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Entry
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- *191010 - TROPOMYOSIN 1; TPM1
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- OMIM
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</ul>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="row">
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<li role="separator" class="divider"></li>
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<li>
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<a href="/history"> Search History </a>
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</ul>
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</form>
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<p />
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</div>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*191010</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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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="#description">Description</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="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
|
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<li role="presentation" style="margin-left: 1em">
|
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<a href="/allelicVariants/191010">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
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<div style="display: table-row">
|
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
|
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</div>
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</a>
|
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
|
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</span>
|
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</span>
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000140416;t=ENST00000403994" 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=7168" 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=191010" 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=ENSG00000140416;t=ENST00000403994" 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_000366,NM_001018004,NM_001018005,NM_001018006,NM_001018007,NM_001018008,NM_001018020,NM_001301244,NM_001301289,NM_001330344,NM_001330346,NM_001330351,NM_001365776,NM_001365777,NM_001365778,NM_001365779,NM_001365780,NM_001365781,NM_001365782,NM_001407322,NM_001407323,NM_001407324,NM_001407325,NM_001407326,NM_001407327,NM_001407328,NM_001407329,NM_001407330,NM_001407331,NM_001407332,NM_001407333,NM_001407334,NM_001407335,NM_001407336,NM_001407337,NM_001407338,NM_001407340,NM_001407341,NM_001407342,NM_001407344,NR_176337,NR_176338,NR_176339,NR_176340,NR_176341,NR_176342,NR_176343,NR_176344,NR_176345,NR_176346,NR_176347,NR_176348,NR_176349,NR_176350,NR_176351,NR_176352,NR_176353,XM_047433001" 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_001018005" 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=191010" 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=01839&isoform_id=01839_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/TPM1" 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/136092,339950,339954,339956,339958,339971,825723,2370090,2370094,13938565,19072647,27597085,29792232,31565806,34526581,47077229,49660012,49660014,52545514,62087662,63252896,63252898,63252900,63252902,63252904,63252906,89954539,119598025,119598026,119598027,119598028,119598029,119598030,119598031,119598032,119598033,119598034,119598035,119598036,119598037,119598038,119598039,119598040,119598041,221042310,221042692,221043562,258676353,302313151,302313153,302313155,302313157,302313159,302313161,302313163,669250879,669633301,957950300,957950303,1057867570,1057867583,1057867587,1475409280,1475409292,1475409295,1475409303,1475409318,1475409324,1475928840,2217302502,2246873493,2246873495,2246873504,2246873516,2246873518,2246873530,2246873534,2246873553,2246873557,2246873566,2246873570,2246873576,2246873585,2246873599,2246873603,2246873605,2246873611,2246873613,2246873615,2246873626,2246873631,2462545752" 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/P09493" 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=7168" 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=ENSG00000140416;t=ENST00000403994" 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=TPM1" 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=TPM1" 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+7168" 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/TPM1" 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:7168" 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/7168" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr15&hgg_gene=ENST00000403994.9&hgg_start=63042747&hgg_end=63071915&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:12010" 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:12010" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=191010[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=191010[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/TPM1/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/ENSG00000140416" 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=TPM1" 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=TPM1" 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=TPM1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://genepath.med.harvard.edu/~seidman/cg3/genes/TPM1_info.html" title="Sarcomere Protein Gene Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Sarcomere Protein Gene Mut…</a></div><div style="margin-left: 0.5em;"><a href="http://www.angis.org.au/Databases/Heart/heartbreak.html" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">FHC Mutation Database</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TPM1&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/PA36690" 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:12010" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0003721.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:98809" 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/TPM1#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:98809" 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/7168/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=7168" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00002978;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-854" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7168" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=TPM1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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191010
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</span>
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</span>
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TROPOMYOSIN 1; TPM1
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TROPOMYOSIN, SKELETAL MUSCLE ALPHA; TMSA
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TPM1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TPM1</a></em></strong>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:63042747-63071915&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">15:63,042,747-63,071,915</a> </span>
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Phenotype
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View Clinical Synopses
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Phenotype <br /> MIM number
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Inheritance
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15q22.2
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Cardiomyopathy, dilated, 1Y
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Cardiomyopathy, hypertrophic, 3
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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Left ventricular noncompaction 9
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<a href="/entry/611878"> 611878 </a>
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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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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/191010" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/191010" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<div>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Description</strong>
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<p>Tropomyosins are a family of actin-binding proteins encoded by 4 distinct genes. Each gene generates multiple striated muscle, smooth muscle, and cytoskeletal variants by alternative splicing, alternative promoter usage, and differential 3-prime end processing. Of the 4 human tropomyosin genes, TPM1 is the most versatile and encodes at least 10 tissue-specific variants via alternative splicing and/or the use of 2 promoters. The TPM1 variants encode proteins of either 248 or 284 amino acids (summary by <a href="#4" class="mim-tip-reference" title="Denz, C. R., Narshi, A., Zajdel, R. W., Dube, D. K. <strong>Expression of a novel cardiac-specific tropomyosin isoform in humans.</strong> Biochem. Biophys. Res. Commun. 320: 1291-1297, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15249230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15249230</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.06.084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15249230">Denz et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15249230" 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="#9" class="mim-tip-reference" title="MacLeod, A. R., Gooding, C. <strong>Human hTM-alpha gene: expression in muscle and nonmuscle tissue.</strong> Molec. Cell. Biol. 8: 433-440, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3336363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3336363</a>] [<a href="https://doi.org/10.1128/mcb.8.1.433-440.1988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3336363">MacLeod and Gooding (1988)</a> isolated a cDNA clone from a human skeletal muscle library that contains the complete protein-coding sequence of a skeletal muscle alpha-tropomyosin. In cultured human fibroblasts, the TMSA gene was found to encode both skeletal muscle and smooth muscle type of alpha-tropomyosins by using an alternative splicing mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3336363" 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="Lees-Miller, J. P., Helfman, D. M. <strong>The molecular basis for tropomyosin isoform diversity.</strong> BioEssays 13: 429-437, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1796905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1796905</a>] [<a href="https://doi.org/10.1002/bies.950130902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1796905">Lees-Miller and Helfman (1991)</a> discussed the molecular basis for tropomyosin diversity. Tropomyosins are ubiquitous proteins of 35 to 45 kD associated with the actin filaments of myofibrils and stress fibers. The vertebrate alpha-tropomyosin gene consists of 15 exons, 5 of which are found in all transcripts, and 10 of which are alternatively used in different alpha-tropomyosin RNAs. The striated muscle isoform is expressed in both cardiac and skeletal muscle tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1796905" 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 RT-PCR of total human heart RNA, <a href="#4" class="mim-tip-reference" title="Denz, C. R., Narshi, A., Zajdel, R. W., Dube, D. K. <strong>Expression of a novel cardiac-specific tropomyosin isoform in humans.</strong> Biochem. Biophys. Res. Commun. 320: 1291-1297, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15249230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15249230</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.06.084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15249230">Denz et al. (2004)</a> cloned a TPM1 splice variant that they called TPM1-kappa. The TPM1-kappa transcript is identical to the TPM1-alpha striated muscle variant except that it contains exon 2a, found in the TPM1-beta smooth muscle variant, rather than exon 2b. The deduced TPM1-kappa protein contains 284 amino acids. PCR analysis detected TPM1-alpha in all adult and fetal skeletal muscle and heart samples tested, whereas TPM1-kappa was detected in adult and fetal heart only. Database analysis revealed species-specific distribution of Tpm1 splice variants in axolotl and bird striated muscle and during development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15249230" 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 quantitative RT-PCR and Western blot analysis, <a href="#16" class="mim-tip-reference" title="Rajan, S., Jagatheesan, G., Karam, C. N., Alves, M. L., Bodi, I., Schwartz, A., Bulcao, C. F., D'Souza, K. M., Akhter, S. A., Boivin, G. P., Dube, D. K., Petrashevskaya, N., Herr, A. B., Hullin, R., Liggett, S. B., Wolska, B. M., Solaro, R. J., Wieczorek, D. F. <strong>Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform.</strong> Circulation 121: 410-418, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20065163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20065163</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20065163[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.109.889725" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20065163">Rajan et al. (2010)</a> found a discordance between expression of TPM1 splice variants and protein isoforms. Both TPM1-alpha and TPM1-kappa transcripts were equally expressed in fetal and adult human heart, with higher expression of both in adult heart. However, over 90% of total tropomyosin protein in adult heart was TPM1-alpha, with TPM1-kappa and TPM1-beta making up the remaining tropomyosin content. TPM1-kappa protein content was increased in dilated cardiomyopathy and heart failure patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20065163" 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="#4" class="mim-tip-reference" title="Denz, C. R., Narshi, A., Zajdel, R. W., Dube, D. K. <strong>Expression of a novel cardiac-specific tropomyosin isoform in humans.</strong> Biochem. Biophys. Res. Commun. 320: 1291-1297, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15249230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15249230</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.06.084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15249230">Denz et al. (2004)</a> stated that the TPM1 gene contains 15 exons. Exons 3, 4, 5, 7, and 8 are found in all TPM1 variants, and exons 1a, 1b, 2a, 2b, 6a, 6b, 9a, 9b, 9c, and 9d are alternatively spliced. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15249230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Eyre, H., Akkari, P. A., Wilton, S. D., Callen, D. C., Baker, E., Laing, N. G. <strong>Assignment of the human skeletal muscle alpha-tropomyosin gene (TPM1) to band 15q22 by fluorescence in situ hybridization.</strong> Cytogenet. Cell Genet. 69: 15-17, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7835079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7835079</a>] [<a href="https://doi.org/10.1159/000133928" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7835079">Eyre et al. (1995)</a> developed a sequence tagged site (STS) for the TPM1 gene and used it to isolate a genomic clone containing part of the gene. Using this clone, they localized TPM1 to chromosome 15q22 by fluorescence in situ hybridization. By PCR of radiation hybrids, <a href="#20" class="mim-tip-reference" title="Tiso, N., Rampoldi, L., Pallavicini, A., Zimbello, R., Pandolfo, D., Valle, G., Lanfranchi, G., Danieli, G. A. <strong>Fine mapping of five human skeletal muscle genes: alpha-tropomyosin, beta-tropomyosin, troponin-I slow-twitch, troponin-I fast-twitch, and troponin-C fast.</strong> Biochem. Biophys. Res. Commun. 230: 347-350, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9016781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9016781</a>] [<a href="https://doi.org/10.1006/bbrc.1996.5958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9016781">Tiso et al. (1997)</a> mapped the TPM1 gene more precisely to chromosome 15q22.1. <a href="#18" class="mim-tip-reference" title="Schleef, M., Werner, K., Satzger, U., Kaupmann, K., Jockusch, H. <strong>Chromosomal localization and genomic cloning of the mouse alpha-tropomyosin gene Tpm-1.</strong> Genomics 17: 519-521, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8406508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8406508</a>] [<a href="https://doi.org/10.1006/geno.1993.1361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8406508">Schleef et al. (1993)</a> mapped the mouse homolog, Tpm1, to the d-se region of chromosome 9, using interspecies backcrosses. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9016781+8406508+7835079" 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 href="#2" class="mim-tip-reference" title="Brown, J. H., Kim, K.-H., Jun, G., Greenfield, N. J., Dominguez, R., Volkmann, N., Hitchcock-DeGregori, S. E., Cohen, C. <strong>Deciphering the design of the tropomyosin molecule.</strong> Proc. Nat. Acad. Sci. 98: 8496-8501, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11438684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11438684</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11438684[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.131219198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11438684">Brown et al. (2001)</a> described the crystal structure of the tropomyosin molecule. Their results revealed the effects of clusters of core alanines on the axial register, symmetry, and conformational variability of 2-stranded coiled coils that appear to be important for tropomyosin's role in the regulation of muscle contraction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11438684" 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>Cardiac-mutant Mexican axolotls deficient in tropomyosin do not have organized cardiac myofibrils and, consequently, their hearts do not beat. <a href="#4" class="mim-tip-reference" title="Denz, C. R., Narshi, A., Zajdel, R. W., Dube, D. K. <strong>Expression of a novel cardiac-specific tropomyosin isoform in humans.</strong> Biochem. Biophys. Res. Commun. 320: 1291-1297, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15249230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15249230</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.06.084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15249230">Denz et al. (2004)</a> found that human TPM1-alpha or TPM1-kappa was incorporated into organized myofibrils in both normal and cardiac-mutant axolotl hearts, revealing a high degree of functional conservation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15249230" 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 2-dimensional differentiation in-gel electrophoresis to examine tumors derived from MCF-7 breast cancer cells that were either treated or untreated with anti-microRNA-21 (MIRN21; <a href="/entry/611020">611020</a>), <a href="#23" class="mim-tip-reference" title="Zhu, S., Si, M.-L., Wu, H., Mo, Y.-Y. <strong>MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1).</strong> J. Biol. Chem. 282: 14328-14336, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17363372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17363372</a>] [<a href="https://doi.org/10.1074/jbc.M611393200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17363372">Zhu et al. (2007)</a> identified the tumor suppressor TPM1 as an MIRN21 target. They identified a putative MIRN21-binding site in the 3-prime UTRs of 2 TPM1 splice variants, V1 and V5. <a href="#23" class="mim-tip-reference" title="Zhu, S., Si, M.-L., Wu, H., Mo, Y.-Y. <strong>MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1).</strong> J. Biol. Chem. 282: 14328-14336, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17363372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17363372</a>] [<a href="https://doi.org/10.1074/jbc.M611393200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17363372">Zhu et al. (2007)</a> cloned the 3-prime UTR of TPM1 into a luciferase reporter construct and found that MIRN21 downregulated reporter activity, whereas anti-MIRN21 upregulated it. Deletion of the MIRN21-binding site abolished the effect of MIRN21 on luciferase activity. Western blot and RT-PCR analyses showed that TPM1 mRNA level was unchanged in the presence of MIRN21, but TPM1 protein level was reduced, implying that MIRN21 blocked TPM1 translation. Overexpression of TPM1 in MCF-7 cells suppressed anchorage-independent growth, whereas overexpression of MIRN21 increased tumor growth. <a href="#23" class="mim-tip-reference" title="Zhu, S., Si, M.-L., Wu, H., Mo, Y.-Y. <strong>MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1).</strong> J. Biol. Chem. 282: 14328-14336, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17363372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17363372</a>] [<a href="https://doi.org/10.1074/jbc.M611393200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17363372">Zhu et al. (2007)</a> concluded that MIRN21 acts as an oncogene by suppressing TPM1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17363372" 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="Rajan, S., Jagatheesan, G., Karam, C. N., Alves, M. L., Bodi, I., Schwartz, A., Bulcao, C. F., D'Souza, K. M., Akhter, S. A., Boivin, G. P., Dube, D. K., Petrashevskaya, N., Herr, A. B., Hullin, R., Liggett, S. B., Wolska, B. M., Solaro, R. J., Wieczorek, D. F. <strong>Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform.</strong> Circulation 121: 410-418, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20065163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20065163</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20065163[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.109.889725" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20065163">Rajan et al. (2010)</a> overexpressed human TPM1-kappa in transgenic mouse hearts. Expression of TPM1-kappa was coupled with concomitant downregulation of endogenous Tpm1-alpha, with total tropomyosin levels unchanged. Transgenic hearts appeared normal and functioned normally in many tests; however, they showed increased end-systolic and end-diastolic left ventricular dimensions and increased myofilament calcium sensitivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20065163" 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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To assess linkage between the human TPM1 gene and type 3 familial hypertrophic cardiomyopathy (CMH3; <a href="/entry/115196">115196</a>), which had previously been mapped to 15q2, <a href="#19" class="mim-tip-reference" title="Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. <strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong> Cell 77: 701-712, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205619</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90054-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205619">Thierfelder et al. (1994)</a> identified a short tandem repeat polymorphism (STR). A combined maximum 2-point lod score of 6.94 at theta = 0.0 was obtained for linkage of the TPM1 marker to CMH3 in 2 families. A point mutation was identified in each of the 2 families used in the linkage study: asp175-to-asn (<a href="#0002">191010.0002</a>) in one, and glu180-to-gly (<a href="#0001">191010.0001</a>) in the other. <a href="#22" class="mim-tip-reference" title="Watkins, H., McKenna, W. J., Thierfelder, L., Suk, H. J., Anan, R., O'Donoghue, A., Spirito, P., Matsumori, A., Moravec, C. S., Seidman, J. G., Seidman, C. E. <strong>Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.</strong> New Eng. J. Med. 332: 1058-1064, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7898523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7898523</a>] [<a href="https://doi.org/10.1056/NEJM199504203321603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7898523">Watkins et al. (1995)</a> concluded that mutations in the TPM1 gene are a rare cause of CMH, accounting for approximately 3% of cases. These mutations, like those in the cardiac troponin T gene (TNNT2; <a href="/entry/191045">191045</a>), are characterized by relatively mild and sometimes subclinical hypertrophy but a high incidence of sudden death. Genetic testing may therefore be especially important in this group. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8205619+7898523" 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>Dilated Cardiomyopathy 1Y</em></strong></p><p>
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Using a candidate gene approach, <a href="#13" class="mim-tip-reference" title="Olson, T. M., Kishimoto, N. Y., Whitby, F. G., Michels, V. V. <strong>Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy.</strong> J. Molec. Cell Cardiol. 33: 723-732, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11273725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11273725</a>] [<a href="https://doi.org/10.1006/jmcc.2000.1339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11273725">Olson et al. (2001)</a> analyzed the TPM1 gene in 350 unrelated patients with sporadic and familial dilated cardiomyopathy (see CMD1Y, <a href="/entry/611878">611878</a>) and identified heterozygous missense mutations in 2 familial cases: E54K (<a href="#0004">191010.0004</a>) and E40K (<a href="#0005">191010.0005</a>), respectively. Each substitution was predicted to create a strong local increase in positive charge in an otherwise relatively negatively charged and highly conserved region of the molecule. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11273725" 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>Left Ventricular Noncompaction 9</em></strong></p><p>
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In a cohort of 63 unrelated white patients of western European descent with left ventricular noncompaction (LVNC9; see <a href="/entry/611878">611878</a>), <a href="#14" class="mim-tip-reference" title="Probst, S., Oechslin, E., Schuler, P., Greutmann, M., Boye, P., Knirsch, W., Berger, F., Thierfelder, L., Jenni, R., Klaassen, S. <strong>Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype.</strong> Circ. Cardiovasc. Genet. 4: 367-374, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21551322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21551322</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.110.959270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21551322">Probst et al. (2011)</a> analyzed 8 sarcomere genes and identified 2 probands with heterozygous missense mutations in the TPM1 gene (<a href="#0006">191010.0006</a> and <a href="#0007">191010.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21551322" 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 2-year-old girl with LVNC and Ebstein anomaly of the tricuspid valve, <a href="#7" class="mim-tip-reference" title="Kelle, A. M., Bentley, S. J., Rohena, L. O., Cabalka, A. K., Olson, T. M. <strong>Ebstein anomaly, left ventricular non-compaction, and early onset heart failure associated with a de novo alpha-tropomyosin gene mutation.</strong> Am. J. Med. Genet. 170A: 2186-2190, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27177193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27177193</a>] [<a href="https://doi.org/10.1002/ajmg.a.37745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27177193">Kelle et al. (2016)</a> identified heterozygosity for a de novo missense mutation in the TPM1 gene (D159N; <a href="#0008">191010.0008</a>). The authors stated that the D159N mutation had previously been identified in a patient with dilated cardiomyopathy, although it was not reported in the published literature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27177193" 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 5 affected members of a 2-generation family with LVNC with or without Ebstein anomaly and/or mitral valve insufficiency, <a href="#12" class="mim-tip-reference" title="Nijak, A., Alaerts, M., Kuiperi, C., Corveleyn, A., Suys, B., Paelinck, B., Saenen, J., Van Craenenbroeck, E., Van Laer, L., Loeys, B., Verstraeten, A. <strong>Left ventricular non-compaction with Ebstein anomaly attributed to a TPM1 mutation.</strong> Europ. J. Med. Genet. 61: 8-10, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29024827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29024827</a>] [<a href="https://doi.org/10.1016/j.ejmg.2017.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29024827">Nijak et al. (2018)</a> identified heterozygosity for a missense mutation in the TPM1 gene (L113V; <a href="#0009">191010.0009</a>) that segregated with disease and was not found in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29024827" 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 depletion and reconstitution of TPM1 and troponin in porcine cardiac myofibrils, <a href="#3" class="mim-tip-reference" title="Chang, A. N., Harada, K., Ackerman, M. J., Potter, J. D. <strong>Functional consequences of hypertrophic and dilated cardiomyopathy-causing mutations in alpha-tropomyosin.</strong> J. Biol. Chem. 280: 34343-34349, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16043485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16043485</a>] [<a href="https://doi.org/10.1074/jbc.M505014200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16043485">Chang et al. (2005)</a> studied 3 CMH-associated TPM1 mutations (E62Q; E180G, <a href="/entry/190010#0001">190010.0001</a>; and L185R) and 2 CMD-associated mutations (E54K and E40K) and found that all CMH-associated mutations increased the Ca(2+) sensitivity of ATPase activity and had decreased abilities to inhibit ATPase activity, whereas the CMD-associated mutations decreased the Ca(2+) sensitivity of ATPase activity and had no effect on the inhibition of ATPase activity. <a href="#3" class="mim-tip-reference" title="Chang, A. N., Harada, K., Ackerman, M. J., Potter, J. D. <strong>Functional consequences of hypertrophic and dilated cardiomyopathy-causing mutations in alpha-tropomyosin.</strong> J. Biol. Chem. 280: 34343-34349, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16043485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16043485</a>] [<a href="https://doi.org/10.1074/jbc.M505014200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16043485">Chang et al. (2005)</a> concluded that mutations that cause CMH and CMD disrupt discrete mechanisms, and suggested that this may explain the manifestation of distinct cardiomyopathic phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16043485" 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="Mirza, M., Marston, S., Willott, R., Ashley, C., Mogensen, J., McKenna, W., Robinson, P., Redwood, C., Watkins, H. <strong>Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.</strong> J. Biol. Chem. 280: 28498-28506, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15923195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15923195</a>] [<a href="https://doi.org/10.1074/jbc.M412281200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15923195">Mirza et al. (2005)</a> studied all 8 published mutations causing dilated cardiomyopathy (CMD), including 5 in the TNNT2 gene (lys210del, R141W, R131W, R205L, and D270N; <a href="/entry/191045#0006">191045.0006</a>-<a href="/entry/191045#0010">191045.0010</a>, respectively), 2 in the TPM1 gene (E54K and E40K), and 1 in the TNNC1 gene (G159D, <a href="/entry/191040#0001">191040.0001</a>). Thin filaments, reconstituted with a 1:1 ratio of mutant:wildtype proteins, all showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays, and, except for the E54K alpha-tropomyosin mutant which showed no effect, all showed lower maximum Ca(2+) activation. Incorporation of the TNNT2 mutations R141W and R205L into skinned guinea pig cardiac trabeculae also decreased Ca(2+) sensitivity of force generation. Thus, diverse thin filament CMD mutations appeared to affect different aspects of regulatory function yet change contractility in a consistent manner. <a href="#10" class="mim-tip-reference" title="Mirza, M., Marston, S., Willott, R., Ashley, C., Mogensen, J., McKenna, W., Robinson, P., Redwood, C., Watkins, H. <strong>Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.</strong> J. Biol. Chem. 280: 28498-28506, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15923195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15923195</a>] [<a href="https://doi.org/10.1074/jbc.M412281200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15923195">Mirza et al. (2005)</a> stated that the CMD mutations depressed myofibrillar function, an effect opposite to that of CMH-causing thin filament mutations, and suggested that decreased contractility might trigger pathways that ultimately lead to the clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15923195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Robinson, P., Griffiths, P. J., Watkins, H., Redwood, C. S. <strong>Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha-tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments.</strong> Circ. Res. 101: 1266-1273, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17932326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17932326</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.107.156380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17932326">Robinson et al. (2007)</a> used a fluorescent probe to assess Ca(2+) binding of CMH-causing mutations in the TNNT2 (R92Q; <a href="/entry/191045#0002">191045.0002</a>) and TNNI3 (R145G; <a href="/entry/191044#0001">191044.0001</a>) genes, and CMD-causing mutations in the TNNT2 (e.g., lys210del and R141W), TNNC1 (G159D), and TPM1 (E45K and E40K) genes. Both CMH mutations increased Ca(2+) affinity, whereas the CMD mutations decreased affinity, except for 1 in TNNT2, which caused a significant decrease in cooperativity. <a href="#17" class="mim-tip-reference" title="Robinson, P., Griffiths, P. J., Watkins, H., Redwood, C. S. <strong>Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha-tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments.</strong> Circ. Res. 101: 1266-1273, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17932326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17932326</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.107.156380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17932326">Robinson et al. (2007)</a> suggested that Ca(2+) affinity changes caused by cardiomyopathy mutant proteins may directly affect the Ca(2+) transient and hence Ca(2+)-sensitive disease state remodeling pathways in vivo, representing a novel mechanism for this class of mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17932326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Blanchard, E. M., Iizuka, K., Christe, M., Conner, D. A., Geisterfer-Lowrance, A., Schoen, F. J., Maughan, D. W., Seidman, C. E., Seidman, J. G. <strong>Targeted ablation of the murine alpha-tropomyosin gene.</strong> Circulation Res. 81: 1005-1010, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9400381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9400381</a>] [<a href="https://doi.org/10.1161/01.res.81.6.1005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9400381">Blanchard et al. (1997)</a> used gene targeting in embryonic stem cells and blastocyst-mediated transgenesis to create functional mouse alpha-tropomyosin knockouts. Homozygous mice died in utero between embryonic days 9.5 and 13.5 and lacked alpha-tropomyosin mRNA. Heterozygotes had an approximately 50% reduction in alpha-tropomyosin mRNA levels but no reduction in alpha-tropomyosin protein. No differences in myofibrillar ultrastructure or contractile function were found. The authors postulated that mice have a regulatory mechanism that maintains the level of myofibrillar tropomyosin despite a reduction in mRNA. Furthermore, they concluded that, assuming human and mouse cardiac muscle are similar, simple haploinsufficiency for alpha-tropomyosin would not cause the pathologic changes seen in human type 3 hypertrophic cardiomyopathy (<a href="/entry/115196">115196</a>) and that alterations in protein stoichiometry may produce a poison polypeptide that disrupts myofibrillar organization on incorporation into the sarcomere. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9400381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Muthuchamy, M., Pieples, K., Rethinasamy, P., Hoit, B., Grupp, I. L., Boivin, G. P., Wolska, B., Evans, C., Solaro, R. J., Wieczorek, D. F. <strong>Mouse model of a familial hypertrophic cardiomyopathy mutation in alpha-tropomyosin manifests cardiac dysfunction.</strong> Circ. Res. 85: 47-56, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10400910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10400910</a>] [<a href="https://doi.org/10.1161/01.res.85.1.47" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10400910">Muthuchamy et al. (1999)</a> constructed a transgenic mouse model of CMH3 by introducing the missense mutation asp175 to asn (<a href="#0002">191010.0002</a>) by site-directed mutagenesis. This mutation occurs in a cardiac troponin T-binding region. The transgenic CMH3 mice exhibited significant in vivo and in vitro evidence of myocardial functional impairment. Histologic analysis of transgenic myocardium showed variable myocyte disarray and hypertrophy, as reported in the human form of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10400910" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Rajan, S., Ahmed, R. P. H., Jagatheesan, G., Petrashevskaya, N., Boivin, G. P., Urboniene, D., Arteaga, G. M., Wolska, B. M., Solaro, R. J., Liggett, S. B., Wieczorek, D. F. <strong>Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity.</strong> Circ. Res. 101: 205-214, 2007. Note: Erratum: Circ. Res. 101: e80, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17556658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17556658</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.107.148379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17556658">Rajan et al. (2007)</a> generated transgenic mice expressing E54K Tpm1 in the adult heart and observed the development of dilated cardiomyopathy with progression to heart failure and frequently death by 6 months. Echocardiographic analyses confirmed the dilated cardiac phenotype with a significant decrease in left ventricular fractional shortening; work-performing heart analyses showed significantly impaired systolic and diastolic function, and force measurements revealed that cardiac myofilaments had significantly decreased Ca(2+) sensitivity and tension generation. Real-time RT-PCR quantification demonstrated increased expression of beta-myosin heavy chain (MYH7; <a href="/entry/160760">160760</a>), brain natriuretic peptide (see NPPA, <a href="/entry/108780">108780</a>), and skeletal actin (see ACTA1, <a href="/entry/102610">102610</a>), and decreased expression of sarcoplasmic reticulum Ca(2+) ATPase (ATP2A2; <a href="/entry/108740">108740</a>) and ryanodine receptor (RYR2; <a href="/entry/180902">180902</a>). The thermal denaturation curve of the mutant protein shifted to the right compared to wildtype, implying a decrease in flexibility. <a href="#15" class="mim-tip-reference" title="Rajan, S., Ahmed, R. P. H., Jagatheesan, G., Petrashevskaya, N., Boivin, G. P., Urboniene, D., Arteaga, G. M., Wolska, B. M., Solaro, R. J., Liggett, S. B., Wieczorek, D. F. <strong>Dilated cardiomyopathy mutant tropomyosin mice develop cardiac dysfunction with significantly decreased fractional shortening and myofilament calcium sensitivity.</strong> Circ. Res. 101: 205-214, 2007. Note: Erratum: Circ. Res. 101: e80, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17556658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17556658</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.107.148379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17556658">Rajan et al. (2007)</a> stated that these findings are consistent with those seen in human CMD and heart failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17556658" 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">rs104894502 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894502;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=rs104894502" 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=rs104894502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In members of family MZ with a form of familial hypertrophic cardiomyopathy linked to 15q (CMH3; <a href="/entry/115196">115196</a>), <a href="#19" class="mim-tip-reference" title="Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. <strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong> Cell 77: 701-712, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205619</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90054-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205619">Thierfelder et al. (1994)</a> identified an A-to-G transition at nucleotide 595 in exon 5 of the TPM1 gene in heterozygous state. The substitution changed codon 180 from GAG to GGG and predicted that a negatively charged glutamic acid residue is replaced by a neutral glycine residue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8205619" 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> rs104894503 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894503;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/rs104894503?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=rs104894503" 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=rs104894503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In members of family MI with a form of familial hypertrophic cardiomyopathy linked to 15q (CMH3; <a href="/entry/115196">115196</a>), <a href="#19" class="mim-tip-reference" title="Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. <strong>Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.</strong> Cell 77: 701-712, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205619</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90054-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205619">Thierfelder et al. (1994)</a> found heterozygosity for a G-to-A transition at nucleotide 579 that altered codon 175 from GAC to AAC. The substitution predicted that the mutated allele present in affected individuals would encode a neutral asparagine residue instead of the negatively charged aspartic acid residue found in unaffected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8205619" 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="Watkins, H., Anan, R., Coviello, D. A., Spirito, P., Seidman, J. G., Seidman, C. E. <strong>A de novo mutation in alpha-tropomyosin that causes hypertrophic cardiomyopathy.</strong> Circulation 91: 2302-2305, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7729014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7729014</a>] [<a href="https://doi.org/10.1161/01.cir.91.9.2302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7729014">Watkins et al. (1995)</a> investigated whether the D175N mutation was really responsible for hypertrophic cardiomyopathy or was only a polymorphism, because some features of the 2 identified mutations in the alpha-tropomyosin gene contrasted with those of mutations in other disease genes for CMH. Unlike the beta-cardiac myosin heavy chain gene (MYH7; <a href="/entry/160760">160760</a>) and the cardiac troponin-T gene, the alpha-tropomyosin gene is expressed ubiquitously, yet the disease phenotype is limited to cardiac muscle. <a href="#21" class="mim-tip-reference" title="Watkins, H., Anan, R., Coviello, D. A., Spirito, P., Seidman, J. G., Seidman, C. E. <strong>A de novo mutation in alpha-tropomyosin that causes hypertrophic cardiomyopathy.</strong> Circulation 91: 2302-2305, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7729014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7729014</a>] [<a href="https://doi.org/10.1161/01.cir.91.9.2302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7729014">Watkins et al. (1995)</a> found that the D175N mutation was present in the proband and 2 affected offspring, but in none of the proband's 3 sibs. Although both parents were deceased, the haplotypes of the 4 parental chromosomes could be reconstructed. (The haplotypes made use of an intragenic polymorphism in 10 flanking polymorphisms spanning a region of 35 cM.) One parental chromosome was transmitted to 2 offspring: 1 bearing the D175N mutation (the affected proband) and 1 clinically unaffected sib who lacked the mutation. Thus the D175N mutation must have arisen de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7729014" 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 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 3</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">rs104894504 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894504;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=rs104894504" 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=rs104894504" 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=RCV000013273 OR RCV000159356 OR RCV000211870 OR RCV000619092" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013273, RCV000159356, RCV000211870, RCV000619092" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013273...</a>
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<p><a href="#6" class="mim-tip-reference" title="Karibe, A., Tobacman, L. S., Strand, J., Butters, C., Back, N., Bachinski, L. L., Arai, A. E., Ortiz, A., Roberts, R., Homsher, E., Fananapazir, L. <strong>Hypertrophic cardiomyopathy caused by a novel alpha-tropomyosin mutation (V95A) is associated with mild cardiac phenotype, abnormal calcium binding to troponin, abnormal myosin cycling, and poor prognosis.</strong> Circulation 103: 65-71, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11136687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11136687</a>] [<a href="https://doi.org/10.1161/01.cir.103.1.65" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11136687">Karibe et al. (2001)</a> described a large Spanish American family in which multiple members had hypertrophic cardiomyopathy (CMH3; <a href="/entry/115196">115196</a>). They found a novel val95-to-ala (V95A) mutation in TPM1 to segregate with the disease phenotype. This mutation was associated with the same mild degree of left ventricular hypertrophy as seen in some CMH1 families harboring specific mutations in MYH7 (<a href="/entry/160760#0010">160760.0010</a>, <a href="/entry/160760#0012">160760.0012</a>, <a href="/entry/160760#0001">160760.0001</a>). Penetrance was estimated at 53% on the basis of an abnormal echocardiogram; however, 2 mutation carriers with normal echocardiograms and normal ECGs were only in their mid-thirties at the time of the study. Penetrance could not be accurately assessed by ECG, since 6 older mutation-negative family members had minor T-wave changes. Cumulative survival rates in this family were 73% +/- 10% at 40 years and 32% +/- 13% at 60 years. Expression of mutant and control tropomyosin in a bacterial system allowed a functional assessment of this mutation. An increase in calcium binding and abnormal myosin cycling were observed; both were felt to be important contributors to disease pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11136687" 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">rs104894505 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894505;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=rs104894505" 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=rs104894505" 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=RCV000013274 OR RCV000159370 OR RCV001317675" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013274, RCV000159370, RCV001317675" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013274...</a>
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<p>In a 27-year-old man with dilated cardiomyopathy (CMD1Y; <a href="/entry/611878">611878</a>) who died while awaiting cardiac transplantation, <a href="#13" class="mim-tip-reference" title="Olson, T. M., Kishimoto, N. Y., Whitby, F. G., Michels, V. V. <strong>Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy.</strong> J. Molec. Cell Cardiol. 33: 723-732, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11273725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11273725</a>] [<a href="https://doi.org/10.1006/jmcc.2000.1339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11273725">Olson et al. (2001)</a> identified heterozygosity for a G-A transition in exon 2 of the TPM1 gene, resulting in a glu54-to-lys (E54K) substitution at a highly conserved residue. The mutation was not found in 348 unrelated CMD patients or 160 unrelated controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11273725" 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 CARDIOMYOPATHY, DILATED, 1Y</strong>
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TPM1, GLU40LYS
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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> rs104894501 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894501;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/rs104894501?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=rs104894501" 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=rs104894501" 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=RCV000013275 OR RCV002513006" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013275, RCV002513006" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013275...</a>
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<p>In a girl with dilated cardiomyopathy (CMD1Y; <a href="/entry/611878">611878</a>) who underwent cardiac transplantation at 10 years of age, <a href="#13" class="mim-tip-reference" title="Olson, T. M., Kishimoto, N. Y., Whitby, F. G., Michels, V. V. <strong>Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy.</strong> J. Molec. Cell Cardiol. 33: 723-732, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11273725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11273725</a>] [<a href="https://doi.org/10.1006/jmcc.2000.1339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11273725">Olson et al. (2001)</a> identified heterozygosity for a G-A transition in exon 2 of the TPM1 gene, resulting in a glu40-to-lys (E40K) substitution at a highly conserved residue. Her affected mother also carried the mutation, which was not found in 3 unaffected family members, 348 unrelated CMD patients, or 160 unrelated controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11273725" 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 LEFT VENTRICULAR NONCOMPACTION 9</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">rs199476319 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476319;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=rs199476319" 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=rs199476319" 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=RCV000024597 OR RCV000054794" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024597, RCV000054794" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024597...</a>
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<p>In 4 affected individuals over 3 generations of a white family of western European descent with left ventricular noncompaction (LVNC9; see <a href="/entry/611878">611878</a>), <a href="#14" class="mim-tip-reference" title="Probst, S., Oechslin, E., Schuler, P., Greutmann, M., Boye, P., Knirsch, W., Berger, F., Thierfelder, L., Jenni, R., Klaassen, S. <strong>Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype.</strong> Circ. Cardiovasc. Genet. 4: 367-374, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21551322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21551322</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.110.959270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21551322">Probst et al. (2011)</a> identified heterozygosity for a c.933A-G transition in exon 8 of the TPM1 gene, resulting in a lys248-to-glu (K248E) substitution at an evolutionarily conserved residue. The male proband presented at age 63 years with congestive heart failure. He had 2 affected but asymptomatic children. The father had noncompacted segments at the apex and midventricular wall by echocardiography, whereas his son and daughter were affected only at the apex. A granddaughter who carried the mutation had severe congestive heart failure requiring cardiac transplantation at 5 years of age; she was diagnosed with dilated cardiomyopathy and did not show signs of LVNC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21551322" 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 LEFT VENTRICULAR NONCOMPACTION 9</strong>
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TPM1, GLU192LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476315 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476315;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=rs199476315" 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=rs199476315" 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=RCV000024578 OR RCV000054795 OR RCV000208146 OR RCV000526765 OR RCV000578109 OR RCV002345253 OR RCV003149576" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024578, RCV000054795, RCV000208146, RCV000526765, RCV000578109, RCV002345253, RCV003149576" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024578...</a>
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<p>In a 55-year-old white man of western European descent with left ventricular noncompaction (LVNC9; see <a href="/entry/611878">611878</a>), <a href="#14" class="mim-tip-reference" title="Probst, S., Oechslin, E., Schuler, P., Greutmann, M., Boye, P., Knirsch, W., Berger, F., Thierfelder, L., Jenni, R., Klaassen, S. <strong>Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype.</strong> Circ. Cardiovasc. Genet. 4: 367-374, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21551322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21551322</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.110.959270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21551322">Probst et al. (2011)</a> identified heterozygosity for a c.765G-A transition in exon 6 of the TPM1 gene, resulting in a glu192-to-lys (E192K) substitution at a highly conserved residue. Echocardiography revealed pronounced noncompaction of the apex and left midventricular wall, as well as increased right ventricular trabeculations. His son, who did not carry the mutation, showed normal left ventricular morphology and function on echocardiogram. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21551322" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 LEFT VENTRICULAR NONCOMPACTION 9</strong>
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TPM1, ASP159ASN (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397516373;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs397516373</a>)
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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> rs397516373 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397516373;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/rs397516373?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=rs397516373" 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=rs397516373" 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=RCV000036335 OR RCV000159410 OR RCV000679884 OR RCV000694039 OR RCV000722121 OR RCV000736013 OR RCV001334675 OR RCV002470728" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000036335, RCV000159410, RCV000679884, RCV000694039, RCV000722121, RCV000736013, RCV001334675, RCV002470728" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000036335...</a>
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<p>In a 2-year-old girl with severe heart failure and left ventricular noncompaction (LVNC9; see <a href="/entry/611878">611878</a>), who also exhibited Ebstein anomaly of the tricuspid valve, <a href="#7" class="mim-tip-reference" title="Kelle, A. M., Bentley, S. J., Rohena, L. O., Cabalka, A. K., Olson, T. M. <strong>Ebstein anomaly, left ventricular non-compaction, and early onset heart failure associated with a de novo alpha-tropomyosin gene mutation.</strong> Am. J. Med. Genet. 170A: 2186-2190, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27177193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27177193</a>] [<a href="https://doi.org/10.1002/ajmg.a.37745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27177193">Kelle et al. (2016)</a> identified heterozygosity for a de novo c.475G-A transition (c.475G-A, NM_001018005.1) in exon 4 of the TPM1 gene, resulting in an asp159-to-asn (D159N) substitution at a highly conserved residue adjacent to a likely actin-binding site. The mutation was not found in her unaffected parents or in the ExAC database. The authors stated that the mutation had previously been identified in a patient with dilated cardiomyopathy, although it was not reported in the published literature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27177193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 LEFT VENTRICULAR NONCOMPACTION 9</strong>
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TPM1, LEU113VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397516369 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397516369;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=rs397516369" 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=rs397516369" 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=RCV000036327 OR RCV000412875 OR RCV000736014 OR RCV001235507 OR RCV002453302" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000036327, RCV000412875, RCV000736014, RCV001235507, RCV002453302" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000036327...</a>
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<p>In 5 affected individuals over 2 generations of a family with left ventricular noncompaction (LVNC9; see <a href="/entry/611878">611878</a>), who also exhibited mitral valve insufficiency and/or Ebstein anomaly of the tricuspid valve, <a href="#12" class="mim-tip-reference" title="Nijak, A., Alaerts, M., Kuiperi, C., Corveleyn, A., Suys, B., Paelinck, B., Saenen, J., Van Craenenbroeck, E., Van Laer, L., Loeys, B., Verstraeten, A. <strong>Left ventricular non-compaction with Ebstein anomaly attributed to a TPM1 mutation.</strong> Europ. J. Med. Genet. 61: 8-10, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29024827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29024827</a>] [<a href="https://doi.org/10.1016/j.ejmg.2017.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29024827">Nijak et al. (2018)</a> identified heterozygosity for a c.377C-G transversion (c.377C-G, NM_001018007) in the TPM1 gene, resulting in a leu113-to-val (L113V) substitution at a highly conserved residue. The mutation was not found in the ExAC, Exome Variant Server, or 1000 Genomes Project databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29024827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Blanchard1997" class="mim-anchor"></a>
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Blanchard, E. M., Iizuka, K., Christe, M., Conner, D. A., Geisterfer-Lowrance, A., Schoen, F. J., Maughan, D. W., Seidman, C. E., Seidman, J. G.
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<strong>Targeted ablation of the murine alpha-tropomyosin gene.</strong>
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Circulation Res. 81: 1005-1010, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9400381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9400381</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9400381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/01.res.81.6.1005" target="_blank">Full Text</a>]
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Brown, J. H., Kim, K.-H., Jun, G., Greenfield, N. J., Dominguez, R., Volkmann, N., Hitchcock-DeGregori, S. E., Cohen, C.
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<strong>Deciphering the design of the tropomyosin molecule.</strong>
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Proc. Nat. Acad. Sci. 98: 8496-8501, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11438684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11438684</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11438684[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=11438684" 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.131219198" target="_blank">Full Text</a>]
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<a id="Chang2005" class="mim-anchor"></a>
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Chang, A. N., Harada, K., Ackerman, M. J., Potter, J. D.
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<strong>Functional consequences of hypertrophic and dilated cardiomyopathy-causing mutations in alpha-tropomyosin.</strong>
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J. Biol. Chem. 280: 34343-34349, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16043485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16043485</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16043485" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M505014200" target="_blank">Full Text</a>]
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Denz, C. R., Narshi, A., Zajdel, R. W., Dube, D. K.
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<strong>Expression of a novel cardiac-specific tropomyosin isoform in humans.</strong>
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Biochem. Biophys. Res. Commun. 320: 1291-1297, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15249230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15249230</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15249230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2004.06.084" target="_blank">Full Text</a>]
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Eyre, H., Akkari, P. A., Wilton, S. D., Callen, D. C., Baker, E., Laing, N. G.
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<strong>Assignment of the human skeletal muscle alpha-tropomyosin gene (TPM1) to band 15q22 by fluorescence in situ hybridization.</strong>
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Cytogenet. Cell Genet. 69: 15-17, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7835079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7835079</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7835079" 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/10.1159/000133928" target="_blank">Full Text</a>]
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Karibe, A., Tobacman, L. S., Strand, J., Butters, C., Back, N., Bachinski, L. L., Arai, A. E., Ortiz, A., Roberts, R., Homsher, E., Fananapazir, L.
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<strong>Hypertrophic cardiomyopathy caused by a novel alpha-tropomyosin mutation (V95A) is associated with mild cardiac phenotype, abnormal calcium binding to troponin, abnormal myosin cycling, and poor prognosis.</strong>
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Circulation 103: 65-71, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11136687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11136687</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11136687" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/01.cir.103.1.65" target="_blank">Full Text</a>]
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Kelle, A. M., Bentley, S. J., Rohena, L. O., Cabalka, A. K., Olson, T. M.
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<strong>Ebstein anomaly, left ventricular non-compaction, and early onset heart failure associated with a de novo alpha-tropomyosin gene mutation.</strong>
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Am. J. Med. Genet. 170A: 2186-2190, 2016.
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[<a href="https://doi.org/10.1002/ajmg.a.37745" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/bies.950130902" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M412281200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.res.85.1.47" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ejmg.2017.10.003" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/jmcc.2000.1339" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/CIRCRESAHA.107.148379" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/CIRCULATIONAHA.109.889725" target="_blank">Full Text</a>]
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</li>
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</ol>
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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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Marla J. F. O'Neill - updated : 01/15/2019
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 04/16/2014<br>Patricia A. Hartz - updated : 4/15/2014<br>Marla J. F. O'Neill - updated : 9/3/2013<br>Marla J. F. O'Neill - updated : 12/2/2008<br>Marla J. F. O'Neill - updated : 3/6/2008<br>Marla J. F. O'Neill - updated : 3/5/2008<br>Alan F. Scott - updated : 5/11/2007<br>Paul Brennan - updated : 4/18/2002<br>Victor A. McKusick - updated : 9/26/2001<br>Paul Brennan - updated : 4/3/2000<br>Paul Brennan - updated : 5/2/1998<br>Rebekah S. Rasooly - updated : 3/4/1998
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</span>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 2/25/1988
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/18/2023
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 01/15/2019<br>mgross : 04/16/2014<br>mcolton : 4/15/2014<br>carol : 9/3/2013<br>carol : 9/3/2013<br>terry : 7/9/2012<br>terry : 7/6/2012<br>wwang : 6/10/2011<br>wwang : 12/4/2008<br>terry : 12/2/2008<br>carol : 3/6/2008<br>carol : 3/5/2008<br>mgross : 5/11/2007<br>alopez : 7/9/2003<br>terry : 7/7/2003<br>alopez : 4/18/2002<br>alopez : 4/18/2002<br>mcapotos : 10/9/2001<br>mcapotos : 9/26/2001<br>alopez : 4/3/2000<br>carol : 10/20/1999<br>mgross : 4/8/1999<br>carol : 6/25/1998<br>carol : 5/2/1998<br>alopez : 3/4/1998<br>terry : 6/13/1996<br>mark : 7/3/1995<br>pfoster : 4/3/1995<br>jason : 6/17/1994<br>carol : 8/25/1993<br>carol : 8/28/1992<br>supermim : 3/16/1992
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</span>
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</div>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 191010
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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TROPOMYOSIN 1; TPM1
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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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<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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<h4>
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<span class="mim-font">
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TROPOMYOSIN, SKELETAL MUSCLE ALPHA; TMSA
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</span>
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TPM1</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 15q22.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:63,042,747-63,071,915 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
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15q22.2
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</span>
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</td>
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<td>
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<span class="mim-font">
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Cardiomyopathy, dilated, 1Y
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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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611878
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<tr>
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<td>
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<span class="mim-font">
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Cardiomyopathy, hypertrophic, 3
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</span>
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</td>
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<td>
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<span class="mim-font">
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115196
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Left ventricular noncompaction 9
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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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611878
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Tropomyosins are a family of actin-binding proteins encoded by 4 distinct genes. Each gene generates multiple striated muscle, smooth muscle, and cytoskeletal variants by alternative splicing, alternative promoter usage, and differential 3-prime end processing. Of the 4 human tropomyosin genes, TPM1 is the most versatile and encodes at least 10 tissue-specific variants via alternative splicing and/or the use of 2 promoters. The TPM1 variants encode proteins of either 248 or 284 amino acids (summary by Denz et al., 2004). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>MacLeod and Gooding (1988) isolated a cDNA clone from a human skeletal muscle library that contains the complete protein-coding sequence of a skeletal muscle alpha-tropomyosin. In cultured human fibroblasts, the TMSA gene was found to encode both skeletal muscle and smooth muscle type of alpha-tropomyosins by using an alternative splicing mechanism. </p><p>Lees-Miller and Helfman (1991) discussed the molecular basis for tropomyosin diversity. Tropomyosins are ubiquitous proteins of 35 to 45 kD associated with the actin filaments of myofibrils and stress fibers. The vertebrate alpha-tropomyosin gene consists of 15 exons, 5 of which are found in all transcripts, and 10 of which are alternatively used in different alpha-tropomyosin RNAs. The striated muscle isoform is expressed in both cardiac and skeletal muscle tissues. </p><p>By RT-PCR of total human heart RNA, Denz et al. (2004) cloned a TPM1 splice variant that they called TPM1-kappa. The TPM1-kappa transcript is identical to the TPM1-alpha striated muscle variant except that it contains exon 2a, found in the TPM1-beta smooth muscle variant, rather than exon 2b. The deduced TPM1-kappa protein contains 284 amino acids. PCR analysis detected TPM1-alpha in all adult and fetal skeletal muscle and heart samples tested, whereas TPM1-kappa was detected in adult and fetal heart only. Database analysis revealed species-specific distribution of Tpm1 splice variants in axolotl and bird striated muscle and during development. </p><p>Using quantitative RT-PCR and Western blot analysis, Rajan et al. (2010) found a discordance between expression of TPM1 splice variants and protein isoforms. Both TPM1-alpha and TPM1-kappa transcripts were equally expressed in fetal and adult human heart, with higher expression of both in adult heart. However, over 90% of total tropomyosin protein in adult heart was TPM1-alpha, with TPM1-kappa and TPM1-beta making up the remaining tropomyosin content. TPM1-kappa protein content was increased in dilated cardiomyopathy and heart failure patients. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p>Denz et al. (2004) stated that the TPM1 gene contains 15 exons. Exons 3, 4, 5, 7, and 8 are found in all TPM1 variants, and exons 1a, 1b, 2a, 2b, 6a, 6b, 9a, 9b, 9c, and 9d are alternatively spliced. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Eyre et al. (1995) developed a sequence tagged site (STS) for the TPM1 gene and used it to isolate a genomic clone containing part of the gene. Using this clone, they localized TPM1 to chromosome 15q22 by fluorescence in situ hybridization. By PCR of radiation hybrids, Tiso et al. (1997) mapped the TPM1 gene more precisely to chromosome 15q22.1. Schleef et al. (1993) mapped the mouse homolog, Tpm1, to the d-se region of chromosome 9, using interspecies backcrosses. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
|
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Brown et al. (2001) described the crystal structure of the tropomyosin molecule. Their results revealed the effects of clusters of core alanines on the axial register, symmetry, and conformational variability of 2-stranded coiled coils that appear to be important for tropomyosin's role in the regulation of muscle contraction. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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<strong>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Cardiac-mutant Mexican axolotls deficient in tropomyosin do not have organized cardiac myofibrils and, consequently, their hearts do not beat. Denz et al. (2004) found that human TPM1-alpha or TPM1-kappa was incorporated into organized myofibrils in both normal and cardiac-mutant axolotl hearts, revealing a high degree of functional conservation. </p><p>Using 2-dimensional differentiation in-gel electrophoresis to examine tumors derived from MCF-7 breast cancer cells that were either treated or untreated with anti-microRNA-21 (MIRN21; 611020), Zhu et al. (2007) identified the tumor suppressor TPM1 as an MIRN21 target. They identified a putative MIRN21-binding site in the 3-prime UTRs of 2 TPM1 splice variants, V1 and V5. Zhu et al. (2007) cloned the 3-prime UTR of TPM1 into a luciferase reporter construct and found that MIRN21 downregulated reporter activity, whereas anti-MIRN21 upregulated it. Deletion of the MIRN21-binding site abolished the effect of MIRN21 on luciferase activity. Western blot and RT-PCR analyses showed that TPM1 mRNA level was unchanged in the presence of MIRN21, but TPM1 protein level was reduced, implying that MIRN21 blocked TPM1 translation. Overexpression of TPM1 in MCF-7 cells suppressed anchorage-independent growth, whereas overexpression of MIRN21 increased tumor growth. Zhu et al. (2007) concluded that MIRN21 acts as an oncogene by suppressing TPM1. </p><p>Rajan et al. (2010) overexpressed human TPM1-kappa in transgenic mouse hearts. Expression of TPM1-kappa was coupled with concomitant downregulation of endogenous Tpm1-alpha, with total tropomyosin levels unchanged. Transgenic hearts appeared normal and functioned normally in many tests; however, they showed increased end-systolic and end-diastolic left ventricular dimensions and increased myofilament calcium sensitivity. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Hypertrophic Cardiomyopathy 3</em></strong></p><p>
|
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To assess linkage between the human TPM1 gene and type 3 familial hypertrophic cardiomyopathy (CMH3; 115196), which had previously been mapped to 15q2, Thierfelder et al. (1994) identified a short tandem repeat polymorphism (STR). A combined maximum 2-point lod score of 6.94 at theta = 0.0 was obtained for linkage of the TPM1 marker to CMH3 in 2 families. A point mutation was identified in each of the 2 families used in the linkage study: asp175-to-asn (191010.0002) in one, and glu180-to-gly (191010.0001) in the other. Watkins et al. (1995) concluded that mutations in the TPM1 gene are a rare cause of CMH, accounting for approximately 3% of cases. These mutations, like those in the cardiac troponin T gene (TNNT2; 191045), are characterized by relatively mild and sometimes subclinical hypertrophy but a high incidence of sudden death. Genetic testing may therefore be especially important in this group. </p><p><strong><em>Dilated Cardiomyopathy 1Y</em></strong></p><p>
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Using a candidate gene approach, Olson et al. (2001) analyzed the TPM1 gene in 350 unrelated patients with sporadic and familial dilated cardiomyopathy (see CMD1Y, 611878) and identified heterozygous missense mutations in 2 familial cases: E54K (191010.0004) and E40K (191010.0005), respectively. Each substitution was predicted to create a strong local increase in positive charge in an otherwise relatively negatively charged and highly conserved region of the molecule. </p><p><strong><em>Left Ventricular Noncompaction 9</em></strong></p><p>
|
|
In a cohort of 63 unrelated white patients of western European descent with left ventricular noncompaction (LVNC9; see 611878), Probst et al. (2011) analyzed 8 sarcomere genes and identified 2 probands with heterozygous missense mutations in the TPM1 gene (191010.0006 and 191010.0007). </p><p>In a 2-year-old girl with LVNC and Ebstein anomaly of the tricuspid valve, Kelle et al. (2016) identified heterozygosity for a de novo missense mutation in the TPM1 gene (D159N; 191010.0008). The authors stated that the D159N mutation had previously been identified in a patient with dilated cardiomyopathy, although it was not reported in the published literature. </p><p>In 5 affected members of a 2-generation family with LVNC with or without Ebstein anomaly and/or mitral valve insufficiency, Nijak et al. (2018) identified heterozygosity for a missense mutation in the TPM1 gene (L113V; 191010.0009) that segregated with disease and was not found in public variant databases. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using depletion and reconstitution of TPM1 and troponin in porcine cardiac myofibrils, Chang et al. (2005) studied 3 CMH-associated TPM1 mutations (E62Q; E180G, 190010.0001; and L185R) and 2 CMD-associated mutations (E54K and E40K) and found that all CMH-associated mutations increased the Ca(2+) sensitivity of ATPase activity and had decreased abilities to inhibit ATPase activity, whereas the CMD-associated mutations decreased the Ca(2+) sensitivity of ATPase activity and had no effect on the inhibition of ATPase activity. Chang et al. (2005) concluded that mutations that cause CMH and CMD disrupt discrete mechanisms, and suggested that this may explain the manifestation of distinct cardiomyopathic phenotypes. </p><p>Mirza et al. (2005) studied all 8 published mutations causing dilated cardiomyopathy (CMD), including 5 in the TNNT2 gene (lys210del, R141W, R131W, R205L, and D270N; 191045.0006-191045.0010, respectively), 2 in the TPM1 gene (E54K and E40K), and 1 in the TNNC1 gene (G159D, 191040.0001). Thin filaments, reconstituted with a 1:1 ratio of mutant:wildtype proteins, all showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays, and, except for the E54K alpha-tropomyosin mutant which showed no effect, all showed lower maximum Ca(2+) activation. Incorporation of the TNNT2 mutations R141W and R205L into skinned guinea pig cardiac trabeculae also decreased Ca(2+) sensitivity of force generation. Thus, diverse thin filament CMD mutations appeared to affect different aspects of regulatory function yet change contractility in a consistent manner. Mirza et al. (2005) stated that the CMD mutations depressed myofibrillar function, an effect opposite to that of CMH-causing thin filament mutations, and suggested that decreased contractility might trigger pathways that ultimately lead to the clinical phenotype. </p><p>Robinson et al. (2007) used a fluorescent probe to assess Ca(2+) binding of CMH-causing mutations in the TNNT2 (R92Q; 191045.0002) and TNNI3 (R145G; 191044.0001) genes, and CMD-causing mutations in the TNNT2 (e.g., lys210del and R141W), TNNC1 (G159D), and TPM1 (E45K and E40K) genes. Both CMH mutations increased Ca(2+) affinity, whereas the CMD mutations decreased affinity, except for 1 in TNNT2, which caused a significant decrease in cooperativity. Robinson et al. (2007) suggested that Ca(2+) affinity changes caused by cardiomyopathy mutant proteins may directly affect the Ca(2+) transient and hence Ca(2+)-sensitive disease state remodeling pathways in vivo, representing a novel mechanism for this class of mutation. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Blanchard et al. (1997) used gene targeting in embryonic stem cells and blastocyst-mediated transgenesis to create functional mouse alpha-tropomyosin knockouts. Homozygous mice died in utero between embryonic days 9.5 and 13.5 and lacked alpha-tropomyosin mRNA. Heterozygotes had an approximately 50% reduction in alpha-tropomyosin mRNA levels but no reduction in alpha-tropomyosin protein. No differences in myofibrillar ultrastructure or contractile function were found. The authors postulated that mice have a regulatory mechanism that maintains the level of myofibrillar tropomyosin despite a reduction in mRNA. Furthermore, they concluded that, assuming human and mouse cardiac muscle are similar, simple haploinsufficiency for alpha-tropomyosin would not cause the pathologic changes seen in human type 3 hypertrophic cardiomyopathy (115196) and that alterations in protein stoichiometry may produce a poison polypeptide that disrupts myofibrillar organization on incorporation into the sarcomere. </p><p>Muthuchamy et al. (1999) constructed a transgenic mouse model of CMH3 by introducing the missense mutation asp175 to asn (191010.0002) by site-directed mutagenesis. This mutation occurs in a cardiac troponin T-binding region. The transgenic CMH3 mice exhibited significant in vivo and in vitro evidence of myocardial functional impairment. Histologic analysis of transgenic myocardium showed variable myocyte disarray and hypertrophy, as reported in the human form of the disease. </p><p>Rajan et al. (2007) generated transgenic mice expressing E54K Tpm1 in the adult heart and observed the development of dilated cardiomyopathy with progression to heart failure and frequently death by 6 months. Echocardiographic analyses confirmed the dilated cardiac phenotype with a significant decrease in left ventricular fractional shortening; work-performing heart analyses showed significantly impaired systolic and diastolic function, and force measurements revealed that cardiac myofilaments had significantly decreased Ca(2+) sensitivity and tension generation. Real-time RT-PCR quantification demonstrated increased expression of beta-myosin heavy chain (MYH7; 160760), brain natriuretic peptide (see NPPA, 108780), and skeletal actin (see ACTA1, 102610), and decreased expression of sarcoplasmic reticulum Ca(2+) ATPase (ATP2A2; 108740) and ryanodine receptor (RYR2; 180902). The thermal denaturation curve of the mutant protein shifted to the right compared to wildtype, implying a decrease in flexibility. Rajan et al. (2007) stated that these findings are consistent with those seen in human CMD and heart failure. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 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 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TPM1, GLU180GLY
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<br />
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SNP: rs104894502,
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ClinVar: RCV000013271, RCV000159367, RCV002513005
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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 members of family MZ with a form of familial hypertrophic cardiomyopathy linked to 15q (CMH3; 115196), Thierfelder et al. (1994) identified an A-to-G transition at nucleotide 595 in exon 5 of the TPM1 gene in heterozygous state. The substitution changed codon 180 from GAG to GGG and predicted that a negatively charged glutamic acid residue is replaced by a neutral glycine residue. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TPM1, ASP175ASN
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<br />
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SNP: rs104894503,
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gnomAD: rs104894503,
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ClinVar: RCV000013272, RCV000036340, RCV000159366, RCV000474684, RCV000622165, RCV001170568, RCV001197088
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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 members of family MI with a form of familial hypertrophic cardiomyopathy linked to 15q (CMH3; 115196), Thierfelder et al. (1994) found heterozygosity for a G-to-A transition at nucleotide 579 that altered codon 175 from GAC to AAC. The substitution predicted that the mutated allele present in affected individuals would encode a neutral asparagine residue instead of the negatively charged aspartic acid residue found in unaffected individuals. </p><p>Watkins et al. (1995) investigated whether the D175N mutation was really responsible for hypertrophic cardiomyopathy or was only a polymorphism, because some features of the 2 identified mutations in the alpha-tropomyosin gene contrasted with those of mutations in other disease genes for CMH. Unlike the beta-cardiac myosin heavy chain gene (MYH7; 160760) and the cardiac troponin-T gene, the alpha-tropomyosin gene is expressed ubiquitously, yet the disease phenotype is limited to cardiac muscle. Watkins et al. (1995) found that the D175N mutation was present in the proband and 2 affected offspring, but in none of the proband's 3 sibs. Although both parents were deceased, the haplotypes of the 4 parental chromosomes could be reconstructed. (The haplotypes made use of an intragenic polymorphism in 10 flanking polymorphisms spanning a region of 35 cM.) One parental chromosome was transmitted to 2 offspring: 1 bearing the D175N mutation (the affected proband) and 1 clinically unaffected sib who lacked the mutation. Thus the D175N mutation must have arisen de novo. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TPM1, VAL95ALA
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<br />
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SNP: rs104894504,
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ClinVar: RCV000013273, RCV000159356, RCV000211870, RCV000619092
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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>Karibe et al. (2001) described a large Spanish American family in which multiple members had hypertrophic cardiomyopathy (CMH3; 115196). They found a novel val95-to-ala (V95A) mutation in TPM1 to segregate with the disease phenotype. This mutation was associated with the same mild degree of left ventricular hypertrophy as seen in some CMH1 families harboring specific mutations in MYH7 (160760.0010, 160760.0012, 160760.0001). Penetrance was estimated at 53% on the basis of an abnormal echocardiogram; however, 2 mutation carriers with normal echocardiograms and normal ECGs were only in their mid-thirties at the time of the study. Penetrance could not be accurately assessed by ECG, since 6 older mutation-negative family members had minor T-wave changes. Cumulative survival rates in this family were 73% +/- 10% at 40 years and 32% +/- 13% at 60 years. Expression of mutant and control tropomyosin in a bacterial system allowed a functional assessment of this mutation. An increase in calcium binding and abnormal myosin cycling were observed; both were felt to be important contributors to disease pathogenesis. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 CARDIOMYOPATHY, DILATED, 1Y</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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TPM1, GLU54LYS
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<br />
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SNP: rs104894505,
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|
|
ClinVar: RCV000013274, RCV000159370, RCV001317675
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 27-year-old man with dilated cardiomyopathy (CMD1Y; 611878) who died while awaiting cardiac transplantation, Olson et al. (2001) identified heterozygosity for a G-A transition in exon 2 of the TPM1 gene, resulting in a glu54-to-lys (E54K) substitution at a highly conserved residue. The mutation was not found in 348 unrelated CMD patients or 160 unrelated controls. </p>
|
|
</span>
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</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CARDIOMYOPATHY, DILATED, 1Y</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TPM1, GLU40LYS
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894501,
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|
|
|
|
|
gnomAD: rs104894501,
|
|
|
|
|
|
ClinVar: RCV000013275, RCV002513006
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with dilated cardiomyopathy (CMD1Y; 611878) who underwent cardiac transplantation at 10 years of age, Olson et al. (2001) identified heterozygosity for a G-A transition in exon 2 of the TPM1 gene, resulting in a glu40-to-lys (E40K) substitution at a highly conserved residue. Her affected mother also carried the mutation, which was not found in 3 unaffected family members, 348 unrelated CMD patients, or 160 unrelated controls. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LEFT VENTRICULAR NONCOMPACTION 9</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TPM1, LYS248GLU
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|
|
<br />
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|
|
SNP: rs199476319,
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|
|
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|
|
ClinVar: RCV000024597, RCV000054794
|
|
|
|
|
|
</span>
|
|
</div>
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 affected individuals over 3 generations of a white family of western European descent with left ventricular noncompaction (LVNC9; see 611878), Probst et al. (2011) identified heterozygosity for a c.933A-G transition in exon 8 of the TPM1 gene, resulting in a lys248-to-glu (K248E) substitution at an evolutionarily conserved residue. The male proband presented at age 63 years with congestive heart failure. He had 2 affected but asymptomatic children. The father had noncompacted segments at the apex and midventricular wall by echocardiography, whereas his son and daughter were affected only at the apex. A granddaughter who carried the mutation had severe congestive heart failure requiring cardiac transplantation at 5 years of age; she was diagnosed with dilated cardiomyopathy and did not show signs of LVNC. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
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|
</div>
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</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 LEFT VENTRICULAR NONCOMPACTION 9</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
TPM1, GLU192LYS
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|
|
<br />
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|
|
SNP: rs199476315,
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|
|
ClinVar: RCV000024578, RCV000054795, RCV000208146, RCV000526765, RCV000578109, RCV002345253, RCV003149576
|
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|
|
</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 55-year-old white man of western European descent with left ventricular noncompaction (LVNC9; see 611878), Probst et al. (2011) identified heterozygosity for a c.765G-A transition in exon 6 of the TPM1 gene, resulting in a glu192-to-lys (E192K) substitution at a highly conserved residue. Echocardiography revealed pronounced noncompaction of the apex and left midventricular wall, as well as increased right ventricular trabeculations. His son, who did not carry the mutation, showed normal left ventricular morphology and function on echocardiogram. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LEFT VENTRICULAR NONCOMPACTION 9</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
TPM1, ASP159ASN ({dbSNP rs397516373})
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|
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<br />
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|
|
SNP: rs397516373,
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|
|
gnomAD: rs397516373,
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|
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ClinVar: RCV000036335, RCV000159410, RCV000679884, RCV000694039, RCV000722121, RCV000736013, RCV001334675, RCV002470728
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 2-year-old girl with severe heart failure and left ventricular noncompaction (LVNC9; see 611878), who also exhibited Ebstein anomaly of the tricuspid valve, Kelle et al. (2016) identified heterozygosity for a de novo c.475G-A transition (c.475G-A, NM_001018005.1) in exon 4 of the TPM1 gene, resulting in an asp159-to-asn (D159N) substitution at a highly conserved residue adjacent to a likely actin-binding site. The mutation was not found in her unaffected parents or in the ExAC database. The authors stated that the mutation had previously been identified in a patient with dilated cardiomyopathy, although it was not reported in the published literature. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 LEFT VENTRICULAR NONCOMPACTION 9</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
TPM1, LEU113VAL
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<br />
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|
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SNP: rs397516369,
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ClinVar: RCV000036327, RCV000412875, RCV000736014, RCV001235507, RCV002453302
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 5 affected individuals over 2 generations of a family with left ventricular noncompaction (LVNC9; see 611878), who also exhibited mitral valve insufficiency and/or Ebstein anomaly of the tricuspid valve, Nijak et al. (2018) identified heterozygosity for a c.377C-G transversion (c.377C-G, NM_001018007) in the TPM1 gene, resulting in a leu113-to-val (L113V) substitution at a highly conserved residue. The mutation was not found in the ExAC, Exome Variant Server, or 1000 Genomes Project databases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
|
|
<ol>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Blanchard, E. M., Iizuka, K., Christe, M., Conner, D. A., Geisterfer-Lowrance, A., Schoen, F. J., Maughan, D. W., Seidman, C. E., Seidman, J. G.
|
|
<strong>Targeted ablation of the murine alpha-tropomyosin gene.</strong>
|
|
Circulation Res. 81: 1005-1010, 1997.
|
|
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|
|
[PubMed: 9400381]
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|
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[Full Text: https://doi.org/10.1161/01.res.81.6.1005]
|
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
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Brown, J. H., Kim, K.-H., Jun, G., Greenfield, N. J., Dominguez, R., Volkmann, N., Hitchcock-DeGregori, S. E., Cohen, C.
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