcapotos : 7/18/2001<br>mcapotos : 7/13/2001<br>terry : 7/8/1997<br>mark : 12/7/1995<br>terry : 12/7/1995<br>terry : 12/7/1995<br>terry : 12/7/1995<br>terry : 12/7/1995<br>carol : 1/17/1995<br>supermim : 3/16/1992<br>supermim : 5/15/1990<br>supermim : 3/24/1990<br>supermim : 3/20/1990<br>ddp : 10/27/1989
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 190230
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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TRANSFORMING GROWTH FACTOR, BETA-3; TGFB3
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TGFB3</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 14q24.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 14:75,958,097-75,983,011 </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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<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-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
|
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<span class="mim-font">
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14q24.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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Arrhythmogenic right ventricular dysplasia 1
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
107970
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</span>
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</td>
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<td>
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<span class="mim-font">
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|
Autosomal dominant
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
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Loeys-Dietz syndrome 5
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
615582
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Autosomal dominant
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
|
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Beta-type transforming growth factors are polypeptides that act hormonally to control the proliferation and differentiation of multiple cell types. A cDNA clone for a third form of TGFB was isolated by ten Dijke et al. (1988). The C-terminal 112 amino acids of TGF-beta-3 share approximately 80% sequence identity with beta-1 (190180) and beta-2 (190220). </p><p>Moren et al. (1992) isolated full-length cDNAs for TGFB3 from a human placenta cDNA library. The coding region encoded a protein of 849 amino acids with a single transmembrane domain and a short stretch of the intracellular domain. </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">
|
|
<p>By Southern analysis of DNA prepared from somatic cell hybrids and by in situ hybridization, ten Dijke et al. (1988) assigned the TGFB3 gene to chromosome 14q23-q24. Barton et al. (1988) likewise assigned the TGFB3 gene to chromosome 14 and regionalized it to 14q24 by Southern blot analysis of hybrid cell DNAs and by in situ hybridization. </p><p>The mouse Tgfb3 gene was mapped to chromosome 12 (Barton et al., 1988; Dickinson et al., 1990). </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">
|
|
<strong>Gene Function</strong>
|
|
</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Graycar et al. (1989) purified to apparent homogeneity human TGFB3 and evaluated its activities in comparison to TGFB1 and TGFB2. </p><p>Lee and Nowak (2001) compared expression of the TGFB isoforms in normal myometrium and benign leiomyoma tumors of the uterus (150699) and examined the effects of TGFBs on cell proliferation and collagen production by these cells in vitro. Northern blot analysis showed that the levels of TGFB1 mRNA were similar between leiomyoma and myometrium, whereas leiomyoma showed 5-fold higher levels of expression of TGFB3 mRNA than autologous myometrium. Expression of TGFB3 protein detected by immunohistochemistry was much more intense in leiomyoma tissues than in corresponding myometrium. The authors concluded that their results support the hypothesis that alterations in the TGFB system produce loss of sensitivity to the antiproliferative effects of TGFB, and increased expression of TGFB3 may contribute to the growth of these tumors. </p><p>Epithelial mesenchymal transformation (EMT) of the medial edge epithelial seam creates palatal confluence. Nawshad and Hay (2003) showed that Tgfb3 brought about palatal seam EMT in mice by stimulating expression of Lef1 (153245) in medial edge epithelial cells. Tgfb3 activated Lef1 in the absence of beta-catenin (CTNNB1; 116806) via nuclear phospho-Smad2 (601366) and Smad4 (600993). </p><p>Using transfected 293 EBNA cells, Venza et al. (2011) showed that MSX1 (142983) and TGFB3 are direct targets of the forkhead transcription factor FOXE1 (602617). They found that mutations in the FOXE1 forkhead domain, which are linked to Bamforth-Lazarus syndrome (241850), reduced or eliminated FOXE1-dependent MSX1 and TGFB3 upregulation. </p>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</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>Arrhythmogenic Right Ventricular Dysplasia 1</em></strong></p><p>
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Beffagna et al. (2005) screened 38 members of a 4-generation Italian family with arrhythmogenic right ventricular dysplasia-1 (ARVD1; 107970), previously reported by Rampazzo et al. (2003), and identified a mutation (190230.0001) in the 5-prime UTR of the TGFB3 gene. Subsequent screening of 30 unrelated individuals with ARVD1 led to the identification of an additional mutation (190230.0002) in the 3-prime UTR of the TGFB3 gene in 1 patient. In transfection studies, both mutations showed significantly higher luciferase reporter activity (about 2.5-fold, p less than 0.01) compared to wildtype. </p><p>In a case-control study of 711 Japanese individuals with ossification of the posterior longitudinal ligament of the spine (OPLL; 602475) and 896 controls, Horikoshi et al. (2006) found an association between an intronic SNP in the TGFB3 gene (rs2268624) and OPLL. </p><p><strong><em>Loeys-Dietz Syndrome 5</em></strong></p><p>
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|
In a 9-year-old girl with low muscle mass, growth retardation, and distal arthrogryposis, who also exhibited features of Loeys-Dietz syndrome (LDS5; 615582) as well as Marfan (154700) and Beals (121050) syndromes, but who did not meet the diagnostic criteria for those syndromes, Rienhoff et al. (2013) analyzed 6 genes known to be associated with those disorders, including TGFB2 (190220), TGFBR1 (190181), TGFBR2 (190182), SMAD3 (603109), FBN1 (134797), and FBN2 (612570), but found no mutations. Exome sequencing revealed a de novo missense mutation in the TGFB3 gene (C409Y; 190230.0003), encoding a nonfunctional TGFB3 ligand. </p><p>In a 10.5-year-old girl with low muscle mass, marfanoid features, and bifid uvula, who was negative for mutation in FBN1, TGFBR1, TGFBR2, TGFB2, and SMAD3, Matyas et al. (2014) identified heterozygosity for a de novo missense mutation in the TGFB3 gene (R300Q; 190230.0004). </p><p>In a large Dutch pedigree with syndromic aortic aneurysm, negative for mutation in 15 known thoracic aortic aneurysm/dissection (TAAD)-associated genes, Bertoli-Avella et al. (2015) identified heterozygosity for a splice site mutation in the TGFB3 gene (190230.0005). The mutation, which segregated with disease in the family, was not found in variant databases. Analysis of TGFB3 in an additional 470 probands with syndromic or nonsyndromic TAAD, the majority of whom had been screened for mutation in all known TAAD genes, revealed TGFB3 mutations in 10 probands, including 4 different missense mutations, 2 single-base deletions, and 1 nonsense mutation (see, e.g., 190230.0006-190230.0008). The authors noted that although studies in a Xenopus model led Rienhoff et al. (2013) to hypothesize that the mutated C409Y allele results in a nonfunctional protein, Bertoli-Avella et al. (2015) observed increased TGFB signaling in aortic tissue from a patient with a different missense mutation (D263H; 190230.0008). </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>Proetzel et al. (1995) produced Tgfb3-null mice in which exon 6 of the Tgfb3 gene was replaced by the neomycin-resistance gene. Whereas heterozygotes had no apparent phenotypic change, homozygotes had an incompletely penetrant failure of the palatal shelves to fuse, leading to cleft palate. The defect appeared to result from impaired adhesion of the apposing medial edge epithelial of the palatal shelves and subsequent elimination of the midline epithelial seam. No craniofacial abnormalities were observed. Defective palatogenesis was also found in homozygous Tgfb3-null mutant mice by Kaartinen et al. (1995) who also found a consistent delay in pulmonary development. They suggested that the study demonstrates an essential function for TGF-beta-3 in normal palate and lung morphogenesis and implicates this cytokine in epithelial-mesenchymal interaction. </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>8 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 ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA 1</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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TGFB3, -36G-A, 5-PRIME UTR
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<br />
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SNP: rs770828281,
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gnomAD: rs770828281,
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ClinVar: RCV000013292, RCV002464063, RCV002504779, RCV002513008, RCV004739302
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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 9 affected and 3 unaffected members of a 4-generation Italian family with arrhythmogenic right ventricular dysplasia-1 (ARVD1; 107970) previously reported by Rampazzo et al. (2003), Beffagna et al. (2005) identified a G-to-A transition at cDNA position -36 in the 5-prime UTR of the TGFB3 gene (c.-36G-A, NM_003239). In transfection studies, the mutant construct showed significantly higher luciferase reporter activity (about 2.5-fold, p less than 0.01) compared to wildtype constructs. All clinically affected members of the family had the mutation; Beffagna et al. (2005) stated that detection of the mutation in 3 apparently healthy individuals was consistent with reduced penetrance. </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 ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA 1</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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TGFB3, 1723C-T, 3-PRIME UTR
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<br />
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SNP: rs387906514,
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ClinVar: RCV000013293, RCV002513009, RCV003914833
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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 young man with arrhythmogenic right ventricular dysplasia-1 (ARVD1; 107970), Beffagna et al. (2005) identified a C-to-T transition at cDNA position 1723 in the 3-prime UTR of the TGFB3 gene (c.1723C-T, NM_003239). In transfection studies, the mutant construct showed significantly higher luciferase reporter activity (about 2.5-fold, p less than 0.01) compared to wildtype constructs. The patient had a brother who died suddenly at the age of 16 and was found to have ARVD at autopsy. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0003 LOEYS-DIETZ SYNDROME 5</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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TGFB3, CYS409TYR
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<br />
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SNP: rs398122984,
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ClinVar: RCV000077765
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 9-year-old girl with low muscle mass, growth retardation, and distal arthrogryposis, who also exhibited blue sclerae, bifid uvula, and hyperextensibility of the large joints (LDS5; 615582), Rienhoff et al. (2013) identified heterozygosity for a de novo c.1226G-A transition in the TGFB3 gene, resulting in a cys409-to-tyr (C409Y) substitution. The mutation was not found in the dbSNP (build 130), Exome Variant Server, or 1000 Genomes Project databases. Functional analysis in transfected HEK293T cells showed that wildtype TGFB3 generated a transcriptional signal whereas the C409Y mutant did not. In Xenopus embryos, a 1:1 ratio of mutant to wildtype TGFB3 RNA diminished the SMAD2 (601366) and ERK1 (601795)/2 (176948) signals to approximately 40% and 60% of that generated by wildtype TGFB3 RNA alone. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 LOEYS-DIETZ SYNDROME 5</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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TGFB3, ARG300GLN
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<br />
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|
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SNP: rs587777617,
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|
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ClinVar: RCV000133467, RCV000417684
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 10.5-year-old girl with Loeys-Dietz syndrome-5 (LDS5; 615582), Matyas et al. (2014) identified heterozygosity for a de novo c.899G-A transition in the TGFB3 gene, resulting in an arg300-to-gln (R300Q) substitution at the last residue of the potential furin (136950) cleavage site in the C-terminal end of the LAP domain. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 LOEYS-DIETZ SYNDROME 5</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
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|
|
TGFB3, IVS4DS, T-C, +2
|
|
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|
|
|
<br />
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|
|
SNP: rs875989816,
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|
|
|
|
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|
|
ClinVar: RCV000185629
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 affected individuals over 3 generations of a large Dutch family with Loeys-Dietz syndrome-5 (LDS5; 615582), Bertoli-Avella et al. (2015) identified heterozygosity for a c.754+2T-C transition (c.754+2T-C, NM_003239.2) in intron 4 of the TGFB3 gene. The mutation, which segregated with disease in the family, was not found in the Exome Variant Server, Genome of the Netherlands, or 1000 Genomes Project databases. Analysis of cDNA from 2 affected individuals confirmed that the mutation causes skipping of exon 4, resulting in an in-frame deletion of 36 amino acids (Glu216_Lys251del) involving a central beta strand and subsequent surface loop in the LAP domain. </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LOEYS-DIETZ SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TGFB3, ARG300TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs796051885,
|
|
|
|
|
|
|
|
ClinVar: RCV000185630, RCV000332014, RCV001171230
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 4 unrelated families with Loeys-Dietz syndrome-5 (LDS5; 615582), Bertoli-Avella et al. (2015) identified heterozygosity for a c.898C-T transition (c.898C-T, NM_003239.2) in exon 5 of the TGFB3 gene, resulting in an arg300-to-trp (R300W) substitution at the highly conserved last residue of the RKKR minimal recognition motif of the furin (136950) or related protease cleavage site. The mutation, which segregated with disease in each of the families, was not found in the Exome Variant Server, 1000 Genomes Project, or Genome of the Netherlands databases. The youngest patient to carry this mutation was a 3-year-old Japanese girl who had a 19.5-mm aortic root aneurysm and atrial and ventricular septal defects, as well as other features of LDS, including hypertelorism, bifid uvula, and osteoarthritis. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 LOEYS-DIETZ SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TGFB3, 1-BP DEL, 704A
|
|
|
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|
|
<br />
|
|
|
|
SNP: rs875989817,
|
|
|
|
|
|
|
|
ClinVar: RCV000185631
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese mother and son with Loeys-Dietz syndrome-5 (LDS5; 615582), Bertoli-Avella et al. (2015) identified heterozygosity for a 1-bp deletion (c.704delA, NM_003239.2) in exon 4 of the TGFB3 gene, causing a frameshift predicted to result in a premature termination codon (Asn235MetfsTer11). The mutation was not found in an unaffected daughter or in the Exome Variant Server, 1000 Genomes Project, or Genome of the Netherlands databases. The 67-year-old mother and 43-year-old son were both diagnosed with thoracic aortic aneurysm with type A dissections at age 59 and 40 years of age, respectively, and both were tall; in addition, the mother had arachnodactyly, inguinal hernia, and myopia, whereas the son exhibited kyphoscoliosis and pectus deformity, retrognathia, and flat occiput. The maternal grandfather had died of thoracic aortic aneurysm dissection at age 80 years. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
|
|
</div>
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|
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</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LOEYS-DIETZ SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TGFB3, ASP263HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs796051886,
|
|
|
|
|
|
|
|
ClinVar: RCV000185632, RCV000498355
|
|
|
|
|
|
</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 31-year-old man who had thoracic aortic aneurysm dissection (TAAD) at age 30 with a 70-mm aortic root and who also exhibited dolichocephaly, high-arched palate, severe retrognathia, delayed puberty, and short stature (LDS5; 615582), Bertoli-Avella et al. (2015) identified heterozygosity for a c.787G-C transversion (c.787G-C, NM_003239.2) in exon 5 of the TGFB3 gene, resulting in an asp263-to-his (D263H) substitution at a highly conserved residue in the RGD motif of the LAP domain. The mutation was present in his 70-year-old maternal aunt, who had a 38-mm aortic sinus diameter and mild mitral insufficiency; it was also found in his 64-year-old mother, who had mild mitral insufficiency but an aortic sinus diameter of only 34 mm, and in his asymptomatic 34-year-old brother, who had an aortic sinus diameter of 32 mm. Microscopic examination of the proband's dissected aortic wall showed elastic fiber fragmentation with higher collagen and proteoglycan deposition. Immunohistochemical analysis of aortic tissue showed paradoxically enhanced TGF-beta (TGFB1; 190180) signaling, as shown by increased levels of SMAD2 (601366) and ERK (see 601795) as well as elevated TGFB1 mRNA. </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>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Barton, D. E., Foellmer, B. E., Du, J., Tamm, J., Derynck, R., Francke, U.
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<strong>Chromosomal mapping of genes for transforming growth factors beta-2 and beta-3 in man and mouse: dispersion of TGF-beta gene family.</strong>
|
|
Oncogene Res. 3: 323-331, 1988.
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[PubMed: 3226728]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Beffagna, G., Occhi, G., Nava, A., Vitiello, L., Ditadi, A., Basso, C., Bauce, B., Carraro, G., Thiene, G., Towbin, J. A., Danieli, G. A., Rampazzo, A.
|
|
<strong>Regulatory mutations in transforming growth factor-beta-3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1.</strong>
|
|
Cardiovasc. Res. 65: 366-373, 2005.
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[PubMed: 15639475]
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[Full Text: https://doi.org/10.1016/j.cardiores.2004.10.005]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Bertoli-Avella, A. M., Gillis, E., Morisaki, H., Verhagen, J. M. A., de Graaf, B. M., van de Beek, G., Gallo, E., Kruithof, B. P. T., Venselaar, H., Myers, L. A., Laga, S., Doyle, A. J., and 33 others.
|
|
<strong>Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections.</strong>
|
|
J. Am. Coll. Cardiol. 65: 1324-1336, 2015.
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[PubMed: 25835445]
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[Full Text: https://doi.org/10.1016/j.jacc.2015.01.040]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Dickinson, M. E., Kobrin, M. S., Silan, C. M., Kingsley, D. M., Justice, M. J., Miller, D. A., Ceci, J. D., Lock, L. F., Lee, A., Buchberg, A. M., Siracusa, L. D., Lyons, K. M., Derynck, R., Hogan, B. L. M., Copeland, N. G., Jenkins, N. A.
|
|
<strong>Chromosomal localization of seven members of the murine TGF-beta superfamily suggests close linkage to several morphogenetic mutant loci.</strong>
|
|
Genomics 6: 505-520, 1990.
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[PubMed: 1970330]
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