4584 lines
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Entry
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- *601620 - T-BOX TRANSCRIPTION FACTOR 5; TBX5
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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">*601620</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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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601620">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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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=ENSG00000089225;t=ENST00000405440" 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=6910" 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=601620" 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=ENSG00000089225;t=ENST00000405440" 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_000192,NM_080717,NM_181486,XM_017019912" 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_181486" 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=601620" 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=03372&isoform_id=03372_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/TBX5" 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/1772561,2281319,2920821,6979932,12644474,14041802,18201892,18201894,20379839,31652232,119618471,119618472,119618473,158254654,194390516,1034581420" 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/Q99593" 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=6910" 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=ENSG00000089225;t=ENST00000405440" 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=TBX5" 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=TBX5" 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+6910" 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/TBX5" 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:6910" 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/6910" 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=chr12&hgg_gene=ENST00000405440.7&hgg_start=114353911&hgg_end=114408442&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:11604" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11604" 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/tbx5" 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=601620[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=601620[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/TBX5/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/ENSG00000089225" 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=TBX5" 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=TBX5" 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=TBX5" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TBX5&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/PA36367" 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:11604" 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:102541" 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/TBX5#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:102541" 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/6910/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://omia.org/OMIA000839/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=6910" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006545;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006545 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006546;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006546 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-060601-2" 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://reactome.org/content/query?q=TBX5&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 19092004<br />
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<strong>ICD10CM:</strong> Q87.2<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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601620
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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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T-BOX TRANSCRIPTION FACTOR 5; TBX5
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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T-BOX 5
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TBX5" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TBX5</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/12/842?start=-3&limit=10&highlight=842">12q24.21</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:114353911-114408442&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'})">12:114,353,911-114,408,442</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>
|
|
<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>
|
|
Location
|
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</th>
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<th>
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Phenotype
|
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</th>
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<th>
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|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
|
|
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|
<tr>
|
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<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/12/842?start=-3&limit=10&highlight=842">
|
|
12q24.21
|
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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">
|
|
Holt-Oram syndrome
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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|
<a href="/entry/142900"> 142900 </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;">
|
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<li><a href="/graph/linear/601620" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<p>Using exon trap analysis of genomic clones from an interval on chromosome 12q2 containing the locus for Holt-Oram syndrome (HOS; <a href="/entry/142900">142900</a>) (<a href="#30" class="mim-tip-reference" title="Terrett, J. A., Newbury-Ecob, R., Cross, G. S., Fenton, I., Raeburn, J. A., Young, I. D., Brook, J. D. <strong>Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q.</strong> Nature Genet. 6: 401-404, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8054982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8054982</a>] [<a href="https://doi.org/10.1038/ng0494-401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8054982">Terrett et al., 1994</a>), a developmental disorder affecting the heart and limbs, <a href="#17" class="mim-tip-reference" title="Li, Q. Y., Newbury-Ecob, R. A., Terrett, J. A., Wilson, D. I., Curtis, A. R. J., Yi, C. H., Gebuhr, T., Bullen, P. J., Robson, S. C., Strachan, T., Bonnet, D., Lyonnet, S., Young, I. D., Raeburn, J. A., Buckler, A. J., Law, D. J., Brook, J. D. <strong>Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family.</strong> Nature Genet. 15: 21-29, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988164</a>] [<a href="https://doi.org/10.1038/ng0197-21" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988164">Li et al. (1997)</a> identified 2 developmentally expressed genes of the Brachyury (T) family. These genes share a common DNA-binding motif (T-box) and were designated TBX3 (<a href="/entry/601621">601621</a>) and TBX5, in line with their mouse homologs. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8054982+8988164" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Basson, C. T., Bachinsky, D. R., Lin, R. C., Levi, T., Elkins, J. A., Soults, J., Grayzel, D., Kroumpouzou, E., Traill, T. A., Leblanc-Straceski, J., Renault, B., Kucherlapati, R., Seidman, J. G., Seidman, C. E. <strong>Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome.</strong> Nature Genet. 15: 30-35, 1997. Note: Erratum: Nature Genet. 15: 411 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988165</a>] [<a href="https://doi.org/10.1038/ng0197-30" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988165">Basson et al. (1997)</a> refined the mapping of the HOS locus to 12q24.1 by fluorescence in situ hybridization using a cosmid containing D12S129, which was tightly linked to HOS. From the critical region they likewise isolated a gene with a high degree of homology to mouse Tbx5 and identified several mutations in TBX5 in affected members of HOS families. Members of the T-box gene family act as transcription factors and the conserved T-box domain serves as a DNA binding domain. In addition to heart and forelimb, murine Tbx5 transcripts are expressed in genital papilla, lung, pharynx, and thorax body wall, all tissues that are not affected in HOS patients. <a href="#3" class="mim-tip-reference" title="Basson, C. T., Bachinsky, D. R., Lin, R. C., Levi, T., Elkins, J. A., Soults, J., Grayzel, D., Kroumpouzou, E., Traill, T. A., Leblanc-Straceski, J., Renault, B., Kucherlapati, R., Seidman, J. G., Seidman, C. E. <strong>Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome.</strong> Nature Genet. 15: 30-35, 1997. Note: Erratum: Nature Genet. 15: 411 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988165</a>] [<a href="https://doi.org/10.1038/ng0197-30" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988165">Basson et al. (1997)</a> commented that this observation may suggest a more restricted pattern of expression of human TBX5; alternatively, the consequences of TBX5 haploinsufficiency on organ morphogenesis may differ between tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988165" 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="Hiroi, Y., Kudoh, S., Monzen, K., Ikeda, Y., Yazaki, Y., Nagai, R., Komuro, I. <strong>Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation.</strong> Nature Genet. 28: 276-280, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431700</a>] [<a href="https://doi.org/10.1038/90123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431700">Hiroi et al. (2001)</a> found that TBX5 associates with NKX2-5 (<a href="/entry/600584">600584</a>) and synergistically promotes cardiomyocyte differentiation. Both directly bind to the promoter of the gene encoding cardiac-specific natriuretic peptide precursor type A (NPPA; <a href="/entry/108780">108780</a>) in tandem, and the 2 transcription factors show synergistic activation. P19CL6 cells efficiently differentiate into beating cardiomyocytes expressing cardiac-specific genes after treatment with 1% dimethyl sulfoxide (DMSO). <a href="#12" class="mim-tip-reference" title="Hiroi, Y., Kudoh, S., Monzen, K., Ikeda, Y., Yazaki, Y., Nagai, R., Komuro, I. <strong>Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation.</strong> Nature Genet. 28: 276-280, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431700</a>] [<a href="https://doi.org/10.1038/90123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431700">Hiroi et al. (2001)</a> found that P19CL6 cell lines overexpressing wildtype Tbx5 started to beat earlier and expressed cardiac-specific genes more abundantly than did parental P19CL6 cells, whereas cell lines expressing the G80R mutation (<a href="#0004">601620.0004</a>), which causes substantial cardiac defects with minor skeletal abnormalities in HOS, did not differentiate into beating cardiomyocytes. Contrariwise, the R237Q mutation (<a href="#0003">601620.0003</a>), which causes upper limb malformations without cardiac abnormalities, activated the Nppa promoter to an extent similar to that of wildtype TBX5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431700" 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="Garg, V., Kathiriya, I. S., Barnes, R., Schluterman, M. K., King, I. N., Butler, C. A., Rothrock, C. R., Eapen, R. S., Hirayama-Yamada, K., Joo, K., Matsuoka, R., Cohen, J. C., Srivastava, D. <strong>GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5.</strong> Nature 424: 443-447, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12845333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12845333</a>] [<a href="https://doi.org/10.1038/nature01827" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12845333">Garg et al. (2003)</a> demonstrated that GATA4 (<a href="/entry/600576">600576</a>) interacts with TBX5 and showed that a missense mutation in GATA4, G296S (<a href="/entry/600576#0001">600576.0001</a>), abrogated this interaction. Conversely, interaction of GATA4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects. <a href="#8" class="mim-tip-reference" title="Garg, V., Kathiriya, I. S., Barnes, R., Schluterman, M. K., King, I. N., Butler, C. A., Rothrock, C. R., Eapen, R. S., Hirayama-Yamada, K., Joo, K., Matsuoka, R., Cohen, J. C., Srivastava, D. <strong>GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5.</strong> Nature 424: 443-447, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12845333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12845333</a>] [<a href="https://doi.org/10.1038/nature01827" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12845333">Garg et al. (2003)</a> concluded that their results implicate GATA4 as a genetic cause of human cardiac septal defects, perhaps through its interaction with TBX5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12845333" 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="#21" class="mim-tip-reference" title="Murakami, M., Nakagawa, M., Olson, E. N., Nakagawa, O. <strong>A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome.</strong> Proc. Nat. Acad. Sci. 102: 18034-18039, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16332960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16332960</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16332960[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0509109102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16332960">Murakami et al. (2005)</a> found that TAZ (WWTR1; <a href="/entry/300394">300394</a>) was a potent TBX5 transactivator. TAZ associated with TBX5 and stimulated TBX5-dependent promoters by interacting with the histone acetyltransferases p300 (EP300; <a href="/entry/602700">602700</a>) and PCAF (<a href="/entry/602303">602303</a>). YAP (<a href="/entry/606608">606608</a>), a TAZ-related protein, also stimulated TBX5-dependent transcription. TBX5 with HOS-associated truncation mutations could not be stimulated by TAZ, but TBX5 with HOS-associated point mutations was unimpaired in its ability to respond to TAZ. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16332960" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By microdissection of the mouse ventricular conduction system, followed by serial analysis of gene expression (SAGE) of the left bundle branch, <a href="#20" class="mim-tip-reference" title="Moskowitz, I. P. G., Kim, J. B., Moore, M. L., Wolf, C. M., Peterson, M. A., Shendure, J., Nobrega, M. A., Yokota, Y., Berul, C., Izumo, S., Seidman, J. G., Seidman, C. E. <strong>A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development.</strong> Cell 129: 1365-1376, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17604724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17604724</a>] [<a href="https://doi.org/10.1016/j.cell.2007.04.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17604724">Moskowitz et al. (2007)</a> identified Id2 (<a href="/entry/600386">600386</a>) as a conduction system-specific transcript. Analysis of the Id2 promoter showed that conduction system-specific expression of Id2 was dependent on Nkx2.5 and Tbx5. <a href="#20" class="mim-tip-reference" title="Moskowitz, I. P. G., Kim, J. B., Moore, M. L., Wolf, C. M., Peterson, M. A., Shendure, J., Nobrega, M. A., Yokota, Y., Berul, C., Izumo, S., Seidman, J. G., Seidman, C. E. <strong>A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development.</strong> Cell 129: 1365-1376, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17604724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17604724</a>] [<a href="https://doi.org/10.1016/j.cell.2007.04.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17604724">Moskowitz et al. (2007)</a> concluded that a molecular pathway including Id2, Nkx2.5, and Tbx5 coordinates specification of ventricular myocytes into the ventricular conduction system lineage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17604724" 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="#29" class="mim-tip-reference" title="Takeuchi, J. K., Bruneau, B. G. <strong>Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors.</strong> Nature 459: 708-711, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396158</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19396158[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/nature08039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396158">Takeuchi and Bruneau (2009)</a> defined the minimal requirements for transdifferentiation of mouse mesoderm to cardiac myocytes. They showed that 2 cardiac transcription factors, Gata4 and Tbx5, and a cardiac-specific subunit of BAF chromatin-remodeling complexes, Baf60c (SMARCD3; <a href="/entry/601737">601737</a>), can direct ectopic differentiation of mouse mesoderm into beating cardiomyocytes, including the normally noncardiogenic posterior mesoderm and the extraembryonic mesoderm of the amnion. Gata4 and Baf60c initiated ectopic cardiac gene expression. Addition of Tbx5 allowed differentiation into contracting cardiomyocytes and repression of noncardiac mesodermal genes. Baf60c was essential for the ectopic cardiogenic activity of Gata4 and Tbx5, partly by permitting binding of Gata4 to cardiac genes, indicating a novel instructive role for BAF complexes in tissue-specific regulation. <a href="#29" class="mim-tip-reference" title="Takeuchi, J. K., Bruneau, B. G. <strong>Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors.</strong> Nature 459: 708-711, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396158</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19396158[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/nature08039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396158">Takeuchi and Bruneau (2009)</a> concluded that the combined function of these factors establishes a robust mechanism for controlling cellular differentiation, and may allow reprogramming of new cardiomyocytes for regenerative purposes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19396158" 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="Gros, J., Tabin, C. J. <strong>Vertebrate limb bud formation is initiated by localized epithelial-to-mesenchymal transition.</strong> Science 343: 1253-1256, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24626928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24626928</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24626928[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/10.1126/science.1248228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24626928">Gros and Tabin (2014)</a> showed that mesenchymal limb progenitors arise through localized epithelial-to-mesenchymal transition (EMT) of the coelomic epithelium specifically within the presumptive limb fields. This EMT is regulated at least in part by TBX5 and FGF10 (<a href="/entry/602115">602115</a>), 2 genes known to control limb initiation. <a href="#10" class="mim-tip-reference" title="Gros, J., Tabin, C. J. <strong>Vertebrate limb bud formation is initiated by localized epithelial-to-mesenchymal transition.</strong> Science 343: 1253-1256, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24626928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24626928</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24626928[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/10.1126/science.1248228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24626928">Gros and Tabin (2014)</a> showed that limb buds initiate earlier than had been thought, as a result of localized EMT rather than differential proliferation rates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24626928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Nadadur, R. D., Broman, M. T., Boukens, B., Mazurek, S. R., Yang, X., van den Boogaard, M., Bekeny, J., Gadek, M., Ward, T., Zhang, M., Qiao, Y., Martin, J. F., Seidman, C. E., Seidman, J., Christoffels, V., Efimov, I. R., McNally, E. M., Weber, C. R., Moskowitz, I. P. <strong>Pitx2 modulates a Tbx5-dependent gene regulatory network to maintain atrial rhythm.</strong> Sci. Transl. Med. 8: 354ra115, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27582060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27582060</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27582060[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/10.1126/scitranslmed.aaf4891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27582060">Nadadur et al. (2016)</a> identified a cis regulatory element containing a functional T-box-binding site in the promoter of PITX2 (<a href="/entry/601542">601542</a>) that was bound by TBX5. The major T allele of a common SNP, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1906595;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1906595</a>, disrupted the central nucleotide of the T-box-binding motif, whereas the minor G allele of the SNP completed the canonical T-box-binding element. The major allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1906595;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1906595</a> completely abolished cis regulatory element activity in response to TBX5 in transfected HEK293 cells and in HL-1 mouse atrial cardiomyocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27582060" 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>Shox2 (<a href="/entry/602504">602504</a>) is essential for the formation of the sinoatrial valves and for the development of the pacemaking system of the heart. <a href="#26" class="mim-tip-reference" title="Puskaric, S., Schmitteckert, S., Mori, A. D., Glaser, A., Schneider, K. U., Bruneau, B. G., Blaschke, R. J., Steinbeisser, H., Rappold, G. <strong>Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart.</strong> Hum. Molec. Genet. 19: 4625-4633, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20858598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20858598</a>] [<a href="https://doi.org/10.1093/hmg/ddq393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20858598">Puskaric et al. (2010)</a> analyzed putative targets of Shox2 and identified Bmp4 (<a href="/entry/112262">112262</a>) as a direct target. Shox2 interacted directly with the Bmp4 promoter and activated transcription. Ectopic expression of Shox2 in Xenopus embryos stimulated transcription of Bmp4, and silencing of Shox2 in cardiomyocytes led to a reduction in the expression of Bmp4. Using Tbx5 del/+ mice, a model for Holt-Oram syndrome (<a href="/entry/142900">142900</a>), and Shox2 -/- mice, <a href="#26" class="mim-tip-reference" title="Puskaric, S., Schmitteckert, S., Mori, A. D., Glaser, A., Schneider, K. U., Bruneau, B. G., Blaschke, R. J., Steinbeisser, H., Rappold, G. <strong>Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart.</strong> Hum. Molec. Genet. 19: 4625-4633, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20858598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20858598</a>] [<a href="https://doi.org/10.1093/hmg/ddq393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20858598">Puskaric et al. (2010)</a> showed that the T-box transcription factor Tbx5 was a regulator of Shox2 expression in the inflow tract, and that Bmp4 was regulated by Shox2 in this compartment of the embryonic heart. In addition, Tbx5 acted cooperatively with Nkx2-5 (<a href="/entry/600584">600584</a>) to regulate the expression of Shox2 and Bmp4. <a href="#26" class="mim-tip-reference" title="Puskaric, S., Schmitteckert, S., Mori, A. D., Glaser, A., Schneider, K. U., Bruneau, B. G., Blaschke, R. J., Steinbeisser, H., Rappold, G. <strong>Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart.</strong> Hum. Molec. Genet. 19: 4625-4633, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20858598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20858598</a>] [<a href="https://doi.org/10.1093/hmg/ddq393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20858598">Puskaric et al. (2010)</a> concluded that their work established a functional link between Tbx5, Shox2, and Bmp4 in the pacemaker region of the developing heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20858598" 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="#32" class="mim-tip-reference" title="Yi, C.-H., Russ, A., Brook, J. D. <strong>Virtual cloning and physical mapping of a human T-box gene, TBX4.</strong> Genomics 67: 92-95, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10945475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10945475</a>] [<a href="https://doi.org/10.1006/geno.2000.6222" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10945475">Yi et al. (2000)</a> determined that the TBX5 gene contains 9 exons and spans more than 47 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10945475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Osterwalder, M., Barozzi, I., Tissieres, V., Fukuda-Yuzawa, Y., Mannion, B. J., Afzal, S. Y., Lee, E. A., Zhu, Y., Plajzer-Frick, I., Pickle, C. S., Kato, M., Garvin, T. H., Pham, Q. T., Harrington, A. N., Akiyama, J. A., Afzal, V., Lopez-Rios, J., Dickel, D. E., Visel, A., Pennacchio, L. A. <strong>Enhancer redundancy provides phenotypic robustness in mammalian development.</strong> Nature 554: 239-243, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29420474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29420474</a>] [<a href="https://doi.org/10.1038/nature25461" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29420474">Osterwalder et al. (2018)</a> showed that the pervasive presence of multiple enhancers with similar activities near the same gene confers phenotypic robustness to loss-of-function mutations in individual enhancers. <a href="#23" class="mim-tip-reference" title="Osterwalder, M., Barozzi, I., Tissieres, V., Fukuda-Yuzawa, Y., Mannion, B. J., Afzal, S. Y., Lee, E. A., Zhu, Y., Plajzer-Frick, I., Pickle, C. S., Kato, M., Garvin, T. H., Pham, Q. T., Harrington, A. N., Akiyama, J. A., Afzal, V., Lopez-Rios, J., Dickel, D. E., Visel, A., Pennacchio, L. A. <strong>Enhancer redundancy provides phenotypic robustness in mammalian development.</strong> Nature 554: 239-243, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29420474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29420474</a>] [<a href="https://doi.org/10.1038/nature25461" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29420474">Osterwalder et al. (2018)</a> used genome editing to create 23 mouse deletion lines and intercrosses, including both single and combinatorial enhancer deletions at 7 distinct loci required for limb development including GlI3 (<a href="/entry/165240">165240</a>), Shox2, Tbx3 (<a href="/entry/601621">601621</a>), Tbx5, and Lhx5 (<a href="/entry/605992">605992</a>). Unexpectedly, none of the 10 deletions of individual enhancers caused noticeable changes in limb morphology. By contrast, the removal of pairs of limb enhancers near the same gene resulted in discernible phenotypes, indicating that enhancers function redundantly in establishing normal morphology. In a genetic background sensitized by reduced baseline expression of the target gene, even single enhancer deletions caused limb abnormalities, suggesting that functional redundancy is conferred by additive effects of enhancers on gene expression levels. A genomewide analysis integrating epigenomic and transcriptomic data from 29 developmental mouse tissues revealed that mammalian genes are very commonly associated with multiple enhancers that have similar spatiotemporal activity. Systematic exploration of 3 representative developmental structures (limb, brain, and heart) uncovered more than 1,000 cases in which 5 or more enhancers with redundant activity patterns were found near the same gene. <a href="#23" class="mim-tip-reference" title="Osterwalder, M., Barozzi, I., Tissieres, V., Fukuda-Yuzawa, Y., Mannion, B. J., Afzal, S. Y., Lee, E. A., Zhu, Y., Plajzer-Frick, I., Pickle, C. S., Kato, M., Garvin, T. H., Pham, Q. T., Harrington, A. N., Akiyama, J. A., Afzal, V., Lopez-Rios, J., Dickel, D. E., Visel, A., Pennacchio, L. A. <strong>Enhancer redundancy provides phenotypic robustness in mammalian development.</strong> Nature 554: 239-243, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29420474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29420474</a>] [<a href="https://doi.org/10.1038/nature25461" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29420474">Osterwalder et al. (2018)</a> concluded that their data indicated that enhancer redundancy is a remarkably widespread feature of mammalian genomes that provides an effective regulatory buffer to prevent deleterious phenotypic consequences upon the loss of individual enhancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29420474" 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="#3" class="mim-tip-reference" title="Basson, C. T., Bachinsky, D. R., Lin, R. C., Levi, T., Elkins, J. A., Soults, J., Grayzel, D., Kroumpouzou, E., Traill, T. A., Leblanc-Straceski, J., Renault, B., Kucherlapati, R., Seidman, J. G., Seidman, C. E. <strong>Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome.</strong> Nature Genet. 15: 30-35, 1997. Note: Erratum: Nature Genet. 15: 411 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988165</a>] [<a href="https://doi.org/10.1038/ng0197-30" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988165">Basson et al. (1997)</a> positionally cloned the TBX5 gene from the HOS critical region on 12q24.1. <a href="#32" class="mim-tip-reference" title="Yi, C.-H., Russ, A., Brook, J. D. <strong>Virtual cloning and physical mapping of a human T-box gene, TBX4.</strong> Genomics 67: 92-95, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10945475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10945475</a>] [<a href="https://doi.org/10.1006/geno.2000.6222" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10945475">Yi et al. (2000)</a> estimated that the TBX3 gene(<a href="/entry/601621">601621</a>) and the TBX5 gene are about 350 kb apart on chromosome 12q23-q24. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10945475+8988165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using SSCP analysis and direct sequencing of amplified products, <a href="#17" class="mim-tip-reference" title="Li, Q. Y., Newbury-Ecob, R. A., Terrett, J. A., Wilson, D. I., Curtis, A. R. J., Yi, C. H., Gebuhr, T., Bullen, P. J., Robson, S. C., Strachan, T., Bonnet, D., Lyonnet, S., Young, I. D., Raeburn, J. A., Buckler, A. J., Law, D. J., Brook, J. D. <strong>Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family.</strong> Nature Genet. 15: 21-29, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988164</a>] [<a href="https://doi.org/10.1038/ng0197-21" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988164">Li et al. (1997)</a> showed that the TBX5 gene was mutated in cases of familial and sporadic Holt-Oram syndrome (HOS; <a href="/entry/142900">142900</a>) (see, e.g., <a href="#0001">601620.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988164" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Basson, C. T., Huang, T., Lin, R. C., Bachinsky, D. R., Weremowicz, S., Vaglio, A., Bruzzone, R., Quadrelli, R., Lerone, M., Romeo, G., Silengo, M., Pereira, A., Krieger, J., Mesquita, S. F., Kamisago, M., Morton, C. C., Pierpont, M. E. M., Muller, C. W., Seidman, J. G., Seidman, C. E. <strong>Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations.</strong> Proc. Nat. Acad. Sci. 96: 2919-2924, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10077612[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.6.2919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10077612">Basson et al. (1999)</a> identified heterozygous mutations in the TBX5 gene in affected members of several families segregating HOS (see, e.g., <a href="#0002">601620.0002</a>-<a href="#0005">601620.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Packham, E. A., Brook, J. D. <strong>T-box genes in human disorders.</strong> Hum. Molec. Genet. 12(R1): R37-R44, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668595</a>] [<a href="https://doi.org/10.1093/hmg/ddg077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12668595">Packham and Brook (2003)</a> reviewed the human disorders that have been linked to mutations in T-box genes: Holt-Oram syndrome, ulnar-mammary syndrome (UMS; <a href="/entry/181450">181450</a>), DiGeorge syndrome (DGS; <a href="/entry/188400">188400</a>), ACTH deficiency (<a href="/entry/201400">201400</a>), and cleft palate with ankyloglossia (CPX; <a href="/entry/303400">303400</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668595" 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 Czech mother and 2 daughters diagnosed with Holt-Oram syndrome, <a href="#5" class="mim-tip-reference" title="Borozdin, W., Bravo-Ferrer Acosta, A. M., Seemanova, E., Leipoldt, M., Bamshad, M. J., Unger, S., Kohlhase, J. <strong>Contiguous hemizygous deletion of TBX5, TBX3, and RBM19 resulting in a combined phenotype of Holt-Oram and ulnar-mammary syndromes.</strong> Am. J. Med. Genet. 140A: 1880-1886, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16892408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16892408</a>] [<a href="https://doi.org/10.1002/ajmg.a.31340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16892408">Borozdin et al. (2006)</a> identified a 2.19 to 2.27-Mb contiguous deletion encompassing the TBX5 and TBX3 genes. Clinical reexamination confirmed the presence of features of ulnar-mammary syndrome that were previously unrecognized. <a href="#5" class="mim-tip-reference" title="Borozdin, W., Bravo-Ferrer Acosta, A. M., Seemanova, E., Leipoldt, M., Bamshad, M. J., Unger, S., Kohlhase, J. <strong>Contiguous hemizygous deletion of TBX5, TBX3, and RBM19 resulting in a combined phenotype of Holt-Oram and ulnar-mammary syndromes.</strong> Am. J. Med. Genet. 140A: 1880-1886, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16892408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16892408</a>] [<a href="https://doi.org/10.1002/ajmg.a.31340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16892408">Borozdin et al. (2006)</a> noted that the contiguous deletion also included the RBM19 gene (<a href="/entry/616444">616444</a>), but commented that it was unlikely to contribute to or modify the phenotype since all the anomalies present in the affected individuals could be explained by either TBX5 or TBX3 haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16892408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Somatic Mutations</em></strong></p><p>
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In diseased cardiac tissues from 2 of 52 explanted hearts of unrelated patients with complex cardiac malformations, notably ventricular (VSD) and atrioventricular septal defects (AVSD), <a href="#27" class="mim-tip-reference" title="Reamon-Buettner, S. M., Borlak, J. <strong>HEY2 mutations in malformed hearts.</strong> Hum. Mutat. 27: 118 only, 2006. Note: Full article online.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16329098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16329098</a>] [<a href="https://doi.org/10.1002/humu.9390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16329098">Reamon-Buettner and Borlak (2006)</a> found 3 nonsynonymous mutations in the HEY2 gene (<a href="/entry/604674">604674</a>). Since the 2 AVSD patients also carried binding domain mutations in other cardiac-specific transcription factors, e.g., NKX2-5 (<a href="/entry/600584">600584</a>), TBX5, and GATA4 (<a href="/entry/600576">600576</a>), <a href="#27" class="mim-tip-reference" title="Reamon-Buettner, S. M., Borlak, J. <strong>HEY2 mutations in malformed hearts.</strong> Hum. Mutat. 27: 118 only, 2006. Note: Full article online.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16329098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16329098</a>] [<a href="https://doi.org/10.1002/humu.9390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16329098">Reamon-Buettner and Borlak (2006)</a> concluded that breakdown of combinatorial interactions of transcription factors may have contributed to the complexity of their cardiac malformations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16329098" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>To understand better the role of TBX5 in forelimb and heart development, <a href="#4" class="mim-tip-reference" title="Basson, C. T., Huang, T., Lin, R. C., Bachinsky, D. R., Weremowicz, S., Vaglio, A., Bruzzone, R., Quadrelli, R., Lerone, M., Romeo, G., Silengo, M., Pereira, A., Krieger, J., Mesquita, S. F., Kamisago, M., Morton, C. C., Pierpont, M. E. M., Muller, C. W., Seidman, J. G., Seidman, C. E. <strong>Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations.</strong> Proc. Nat. Acad. Sci. 96: 2919-2924, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10077612[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.6.2919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10077612">Basson et al. (1999)</a> studied the clinical features of Holt-Oram syndrome caused by 10 different TBX5 mutations. Defects predicted to create null alleles caused substantial abnormalities in both limb and heart. In contrast, missense mutations produced distinct phenotypes: gly80-to-arg (<a href="#0004">601620.0004</a>) caused significant cardiac malformations but only minor skeletal abnormalities, whereas arg237-to-gln (<a href="#0003">601620.0003</a>) and arg237-to-trp (<a href="#0005">601620.0005</a>) caused extensive upper limb malformations but less significant cardiac abnormalities. Amino acids altered by missense mutations were located on the 3-dimensional structure of a related T-box transcription factor, Xbra (of X. laevis), bound to DNA. Residue 80 is highly conserved within T-box sequences that interact with the major groove of target DNA; residue 237 is located in the T-box domain that selectively binds to the minor groove of DNA. These structural data, taken together with the predominant cardiac or skeletal phenotype produced by each missense mutation, suggested that organ-specific gene activation by TBX5 is predicated on biophysical interactions with different target DNA sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077612" 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 study of 55 probands with Holt-Oram syndrome, <a href="#6" class="mim-tip-reference" title="Brassington, A.-M. E., Sung, S. S., Toydemir, R. M., Le, T., Roeder, A. D., Rutherford, A. E., Whitby, F. G., Jorde, L. B., Bamshad, M. J. <strong>Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype.</strong> Am. J. Hum. Genet. 73: 74-85, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12789647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12789647</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12789647[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/10.1086/376436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12789647">Brassington et al. (2003)</a> found 17 mutations, including 6 missense mutations, in TBX5 and 2 mutations in the SALL4 gene (<a href="/entry/607343">607343</a>), which is the site of mutations causing some cases of Duane-radial ray syndrome (<a href="/entry/607323">607323</a>). Their results suggested that neither the type of mutation in TBX5 nor the location of the mutation in the T box is predictive of the expressivity of malformations in individuals with HOS. <a href="#2" class="mim-tip-reference" title="Bamshad, M. J. <strong>Personal Communication.</strong> Salt Lake City, Utah 6/26/2003."None>Bamshad (2003)</a> stated that 2 cases in which SALL4 mutations were found in the report of <a href="#6" class="mim-tip-reference" title="Brassington, A.-M. E., Sung, S. S., Toydemir, R. M., Le, T., Roeder, A. D., Rutherford, A. E., Whitby, F. G., Jorde, L. B., Bamshad, M. J. <strong>Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype.</strong> Am. J. Hum. Genet. 73: 74-85, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12789647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12789647</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12789647[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/10.1086/376436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12789647">Brassington et al. (2003)</a> had been referred to him and his coworkers and were not personally examined by them. He said that in 1 case, after a mutation in SALL4 was found, the primary care physician reexamined the patient and noted the presence of ophthalmoplegia, making the diagnosis of Duane-radial ray syndrome. Furthermore, <a href="#2" class="mim-tip-reference" title="Bamshad, M. J. <strong>Personal Communication.</strong> Salt Lake City, Utah 6/26/2003."None>Bamshad (2003)</a> had not considered kidney defects typical of HOS and the affected mother of the patient who was later diagnosed with Duane-radial ray syndrome had pelvic kidneys. <a href="#13" class="mim-tip-reference" title="Kohlhase, J. <strong>Personal Communication.</strong> Goettingen, Germany 7/16/2003."None>Kohlhase (2003)</a> suggested that the SALL4 mutation in the second 'HOS' case of <a href="#6" class="mim-tip-reference" title="Brassington, A.-M. E., Sung, S. S., Toydemir, R. M., Le, T., Roeder, A. D., Rutherford, A. E., Whitby, F. G., Jorde, L. B., Bamshad, M. J. <strong>Expressivity of Holt-Oram syndrome is not predicted by TBX5 genotype.</strong> Am. J. Hum. Genet. 73: 74-85, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12789647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12789647</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12789647[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/10.1086/376436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12789647">Brassington et al. (2003)</a> was actually a rare polymorphism, as it did not affect a functional domain, was not conserved between mouse and man, and the unaffected parent also carried the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12789647" 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 the mouse, 4 of the T-box genes, i.e., the T locus (<a href="/entry/601397">601397</a>), Tbx1 (<a href="/entry/602054">602054</a>), Tbx6 (<a href="/entry/602427">602427</a>), and Tbr1, are dispersed throughout the genome. <a href="#17" class="mim-tip-reference" title="Li, Q. Y., Newbury-Ecob, R. A., Terrett, J. A., Wilson, D. I., Curtis, A. R. J., Yi, C. H., Gebuhr, T., Bullen, P. J., Robson, S. C., Strachan, T., Bonnet, D., Lyonnet, S., Young, I. D., Raeburn, J. A., Buckler, A. J., Law, D. J., Brook, J. D. <strong>Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family.</strong> Nature Genet. 15: 21-29, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988164</a>] [<a href="https://doi.org/10.1038/ng0197-21" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988164">Li et al. (1997)</a> noted that the other family members, Tbx2 (<a href="/entry/600747">600747</a>) to Tbx5, exist as 2 clusters, having evolved from a common ancestor by 2 duplication events. Tbx2 and Tbx4 (<a href="/entry/601719">601719</a>) map together on mouse chromosome 11 (TBX2 is on 17q in the human), and Tbx3 and Tbx5 map on mouse chromosome 5 and human chromosome 12, respectively. However, it is Tbx2 and Tbx3 that form a cognate pair, likewise Tbx4 and Tbx5, with each pair showing related limb-associated expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988164" 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>Pitx1 (<a href="/entry/602149">602149</a>) and Tbx4 encode transcription factors that are expressed throughout the developing hindlimb, but not in forelimb buds. <a href="#18" class="mim-tip-reference" title="Logan, M., Tabin, C. J. <strong>Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity.</strong> Science 283: 1736-1739, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10073939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10073939</a>] [<a href="https://doi.org/10.1126/science.283.5408.1736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10073939">Logan and Tabin (1999)</a> injected a retroviral vector carrying Pitx1 into the wing field of chicken embryos. Misexpression of Pitx1 in the chick wing bud induced distal expression of Tbx4, as well as HoxC10 and HoxC11, which are normally restricted to hindlimb expression domains. Wing buds in which Pitx1 was misexpressed developed into limbs with some morphologic characteristics of hindlimbs: the flexure was altered to that normally observed in legs, the digits were more toe-like in the relative size and shape, and the muscle pattern was transformed to that of a leg. Expression of Tbx5, normally expressed only in the forelimb, was not altered by Pitx1 misexpression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10073939" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Koshiba-Takeuchi, K., Takeuchi, J. K., Matsumoto, K., Momose, T., Uno, K., Hoepker, V., Ogura, K., Takahashi, N., Nakamura, H., Yasuda, K., Ogura, T. <strong>Tbx5 and the retinotectum projection.</strong> Science 287: 134-137, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10615048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10615048</a>] [<a href="https://doi.org/10.1126/science.287.5450.134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10615048">Koshiba-Takeuchi et al. (2000)</a> studied Tbx5 gene expression in developing chick eye. Expression was first detected in a broad area at stage 11 and then became restricted to the dorsal half of the eye in a graded fashion, with the strongest signal in the dorsal-most end. Misexpression of the Tbx5 gene in the ventral side of the eye induced dorsalization of the ventral side and altered projections of retinal ganglion cell axons. Thus, in the chick, Tbx5 is involved in eye morphogenesis and is a topographic determinant of the visual projections between retina and tectum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10615048" 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="#28" class="mim-tip-reference" title="Sowden, J. C., Holt, J. K. L., Meins, M., Smith, H. K., Bhattacharya, S. S. <strong>Expression of Drosophila omb-related T-box genes in the developing human and mouse neural retina.</strong> Invest. Ophthal. Vis. Sci. 42: 3095-3102, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11726608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11726608</a>]" pmid="11726608">Sowden et al. (2001)</a> examined the role of Drosophila 'optomotor blind' (omb)-related T-box genes in the development of human and mouse retina. Murine Tbx2, Tbx3, and Tbx5 and human TBX2 cDNAs were isolated from retina cDNA libraries by hybridization to the Drosophila omb gene. Human and mouse TBX2, TBX3, and TBX5 were expressed asymmetrically across the embryonic neural retina, with highest levels of mRNA within dorsal and peripheral retina. The dorsoventral gradient of TBX2 expression disappeared before the ganglion cell layer (GCL) formed. Its expression became restricted to the inner neuroblastic retina and later to the GCL and inner nuclear layer (INL). The dorsal expression domains of TBX5 and TBX3 were maintained during formation of the GCL. As the retina matured, TBX3 expression was restricted to the INL, and TBX5 was expressed within the GCL. The authors concluded that the expression patterns of TBX2, TBX3, and TBX5 within the developing retina support the idea that the encoded transcription factors play a role in providing positional information important for topographic mapping in differentiation of distinct cell types across the laminar axis of the retina. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11726608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Bruneau, B. G., Nemer, G., Schmitt, J. P., Charron, F., Robitaille, L., Caron, S., Conner, D. A., Gessler, M., Nemer, M., Seidman, C. E., Seidman, J. G. <strong>A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease.</strong> Cell 106: 709-721, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11572777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11572777</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00493-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11572777">Bruneau et al. (2001)</a> generated heterozygous Tbx5 -/+ mice to study the mechanisms by which TBX5 haploinsufficiency causes cardiac and forelimb abnormalities in Holt-Oram syndrome. Tbx5 deficiency in homozygous mice (Tbx5 -/-) decreased expression of multiple genes and caused severe hypoplasia of posterior domains in the developing heart. Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (Anf, or Nppa) and connexin-40 (Cx40; <a href="/entry/121013">121013</a>) transcription, implicating these as Tbx5 target genes and providing a mechanism by which 50% reduction of T-box transcription factors causes disease. Direct and cooperative transactivation of the Anf and Cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated. These studies provided a potential explanation for Holt-Oram syndrome conduction system defects, suggested mechanisms for intrafamilial phenotypic variability, and accounted for related cardiac malformations caused by other transcription factor mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11572777" 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>T protein (<a href="/entry/601397">601397</a>) is vital for the formation and differentiation of posterior mesoderm and for axial development in all vertebrates. A mutation in this gene underlies the mouse Brachyury phenotype, a lethal phenotype manifested by abnormal notochord, absent somites, and reduced allantois. <a href="#9" class="mim-tip-reference" title="Ghosh, T. K., Packham, E. A., Bonser, A. J., Robinson, T. E., Cross, S. J., Brook, J. D. <strong>Characterization of the TBX5 binding site and analysis of mutations that cause Holt-Oram syndrome.</strong> Hum. Molec. Genet. 10: 1983-1994, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11555635/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11555635</a>] [<a href="https://doi.org/10.1093/hmg/10.18.1983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11555635">Ghosh et al. (2001)</a> identified an 8-bp core sequence that is part of the Brachyury consensus-binding site. TBX5 bound to the full palindromic Brachyury binding site and to the half-palindrome, whereas Brachyury did not bind to the TBX5 site. Amino acids 1-237 of TBX5 were required for DNA binding. Analysis of the effects of specific substitution mutations that arise in Holt-Oram patients indicated that gly80 to arg (G80R; <a href="#0004">601620.0004</a>) and arg237 to gln (R237Q; <a href="#0003">601620.0003</a>) eliminated binding to the target site. Similar target sites are present in the upstream regions of several cardiac-expressed genes, including cardiac alpha-actin (<a href="/entry/102540">102540</a>), atrial natriuretic factor (<a href="/entry/108780">108780</a>), cardiac myosin heavy chain alpha (<a href="/entry/160710">160710</a>), cardiac myosin heavy chain beta (<a href="/entry/160760">160760</a>), myosin light chain 1A, myosin light chain 1V, and Nkx2.5 (<a href="/entry/600584">600584</a>). Cell transfection studies demonstrated that TBX5 activated the transcription of an atrial natriuretic factor reporter construct and this effect was significantly reduced by deletion of the TBX5 binding site. The authors proposed that the presence of TBX5 binding sites in the upstream regions of these cardiac-expressed genes suggests a role for TBX5 in their regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11555635" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Ahn, D., Kourakis, M. J., Rohde, L. A., Silver, L. M., Ho, R. K. <strong>T-box gene tbx5 is essential for formation of the pectoral limb bud.</strong> Nature 417: 754-758, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12066188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12066188</a>] [<a href="https://doi.org/10.1038/nature00814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12066188">Ahn et al. (2002)</a> demonstrated that in zebrafish, Tbx5 has an early function that precedes the formation of the limb bud itself. Functional knockdown of zebrafish Tbx5 through the use of an antisense oligonucleotide resulted in a failure to initiate fin bud formation, leading to the complete loss of pectoral fins. The function of the Tbx5 gene in the development of zebrafish forelimbs seems to involve the directed migration of individual lateral-plate mesodermal cells into the future limb-bud-producing region. The primary defect seen in the Tbx5-knockdown phenotype is similar to the primary defects described in known T-box gene mutants such as the spadetail mutant of zebrafish and the Brachyury mutant of the mouse (see <a href="/entry/601397">601397</a>), which both similarly exhibited an altered migration of mesodermal cells. <a href="#1" class="mim-tip-reference" title="Ahn, D., Kourakis, M. J., Rohde, L. A., Silver, L. M., Ho, R. K. <strong>T-box gene tbx5 is essential for formation of the pectoral limb bud.</strong> Nature 417: 754-758, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12066188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12066188</a>] [<a href="https://doi.org/10.1038/nature00814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12066188">Ahn et al. (2002)</a> suggested that a common function for many of the T-box genes might therefore be in mediating the proper migration and/or changes in adhesive properties of early embryonic cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12066188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By gene targeting and transgenic methods, <a href="#19" class="mim-tip-reference" title="Minguillon, C., Del Buono, J., Logan, M. P. <strong>Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth.</strong> Dev. Cell 8: 75-84, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15621531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15621531</a>] [<a href="https://doi.org/10.1016/j.devcel.2004.11.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15621531">Minguillon et al. (2005)</a> examined the ability of Tbx4 and Pitx1 to rescue the no-forelimb phenotype of mutant mice with Tbx5 knockout restricted to limbs. Tbx4 could replace Tbx5 and rescue limb outgrowth, but Pitx1 could not. In contrast to previous chick misexpression studies, Tbx4-rescued limbs had a forelimb-like phenotype, suggesting that Tbx4 alone does not dictate hindlimb morphology and that forelimb characteristics can develop in the absence of Tbx5. To determine the role of Pitx1 in defining hindlimb characteristics, <a href="#19" class="mim-tip-reference" title="Minguillon, C., Del Buono, J., Logan, M. P. <strong>Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth.</strong> Dev. Cell 8: 75-84, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15621531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15621531</a>] [<a href="https://doi.org/10.1016/j.devcel.2004.11.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15621531">Minguillon et al. (2005)</a> introduced forelimb-targeted Pitx1 into mice expressing endogenous Tbx5 and into mutant mice rescued by Tbx4. In both cases, forelimb-targeted Pitx1 expression caused a partial forelimb-to-hindlimb transformation, indicating that Pitx1 has a role in directing hindlimb morphology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15621531" 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>Human mutations in TBX5, a gene encoding a T-box transcription factor, and SALL4 (<a href="/entry/607343">607343</a>), a gene encoding a zinc finger transcription factor, cause similar upper limb and heart defects. Mutations in SALL4 are responsible for the Duane-radial ray syndrome (<a href="/entry/607323">607323</a>); mutations in TBX5 are responsible for the Holt-Oram syndrome (<a href="/entry/142900">142900</a>). <a href="#15" class="mim-tip-reference" title="Koshiba-Takeuchi, K., Takeuchi, J. K., Arruda, E. P., Kathiriya, I. S., Mo, R., Hui, C., Srivastava, D., Bruneau, B. G. <strong>Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart.</strong> Nature Genet. 38: 175-183, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16380715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16380715</a>] [<a href="https://doi.org/10.1038/ng1707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16380715">Koshiba-Takeuchi et al. (2006)</a> showed that Tbx5 regulates Sall4 expression in the developing mouse forelimb and heart; mice heterozygous for a gene trap allele of Sall4 showed limb and heart defects that modeled human disease. Tbx5 and Sall4 interacted both positively and negatively to finely regulate patterning and morphogenesis of the anterior forelimb and heart. Thus, a positive and negative feed-forward circuit between Tbx5 and Sall4 ensures precise patterning of embryonic limb and heart and provides a unifying mechanism for heart/hand syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16380715" 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="#33" class="mim-tip-reference" title="Zhu, Y., Gramolini, A. O., Walsh, M. A., Zhou, Y.-Q., Slorach, C., Friedberg, M. K., Takeuchi, J. K., Sun, H., Henkelman, R. M., Backx, P. H., Redington, A. N., MacLennan, D. H., Bruneau, B. G. <strong>Tbx5-dependent pathway regulating diastolic function in congenital heart disease.</strong> Proc. Nat. Acad. Sci. 105: 5519-5524, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18378906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18378906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18378906[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0801779105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18378906">Zhu et al. (2008)</a> generated mice with haploinsufficiency of Tbx5 in ventricular myocytes only and observed diastolic dysfunction due to a cell-autonomous defect in myocyte relaxation but no atrial or ventricular septal defects or conduction defects. Tbx5-haploinsufficient mice had significantly decreased left ventricular protein levels of SERCA2a (ATP2A2; <a href="/entry/108740">108740</a>) and decreased mRNA levels of Tbx5 and Atp2a2. Similarly, there was a decrease in rate and amplitude of Ca(2+) uptake and Ca(2+) transient prolongation in left ventricular tissue. The authors demonstrated that Tbx5 activated an Atp2a2 promoter-reporter construct. Doppler analysis of 8 patients with clinically diagnosed Holt-Oram syndrome, 1 of whom was known to carry a mutation in the TBX5 gene, showed diastolic filling abnormalities of variable severity and type. <a href="#33" class="mim-tip-reference" title="Zhu, Y., Gramolini, A. O., Walsh, M. A., Zhou, Y.-Q., Slorach, C., Friedberg, M. K., Takeuchi, J. K., Sun, H., Henkelman, R. M., Backx, P. H., Redington, A. N., MacLennan, D. H., Bruneau, B. G. <strong>Tbx5-dependent pathway regulating diastolic function in congenital heart disease.</strong> Proc. Nat. Acad. Sci. 105: 5519-5524, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18378906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18378906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18378906[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0801779105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18378906">Zhu et al. (2008)</a> concluded that there is a direct genetic pathway regulating cardiac diastolic function, and that patients with structural congenital heart defects may also have underlying anomalies in heart function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18378906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Koshiba-Takeuchi, K., Mori, A. D., Kaynak, B. L., Cebra-Thomas, J., Sukonnik, T., Georges, R. O., Latham, S., Beck, L., Henkelman, R. M., Black, B. L., Olson, E. N., Wade, J., Takeuchi, J. K., Nemer, M., Gilbert, S. F., Bruneau, B. G. <strong>Reptilian heart development and the molecular basis of cardiac chamber evolution.</strong> Nature 461: 95-98, 2009. Note: Erratum: Nature 461: 550 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19727199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19727199</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19727199[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/nature08324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19727199">Koshiba-Takeuchi et al. (2009)</a> examined heart development in the red-eared slider turtle, Trachemys scripta elegans (a chelonian), and the green anole, Anolis carolinensis (a squamate), focusing on gene expression in the developing ventricles. Both reptiles initially form a ventricular chamber that homogeneously expresses the T-box transcription factor gene Tbx5. In contrast, in birds and mammals, Tbx5 is restricted to the left ventricle precursors. In later stages, Tbx5 expression in the turtle (but not anole) heart is gradually restricted to a distinct left ventricle, forming a left-right gradient. This suggests that Tbx5 expression was refined during evolution to pattern the ventricles. In support of this hypothesis, <a href="#14" class="mim-tip-reference" title="Koshiba-Takeuchi, K., Mori, A. D., Kaynak, B. L., Cebra-Thomas, J., Sukonnik, T., Georges, R. O., Latham, S., Beck, L., Henkelman, R. M., Black, B. L., Olson, E. N., Wade, J., Takeuchi, J. K., Nemer, M., Gilbert, S. F., Bruneau, B. G. <strong>Reptilian heart development and the molecular basis of cardiac chamber evolution.</strong> Nature 461: 95-98, 2009. Note: Erratum: Nature 461: 550 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19727199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19727199</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19727199[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/nature08324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19727199">Koshiba-Takeuchi et al. (2009)</a> showed that loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation. Importantly, misexpression of Tbx5 throughout the developing myocardium to mimic the reptilian expression pattern also results in a single mispatterned ventricular chamber lacking septation. Thus, <a href="#14" class="mim-tip-reference" title="Koshiba-Takeuchi, K., Mori, A. D., Kaynak, B. L., Cebra-Thomas, J., Sukonnik, T., Georges, R. O., Latham, S., Beck, L., Henkelman, R. M., Black, B. L., Olson, E. N., Wade, J., Takeuchi, J. K., Nemer, M., Gilbert, S. F., Bruneau, B. G. <strong>Reptilian heart development and the molecular basis of cardiac chamber evolution.</strong> Nature 461: 95-98, 2009. Note: Erratum: Nature 461: 550 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19727199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19727199</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19727199[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/nature08324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19727199">Koshiba-Takeuchi et al. (2009)</a> concluded that ventricular septation is established by a steep and correctly positioned Tbx5 gradient, and that their findings provided a molecular mechanism for the evolution of the amniote ventricle and supported the concept that altered expression of developmental regulators is a key mechanism of vertebrate evolution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19727199" 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 conditional mouse haploinsufficiency models, <a href="#22" class="mim-tip-reference" title="Nadadur, R. D., Broman, M. T., Boukens, B., Mazurek, S. R., Yang, X., van den Boogaard, M., Bekeny, J., Gadek, M., Ward, T., Zhang, M., Qiao, Y., Martin, J. F., Seidman, C. E., Seidman, J., Christoffels, V., Efimov, I. R., McNally, E. M., Weber, C. R., Moskowitz, I. P. <strong>Pitx2 modulates a Tbx5-dependent gene regulatory network to maintain atrial rhythm.</strong> Sci. Transl. Med. 8: 354ra115, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27582060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27582060</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27582060[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/10.1126/scitranslmed.aaf4891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27582060">Nadadur et al. (2016)</a> found that Tbx5 and Ptx2 antagonistically regulated gene expression in atria. Reduced Tbx5 expression profoundly disrupted cardiac channel gene expression and caused action potential abnormalities leading to primary, spontaneous atrial fibrillation. Concomitant haploinsufficiency for Pitx2 rescued the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27582060" 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 2 apparently unrelated Holt-Oram syndrome (HOS; <a href="/entry/142900">142900</a>) families, <a href="#17" class="mim-tip-reference" title="Li, Q. Y., Newbury-Ecob, R. A., Terrett, J. A., Wilson, D. I., Curtis, A. R. J., Yi, C. H., Gebuhr, T., Bullen, P. J., Robson, S. C., Strachan, T., Bonnet, D., Lyonnet, S., Young, I. D., Raeburn, J. A., Buckler, A. J., Law, D. J., Brook, J. D. <strong>Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family.</strong> Nature Genet. 15: 21-29, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988164</a>] [<a href="https://doi.org/10.1038/ng0197-21" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988164">Li et al. (1997)</a> found the identical mutation, a C-to-T change at position 1491 resulting in a stop codon (TGA). Two families showed different haplotypes of 3 markers around the HOS1 locus, indicating that they probably did not share a recent common ancestor. The same mutation occurring in exon G was found also in a sporadic case of Holt-Oram syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988164" 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> rs104894377 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894377;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/rs104894377?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=rs104894377" 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=rs104894377" 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=RCV000008456 OR RCV000760324" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008456, RCV000760324" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008456...</a>
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<p><a href="#3" class="mim-tip-reference" title="Basson, C. T., Bachinsky, D. R., Lin, R. C., Levi, T., Elkins, J. A., Soults, J., Grayzel, D., Kroumpouzou, E., Traill, T. A., Leblanc-Straceski, J., Renault, B., Kucherlapati, R., Seidman, J. G., Seidman, C. E. <strong>Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome.</strong> Nature Genet. 15: 30-35, 1997. Note: Erratum: Nature Genet. 15: 411 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988165</a>] [<a href="https://doi.org/10.1038/ng0197-30" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988165">Basson et al. (1997)</a> found that all affected members of a family with Holt-Oram syndrome (HOS; <a href="/entry/142900">142900</a>) were heterozygous for a 205G-T transversion which was predicted to convert glutamate-69 (GAA) to a stop codon (TAA). The mutation creates a novel DdeI restriction site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988165" 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>.0003 HOLT-ORAM SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894378 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894378;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/rs104894378?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=rs104894378" 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=rs104894378" 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=RCV000008457 OR RCV000196777 OR RCV000474989 OR RCV002362569" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008457, RCV000196777, RCV000474989, RCV002362569" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008457...</a>
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<p>In their family B, <a href="#3" class="mim-tip-reference" title="Basson, C. T., Bachinsky, D. R., Lin, R. C., Levi, T., Elkins, J. A., Soults, J., Grayzel, D., Kroumpouzou, E., Traill, T. A., Leblanc-Straceski, J., Renault, B., Kucherlapati, R., Seidman, J. G., Seidman, C. E. <strong>Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome.</strong> Nature Genet. 15: 30-35, 1997. Note: Erratum: Nature Genet. 15: 411 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988165</a>] [<a href="https://doi.org/10.1038/ng0197-30" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988165">Basson et al. (1997)</a> demonstrated that all members with Holt-Oram syndrome (HOS; <a href="/entry/142900">142900</a>) had a 710G-A transition predicted to result in the substitution of an arginine (CGG) by a glutamine (CAG) at codon 237. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Basson, C. T., Huang, T., Lin, R. C., Bachinsky, D. R., Weremowicz, S., Vaglio, A., Bruzzone, R., Quadrelli, R., Lerone, M., Romeo, G., Silengo, M., Pereira, A., Krieger, J., Mesquita, S. F., Kamisago, M., Morton, C. C., Pierpont, M. E. M., Muller, C. W., Seidman, J. G., Seidman, C. E. <strong>Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations.</strong> Proc. Nat. Acad. Sci. 96: 2919-2924, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10077612[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.6.2919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10077612">Basson et al. (1999)</a> found that the arg237-to-gln (R237Q) mutation in the TBX5 gene caused upper limb malformations of the type seen in HOS without cardiac abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077612" 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 HOLT-ORAM SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894381 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894381;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=rs104894381" 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=rs104894381" 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=RCV000008458" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008458" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008458</a>
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<p>In a family with Holt-Oram syndrome (HOS; <a href="/entry/142900">142900</a>), <a href="#4" class="mim-tip-reference" title="Basson, C. T., Huang, T., Lin, R. C., Bachinsky, D. R., Weremowicz, S., Vaglio, A., Bruzzone, R., Quadrelli, R., Lerone, M., Romeo, G., Silengo, M., Pereira, A., Krieger, J., Mesquita, S. F., Kamisago, M., Morton, C. C., Pierpont, M. E. M., Muller, C. W., Seidman, J. G., Seidman, C. E. <strong>Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations.</strong> Proc. Nat. Acad. Sci. 96: 2919-2924, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10077612[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.6.2919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10077612">Basson et al. (1999)</a> identified a gly80-to-arg substitution in the TBX5 gene. They found that this mutation caused significant cardiac malformations but only minor skeletal abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 HOLT-ORAM SYNDROME</strong>
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TBX5, ARG237TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894382 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894382;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=rs104894382" 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=rs104894382" 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=RCV000008459 OR RCV000128627 OR RCV000473181 OR RCV002362570" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008459, RCV000128627, RCV000473181, RCV002362570" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008459...</a>
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<p>In families with Holt-Oram syndrome (HOS; <a href="/entry/142900">142900</a>), <a href="#4" class="mim-tip-reference" title="Basson, C. T., Huang, T., Lin, R. C., Bachinsky, D. R., Weremowicz, S., Vaglio, A., Bruzzone, R., Quadrelli, R., Lerone, M., Romeo, G., Silengo, M., Pereira, A., Krieger, J., Mesquita, S. F., Kamisago, M., Morton, C. C., Pierpont, M. E. M., Muller, C. W., Seidman, J. G., Seidman, C. E. <strong>Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations.</strong> Proc. Nat. Acad. Sci. 96: 2919-2924, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10077612[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.6.2919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10077612">Basson et al. (1999)</a> identified an arg237-to-trp substitution in the TBX5 gene. The mutation occurred in the same codon as the arg237-to-gln mutation (<a href="#0003">601620.0003</a>), and the authors found that both mutations caused extensive upper limb malformations but less significant cardiac abnormalities. They found that residue 80 (<a href="#0004">601620.0004</a>) is highly conserved within T-box sequences that interact with the major group of target DNA, whereas residue 237 is located in the T-box domain that selectively binds to the minor group DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077612" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 HOLT-ORAM SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1593880204 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1593880204;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=rs1593880204" 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=rs1593880204" 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=RCV000008460" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008460" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008460</a>
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<p>In a Chinese family with Holt-Oram syndrome (HOS; <a href="/entry/142900">142900</a>), <a href="#31" class="mim-tip-reference" title="Yang, J., Hu, D., Xia, J., Yang, Y., Ying, B., Hu, J., Zhou, X. <strong>Three novel TBX5 mutations in Chinese patients with Holt-Oram syndrome.</strong> Am. J. Med. Genet. 92: 237-240, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10842287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10842287</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000605)92:4<237::aid-ajmg2>3.0.co;2-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10842287">Yang et al. (2000)</a> identified a 1-bp deletion in exon 4 at nucleotide 416, resulting in a frameshift of downstream codons. The 2 affected family members had atrial septal defects and severe upper limb manifestations, including aplasia/hypoplasia of the arms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10842287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 HOLT-ORAM SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894383 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894383;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/rs104894383?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=rs104894383" 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=rs104894383" 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=RCV000008461" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008461" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008461</a>
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<p>In a Chinese family with Holt-Oram syndrome (HOS; <a href="/entry/142900">142900</a>), <a href="#31" class="mim-tip-reference" title="Yang, J., Hu, D., Xia, J., Yang, Y., Ying, B., Hu, J., Zhou, X. <strong>Three novel TBX5 mutations in Chinese patients with Holt-Oram syndrome.</strong> Am. J. Med. Genet. 92: 237-240, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10842287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10842287</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000605)92:4<237::aid-ajmg2>3.0.co;2-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10842287">Yang et al. (2000)</a> identified a missense mutation in exon 2, a C-to-A transversion at nucleotide 145, resulting in a gln49-to-lys substitution. The 2 affected family members had atrial septal defects and mild upper limb manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10842287" 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="0008" class="mim-anchor"></a>
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<strong>.0008 HOLT-ORAM SYNDROME</strong>
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TBX5, ILE54THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894384 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894384;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=rs104894384" 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=rs104894384" 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=RCV000008462" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008462" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008462</a>
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<span class="mim-text-font">
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<p>In a Chinese sporadic case of Holt-Oram syndrome (HOS; <a href="/entry/142900">142900</a>), <a href="#31" class="mim-tip-reference" title="Yang, J., Hu, D., Xia, J., Yang, Y., Ying, B., Hu, J., Zhou, X. <strong>Three novel TBX5 mutations in Chinese patients with Holt-Oram syndrome.</strong> Am. J. Med. Genet. 92: 237-240, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10842287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10842287</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000605)92:4<237::aid-ajmg2>3.0.co;2-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10842287">Yang et al. (2000)</a> identified a missense mutation in exon 2, a T-to-C alteration at nucleotide 161, resulting in an ile54-to-thr substitution. This patient had an atrial septal defect (ASD; <a href="/entry/108800">108800</a>) and an absent left thumb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10842287" 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="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 HOLT-ORAM SYNDROME</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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TBX5, TYR136TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894379 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894379;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=rs104894379" 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=rs104894379" 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=RCV000008463 OR RCV003398470" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008463, RCV003398470" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008463...</a>
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<span class="mim-text-font">
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<p>In 2 unrelated families with Holt-Oram syndrome (HOS; <a href="/entry/142900">142900</a>), <a href="#11" class="mim-tip-reference" title="Gruenauer-Kloevekorn, C., Froster, U. G. <strong>Holt-Oram syndrome: a new mutation in the TBX5 gene in two unrelated families.</strong> Ann. Genet. 46: 19-23, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12818525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12818525</a>] [<a href="https://doi.org/10.1016/s0003-3995(03)00006-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12818525">Gruenauer-Kloevekorn and Froster (2003)</a> identified heterozygosity for a 408C-A transversion in exon 5 of the TBX5 gene, resulting in a tyr136-to-stop substitution, in all affected members. The mutation was not found in unaffected family members or in 200 control samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12818525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 HOLT-ORAM SYNDROME</strong>
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</span>
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</h4>
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TBX5, 48-KB DUP, EX2-9DUP
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000415566" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415566" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415566</a>
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<span class="mim-text-font">
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<p>In affected members of a 5-generation family segregating an atypical form of Holt-Oram syndrome (<a href="/entry/142900">142900</a>), <a href="#25" class="mim-tip-reference" title="Patel, C., Silcock, L., McMullan, D., Brueton, L., Cox, H. <strong>TBX5 intragenic duplication: a family with atypical Holt-Oram syndrome phenotype.</strong> Europ. J. Hum. Genet. 20: 863-86, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22333898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22333898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22333898[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/ejhg.2012.16" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22333898">Patel et al. (2012)</a> identified a 48-kb duplication at chromosome 12q24.21 (chr12.114,795,705-114,844,082, GRCh37) encompassing exons 2 through 9 of the TBX5 gene, with breakpoints within introns 1 and 9. The duplication, which was identified by array CGH and multiplex ligation-dependent probe amplification (MLPA), segregated with the disorder in the family. <a href="#25" class="mim-tip-reference" title="Patel, C., Silcock, L., McMullan, D., Brueton, L., Cox, H. <strong>TBX5 intragenic duplication: a family with atypical Holt-Oram syndrome phenotype.</strong> Europ. J. Hum. Genet. 20: 863-86, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22333898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22333898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22333898[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/ejhg.2012.16" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22333898">Patel et al. (2012)</a> proposed that the intragenic duplication could be in-frame and cause its effects through an elongated protein that leads to a gain of function; an elongated protein with abnormal cellular localization mimicking functional haploinsufficiency; or increased expression of the TBX5 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22333898" 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="Ahn2002" class="mim-anchor"></a>
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Ahn, D., Kourakis, M. J., Rohde, L. A., Silver, L. M., Ho, R. K.
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<strong>T-box gene tbx5 is essential for formation of the pectoral limb bud.</strong>
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Nature 417: 754-758, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12066188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12066188</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12066188" 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/nature00814" target="_blank">Full Text</a>]
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<a id="Bamshad2003" class="mim-anchor"></a>
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Bamshad, M. J.
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<strong>Personal Communication.</strong>
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Salt Lake City, Utah 6/26/2003.
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<a id="Basson1997" class="mim-anchor"></a>
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Basson, C. T., Bachinsky, D. R., Lin, R. C., Levi, T., Elkins, J. A., Soults, J., Grayzel, D., Kroumpouzou, E., Traill, T. A., Leblanc-Straceski, J., Renault, B., Kucherlapati, R., Seidman, J. G., Seidman, C. E.
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<strong>Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome.</strong>
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Nature Genet. 15: 30-35, 1997. Note: Erratum: Nature Genet. 15: 411 only, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988165</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988165" 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/ng0197-30" target="_blank">Full Text</a>]
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<a id="Basson1999" class="mim-anchor"></a>
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Basson, C. T., Huang, T., Lin, R. C., Bachinsky, D. R., Weremowicz, S., Vaglio, A., Bruzzone, R., Quadrelli, R., Lerone, M., Romeo, G., Silengo, M., Pereira, A., Krieger, J., Mesquita, S. F., Kamisago, M., Morton, C. C., Pierpont, M. E. M., Muller, C. W., Seidman, J. G., Seidman, C. E.
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<strong>Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations.</strong>
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Proc. Nat. Acad. Sci. 96: 2919-2924, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077612</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10077612[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=10077612" 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.96.6.2919" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16332960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16332960</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16332960[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=16332960" 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.0509109102" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/scitranslmed.aaf4891" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature25461" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg077" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ejhg.2012.16" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddq393" target="_blank">Full Text</a>]
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<a id="Reamon-Buettner2006" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1002/humu.9390" target="_blank">Full Text</a>]
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<a id="Sowden2001" class="mim-anchor"></a>
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Sowden, J. C., Holt, J. K. L., Meins, M., Smith, H. K., Bhattacharya, S. S.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11726608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11726608</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11726608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Takeuchi2009" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396158</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19396158[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=19396158" 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/nature08039" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8054982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8054982</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8054982" 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/ng0494-401" target="_blank">Full Text</a>]
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<a id="Yang2000" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1002/(sici)1096-8628(20000605)92:4<237::aid-ajmg2>3.0.co;2-g" target="_blank">Full Text</a>]
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<strong>Virtual cloning and physical mapping of a human T-box gene, TBX4.</strong>
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[<a href="https://doi.org/10.1006/geno.2000.6222" target="_blank">Full Text</a>]
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<a id="Zhu2008" class="mim-anchor"></a>
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Zhu, Y., Gramolini, A. O., Walsh, M. A., Zhou, Y.-Q., Slorach, C., Friedberg, M. K., Takeuchi, J. K., Sun, H., Henkelman, R. M., Backx, P. H., Redington, A. N., MacLennan, D. H., Bruneau, B. G.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18378906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18378906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18378906[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=18378906" 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.0801779105" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 04/16/2018
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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George E. Tiller - updated : 06/27/2017<br>Patricia A. Hartz - updated : 01/27/2017<br>Marta Biderman Waberski - updated : 01/11/2017<br>Ada Hamosh - updated : 4/17/2014<br>Marla J. F. O'Neill - updated : 1/25/2012<br>Ada Hamosh - updated : 10/13/2009<br>Ada Hamosh - updated : 6/16/2009<br>Patricia A. Hartz - updated : 6/6/2008<br>Patricia A. Hartz - updated : 8/23/2007<br>Marla J. F. O'Neill - updated : 10/18/2006<br>Carol A. Bocchini - updated : 9/14/2006<br>Victor A. McKusick - updated : 2/7/2006<br>Patricia A. Hartz - updated : 1/17/2006<br>Victor A. McKusick - updated : 12/27/2005<br>George E. Tiller - updated : 3/2/2005<br>Patricia A. Hartz - updated : 2/4/2005<br>Patricia A. Hartz - updated : 5/7/2004<br>Victor A. McKusick - updated : 7/15/2003<br>Ada Hamosh - updated : 7/7/2003<br>Victor A. McKusick - updated : 6/25/2003<br>Victor A. McKusick - updated : 9/19/2002<br>Ada Hamosh - updated : 7/10/2002<br>Jane Kelly - updated : 7/8/2002<br>George E. Tiller - updated : 2/1/2002<br>Stylianos E. Antonarakis - updated : 9/25/2001<br>Victor A. McKusick - updated : 6/25/2001<br>Sonja A. Rasmussen - updated : 7/13/2000<br>Ada Hamosh - updated : 12/29/1999<br>Ada Hamosh - updated : 5/4/1999<br>Victor A. McKusick - updated : 4/16/1999<br>Victor A. McKusick - updated : 6/17/1997
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Victor A. McKusick : 1/10/1997
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carol : 03/20/2020
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alopez : 04/16/2018<br>alopez : 06/27/2017<br>mgross : 01/27/2017<br>carol : 01/11/2017<br>carol : 09/28/2016<br>carol : 09/27/2016<br>mgross : 06/30/2015<br>alopez : 4/17/2014<br>alopez : 1/29/2014<br>terry : 6/6/2012<br>terry : 5/10/2012<br>terry : 1/26/2012<br>terry : 1/26/2012<br>carol : 1/25/2012<br>alopez : 6/29/2010<br>alopez : 6/29/2010<br>alopez : 10/22/2009<br>terry : 10/13/2009<br>alopez : 6/17/2009<br>terry : 6/16/2009<br>wwang : 6/6/2008<br>terry : 6/6/2008<br>mgross : 8/30/2007<br>terry : 8/23/2007<br>wwang : 10/20/2006<br>terry : 10/18/2006<br>carol : 9/14/2006<br>terry : 2/7/2006<br>mgross : 1/18/2006<br>terry : 1/17/2006<br>alopez : 12/28/2005<br>terry : 12/27/2005<br>carol : 7/7/2005<br>ckniffin : 7/6/2005<br>alopez : 3/2/2005<br>mgross : 2/4/2005<br>mgross : 2/4/2005<br>mgross : 5/7/2004<br>alopez : 7/28/2003<br>carol : 7/15/2003<br>terry : 7/15/2003<br>alopez : 7/9/2003<br>terry : 7/7/2003<br>carol : 6/25/2003<br>terry : 6/25/2003<br>tkritzer : 9/24/2002<br>tkritzer : 9/19/2002<br>tkritzer : 9/19/2002<br>tkritzer : 9/19/2002<br>alopez : 7/11/2002<br>terry : 7/10/2002<br>mgross : 7/8/2002<br>cwells : 2/6/2002<br>cwells : 2/1/2002<br>mgross : 9/25/2001<br>alopez : 6/28/2001<br>terry : 6/25/2001<br>terry : 6/25/2001<br>mcapotos : 7/17/2000<br>mcapotos : 7/14/2000<br>mcapotos : 7/13/2000<br>alopez : 12/30/1999<br>terry : 12/29/1999<br>alopez : 5/4/1999<br>mgross : 4/27/1999<br>mgross : 4/21/1999<br>terry : 4/16/1999<br>alopez : 3/9/1998<br>mark : 10/17/1997<br>mark : 10/15/1997<br>mark : 6/17/1997<br>jenny : 1/14/1997<br>mark : 1/10/1997
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<span class="mim-font">
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<strong>*</strong> 601620
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<h3>
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<span class="mim-font">
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T-BOX TRANSCRIPTION FACTOR 5; TBX5
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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T-BOX 5
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TBX5</em></strong>
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<strong>SNOMEDCT:</strong> 19092004;
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<strong>ICD10CM:</strong> Q87.2;
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Cytogenetic location: 12q24.21
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:114,353,911-114,408,442 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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12q24.21
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Holt-Oram syndrome
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142900
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Autosomal dominant
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Cloning and Expression</strong>
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<p>Using exon trap analysis of genomic clones from an interval on chromosome 12q2 containing the locus for Holt-Oram syndrome (HOS; 142900) (Terrett et al., 1994), a developmental disorder affecting the heart and limbs, Li et al. (1997) identified 2 developmentally expressed genes of the Brachyury (T) family. These genes share a common DNA-binding motif (T-box) and were designated TBX3 (601621) and TBX5, in line with their mouse homologs. </p><p>Basson et al. (1997) refined the mapping of the HOS locus to 12q24.1 by fluorescence in situ hybridization using a cosmid containing D12S129, which was tightly linked to HOS. From the critical region they likewise isolated a gene with a high degree of homology to mouse Tbx5 and identified several mutations in TBX5 in affected members of HOS families. Members of the T-box gene family act as transcription factors and the conserved T-box domain serves as a DNA binding domain. In addition to heart and forelimb, murine Tbx5 transcripts are expressed in genital papilla, lung, pharynx, and thorax body wall, all tissues that are not affected in HOS patients. Basson et al. (1997) commented that this observation may suggest a more restricted pattern of expression of human TBX5; alternatively, the consequences of TBX5 haploinsufficiency on organ morphogenesis may differ between tissues. </p>
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<strong>Gene Function</strong>
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<p>Hiroi et al. (2001) found that TBX5 associates with NKX2-5 (600584) and synergistically promotes cardiomyocyte differentiation. Both directly bind to the promoter of the gene encoding cardiac-specific natriuretic peptide precursor type A (NPPA; 108780) in tandem, and the 2 transcription factors show synergistic activation. P19CL6 cells efficiently differentiate into beating cardiomyocytes expressing cardiac-specific genes after treatment with 1% dimethyl sulfoxide (DMSO). Hiroi et al. (2001) found that P19CL6 cell lines overexpressing wildtype Tbx5 started to beat earlier and expressed cardiac-specific genes more abundantly than did parental P19CL6 cells, whereas cell lines expressing the G80R mutation (601620.0004), which causes substantial cardiac defects with minor skeletal abnormalities in HOS, did not differentiate into beating cardiomyocytes. Contrariwise, the R237Q mutation (601620.0003), which causes upper limb malformations without cardiac abnormalities, activated the Nppa promoter to an extent similar to that of wildtype TBX5. </p><p>Garg et al. (2003) demonstrated that GATA4 (600576) interacts with TBX5 and showed that a missense mutation in GATA4, G296S (600576.0001), abrogated this interaction. Conversely, interaction of GATA4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects. Garg et al. (2003) concluded that their results implicate GATA4 as a genetic cause of human cardiac septal defects, perhaps through its interaction with TBX5. </p><p>Murakami et al. (2005) found that TAZ (WWTR1; 300394) was a potent TBX5 transactivator. TAZ associated with TBX5 and stimulated TBX5-dependent promoters by interacting with the histone acetyltransferases p300 (EP300; 602700) and PCAF (602303). YAP (606608), a TAZ-related protein, also stimulated TBX5-dependent transcription. TBX5 with HOS-associated truncation mutations could not be stimulated by TAZ, but TBX5 with HOS-associated point mutations was unimpaired in its ability to respond to TAZ. </p><p>By microdissection of the mouse ventricular conduction system, followed by serial analysis of gene expression (SAGE) of the left bundle branch, Moskowitz et al. (2007) identified Id2 (600386) as a conduction system-specific transcript. Analysis of the Id2 promoter showed that conduction system-specific expression of Id2 was dependent on Nkx2.5 and Tbx5. Moskowitz et al. (2007) concluded that a molecular pathway including Id2, Nkx2.5, and Tbx5 coordinates specification of ventricular myocytes into the ventricular conduction system lineage. </p><p>Takeuchi and Bruneau (2009) defined the minimal requirements for transdifferentiation of mouse mesoderm to cardiac myocytes. They showed that 2 cardiac transcription factors, Gata4 and Tbx5, and a cardiac-specific subunit of BAF chromatin-remodeling complexes, Baf60c (SMARCD3; 601737), can direct ectopic differentiation of mouse mesoderm into beating cardiomyocytes, including the normally noncardiogenic posterior mesoderm and the extraembryonic mesoderm of the amnion. Gata4 and Baf60c initiated ectopic cardiac gene expression. Addition of Tbx5 allowed differentiation into contracting cardiomyocytes and repression of noncardiac mesodermal genes. Baf60c was essential for the ectopic cardiogenic activity of Gata4 and Tbx5, partly by permitting binding of Gata4 to cardiac genes, indicating a novel instructive role for BAF complexes in tissue-specific regulation. Takeuchi and Bruneau (2009) concluded that the combined function of these factors establishes a robust mechanism for controlling cellular differentiation, and may allow reprogramming of new cardiomyocytes for regenerative purposes. </p><p>Gros and Tabin (2014) showed that mesenchymal limb progenitors arise through localized epithelial-to-mesenchymal transition (EMT) of the coelomic epithelium specifically within the presumptive limb fields. This EMT is regulated at least in part by TBX5 and FGF10 (602115), 2 genes known to control limb initiation. Gros and Tabin (2014) showed that limb buds initiate earlier than had been thought, as a result of localized EMT rather than differential proliferation rates. </p><p>Nadadur et al. (2016) identified a cis regulatory element containing a functional T-box-binding site in the promoter of PITX2 (601542) that was bound by TBX5. The major T allele of a common SNP, rs1906595, disrupted the central nucleotide of the T-box-binding motif, whereas the minor G allele of the SNP completed the canonical T-box-binding element. The major allele of rs1906595 completely abolished cis regulatory element activity in response to TBX5 in transfected HEK293 cells and in HL-1 mouse atrial cardiomyocytes. </p><p>Shox2 (602504) is essential for the formation of the sinoatrial valves and for the development of the pacemaking system of the heart. Puskaric et al. (2010) analyzed putative targets of Shox2 and identified Bmp4 (112262) as a direct target. Shox2 interacted directly with the Bmp4 promoter and activated transcription. Ectopic expression of Shox2 in Xenopus embryos stimulated transcription of Bmp4, and silencing of Shox2 in cardiomyocytes led to a reduction in the expression of Bmp4. Using Tbx5 del/+ mice, a model for Holt-Oram syndrome (142900), and Shox2 -/- mice, Puskaric et al. (2010) showed that the T-box transcription factor Tbx5 was a regulator of Shox2 expression in the inflow tract, and that Bmp4 was regulated by Shox2 in this compartment of the embryonic heart. In addition, Tbx5 acted cooperatively with Nkx2-5 (600584) to regulate the expression of Shox2 and Bmp4. Puskaric et al. (2010) concluded that their work established a functional link between Tbx5, Shox2, and Bmp4 in the pacemaker region of the developing heart. </p>
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<strong>Gene Structure</strong>
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<p>Yi et al. (2000) determined that the TBX5 gene contains 9 exons and spans more than 47 kb. </p><p>Osterwalder et al. (2018) showed that the pervasive presence of multiple enhancers with similar activities near the same gene confers phenotypic robustness to loss-of-function mutations in individual enhancers. Osterwalder et al. (2018) used genome editing to create 23 mouse deletion lines and intercrosses, including both single and combinatorial enhancer deletions at 7 distinct loci required for limb development including GlI3 (165240), Shox2, Tbx3 (601621), Tbx5, and Lhx5 (605992). Unexpectedly, none of the 10 deletions of individual enhancers caused noticeable changes in limb morphology. By contrast, the removal of pairs of limb enhancers near the same gene resulted in discernible phenotypes, indicating that enhancers function redundantly in establishing normal morphology. In a genetic background sensitized by reduced baseline expression of the target gene, even single enhancer deletions caused limb abnormalities, suggesting that functional redundancy is conferred by additive effects of enhancers on gene expression levels. A genomewide analysis integrating epigenomic and transcriptomic data from 29 developmental mouse tissues revealed that mammalian genes are very commonly associated with multiple enhancers that have similar spatiotemporal activity. Systematic exploration of 3 representative developmental structures (limb, brain, and heart) uncovered more than 1,000 cases in which 5 or more enhancers with redundant activity patterns were found near the same gene. Osterwalder et al. (2018) concluded that their data indicated that enhancer redundancy is a remarkably widespread feature of mammalian genomes that provides an effective regulatory buffer to prevent deleterious phenotypic consequences upon the loss of individual enhancers. </p>
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<strong>Mapping</strong>
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<p>Basson et al. (1997) positionally cloned the TBX5 gene from the HOS critical region on 12q24.1. Yi et al. (2000) estimated that the TBX3 gene(601621) and the TBX5 gene are about 350 kb apart on chromosome 12q23-q24. </p>
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<strong>Molecular Genetics</strong>
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<p>Using SSCP analysis and direct sequencing of amplified products, Li et al. (1997) showed that the TBX5 gene was mutated in cases of familial and sporadic Holt-Oram syndrome (HOS; 142900) (see, e.g., 601620.0001). </p><p>Basson et al. (1999) identified heterozygous mutations in the TBX5 gene in affected members of several families segregating HOS (see, e.g., 601620.0002-601620.0005). </p><p>Packham and Brook (2003) reviewed the human disorders that have been linked to mutations in T-box genes: Holt-Oram syndrome, ulnar-mammary syndrome (UMS; 181450), DiGeorge syndrome (DGS; 188400), ACTH deficiency (201400), and cleft palate with ankyloglossia (CPX; 303400). </p><p>In a Czech mother and 2 daughters diagnosed with Holt-Oram syndrome, Borozdin et al. (2006) identified a 2.19 to 2.27-Mb contiguous deletion encompassing the TBX5 and TBX3 genes. Clinical reexamination confirmed the presence of features of ulnar-mammary syndrome that were previously unrecognized. Borozdin et al. (2006) noted that the contiguous deletion also included the RBM19 gene (616444), but commented that it was unlikely to contribute to or modify the phenotype since all the anomalies present in the affected individuals could be explained by either TBX5 or TBX3 haploinsufficiency. </p><p><strong><em>Somatic Mutations</em></strong></p><p>
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In diseased cardiac tissues from 2 of 52 explanted hearts of unrelated patients with complex cardiac malformations, notably ventricular (VSD) and atrioventricular septal defects (AVSD), Reamon-Buettner and Borlak (2006) found 3 nonsynonymous mutations in the HEY2 gene (604674). Since the 2 AVSD patients also carried binding domain mutations in other cardiac-specific transcription factors, e.g., NKX2-5 (600584), TBX5, and GATA4 (600576), Reamon-Buettner and Borlak (2006) concluded that breakdown of combinatorial interactions of transcription factors may have contributed to the complexity of their cardiac malformations. </p>
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<p>To understand better the role of TBX5 in forelimb and heart development, Basson et al. (1999) studied the clinical features of Holt-Oram syndrome caused by 10 different TBX5 mutations. Defects predicted to create null alleles caused substantial abnormalities in both limb and heart. In contrast, missense mutations produced distinct phenotypes: gly80-to-arg (601620.0004) caused significant cardiac malformations but only minor skeletal abnormalities, whereas arg237-to-gln (601620.0003) and arg237-to-trp (601620.0005) caused extensive upper limb malformations but less significant cardiac abnormalities. Amino acids altered by missense mutations were located on the 3-dimensional structure of a related T-box transcription factor, Xbra (of X. laevis), bound to DNA. Residue 80 is highly conserved within T-box sequences that interact with the major groove of target DNA; residue 237 is located in the T-box domain that selectively binds to the minor groove of DNA. These structural data, taken together with the predominant cardiac or skeletal phenotype produced by each missense mutation, suggested that organ-specific gene activation by TBX5 is predicated on biophysical interactions with different target DNA sequences. </p><p>In a study of 55 probands with Holt-Oram syndrome, Brassington et al. (2003) found 17 mutations, including 6 missense mutations, in TBX5 and 2 mutations in the SALL4 gene (607343), which is the site of mutations causing some cases of Duane-radial ray syndrome (607323). Their results suggested that neither the type of mutation in TBX5 nor the location of the mutation in the T box is predictive of the expressivity of malformations in individuals with HOS. Bamshad (2003) stated that 2 cases in which SALL4 mutations were found in the report of Brassington et al. (2003) had been referred to him and his coworkers and were not personally examined by them. He said that in 1 case, after a mutation in SALL4 was found, the primary care physician reexamined the patient and noted the presence of ophthalmoplegia, making the diagnosis of Duane-radial ray syndrome. Furthermore, Bamshad (2003) had not considered kidney defects typical of HOS and the affected mother of the patient who was later diagnosed with Duane-radial ray syndrome had pelvic kidneys. Kohlhase (2003) suggested that the SALL4 mutation in the second 'HOS' case of Brassington et al. (2003) was actually a rare polymorphism, as it did not affect a functional domain, was not conserved between mouse and man, and the unaffected parent also carried the mutation. </p>
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<p>In the mouse, 4 of the T-box genes, i.e., the T locus (601397), Tbx1 (602054), Tbx6 (602427), and Tbr1, are dispersed throughout the genome. Li et al. (1997) noted that the other family members, Tbx2 (600747) to Tbx5, exist as 2 clusters, having evolved from a common ancestor by 2 duplication events. Tbx2 and Tbx4 (601719) map together on mouse chromosome 11 (TBX2 is on 17q in the human), and Tbx3 and Tbx5 map on mouse chromosome 5 and human chromosome 12, respectively. However, it is Tbx2 and Tbx3 that form a cognate pair, likewise Tbx4 and Tbx5, with each pair showing related limb-associated expression. </p><p>Pitx1 (602149) and Tbx4 encode transcription factors that are expressed throughout the developing hindlimb, but not in forelimb buds. Logan and Tabin (1999) injected a retroviral vector carrying Pitx1 into the wing field of chicken embryos. Misexpression of Pitx1 in the chick wing bud induced distal expression of Tbx4, as well as HoxC10 and HoxC11, which are normally restricted to hindlimb expression domains. Wing buds in which Pitx1 was misexpressed developed into limbs with some morphologic characteristics of hindlimbs: the flexure was altered to that normally observed in legs, the digits were more toe-like in the relative size and shape, and the muscle pattern was transformed to that of a leg. Expression of Tbx5, normally expressed only in the forelimb, was not altered by Pitx1 misexpression. </p><p>Koshiba-Takeuchi et al. (2000) studied Tbx5 gene expression in developing chick eye. Expression was first detected in a broad area at stage 11 and then became restricted to the dorsal half of the eye in a graded fashion, with the strongest signal in the dorsal-most end. Misexpression of the Tbx5 gene in the ventral side of the eye induced dorsalization of the ventral side and altered projections of retinal ganglion cell axons. Thus, in the chick, Tbx5 is involved in eye morphogenesis and is a topographic determinant of the visual projections between retina and tectum. </p><p>Sowden et al. (2001) examined the role of Drosophila 'optomotor blind' (omb)-related T-box genes in the development of human and mouse retina. Murine Tbx2, Tbx3, and Tbx5 and human TBX2 cDNAs were isolated from retina cDNA libraries by hybridization to the Drosophila omb gene. Human and mouse TBX2, TBX3, and TBX5 were expressed asymmetrically across the embryonic neural retina, with highest levels of mRNA within dorsal and peripheral retina. The dorsoventral gradient of TBX2 expression disappeared before the ganglion cell layer (GCL) formed. Its expression became restricted to the inner neuroblastic retina and later to the GCL and inner nuclear layer (INL). The dorsal expression domains of TBX5 and TBX3 were maintained during formation of the GCL. As the retina matured, TBX3 expression was restricted to the INL, and TBX5 was expressed within the GCL. The authors concluded that the expression patterns of TBX2, TBX3, and TBX5 within the developing retina support the idea that the encoded transcription factors play a role in providing positional information important for topographic mapping in differentiation of distinct cell types across the laminar axis of the retina. </p><p>Bruneau et al. (2001) generated heterozygous Tbx5 -/+ mice to study the mechanisms by which TBX5 haploinsufficiency causes cardiac and forelimb abnormalities in Holt-Oram syndrome. Tbx5 deficiency in homozygous mice (Tbx5 -/-) decreased expression of multiple genes and caused severe hypoplasia of posterior domains in the developing heart. Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (Anf, or Nppa) and connexin-40 (Cx40; 121013) transcription, implicating these as Tbx5 target genes and providing a mechanism by which 50% reduction of T-box transcription factors causes disease. Direct and cooperative transactivation of the Anf and Cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated. These studies provided a potential explanation for Holt-Oram syndrome conduction system defects, suggested mechanisms for intrafamilial phenotypic variability, and accounted for related cardiac malformations caused by other transcription factor mutations. </p><p>T protein (601397) is vital for the formation and differentiation of posterior mesoderm and for axial development in all vertebrates. A mutation in this gene underlies the mouse Brachyury phenotype, a lethal phenotype manifested by abnormal notochord, absent somites, and reduced allantois. Ghosh et al. (2001) identified an 8-bp core sequence that is part of the Brachyury consensus-binding site. TBX5 bound to the full palindromic Brachyury binding site and to the half-palindrome, whereas Brachyury did not bind to the TBX5 site. Amino acids 1-237 of TBX5 were required for DNA binding. Analysis of the effects of specific substitution mutations that arise in Holt-Oram patients indicated that gly80 to arg (G80R; 601620.0004) and arg237 to gln (R237Q; 601620.0003) eliminated binding to the target site. Similar target sites are present in the upstream regions of several cardiac-expressed genes, including cardiac alpha-actin (102540), atrial natriuretic factor (108780), cardiac myosin heavy chain alpha (160710), cardiac myosin heavy chain beta (160760), myosin light chain 1A, myosin light chain 1V, and Nkx2.5 (600584). Cell transfection studies demonstrated that TBX5 activated the transcription of an atrial natriuretic factor reporter construct and this effect was significantly reduced by deletion of the TBX5 binding site. The authors proposed that the presence of TBX5 binding sites in the upstream regions of these cardiac-expressed genes suggests a role for TBX5 in their regulation. </p><p>Ahn et al. (2002) demonstrated that in zebrafish, Tbx5 has an early function that precedes the formation of the limb bud itself. Functional knockdown of zebrafish Tbx5 through the use of an antisense oligonucleotide resulted in a failure to initiate fin bud formation, leading to the complete loss of pectoral fins. The function of the Tbx5 gene in the development of zebrafish forelimbs seems to involve the directed migration of individual lateral-plate mesodermal cells into the future limb-bud-producing region. The primary defect seen in the Tbx5-knockdown phenotype is similar to the primary defects described in known T-box gene mutants such as the spadetail mutant of zebrafish and the Brachyury mutant of the mouse (see 601397), which both similarly exhibited an altered migration of mesodermal cells. Ahn et al. (2002) suggested that a common function for many of the T-box genes might therefore be in mediating the proper migration and/or changes in adhesive properties of early embryonic cells. </p><p>By gene targeting and transgenic methods, Minguillon et al. (2005) examined the ability of Tbx4 and Pitx1 to rescue the no-forelimb phenotype of mutant mice with Tbx5 knockout restricted to limbs. Tbx4 could replace Tbx5 and rescue limb outgrowth, but Pitx1 could not. In contrast to previous chick misexpression studies, Tbx4-rescued limbs had a forelimb-like phenotype, suggesting that Tbx4 alone does not dictate hindlimb morphology and that forelimb characteristics can develop in the absence of Tbx5. To determine the role of Pitx1 in defining hindlimb characteristics, Minguillon et al. (2005) introduced forelimb-targeted Pitx1 into mice expressing endogenous Tbx5 and into mutant mice rescued by Tbx4. In both cases, forelimb-targeted Pitx1 expression caused a partial forelimb-to-hindlimb transformation, indicating that Pitx1 has a role in directing hindlimb morphology. </p><p>Human mutations in TBX5, a gene encoding a T-box transcription factor, and SALL4 (607343), a gene encoding a zinc finger transcription factor, cause similar upper limb and heart defects. Mutations in SALL4 are responsible for the Duane-radial ray syndrome (607323); mutations in TBX5 are responsible for the Holt-Oram syndrome (142900). Koshiba-Takeuchi et al. (2006) showed that Tbx5 regulates Sall4 expression in the developing mouse forelimb and heart; mice heterozygous for a gene trap allele of Sall4 showed limb and heart defects that modeled human disease. Tbx5 and Sall4 interacted both positively and negatively to finely regulate patterning and morphogenesis of the anterior forelimb and heart. Thus, a positive and negative feed-forward circuit between Tbx5 and Sall4 ensures precise patterning of embryonic limb and heart and provides a unifying mechanism for heart/hand syndromes. </p><p>Zhu et al. (2008) generated mice with haploinsufficiency of Tbx5 in ventricular myocytes only and observed diastolic dysfunction due to a cell-autonomous defect in myocyte relaxation but no atrial or ventricular septal defects or conduction defects. Tbx5-haploinsufficient mice had significantly decreased left ventricular protein levels of SERCA2a (ATP2A2; 108740) and decreased mRNA levels of Tbx5 and Atp2a2. Similarly, there was a decrease in rate and amplitude of Ca(2+) uptake and Ca(2+) transient prolongation in left ventricular tissue. The authors demonstrated that Tbx5 activated an Atp2a2 promoter-reporter construct. Doppler analysis of 8 patients with clinically diagnosed Holt-Oram syndrome, 1 of whom was known to carry a mutation in the TBX5 gene, showed diastolic filling abnormalities of variable severity and type. Zhu et al. (2008) concluded that there is a direct genetic pathway regulating cardiac diastolic function, and that patients with structural congenital heart defects may also have underlying anomalies in heart function. </p><p>Koshiba-Takeuchi et al. (2009) examined heart development in the red-eared slider turtle, Trachemys scripta elegans (a chelonian), and the green anole, Anolis carolinensis (a squamate), focusing on gene expression in the developing ventricles. Both reptiles initially form a ventricular chamber that homogeneously expresses the T-box transcription factor gene Tbx5. In contrast, in birds and mammals, Tbx5 is restricted to the left ventricle precursors. In later stages, Tbx5 expression in the turtle (but not anole) heart is gradually restricted to a distinct left ventricle, forming a left-right gradient. This suggests that Tbx5 expression was refined during evolution to pattern the ventricles. In support of this hypothesis, Koshiba-Takeuchi et al. (2009) showed that loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation. Importantly, misexpression of Tbx5 throughout the developing myocardium to mimic the reptilian expression pattern also results in a single mispatterned ventricular chamber lacking septation. Thus, Koshiba-Takeuchi et al. (2009) concluded that ventricular septation is established by a steep and correctly positioned Tbx5 gradient, and that their findings provided a molecular mechanism for the evolution of the amniote ventricle and supported the concept that altered expression of developmental regulators is a key mechanism of vertebrate evolution. </p><p>Using conditional mouse haploinsufficiency models, Nadadur et al. (2016) found that Tbx5 and Ptx2 antagonistically regulated gene expression in atria. Reduced Tbx5 expression profoundly disrupted cardiac channel gene expression and caused action potential abnormalities leading to primary, spontaneous atrial fibrillation. Concomitant haploinsufficiency for Pitx2 rescued the phenotype. </p>
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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>10 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<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 HOLT-ORAM SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TBX5, 1491C-T
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<br />
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SNP: rs863223788,
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ClinVar: RCV000196593, RCV000459213, RCV000782289, RCV003390935
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</span>
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<span class="mim-text-font">
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<p>In 2 apparently unrelated Holt-Oram syndrome (HOS; 142900) families, Li et al. (1997) found the identical mutation, a C-to-T change at position 1491 resulting in a stop codon (TGA). Two families showed different haplotypes of 3 markers around the HOS1 locus, indicating that they probably did not share a recent common ancestor. The same mutation occurring in exon G was found also in a sporadic case of Holt-Oram syndrome. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 HOLT-ORAM SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TBX5, GLU69TER
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<br />
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SNP: rs104894377,
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gnomAD: rs104894377,
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ClinVar: RCV000008456, RCV000760324
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</span>
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<span class="mim-text-font">
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<p>Basson et al. (1997) found that all affected members of a family with Holt-Oram syndrome (HOS; 142900) were heterozygous for a 205G-T transversion which was predicted to convert glutamate-69 (GAA) to a stop codon (TAA). The mutation creates a novel DdeI restriction site. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 HOLT-ORAM SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TBX5, ARG237GLN
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<br />
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SNP: rs104894378,
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gnomAD: rs104894378,
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ClinVar: RCV000008457, RCV000196777, RCV000474989, RCV002362569
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<span class="mim-text-font">
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<p>In their family B, Basson et al. (1997) demonstrated that all members with Holt-Oram syndrome (HOS; 142900) had a 710G-A transition predicted to result in the substitution of an arginine (CGG) by a glutamine (CAG) at codon 237. </p><p>Basson et al. (1999) found that the arg237-to-gln (R237Q) mutation in the TBX5 gene caused upper limb malformations of the type seen in HOS without cardiac abnormalities. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 HOLT-ORAM SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TBX5, GLY80ARG
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<br />
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SNP: rs104894381,
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ClinVar: RCV000008458
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with Holt-Oram syndrome (HOS; 142900), Basson et al. (1999) identified a gly80-to-arg substitution in the TBX5 gene. They found that this mutation caused significant cardiac malformations but only minor skeletal abnormalities. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 HOLT-ORAM SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TBX5, ARG237TRP
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<br />
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SNP: rs104894382,
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ClinVar: RCV000008459, RCV000128627, RCV000473181, RCV002362570
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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 families with Holt-Oram syndrome (HOS; 142900), Basson et al. (1999) identified an arg237-to-trp substitution in the TBX5 gene. The mutation occurred in the same codon as the arg237-to-gln mutation (601620.0003), and the authors found that both mutations caused extensive upper limb malformations but less significant cardiac abnormalities. They found that residue 80 (601620.0004) is highly conserved within T-box sequences that interact with the major group of target DNA, whereas residue 237 is located in the T-box domain that selectively binds to the minor group DNA. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 HOLT-ORAM SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TBX5, 1-BP DEL, 416C
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<br />
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SNP: rs1593880204,
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ClinVar: RCV000008460
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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 Chinese family with Holt-Oram syndrome (HOS; 142900), Yang et al. (2000) identified a 1-bp deletion in exon 4 at nucleotide 416, resulting in a frameshift of downstream codons. The 2 affected family members had atrial septal defects and severe upper limb manifestations, including aplasia/hypoplasia of the arms. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 HOLT-ORAM SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TBX5, GLN49LYS
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<br />
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SNP: rs104894383,
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gnomAD: rs104894383,
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ClinVar: RCV000008461
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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 Chinese family with Holt-Oram syndrome (HOS; 142900), Yang et al. (2000) identified a missense mutation in exon 2, a C-to-A transversion at nucleotide 145, resulting in a gln49-to-lys substitution. The 2 affected family members had atrial septal defects and mild upper limb manifestations. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 HOLT-ORAM SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TBX5, ILE54THR
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<br />
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SNP: rs104894384,
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ClinVar: RCV000008462
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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 Chinese sporadic case of Holt-Oram syndrome (HOS; 142900), Yang et al. (2000) identified a missense mutation in exon 2, a T-to-C alteration at nucleotide 161, resulting in an ile54-to-thr substitution. This patient had an atrial septal defect (ASD; 108800) and an absent left thumb. </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>.0009 HOLT-ORAM SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TBX5, TYR136TER
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<br />
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SNP: rs104894379,
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ClinVar: RCV000008463, RCV003398470
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated families with Holt-Oram syndrome (HOS; 142900), Gruenauer-Kloevekorn and Froster (2003) identified heterozygosity for a 408C-A transversion in exon 5 of the TBX5 gene, resulting in a tyr136-to-stop substitution, in all affected members. The mutation was not found in unaffected family members or in 200 control samples. </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>.0010 HOLT-ORAM SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TBX5, 48-KB DUP, EX2-9DUP
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<br />
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ClinVar: RCV000415566
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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 affected members of a 5-generation family segregating an atypical form of Holt-Oram syndrome (142900), Patel et al. (2012) identified a 48-kb duplication at chromosome 12q24.21 (chr12.114,795,705-114,844,082, GRCh37) encompassing exons 2 through 9 of the TBX5 gene, with breakpoints within introns 1 and 9. The duplication, which was identified by array CGH and multiplex ligation-dependent probe amplification (MLPA), segregated with the disorder in the family. Patel et al. (2012) proposed that the intragenic duplication could be in-frame and cause its effects through an elongated protein that leads to a gain of function; an elongated protein with abnormal cellular localization mimicking functional haploinsufficiency; or increased expression of the TBX5 gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Yang, J., Hu, D., Xia, J., Yang, Y., Ying, B., Hu, J., Zhou, X.
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<strong>Three novel TBX5 mutations in Chinese patients with Holt-Oram syndrome.</strong>
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Am. J. Med. Genet. 92: 237-240, 2000.
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[PubMed: 10842287]
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[Full Text: https://doi.org/10.1002/(sici)1096-8628(20000605)92:4<237::aid-ajmg2>3.0.co;2-g]
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Yi, C.-H., Russ, A., Brook, J. D.
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<strong>Virtual cloning and physical mapping of a human T-box gene, TBX4.</strong>
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Genomics 67: 92-95, 2000.
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[PubMed: 10945475]
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[Full Text: https://doi.org/10.1006/geno.2000.6222]
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Zhu, Y., Gramolini, A. O., Walsh, M. A., Zhou, Y.-Q., Slorach, C., Friedberg, M. K., Takeuchi, J. K., Sun, H., Henkelman, R. M., Backx, P. H., Redington, A. N., MacLennan, D. H., Bruneau, B. G.
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<strong>Tbx5-dependent pathway regulating diastolic function in congenital heart disease.</strong>
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Proc. Nat. Acad. Sci. 105: 5519-5524, 2008.
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[PubMed: 18378906]
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[Full Text: https://doi.org/10.1073/pnas.0801779105]
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Ada Hamosh - updated : 04/16/2018<br>George E. Tiller - updated : 06/27/2017<br>Patricia A. Hartz - updated : 01/27/2017<br>Marta Biderman Waberski - updated : 01/11/2017<br>Ada Hamosh - updated : 4/17/2014<br>Marla J. F. O'Neill - updated : 1/25/2012<br>Ada Hamosh - updated : 10/13/2009<br>Ada Hamosh - updated : 6/16/2009<br>Patricia A. Hartz - updated : 6/6/2008<br>Patricia A. Hartz - updated : 8/23/2007<br>Marla J. F. O'Neill - updated : 10/18/2006<br>Carol A. Bocchini - updated : 9/14/2006<br>Victor A. McKusick - updated : 2/7/2006<br>Patricia A. Hartz - updated : 1/17/2006<br>Victor A. McKusick - updated : 12/27/2005<br>George E. Tiller - updated : 3/2/2005<br>Patricia A. Hartz - updated : 2/4/2005<br>Patricia A. Hartz - updated : 5/7/2004<br>Victor A. McKusick - updated : 7/15/2003<br>Ada Hamosh - updated : 7/7/2003<br>Victor A. McKusick - updated : 6/25/2003<br>Victor A. McKusick - updated : 9/19/2002<br>Ada Hamosh - updated : 7/10/2002<br>Jane Kelly - updated : 7/8/2002<br>George E. Tiller - updated : 2/1/2002<br>Stylianos E. Antonarakis - updated : 9/25/2001<br>Victor A. McKusick - updated : 6/25/2001<br>Sonja A. Rasmussen - updated : 7/13/2000<br>Ada Hamosh - updated : 12/29/1999<br>Ada Hamosh - updated : 5/4/1999<br>Victor A. McKusick - updated : 4/16/1999<br>Victor A. McKusick - updated : 6/17/1997
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Victor A. McKusick : 1/10/1997
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