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<title>
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Entry
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- *191044 - TROPONIN I, CARDIAC; TNNI3
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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="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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</div>
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</form>
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<div class="row">
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<p />
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</div>
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<div id="mimAlertBanner">
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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">*191044</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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</li>
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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>
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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="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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</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="#evolution">Evolution</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/191044">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=ENSG00000129991;t=ENST00000344887" 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=7137" 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=191044" 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=ENSG00000129991;t=ENST00000344887" 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_000363" 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_000363" 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=191044" 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=11769&isoform_id=11769_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/TNNI3" 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/37428,136213,339967,1524066,49456923,49456977,54695904,62898463,64653101,64654230,64654716,68563325,83755091,151101270,157365220,157365222,157365224,157382698,157382700,162133975,162133977,162133979,162133981,162133983,201067595,302313135,1043113219,2314709897" 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/P19429" 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=7137" 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=ENSG00000129991;t=ENST00000344887" 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=TNNI3" 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=TNNI3" 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+7137" 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/TNNI3" 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:7137" 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/7137" 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=chr19&hgg_gene=ENST00000587871.1&hgg_start=55151767&hgg_end=55157732&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:11947" 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:11947" 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=191044[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=191044[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/TNNI3/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/ENSG00000129991" 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=TNNI3" 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=TNNI3" 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=TNNI3" 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/TNNI3_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=TNNI3&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/PA36636" 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:11947" 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/FBgn0283471.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:98783" 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/TNNI3#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:98783" 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/7137/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=7137" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006584;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006584 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006586;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006586 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006764;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006764 </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 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:7137" 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=TNNI3&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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191044
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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TROPONIN I, CARDIAC; TNNI3
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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TROPONIN I, CARDIAC MUSCLE ISOFORM
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TNNI3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TNNI3</a></em></strong>
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</span>
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</p>
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</div>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:55151767-55157732&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'})">19:55,151,767-55,157,732</a> </span>
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<a href="/clinicalSynopsis/table?mimNumber=611880,613286,115210,613690" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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Phenotype <br /> MIM number
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19q13.42
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?Cardiomyopathy, dilated, 2A
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<a href="/entry/611880"> 611880 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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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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Cardiomyopathy, dilated, 1FF
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<a href="/entry/613286"> 613286 </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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Cardiomyopathy, familial restrictive, 1
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<a href="/entry/115210"> 115210 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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Cardiomyopathy, hypertrophic, 7
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<a href="/entry/613690"> 613690 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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/191044" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/191044" 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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<h4>
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<span class="mim-font">
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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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<strong>Description</strong>
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<p>Troponin I (TnI) is one of 3 subunits that form the troponin complex of the thin filaments of striated muscle; see also TNNI1 (<a href="/entry/191042">191042</a>). The others are troponin T (TnT; see <a href="/entry/191041">191041</a>) and troponin C (TnC; see <a href="/entry/191040">191040</a>).</p>
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<p><a href="#24" class="mim-tip-reference" title="Vallins, W. J., Brand, N. J., Dabhade, N., Butler-Browne, G., Yacoub, M. H., Barton, P. J. R. <strong>Molecular cloning of human cardiac troponin I using polymerase chain reaction.</strong> FEBS Lett. 270: 57-61, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2226790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2226790</a>] [<a href="https://doi.org/10.1016/0014-5793(90)81234-f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2226790">Vallins et al. (1990)</a> cloned a full-length cDNA for the human cardiac muscle troponin I. The deduced protein contains 210 amino acids. Northern blot analysis detected TNNI3 expression in 20-week fetal heart, 28-week fetal heart, 9-month postnatal heart, and adult ventricular muscle, but not in adult skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2226790" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Joyce, W., He, K., Zhang, M., Ogunsola, S., Wu, X., Joseph, K. T., Bogomolny, D., Yu, W., Springer, M. S., Xie, J., Signore, A. V., Campbell, K. L. <strong>Genetic excision of the regulatory cardiac troponin I extension in high-heart rate mammal clades.</strong> Science 385: 1466-1471, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39325895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39325895</a>] [<a href="https://doi.org/10.1126/science.adi8146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39325895">Joyce et al. (2024)</a> noted that cardiac troponin, TNNI3, is distinguished from its skeletal muscle paralogs, TNNI1 (<a href="/entry/191042">191042</a>) and TNNI2 (<a href="/entry/191043">191043</a>), by the presence of a regulatory 32-amino acid N-terminal extension that harbors 2 phosphorylatable serines, ser23 and ser24. Phosphorylation of ser23 and ser24 defends diastolic filling by means of an increased cardiomyocyte relaxation rate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39325895" 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>Gene Structure</strong>
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<p><a href="#4" class="mim-tip-reference" title="Bhavsar, P. K., Brand, N. J., Yacoub, M. H., Barton, P. J. R. <strong>Isolation and characterization of the human cardiac troponin I gene (TNNI3).</strong> Genomics 35: 11-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661099</a>] [<a href="https://doi.org/10.1006/geno.1996.0317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661099">Bhavsar et al. (1996)</a> showed that the TNNI3 gene contains 8 exons and spans 6.2 kb of genomic DNA. The authors showed that a 2,300-bp block of 5-prime sequence has promoter activity in both cardiac myocytes and skeletal muscle cells but was inactive in fibroblasts, suggesting that this 5-prime region is necessary but not sufficient for cardiac tissue specificity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661099" 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>Mapping</strong>
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</h4>
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<p><a href="#17" class="mim-tip-reference" title="MacGeoch, C., Barton, P. J. R., Vallins, W. J., Bhavsar, P., Spurr, N. K. <strong>The human cardiac troponin I locus: assignment to chromosome 19p13.2-19q13.2.</strong> Hum. Genet. 88: 101-104, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1959915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1959915</a>] [<a href="https://doi.org/10.1007/BF00204938" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1959915">MacGeoch et al. (1991)</a>, who referred to the gene by the symbol TNNC1, mapped the cardiac troponin I gene to chromosome 19p13.2-q13.2 by analysis of somatic cell hybrids containing various segments of chromosome 19. <a href="#3" class="mim-tip-reference" title="Bermingham, N., Hernandez, D., Balfour, A., Gilmour, F., Martin, J. E., Fisher, E. M. C. <strong>Mapping TNNC1, the gene that encodes cardiac troponin I in the human and mouse.</strong> Genomics 30: 620-622, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8825654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8825654</a>] [<a href="https://doi.org/10.1006/geno.1995.1288" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8825654">Bermingham et al. (1995)</a> mapped the TNNI3 gene to chromosome 19q13.3-q13.4 using a series of somatic cell hybrid DNAs. <a href="#18" class="mim-tip-reference" title="Mogensen, J., Kruse, T. A., Borglum, A. D. <strong>Assignment of the human cardiac troponin I gene (TNNI3) to chromosome 19q13.4 by radiation hybrid mapping.</strong> Cytogenet. Cell Genet. 79: 272-273, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9605869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9605869</a>] [<a href="https://doi.org/10.1159/000134740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9605869">Mogensen et al. (1997)</a> mapped the TNNI3 gene to chromosome 19q13.4 by radiation hybrid mapping. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1959915+9605869+8825654" 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="#2" class="mim-tip-reference" title="Barton, P. J. R., Cullen, M. E., Townsend, P. J., Brand, N. J., Mullen, A. J., Norman, D. A. M., Bhavsar, P. K., Yacoub, M. H. <strong>Close physical linkage of human troponin genes: organization, sequence, and expression of the locus encoding cardiac troponin I and slow skeletal troponin T.</strong> Genomics 57: 102-109, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10191089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10191089</a>] [<a href="https://doi.org/10.1006/geno.1998.5702" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10191089">Barton et al. (1999)</a> determined that the TNNI3 gene and the slow skeletal muscle troponin gene (TNNT1; <a href="/entry/191041">191041</a>) are oriented head to tail, with the TNNI3 gene 2.6 kb upstream of exon 1 of the TNNT1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10191089" 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 interspecific backcross analysis, <a href="#3" class="mim-tip-reference" title="Bermingham, N., Hernandez, D., Balfour, A., Gilmour, F., Martin, J. E., Fisher, E. M. C. <strong>Mapping TNNC1, the gene that encodes cardiac troponin I in the human and mouse.</strong> Genomics 30: 620-622, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8825654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8825654</a>] [<a href="https://doi.org/10.1006/geno.1995.1288" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8825654">Bermingham et al. (1995)</a> assigned the mouse homolog (Tnni3) to a site close to the centromere of chromosome 7. <a href="#10" class="mim-tip-reference" title="Guenet, J.-L., Simon-Chazottes, D., Gravel, M., Hastings, K. E. M., Schiaffino, S. <strong>Cardiac and skeletal muscle troponin I isoforms are encoded by a dispersed gene family on mouse chromosomes 1 and 7.</strong> Mammalian Genome 7: 13-15, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8903721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8903721</a>] [<a href="https://doi.org/10.1007/s003359900004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8903721">Guenet et al. (1996)</a> demonstrated that the Tnni3 gene is located on mouse chromosome 7 in a region of homology to 19q. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8903721+8825654" 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="Bhavsar, P. K., Brand, N. J., Yacoub, M. H., Barton, P. J. R. <strong>Isolation and characterization of the human cardiac troponin I gene (TNNI3).</strong> Genomics 35: 11-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661099</a>] [<a href="https://doi.org/10.1006/geno.1996.0317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661099">Bhavsar et al. (1996)</a> noted that the troponin complex serves as a calcium-sensitive switch that regulates striated muscle contraction. Troponin I binds actin and inhibits actomyosin ATPase activity in the absence of calcium. Cardiac muscle troponin I is expressed only in the heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661099" 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="Labarrere, C. A., Nelson, D. R., Cox, C. J., Pitts, D., Kirlin, P., Halbrook, H. <strong>Cardiac-specific troponin I levels and risk of coronary artery disease and graft failure following heart transplantation.</strong> JAMA 284: 457-464, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10904509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10904509</a>] [<a href="https://doi.org/10.1001/jama.284.4.457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10904509">Labarrere et al. (2000)</a> found that persistent elevation of cardiac troponin I levels after heart transplantation were associated with high risk for developing coronary artery disease and graft failure after cardiac transplantation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10904509" 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="Horwich, T. B., Patel, J., MacLellan, W. R., Fonarow, G. C. <strong>Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure.</strong> Circulation 108: 833-838, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12912820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12912820</a>] [<a href="https://doi.org/10.1161/01.CIR.0000084543.79097.34" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12912820">Horwich et al. (2003)</a> assayed cardiac troponin I (cTnI) in 238 patients with advanced heart failure but no acute coronary syndrome or myocarditis who were referred for cardiac transplantation. Patients with detectable cTnI levels had significantly higher B-type natriuretic peptide (BNP; <a href="/entry/600295">600295</a>) levels (p less than 0.001) and more impaired hemodynamic profiles, including higher pulmonary wedge pressures (p = 0.002) and lower cardiac indexes (p less than 0.0001). A significant correlation was found between detectable cTnI and progressive decline in ejection fraction over time (p less than 0.01), and detectable cTnI was associated with increased mortality risk (relative risk, 2.05; 95% CI, 1.22-3.43) and remained a significant predictor of death even after adjustment for other factors associated with adverse prognosis. Used in conjunction with BNP, cTnI further improved prognostic value. <a href="#11" class="mim-tip-reference" title="Horwich, T. B., Patel, J., MacLellan, W. R., Fonarow, G. C. <strong>Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure.</strong> Circulation 108: 833-838, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12912820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12912820</a>] [<a href="https://doi.org/10.1161/01.CIR.0000084543.79097.34" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12912820">Horwich et al. (2003)</a> concluded that cTnI may be a useful tool in identifying patients with heart failure who are at increased risk for progressive ventricular dysfunction and death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12912820" 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 yeast 2-hybrid analysis and protein pull-down assays, <a href="#5" class="mim-tip-reference" title="Canaider, S., Facchin, F., Griffoni, C., Casadei, R., Vitale, L., Lenzi, L., Frabetti, F., D'Addabbo, P., Carinci, P., Zannotti, M., Strippoli, P. <strong>Proteins encoded by human Down syndrome critical region gene 1-like 2 (DSCR1L2) mRNA and by a novel DSCR1L2 mRNA isoform interact with cardiac troponin I (TNNI3).</strong> Gene 372: 128-136, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16516408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16516408</a>] [<a href="https://doi.org/10.1016/j.gene.2005.12.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16516408">Canaider et al. (2006)</a> showed that DSCR1L2 (RCAN3; <a href="/entry/605860">605860</a>) and a DSCR1L2 isoform, DSCR1L2-E2E5, bound TNNI3 via an N-terminal domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16516408" 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="#23" class="mim-tip-reference" title="Takeda, S., Yamashita, A., Maeda, K., Maeda, Y. <strong>Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form.</strong> Nature 424: 35-41, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12840750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12840750</a>] [<a href="https://doi.org/10.1038/nature01780" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12840750">Takeda et al. (2003)</a> presented the crystal structure of the core domains (relative molecular mass of 46,000 and 52,000) of human cardiac troponin in the calcium-saturated form. Analysis of the 4-molecule structures revealed that the core domain is further divided into structurally distinct subdomains that are connected by flexible linkers, making the entire molecule highly flexible. The alpha-helical coiled-coil formed between TnT and TnI is integrated in a rigid and asymmetric structure about 80 angstroms long, the IT arm, which bridges putative tropomyosin (see <a href="/entry/191010">191010</a>)-anchoring regions. The structures of the troponin ternary complex imply that calcium binding to the regulatory site of TnC removes the carboxy-terminal portion of TnI from actin, thereby altering the mobility and/or flexibility of troponin and tropomyosin on the actin filament. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12840750" 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="#7" class="mim-tip-reference" title="Chien, K. R. <strong>Genotype, phenotype: upstairs, downstairs in the family of cardiomyopathies.</strong> J. Clin. Invest. 111: 175-178, 2003. Note: Erratum: J. Clin. Invest. 11: 1433 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531871</a>] [<a href="https://doi.org/10.1172/JCI17612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531871">Chien (2003)</a> reviewed the molecular defects linked to human cardiomyopathies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12531871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Huang, X., Du, J. <strong>Troponin I, cardiac diastolic dysfunction and restrictive cardiomyopathy.</strong> Acta Pharm. Sin. 25: 1569-1575, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15569399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15569399</a>]" pmid="15569399">Huang and Du (2004)</a> reviewed the role of TNNI3 in cardiac function, the diastolic dysfunction that results from TNNI3 deficiency, and TNNI3 mutation in restrictive cardiomyopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15569399" 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>Hypertrophic Cardiomyopathy 7</em></strong></p><p>
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<a href="#14" class="mim-tip-reference" title="Kimura, A., Harada, H., Park, J.-E., Nishi, H., Satoh, M., Takahashi, M., Hiroi, S., Sasaoka, T., Ohbuchi, N., Nakamura, T., Koyanagi, T., Hwang, T.-H., Choo, J., Chung, K.-S., Hasegawa, A., Nagai, R., Okazaki, O., Nakamura, H., Matsuzaki, M., Sakamoto, T., Toshima, H., Koga, Y., Imaizumi, T., Sasazuki, T. <strong>Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.</strong> Nature Genet. 16: 379-382, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241277</a>] [<a href="https://doi.org/10.1038/ng0897-379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241277">Kimura et al. (1997)</a> analyzed the TNNI3 gene in 184 unrelated patients with hypertrophic cardiomyopathy (CMH7; <a href="/entry/613690">613690</a>) and identified 6 heterozygous mutations in 6 probands, respectively (see, e.g., <a href="#0001">191044.0001</a> and <a href="#0002">191044.0002</a>). Although apical HCM had been associated particularly with CMH4 (<a href="/entry/115197">115197</a>), <a href="#14" class="mim-tip-reference" title="Kimura, A., Harada, H., Park, J.-E., Nishi, H., Satoh, M., Takahashi, M., Hiroi, S., Sasaoka, T., Ohbuchi, N., Nakamura, T., Koyanagi, T., Hwang, T.-H., Choo, J., Chung, K.-S., Hasegawa, A., Nagai, R., Okazaki, O., Nakamura, H., Matsuzaki, M., Sakamoto, T., Toshima, H., Koga, Y., Imaizumi, T., Sasazuki, T. <strong>Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.</strong> Nature Genet. 16: 379-382, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241277</a>] [<a href="https://doi.org/10.1038/ng0897-379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241277">Kimura et al. (1997)</a> found that 3 of 36 (8.3%) patients with apical HCM had mutations in the TNNI3 gene. In addition, all 3 individuals with G203S mutation in the TNNI3 gene (<a href="#0014">191044.0014</a>) exhibited Wolff-Parkinson-White ventricular preexcitation (WPW; <a href="/entry/194200">194200</a>); <a href="#14" class="mim-tip-reference" title="Kimura, A., Harada, H., Park, J.-E., Nishi, H., Satoh, M., Takahashi, M., Hiroi, S., Sasaoka, T., Ohbuchi, N., Nakamura, T., Koyanagi, T., Hwang, T.-H., Choo, J., Chung, K.-S., Hasegawa, A., Nagai, R., Okazaki, O., Nakamura, H., Matsuzaki, M., Sakamoto, T., Toshima, H., Koga, Y., Imaizumi, T., Sasazuki, T. <strong>Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.</strong> Nature Genet. 16: 379-382, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241277</a>] [<a href="https://doi.org/10.1038/ng0897-379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241277">Kimura et al. (1997)</a> noted that although a locus for 'CMH with WPW' had been mapped to chromosome 7q3 (CMH6; <a href="/entry/600858">600858</a>), their findings indicated that more than 1 form of CMH is associated with WPW syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9241277" 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>Restrictive Cardiomyopathy 1</em></strong></p><p>
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<a href="#19" class="mim-tip-reference" title="Mogensen, J., Kubo, T., Duque, M., Uribe, W., Shaw, A., Murphy, R., Gimeno, J. R., Elliott, P., McKenna, W. J. <strong>Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.</strong> J. Clin. Invest. 111: 209-216, 2003. Note: Erratum: J. Clin. Invest.: 111: 925 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12531876[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531876">Mogensen et al. (2003)</a> studied a family segregating both hypertrophic cardiomyopathy and restrictive cardiomyopathy (RCM1; <a href="/entry/115210">115210</a>). Linkage analysis of recognized CMH genes identified TNNI3 as the likely disease gene. Mutation analysis of TNNI3 by direct sequencing identified an asp190-to-gly substitution (D190G; <a href="#0005">191044.0005</a>), which was incorrectly reported as an asp190-to-his substitution, that segregated with the disease in the family (maximum 2-point lod score = 4.8). Analysis of TNNI3 was performed in an additional 9 unrelated patients with idiopathic RCM, 6 of whom were shown to carry TNNI3 mutations (e.g., <a href="#0006">191044.0006</a>-<a href="#0008">191044.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12531876" 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 2A</em></strong></p><p>
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Using a candidate gene approach, <a href="#20" class="mim-tip-reference" title="Murphy, R. T., Mogensen, J., Shaw, A., Kubo, T., Hughes, S., McKenna, W. J. <strong>Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. (Letter)</strong> Lancet 363: 371-372, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15070570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15070570</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)15468-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15070570">Murphy et al. (2004)</a> analyzed the TNNI3 gene in 235 consecutive patients with dilated cardiomyopathy (CMD; see CMD2A, <a href="/entry/611880">611880</a>) and identified homozygosity for a missense mutation (A2V; <a href="#0009">191044.0009</a>) in a man who had undergone cardiac transplantation at 28 years of age. His affected sister was also homozygous for the mutation; the unaffected parents and an unaffected sister were heterozygotes. Functional studies of the A2V mutant cTnI showed impairment of troponin interactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15070570" 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 1FF</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Carballo, S., Robinson, P., Otway, R., Fatkin, D., Jongbloed, J. D. H., de Jonge, N., Blair, E., van tintelen, J. P., Redwood, C., Watkins, H. <strong>Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.</strong> Circ. Res. 105: 375-382, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19590045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19590045</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.109.196055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19590045">Carballo et al. (2009)</a> analyzed the TNNI3 gene in 96 probands with dilated cardiomyopathy in whom screening for mutations in 6 more commonly implicated CMD genes was negative and identified heterozygosity for respective missense mutations (<a href="#0012">191044.0012</a>-<a href="#0013">191044.0013</a>) in the TNNI3 gene in 2 probands with severe, early-onset CMD (CMD1FF; <a href="/entry/613286">613286</a>). Functional analysis revealed that troponin reconstituted with either mutant had lower maximum ATPase rates and reduced Ca(2+) sensitivity compared to wildtype; in addition, mutant thin filaments had lower Ca(2+) affinity than normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19590045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Vikhorev, P. G., Smoktunowicz, N., Munster, A. B., Copeland, O., Kostin, S., Montgiraud, C., Messer, A. E., Toliat, M. R., Li, A., Dos Remedios, C. G., Lal, S., Blair, C. A., Campbell, K. S., Guglin, M., Richter, M., Knoll, R., Marston, S. B. <strong>Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes.</strong> Sci. Rep. 7: 14829, 2017. Note: Erratum: Sci. Rep. 8: 14485, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29093449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29093449</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29093449[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41598-017-13675-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29093449">Vikhorev et al. (2017)</a> compared contractility and passive stiffness of cardiac myofibril samples from 3 unrelated patients with dilated cardiomyopathy (DCM) and 2 different truncation mutations in titin (TTN; <a href="/entry/188840">188840</a>), 3 unrelated DCM patients with mutations in different contractile proteins (lys36 to gln in TNNI3 (<a href="#0012">191044.0012</a>), gly159 to asp in TNNC1 (<a href="/entry/191040#0001">191040.0001</a>)), and glu1426 to lys in MYH7 (<a href="/entry/160760">160760</a>), and controls. All 3 contractile protein mutations, but not the titin mutations, had faster relaxation kinetics than controls. Myofibril passive stiffness was reduced by about 38% in all DCM samples compared with controls, but there was no change in maximum force or titin N2BA/N2B isoform ratio, and there was no titin haploinsufficiency. The authors concluded that decreased myofibril passive stiffness, a common feature in all DCM samples, may be a causative of DCM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29093449" 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 actomyosin ATPase assays, <a href="#9" class="mim-tip-reference" title="Gomes, A. V., Liang, J., Potter, J. D. <strong>Mutations in human cardiac troponin I that are associated with restrictive cardiomyopathy affect basal ATPase activity and the calcium sensitivity of force development.</strong> J. Biol. Chem. 280: 30909-30915, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15961398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15961398</a>] [<a href="https://doi.org/10.1074/jbc.M500287200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15961398">Gomes et al. (2005)</a> showed that wildtype human cTnI inhibited ATPase activity in a concentration-dependent manner. However, cTnI with any of 5 mutations associated with restrictive cardiomyopathy (RCM1; <a href="/entry/115210">115210</a>), leu144 to gln (L144Q; <a href="#0011">191044.0011</a>), ala171 to thr (A171T; <a href="#0010">191044.0010</a>), arg192 to his (R192H; <a href="#0006">191044.0006</a>), lys178 to glu (K178E; <a href="#0007">191044.0007</a>), and arg145 to trp (R145W; <a href="#0008">191044.0008</a>), showed reduced ability to inhibit ATPase activity in the absence of Ca(2+). Mixing wildtype and mutant cTnIs in actomyosin ATPase assays in the absence of Ca(2+) revealed that L144Q, A171T, and R192H were dominant over wildtype cTnI, whereas K178E was equivalent to wildtype cTnI, and R145W was weaker than wildtype cTnI. The L144Q, R145W, and K178E mutants were unable to fully relax contraction in porcine skinned fibers in the absence of Ca(2+). The 2 mutants that showed the greatest inability to inhibit ATPase activity, L144Q and R145W, also showed the worst ability to inhibit force development in porcine fibers at basal Ca(2+) levels. All 5 mutants showed an increase in the Ca(2+) sensitivity of force development compared with wildtype cTnI. The 2 mutants associated with the worst clinical phenotype, K178E and R192H, showed large increases in Ca(2+) sensitivity. <a href="#9" class="mim-tip-reference" title="Gomes, A. V., Liang, J., Potter, J. D. <strong>Mutations in human cardiac troponin I that are associated with restrictive cardiomyopathy affect basal ATPase activity and the calcium sensitivity of force development.</strong> J. Biol. Chem. 280: 30909-30915, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15961398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15961398</a>] [<a href="https://doi.org/10.1074/jbc.M500287200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15961398">Gomes et al. (2005)</a> concluded that mutations in cTnI associated with restrictive cardiomyopathy result in increased Ca(2+) sensitivity of force development and also affect basal and maximal force and basal and maximal actomyosin ATPase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15961398" 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="#13" class="mim-tip-reference" title="Joyce, W., He, K., Zhang, M., Ogunsola, S., Wu, X., Joseph, K. T., Bogomolny, D., Yu, W., Springer, M. S., Xie, J., Signore, A. V., Campbell, K. L. <strong>Genetic excision of the regulatory cardiac troponin I extension in high-heart rate mammal clades.</strong> Science 385: 1466-1471, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39325895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39325895</a>] [<a href="https://doi.org/10.1126/science.adi8146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39325895">Joyce et al. (2024)</a> determined that the 32-amino acid N-terminal extension of cardiac Tnni3 was lost during evolution in shrew and mole lineages due to exon-3 inactivation. An exception was Pyrenean desman, as exon 3 was intact and had the potential to encode ser23 and ser24. However, despite being intact, exon 3 was not present in Tnni3 mRNA in desmans, likely because desman exon 3 evolved under purifying selection and may be alternatively spliced out and skipped. The Tnni3 N-terminal extension was also intact in bats, a family related to shrew and mole lineages with exceptionally high heart rates. However, cardiac Tnni3 exon 3 was alternatively spliced and skipped in bats. As a results, exon 3 was not translated in bats, and the variant isoform was incorporated into cardiac myofibrils, supporting possible alternative splicing of exon 3 in desmans. These results suggested that skipping exon 3 during evolution to mimic ser23 and ser24 phosphorylation in cardiac Tnni3 without adrenergic stimulation might be a mechanism to improve diastolic filling and facilitate evolution of exceptionally high resting heart rates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39325895" 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> rs104894724 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894724;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/rs104894724?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=rs104894724" 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=rs104894724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a large multigenerational Korean family with hypertrophic cardiomyopathy-7 (CMH7; <a href="/entry/613690">613690</a>), <a href="#14" class="mim-tip-reference" title="Kimura, A., Harada, H., Park, J.-E., Nishi, H., Satoh, M., Takahashi, M., Hiroi, S., Sasaoka, T., Ohbuchi, N., Nakamura, T., Koyanagi, T., Hwang, T.-H., Choo, J., Chung, K.-S., Hasegawa, A., Nagai, R., Okazaki, O., Nakamura, H., Matsuzaki, M., Sakamoto, T., Toshima, H., Koga, Y., Imaizumi, T., Sasazuki, T. <strong>Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.</strong> Nature Genet. 16: 379-382, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241277</a>] [<a href="https://doi.org/10.1038/ng0897-379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241277">Kimura et al. (1997)</a> identified a CGG-to-GGG nucleotide change in the TNNI3 gene, resulting in an arg145-to-gly (R145G) substitution at a conserved residue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9241277" 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="Lang, R., Gomes, A. V., Zhao, J., Housmans, P. R., Miller, T., Potter, J. D. <strong>Functional analysis of a troponin I (R145G) mutation associated with familial hypertrophic cardiomyopathy.</strong> J. Biol. Chem. 277: 11670-11678, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11801593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11801593</a>] [<a href="https://doi.org/10.1074/jbc.M108912200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11801593">Lang et al. (2002)</a> showed that the R145G mutation impairs force development and relaxation. These intrinsic contractile changes would likely result in diastolic dysfunction in vivo. Hypertrophy could arise as a compensatory mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11801593" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Wen, Y., Pinto, J. R., Gomes, A. V., Xu, Y., Wang, Y., Wang, Y., Potter, J. D., Kerrick, W. G. L. <strong>Functional consequences of the human cardiac troponin I hypertrophic cardiomyopathy mutation R145G in transgenic mice.</strong> J. Biol. Chem. 283: 20484-20494, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18430738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18430738</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18430738[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M801661200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18430738">Wen et al. (2008)</a> found that skinned papillary fibers from transgenic mice expressing human cTnI with the R145G mutation (Tg-R145G mice) developed significantly decreased maximal Ca(2+)-activated force without changes in maximal ATPase activity compared with transgenic mice expressing wildtype human cTnI (Tg-WT mice). Tg-R145G fibers showed increased Ca(2+) sensitivity in both ATPase and force development compared with Tg-WT fibers. Energy cost calculations demonstrated higher energy consumption in Tg-R145G fibers compared with Tg-WT fibers. Use of a myosin ATPase inhibitor showed that R145G impaired the ability of the cardiac troponin complex to fully inhibit cross-bridge attachment under relaxing conditions. Furthermore, electrical stimulation caused prolonged force and intracellular Ca(2+) concentration transients in intact Tg-R145G papillary muscles compared with Tg-WT papillary muscles. <a href="#26" class="mim-tip-reference" title="Wen, Y., Pinto, J. R., Gomes, A. V., Xu, Y., Wang, Y., Wang, Y., Potter, J. D., Kerrick, W. G. L. <strong>Functional consequences of the human cardiac troponin I hypertrophic cardiomyopathy mutation R145G in transgenic mice.</strong> J. Biol. Chem. 283: 20484-20494, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18430738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18430738</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18430738[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M801661200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18430738">Wen et al. (2008)</a> concluded that hypertrophic cardiomyopathy due to the R145G mutation is likely caused by compensatory changes activated by higher energy cost of cross-bridge formation, slowed rate of fiber relaxation, and the inability of cardiac fibers to completely relax in the absence of Ca(2+). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18430738" 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="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013232" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013232" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013232</a>
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<p>In a Japanese male patient with sporadic hypertrophic cardiomyopathy (CMH7; <a href="/entry/613690">613690</a>), <a href="#14" class="mim-tip-reference" title="Kimura, A., Harada, H., Park, J.-E., Nishi, H., Satoh, M., Takahashi, M., Hiroi, S., Sasaoka, T., Ohbuchi, N., Nakamura, T., Koyanagi, T., Hwang, T.-H., Choo, J., Chung, K.-S., Hasegawa, A., Nagai, R., Okazaki, O., Nakamura, H., Matsuzaki, M., Sakamoto, T., Toshima, H., Koga, Y., Imaizumi, T., Sasazuki, T. <strong>Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.</strong> Nature Genet. 16: 379-382, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241277</a>] [<a href="https://doi.org/10.1038/ng0897-379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241277">Kimura et al. (1997)</a> identified heterozygosity for an A-C transversion in exon 8 of the TNNI3 gene, resulting in a lys206-to-gln (K206Q) substitution at a highly conserved residue. The mutation was not found in the unaffected parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9241277" 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> rs77615401 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77615401;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/rs77615401?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=rs77615401" 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=rs77615401" 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=RCV000013233 OR RCV000036277 OR RCV000224174 OR RCV000229361 OR RCV000238609 OR RCV000252511 OR RCV000271700 OR RCV000277490 OR RCV000367372 OR RCV000852767 OR RCV001133540 OR RCV001135028 OR RCV002482859" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013233, RCV000036277, RCV000224174, RCV000229361, RCV000238609, RCV000252511, RCV000271700, RCV000277490, RCV000367372, RCV000852767, RCV001133540, RCV001135028, RCV002482859" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013233...</a>
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<p><a href="#21" class="mim-tip-reference" title="Niimura, H., Patton, K. K., McKenna, W. J., Soults, J., Maron, B. J., Seidman, J. G., Seidman, C. E. <strong>Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly.</strong> Circulation 105: 446-451, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11815426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11815426</a>] [<a href="https://doi.org/10.1161/hc0402.102990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11815426">Niimura et al. (2002)</a> reported an individual with late-onset hypertrophic cardiomyopathy (CMH7; <a href="/entry/613690">613690</a>) in whom they found a missense mutation in the TNNI3 gene. The individual concerned had no family history of hypertrophic cardiomyopathy. The mutation, a C-to-T transition in exon 5, replaced proline with serine at amino acid position 82 (P82S). Proline-82 is highly conserved in mammalian, avian, and amphibian troponin I molecules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11815426" 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 32-year-old African American woman with severe hypertrophic cardiomyopathy and a family history of CMH and sudden cardiac death, <a href="#8" class="mim-tip-reference" title="Frazier, A., Judge, D. P., Schulman, S. P., Johnson, N., Holmes, K. W., Murphy, A. M. <strong>Familial hypertrophic cardiomyopathy associated with cardiac beta-myosin heavy chain and troponin I mutations.</strong> Pediat. Cardiol. 29: 846-850, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18175163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18175163</a>] [<a href="https://doi.org/10.1007/s00246-007-9177-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18175163">Frazier et al. (2008)</a> identified a heterozygous P82S mutation in the TNNI3 gene and a heterozygous missense mutation in the MYH7 gene (<a href="/entry/160760#0043">160760.0043</a>). Her affected 8-year-old daughter carried only the heterozygous MYH7 mutation, whereas her as yet unaffected 13-year-old son carried only the TNNI3 P82S variant. <a href="#8" class="mim-tip-reference" title="Frazier, A., Judge, D. P., Schulman, S. P., Johnson, N., Holmes, K. W., Murphy, A. M. <strong>Familial hypertrophic cardiomyopathy associated with cardiac beta-myosin heavy chain and troponin I mutations.</strong> Pediat. Cardiol. 29: 846-850, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18175163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18175163</a>] [<a href="https://doi.org/10.1007/s00246-007-9177-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18175163">Frazier et al. (2008)</a> suggested that the P82S variant, which they found in 3% of healthy African Americans, is a disease-modifying mutation in severely affected individuals, and that carriers of the variant might be at increased risk of late-onset cardiac hypertrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18175163" 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> rs104894727 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894727;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/rs104894727?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=rs104894727" 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=rs104894727" 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=RCV000013234 OR RCV000148897 OR RCV000159246 OR RCV000461416 OR RCV000777480 OR RCV002354157 OR RCV002496340" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013234, RCV000148897, RCV000159246, RCV000461416, RCV000777480, RCV002354157, RCV002496340" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013234...</a>
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<p><a href="#21" class="mim-tip-reference" title="Niimura, H., Patton, K. K., McKenna, W. J., Soults, J., Maron, B. J., Seidman, J. G., Seidman, C. E. <strong>Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly.</strong> Circulation 105: 446-451, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11815426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11815426</a>] [<a href="https://doi.org/10.1161/hc0402.102990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11815426">Niimura et al. (2002)</a> reported an individual with late-onset hypertrophic cardiomyopathy (CMH7; <a href="/entry/613690">613690</a>) in whom a missense mutation in TNNI3 was found. The individual concerned had no family history of hypertrophic cardiomyopathy. The mutation, a G-to-A transition in exon 8, replaced aspartic acid with asparagine at amino acid position 196 (D196R). Aspartic acid-196 is highly conserved in mammalian, avian, and amphibian troponin I molecules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11815426" 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">rs104894728 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894728;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=rs104894728" 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=rs104894728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a family with both hypertrophic cardiomyopathy-7 (CMH7; <a href="/entry/613690">613690</a>) and restrictive cardiomyopathy-1 (RCM1; <a href="/entry/115210">115210</a>), <a href="#19" class="mim-tip-reference" title="Mogensen, J., Kubo, T., Duque, M., Uribe, W., Shaw, A., Murphy, R., Gimeno, J. R., Elliott, P., McKenna, W. J. <strong>Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.</strong> J. Clin. Invest. 111: 209-216, 2003. Note: Erratum: J. Clin. Invest.: 111: 925 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12531876[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531876">Mogensen et al. (2003)</a> identified an 87A-G nucleotide transition in exon 8 of the TNNI3 gene, resulting in an asp190-to-gly substitution (D190G), that segregated with the disease (maximum 2-point lod score = 4.8). (<a href="#19" class="mim-tip-reference" title="Mogensen, J., Kubo, T., Duque, M., Uribe, W., Shaw, A., Murphy, R., Gimeno, J. R., Elliott, P., McKenna, W. J. <strong>Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.</strong> J. Clin. Invest. 111: 209-216, 2003. Note: Erratum: J. Clin. Invest.: 111: 925 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12531876[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531876">Mogensen et al. (2003)</a> originally referred to the mutation as asp190 to his, which they later corrected in an erratum.) The mutation was not found in 200 chromosomes from Caucasian control individuals. There were a significant number of premature sudden deaths in the family, suggesting that the R190G substitution is associated with an adverse phenotype. Asp190 is found in the conserved C-terminal region, which is required for normal inhibitory function of troponin I (<a href="#22" class="mim-tip-reference" title="Perry, S. V. <strong>Troponin I: inhibitor or facilitator.</strong> Molec. Cell Biochem. 190: 9-32, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10098965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10098965</a>]" pmid="10098965">Perry, 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10098965+12531876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an individual with restrictive cardiomyopathy (RCM1; <a href="/entry/115210">115210</a>), <a href="#19" class="mim-tip-reference" title="Mogensen, J., Kubo, T., Duque, M., Uribe, W., Shaw, A., Murphy, R., Gimeno, J. R., Elliott, P., McKenna, W. J. <strong>Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.</strong> J. Clin. Invest. 111: 209-216, 2003. Note: Erratum: J. Clin. Invest.: 111: 925 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12531876[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531876">Mogensen et al. (2003)</a> identified a de novo 93G-A transition in exon 8 of the TNNI3 gene, resulting in an arg192-to-his (R92H) substitution. (<a href="#19" class="mim-tip-reference" title="Mogensen, J., Kubo, T., Duque, M., Uribe, W., Shaw, A., Murphy, R., Gimeno, J. R., Elliott, P., McKenna, W. J. <strong>Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.</strong> J. Clin. Invest. 111: 209-216, 2003. Note: Erratum: J. Clin. Invest.: 111: 925 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12531876[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531876">Mogensen et al. (2003)</a> originally referred to the transition as 92C-A, which they later corrected in an erratum.) Arg192 is found in the conserved C-terminal region, which is required for normal inhibitory function of troponin (<a href="#22" class="mim-tip-reference" title="Perry, S. V. <strong>Troponin I: inhibitor or facilitator.</strong> Molec. Cell Biochem. 190: 9-32, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10098965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10098965</a>]" pmid="10098965">Perry, 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10098965+12531876" 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 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 1</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">rs104894730 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894730;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=rs104894730" 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=rs104894730" 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=RCV000013238 OR RCV001331172" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013238, RCV001331172" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013238...</a>
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<p>In a young individual with idiopathic restrictive cardiomyopathy (RCM1;<a href="/entry/115210">115210</a>), <a href="#19" class="mim-tip-reference" title="Mogensen, J., Kubo, T., Duque, M., Uribe, W., Shaw, A., Murphy, R., Gimeno, J. R., Elliott, P., McKenna, W. J. <strong>Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.</strong> J. Clin. Invest. 111: 209-216, 2003. Note: Erratum: J. Clin. Invest.: 111: 925 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12531876[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531876">Mogensen et al. (2003)</a> identified a de novo 886A-G transition in exon 7 of the TNNI3 gene, resulting in a lys178-to-glu (K178E) substitution. Amino acids 173-181 bind to actin and increase the inhibitory effect of troponin I (<a href="#22" class="mim-tip-reference" title="Perry, S. V. <strong>Troponin I: inhibitor or facilitator.</strong> Molec. Cell Biochem. 190: 9-32, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10098965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10098965</a>]" pmid="10098965">Perry, 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10098965+12531876" 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 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894724 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894724;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/rs104894724?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=rs104894724" 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=rs104894724" 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=RCV000013239 OR RCV000159222 OR RCV000498333 OR RCV001170617 OR RCV001254730 OR RCV001787387 OR RCV004549357 OR RCV004795401" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013239, RCV000159222, RCV000498333, RCV001170617, RCV001254730, RCV001787387, RCV004549357, RCV004795401" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013239...</a>
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<p>In 2 unrelated individuals with typical features of restrictive cardiomyopathy (RCM1; <a href="/entry/115210">115210</a>) diagnosed in their late fifties, <a href="#19" class="mim-tip-reference" title="Mogensen, J., Kubo, T., Duque, M., Uribe, W., Shaw, A., Murphy, R., Gimeno, J. R., Elliott, P., McKenna, W. J. <strong>Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.</strong> J. Clin. Invest. 111: 209-216, 2003. Note: Erratum: J. Clin. Invest.: 111: 925 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12531876[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531876">Mogensen et al. (2003)</a> identified a 799C-T transition in the TNNI3 gene, resulting in an arg145-to-trp (R145W) substitution. The sequence required for inhibition of human cardiac troponin I actomyosin ATPase activity consists of 21 amino acid residues (137-148) (<a href="#22" class="mim-tip-reference" title="Perry, S. V. <strong>Troponin I: inhibitor or facilitator.</strong> Molec. Cell Biochem. 190: 9-32, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10098965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10098965</a>]" pmid="10098965">Perry, 1999</a>). Haplotype analysis with respect to the TNNI3 locus on chromosome 19 did not suggest a common founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10098965+12531876" 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 CARDIOMYOPATHY, DILATED, 2A (1 family)</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397516359 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397516359;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/rs397516359?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=rs397516359" 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=rs397516359" 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=RCV000013240 OR RCV000036309 OR RCV000769534 OR RCV001753445 OR RCV002513379 OR RCV004760353 OR RCV004991983" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013240, RCV000036309, RCV000769534, RCV001753445, RCV002513379, RCV004760353, RCV004991983" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013240...</a>
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<p>In a brother and sister from a family with dilated cardiomyopathy (CMD2A; <a href="/entry/611880">611880</a>), <a href="#20" class="mim-tip-reference" title="Murphy, R. T., Mogensen, J., Shaw, A., Kubo, T., Hughes, S., McKenna, W. J. <strong>Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. (Letter)</strong> Lancet 363: 371-372, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15070570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15070570</a>] [<a href="https://doi.org/10.1016/S0140-6736(04)15468-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15070570">Murphy et al. (2004)</a> identified homozygosity for a 4C-T transition in exon 1 of the TNNI3 gene, resulting in an ala2-to-val (A2V) substitution. The unaffected parents and an unaffected sister were heterozygous for the mutation. The parents were unaware of any familial relationship, but analysis of microsatellite markers around the TNNI3 locus showed that they shared the same haplotype of the mutated allele, indicating remote consanguinity. Functional studies showed significant impairment of mutant TNNI3 and wildtype TNNT2 protein interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15070570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Carballo, S., Robinson, P., Otway, R., Fatkin, D., Jongbloed, J. D. H., de Jonge, N., Blair, E., van tintelen, J. P., Redwood, C., Watkins, H. <strong>Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.</strong> Circ. Res. 105: 375-382, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19590045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19590045</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.109.196055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19590045">Carballo et al. (2009)</a> stated that in their analysis of the effect of the A2V mutation on ATPase regulation, troponin function was not significantly altered. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19590045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 1</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">rs121917760 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917760;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=rs121917760" 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=rs121917760" 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=RCV000013241" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013241" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013241</a>
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<p>In a woman with restrictive cardiomyopathy (RCM1; <a href="/entry/115210">115210</a>), <a href="#19" class="mim-tip-reference" title="Mogensen, J., Kubo, T., Duque, M., Uribe, W., Shaw, A., Murphy, R., Gimeno, J. R., Elliott, P., McKenna, W. J. <strong>Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.</strong> J. Clin. Invest. 111: 209-216, 2003. Note: Erratum: J. Clin. Invest.: 111: 925 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12531876[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531876">Mogensen et al. (2003)</a> identified a T-to-A transversion at nucleotide 797 in exon 7 of the TNNI3 gene, resulting in a leu144-to-gln (L144Q) substitution. The patient developed symptoms of heart failure at the age of 17 years, and she died of heart failure at the age of 31 years awaiting cardiac transplantation. Several members of her family had died suddenly, but were not available for investigation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12531876" 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">rs121917761 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917761;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=rs121917761" 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=rs121917761" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a man with restrictive cardiomyopathy (RCM1; <a href="/entry/115210">115210</a>), <a href="#19" class="mim-tip-reference" title="Mogensen, J., Kubo, T., Duque, M., Uribe, W., Shaw, A., Murphy, R., Gimeno, J. R., Elliott, P., McKenna, W. J. <strong>Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.</strong> J. Clin. Invest. 111: 209-216, 2003. Note: Erratum: J. Clin. Invest.: 111: 925 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531876</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12531876[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI16336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531876">Mogensen et al. (2003)</a> identified a G-to-A transition at nucleotide 856 in exon 7 of the TNNI3 gene, resulting in an ala171-to-thr (A171T) substitution. The patient was diagnosed in his late fifties following an embolic stroke. He was an only child, and no clinical data or DNA was available on his deceased parents. Subsequent mutation analysis of his children did not reveal further carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12531876" 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">rs267607130 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607130;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=rs267607130" 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=rs267607130" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a father and 2 sons with dilated cardiomyopathy (CMD1FF; <a href="/entry/613286">613286</a>), <a href="#6" class="mim-tip-reference" title="Carballo, S., Robinson, P., Otway, R., Fatkin, D., Jongbloed, J. D. H., de Jonge, N., Blair, E., van tintelen, J. P., Redwood, C., Watkins, H. <strong>Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.</strong> Circ. Res. 105: 375-382, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19590045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19590045</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.109.196055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19590045">Carballo et al. (2009)</a> identified heterozygosity for a 106A-C transversion in exon 3 of the TNNI3 gene, resulting in a lys36-to-gln (K36Q) substitution at a highly conserved residue. Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase by troponin showed that troponin reconstituted with K36Q had lower maximum ATPase rates and reduced Ca(2+) sensitivity compared to wildtype; in addition, mutant thin filaments had lower Ca(2+) affinity than normal. The father and 1 son had rapidly progressive disease, requiring cardiac transplantation soon after diagnosis at ages 15 years and 6 years, respectively; screening of the other mutation-positive son revealed mild CMD with mildly reduced systolic contractility. The mutation was not found in 280 chromosomes from ethnically matched controls or in the patient's asymptomatic mother and 3 brothers; ECG and echocardiography in the mother and 1 brother confirmed normal cardiac function. Haplotype analysis indicated that the proband inherited the mutation from his father, who died in a traffic accident at age 50 years with no known cardiac disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19590045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Vikhorev, P. G., Smoktunowicz, N., Munster, A. B., Copeland, O., Kostin, S., Montgiraud, C., Messer, A. E., Toliat, M. R., Li, A., Dos Remedios, C. G., Lal, S., Blair, C. A., Campbell, K. S., Guglin, M., Richter, M., Knoll, R., Marston, S. B. <strong>Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes.</strong> Sci. Rep. 7: 14829, 2017. Note: Erratum: Sci. Rep. 8: 14485, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29093449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29093449</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29093449[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41598-017-13675-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29093449">Vikhorev et al. (2017)</a> compared contractility and passive stiffness of cardiac myofibril samples from 3 unrelated patients with dilated cardiomyopathy (DCM) and 2 different truncation mutations in titin (TTN; <a href="/entry/188840">188840</a>), 3 unrelated DCM patients with mutations in different contractile proteins, including K36Q in TNNI3, and controls. All 3 contractile protein mutations, but not the titin mutations, had faster relaxation kinetics than controls. Myofibril passive stiffness was reduced by about 38% in all DCM samples compared with controls, but there was no change in maximum force or titin N2BA/N2B isoform ratio, and there was no titin haploinsufficiency. The authors concluded that decreased myofibril passive stiffness, a common feature in all DCM samples, may be a causative of DCM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29093449" 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">rs267607129 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607129;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=rs267607129" 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=rs267607129" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a man who was diagnosed at age 24 years with severe dilated cardiomyopathy (CMD1FF; <a href="/entry/613286">613286</a>), requiring implantation of a left ventricular assist device within 2 months and undergoing cardiac transplantation 13 months later, <a href="#6" class="mim-tip-reference" title="Carballo, S., Robinson, P., Otway, R., Fatkin, D., Jongbloed, J. D. H., de Jonge, N., Blair, E., van tintelen, J. P., Redwood, C., Watkins, H. <strong>Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.</strong> Circ. Res. 105: 375-382, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19590045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19590045</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.109.196055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19590045">Carballo et al. (2009)</a> identified heterozygosity for a 555C-G transversion in exon 7 of the TNNI3 gene, resulting in an asn185-to-lys (N185K) substitution at a highly conserved residue. Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase by troponin showed that troponin reconstituted with N185K had lower maximum ATPase rates and reduced Ca(2+) sensitivity compared to wildtype; in addition, mutant thin filaments had lower Ca(2+) affinity than normal. The mutation was not found in 280 chromosomes from ethnically matched controls or in the patient's asymptomatic mother and brother, who had normal ECGs and echocardiograms. However, it was detected in a stored DNA sample from his father, who was diagnosed with CMD at 50 years of age and died 4 years later from complications related to cardiac resynchronization therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19590045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7</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">rs267607127 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607127;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=rs267607127" 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=rs267607127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Japanese mother and her son and daughter with hypertrophic cardiomyopathy (CMH7; <a href="/entry/613690">613690</a>), <a href="#14" class="mim-tip-reference" title="Kimura, A., Harada, H., Park, J.-E., Nishi, H., Satoh, M., Takahashi, M., Hiroi, S., Sasaoka, T., Ohbuchi, N., Nakamura, T., Koyanagi, T., Hwang, T.-H., Choo, J., Chung, K.-S., Hasegawa, A., Nagai, R., Okazaki, O., Nakamura, H., Matsuzaki, M., Sakamoto, T., Toshima, H., Koga, Y., Imaizumi, T., Sasazuki, T. <strong>Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.</strong> Nature Genet. 16: 379-382, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241277</a>] [<a href="https://doi.org/10.1038/ng0897-379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241277">Kimura et al. (1997)</a> identified heterozygosity for a G-A transition in exon 8 of the TNNI3 gene, resulting in a gly203-to-ser (G203S) substitution at a highly conserved residue. The affected individuals in this family had cardiac hypertrophy only at the apex (apical CMH), and all 3 also exhibited Wolff-Parkinson-White ventricular preexcitation (WPW; <a href="/entry/194200">194200</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9241277" 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>.0015 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7</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">rs2147283135 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147283135;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=rs2147283135" 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=rs2147283135" 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=RCV000013246" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013246" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013246</a>
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<p>In a Japanese father and son with hypertrophic cardiomyopathy (CMH7; <a href="/entry/613690">613690</a>), <a href="#14" class="mim-tip-reference" title="Kimura, A., Harada, H., Park, J.-E., Nishi, H., Satoh, M., Takahashi, M., Hiroi, S., Sasaoka, T., Ohbuchi, N., Nakamura, T., Koyanagi, T., Hwang, T.-H., Choo, J., Chung, K.-S., Hasegawa, A., Nagai, R., Okazaki, O., Nakamura, H., Matsuzaki, M., Sakamoto, T., Toshima, H., Koga, Y., Imaizumi, T., Sasazuki, T. <strong>Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.</strong> Nature Genet. 16: 379-382, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241277</a>] [<a href="https://doi.org/10.1038/ng0897-379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241277">Kimura et al. (1997)</a> identified heterozygosity for a 3-bp deletion (delAAG) in exon 7 of the TNNI3 gene, resulting in deletion of a lys residue at codon 183 (L183). The father had cardiac hypertrophy only at the apex (apical CMH), whereas the son had ventricular hypertrophy typical of CMH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9241277" 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>.0016 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7</strong>
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TNNI3, ARG21CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607128 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607128;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=rs267607128" 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=rs267607128" 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=RCV000013247 OR RCV001851817 OR RCV002354158" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013247, RCV001851817, RCV002354158" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013247...</a>
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<p>In a proband who was found to have apical hypertrophy (CMH7; <a href="/entry/613690">613690</a>) after presenting with atrial fibrillation, <a href="#1" class="mim-tip-reference" title="Arad, M., Penas-Lado, M., Monserrat, L., Maron, B. J., Sherrid, M., Ho, C. Y., Barr, S., Karim, A., Olson, T. M., Kamisago, M., Seidman, J. G., Seidman, C. E. <strong>Gene mutations in apical hypertrophic cardiomyopathy.</strong> Circulation 112: 2805-2811, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16267253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16267253</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.105.547448" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16267253">Arad et al. (2005)</a> identified a heterozygous arg21-to-cys (R21C) mutation in the TNNI3 gene. The proband's father, 3 sibs, and her 18-year-old daughter all had sudden cardiac death. Clinical evaluation of 3 other mutation carriers in the family revealed that 1 had asymmetric septal hypertrophy, another had isolated left atrial enlargement, and the third had normal cardiac dimensions despite an abnormal electrocardiogram. <a href="#1" class="mim-tip-reference" title="Arad, M., Penas-Lado, M., Monserrat, L., Maron, B. J., Sherrid, M., Ho, C. Y., Barr, S., Karim, A., Olson, T. M., Kamisago, M., Seidman, J. G., Seidman, C. E. <strong>Gene mutations in apical hypertrophic cardiomyopathy.</strong> Circulation 112: 2805-2811, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16267253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16267253</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.105.547448" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16267253">Arad et al. (2005)</a> stated that they also identified the R21C mutation in another CMH family, in which 4 patients had subaortic asymmetric hypertrophy and 1 mutation carrier with normal cardiac dimensions was resuscitated from sudden cardiac death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16267253" 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="Arad2005" class="mim-anchor"></a>
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Arad, M., Penas-Lado, M., Monserrat, L., Maron, B. J., Sherrid, M., Ho, C. Y., Barr, S., Karim, A., Olson, T. M., Kamisago, M., Seidman, J. G., Seidman, C. E.
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<strong>Gene mutations in apical hypertrophic cardiomyopathy.</strong>
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Circulation 112: 2805-2811, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16267253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16267253</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16267253" 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/CIRCULATIONAHA.105.547448" target="_blank">Full Text</a>]
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Barton, P. J. R., Cullen, M. E., Townsend, P. J., Brand, N. J., Mullen, A. J., Norman, D. A. M., Bhavsar, P. K., Yacoub, M. H.
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<strong>Close physical linkage of human troponin genes: organization, sequence, and expression of the locus encoding cardiac troponin I and slow skeletal troponin T.</strong>
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Genomics 57: 102-109, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10191089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10191089</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10191089" 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/10.1006/geno.1998.5702" target="_blank">Full Text</a>]
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<a id="Bermingham1995" class="mim-anchor"></a>
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Bermingham, N., Hernandez, D., Balfour, A., Gilmour, F., Martin, J. E., Fisher, E. M. C.
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<strong>Mapping TNNC1, the gene that encodes cardiac troponin I in the human and mouse.</strong>
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Genomics 30: 620-622, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8825654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8825654</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8825654" 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/10.1006/geno.1995.1288" target="_blank">Full Text</a>]
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Bhavsar, P. K., Brand, N. J., Yacoub, M. H., Barton, P. J. R.
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<strong>Isolation and characterization of the human cardiac troponin I gene (TNNI3).</strong>
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Genomics 35: 11-23, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661099</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661099" 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/10.1006/geno.1996.0317" target="_blank">Full Text</a>]
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Canaider, S., Facchin, F., Griffoni, C., Casadei, R., Vitale, L., Lenzi, L., Frabetti, F., D'Addabbo, P., Carinci, P., Zannotti, M., Strippoli, P.
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<strong>Proteins encoded by human Down syndrome critical region gene 1-like 2 (DSCR1L2) mRNA and by a novel DSCR1L2 mRNA isoform interact with cardiac troponin I (TNNI3).</strong>
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Gene 372: 128-136, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16516408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16516408</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16516408" 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.gene.2005.12.029" target="_blank">Full Text</a>]
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Carballo, S., Robinson, P., Otway, R., Fatkin, D., Jongbloed, J. D. H., de Jonge, N., Blair, E., van tintelen, J. P., Redwood, C., Watkins, H.
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<strong>Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.</strong>
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Circ. Res. 105: 375-382, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19590045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19590045</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19590045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Chien, K. R.
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<strong>Genotype, phenotype: upstairs, downstairs in the family of cardiomyopathies.</strong>
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J. Clin. Invest. 111: 175-178, 2003. Note: Erratum: J. Clin. Invest. 11: 1433 only, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531871</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12531871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Frazier, A., Judge, D. P., Schulman, S. P., Johnson, N., Holmes, K. W., Murphy, A. M.
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<strong>Familial hypertrophic cardiomyopathy associated with cardiac beta-myosin heavy chain and troponin I mutations.</strong>
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Pediat. Cardiol. 29: 846-850, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18175163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18175163</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18175163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Gomes, A. V., Liang, J., Potter, J. D.
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<strong>Mutations in human cardiac troponin I that are associated with restrictive cardiomyopathy affect basal ATPase activity and the calcium sensitivity of force development.</strong>
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J. Biol. Chem. 280: 30909-30915, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15961398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15961398</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15961398" 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.M500287200" target="_blank">Full Text</a>]
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Guenet, J.-L., Simon-Chazottes, D., Gravel, M., Hastings, K. E. M., Schiaffino, S.
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<strong>Cardiac and skeletal muscle troponin I isoforms are encoded by a dispersed gene family on mouse chromosomes 1 and 7.</strong>
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Mammalian Genome 7: 13-15, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8903721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8903721</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8903721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s003359900004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.CIR.0000084543.79097.34" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.adi8146" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0897-379" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/jama.284.4.457" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M108912200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00204938" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000134740" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(04)15468-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/hc0402.102990" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41598-017-13675-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M801661200" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Bao Lige - updated : 11/21/2024
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Bao Lige - updated : 03/21/2024<br>Marla J. F. O'Neill - updated : 8/5/2010<br>Marla J. F. O'Neill - updated : 6/7/2010<br>Marla J. F. O'Neill - updated : 3/25/2010<br>Matthew B. Gross - updated : 1/30/2009<br>Patricia A. Hartz - updated : 1/30/2009<br>Marla J. F. O'Neill - updated : 11/19/2008<br>Marla J. F. O'Neill - updated : 3/6/2008<br>Marla J. F. O'Neill - updated : 2/7/2005<br>Marla J. F. O'Neill - updated : 10/22/2004<br>Ada Hamosh - updated : 7/7/2003<br>Victor A. McKusick - updated : 5/21/2003<br>Denise L. M. Goh - updated : 5/21/2003<br>Victor A. McKusick - updated : 5/21/2003<br>Denise L. M. Goh - updated : 4/18/2003<br>Victor A. McKusick - updated : 5/13/2002<br>Paul Brennan - updated : 3/11/2002<br>Ada Hamosh - updated : 9/13/2000<br>Victor A. McKusick - updated : 5/28/1998<br>Victor A. McKusick - updated : 8/1/1997<br>Mark H. Paalman - edited : 1/23/1997<br>Alan F. Scott - updated : 9/16/1996
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<a id="creationDate" class="mim-anchor"></a>
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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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<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 : 7/5/1990
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </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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mgross : 11/21/2024
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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 : 04/12/2024<br>mgross : 03/21/2024<br>carol : 05/04/2022<br>carol : 08/17/2018<br>carol : 06/27/2018<br>carol : 09/06/2016<br>carol : 01/11/2016<br>carol : 4/30/2015<br>terry : 6/6/2012<br>alopez : 1/14/2011<br>joanna : 1/13/2011<br>wwang : 8/9/2010<br>terry : 8/5/2010<br>carol : 7/13/2010<br>carol : 6/7/2010<br>carol : 3/25/2010<br>carol : 3/25/2010<br>carol : 3/24/2010<br>carol : 3/24/2010<br>wwang : 2/26/2010<br>terry : 6/3/2009<br>mgross : 1/30/2009<br>mgross : 1/30/2009<br>mgross : 1/30/2009<br>carol : 11/19/2008<br>terry : 11/19/2008<br>carol : 3/6/2008<br>tkritzer : 2/8/2005<br>terry : 2/7/2005<br>terry : 2/7/2005<br>tkritzer : 10/25/2004<br>terry : 10/22/2004<br>alopez : 3/17/2004<br>joanna : 9/30/2003<br>alopez : 7/9/2003<br>terry : 7/7/2003<br>carol : 5/21/2003<br>carol : 5/21/2003<br>tkritzer : 5/21/2003<br>terry : 4/18/2003<br>alopez : 5/21/2002<br>terry : 5/13/2002<br>alopez : 3/11/2002<br>alopez : 10/3/2000<br>terry : 9/13/2000<br>carol : 5/30/1998<br>terry : 5/28/1998<br>terry : 12/2/1997<br>mark : 8/7/1997<br>mark : 8/7/1997<br>terry : 8/1/1997<br>mark : 1/23/1997<br>terry : 1/17/1997<br>mark : 9/16/1996<br>mark : 9/16/1996<br>mark : 9/16/1996<br>mark : 2/13/1996<br>terry : 2/7/1996<br>supermim : 3/16/1992<br>carol : 1/3/1992<br>carol : 7/5/1990
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<span class="mim-font">
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<strong>*</strong> 191044
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<h3>
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<span class="mim-font">
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TROPONIN I, CARDIAC; TNNI3
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</h3>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</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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TROPONIN I, CARDIAC MUSCLE ISOFORM
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TNNI3</em></strong>
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</span>
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</p>
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<p>
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<strong>
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<em>
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Cytogenetic location: 19q13.42
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:55,151,767-55,157,732 </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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<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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<th>
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Location
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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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<tbody>
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<span class="mim-font">
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19q13.42
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<td>
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<span class="mim-font">
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?Cardiomyopathy, dilated, 2A
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</td>
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<td>
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<span class="mim-font">
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611880
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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<tr>
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<td>
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<span class="mim-font">
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Cardiomyopathy, dilated, 1FF
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</td>
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<td>
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<span class="mim-font">
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613286
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Cardiomyopathy, familial restrictive, 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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115210
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Cardiomyopathy, hypertrophic, 7
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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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613690
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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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<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>Troponin I (TnI) is one of 3 subunits that form the troponin complex of the thin filaments of striated muscle; see also TNNI1 (191042). The others are troponin T (TnT; see 191041) and troponin C (TnC; see 191040).</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>Vallins et al. (1990) cloned a full-length cDNA for the human cardiac muscle troponin I. The deduced protein contains 210 amino acids. Northern blot analysis detected TNNI3 expression in 20-week fetal heart, 28-week fetal heart, 9-month postnatal heart, and adult ventricular muscle, but not in adult skeletal muscle. </p><p>Joyce et al. (2024) noted that cardiac troponin, TNNI3, is distinguished from its skeletal muscle paralogs, TNNI1 (191042) and TNNI2 (191043), by the presence of a regulatory 32-amino acid N-terminal extension that harbors 2 phosphorylatable serines, ser23 and ser24. Phosphorylation of ser23 and ser24 defends diastolic filling by means of an increased cardiomyocyte relaxation rate. </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>Bhavsar et al. (1996) showed that the TNNI3 gene contains 8 exons and spans 6.2 kb of genomic DNA. The authors showed that a 2,300-bp block of 5-prime sequence has promoter activity in both cardiac myocytes and skeletal muscle cells but was inactive in fibroblasts, suggesting that this 5-prime region is necessary but not sufficient for cardiac tissue specificity. </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>MacGeoch et al. (1991), who referred to the gene by the symbol TNNC1, mapped the cardiac troponin I gene to chromosome 19p13.2-q13.2 by analysis of somatic cell hybrids containing various segments of chromosome 19. Bermingham et al. (1995) mapped the TNNI3 gene to chromosome 19q13.3-q13.4 using a series of somatic cell hybrid DNAs. Mogensen et al. (1997) mapped the TNNI3 gene to chromosome 19q13.4 by radiation hybrid mapping. </p><p>Barton et al. (1999) determined that the TNNI3 gene and the slow skeletal muscle troponin gene (TNNT1; 191041) are oriented head to tail, with the TNNI3 gene 2.6 kb upstream of exon 1 of the TNNT1 gene. </p><p>By interspecific backcross analysis, Bermingham et al. (1995) assigned the mouse homolog (Tnni3) to a site close to the centromere of chromosome 7. Guenet et al. (1996) demonstrated that the Tnni3 gene is located on mouse chromosome 7 in a region of homology to 19q. </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>Bhavsar et al. (1996) noted that the troponin complex serves as a calcium-sensitive switch that regulates striated muscle contraction. Troponin I binds actin and inhibits actomyosin ATPase activity in the absence of calcium. Cardiac muscle troponin I is expressed only in the heart. </p><p>Labarrere et al. (2000) found that persistent elevation of cardiac troponin I levels after heart transplantation were associated with high risk for developing coronary artery disease and graft failure after cardiac transplantation. </p><p>Horwich et al. (2003) assayed cardiac troponin I (cTnI) in 238 patients with advanced heart failure but no acute coronary syndrome or myocarditis who were referred for cardiac transplantation. Patients with detectable cTnI levels had significantly higher B-type natriuretic peptide (BNP; 600295) levels (p less than 0.001) and more impaired hemodynamic profiles, including higher pulmonary wedge pressures (p = 0.002) and lower cardiac indexes (p less than 0.0001). A significant correlation was found between detectable cTnI and progressive decline in ejection fraction over time (p less than 0.01), and detectable cTnI was associated with increased mortality risk (relative risk, 2.05; 95% CI, 1.22-3.43) and remained a significant predictor of death even after adjustment for other factors associated with adverse prognosis. Used in conjunction with BNP, cTnI further improved prognostic value. Horwich et al. (2003) concluded that cTnI may be a useful tool in identifying patients with heart failure who are at increased risk for progressive ventricular dysfunction and death. </p><p>Using yeast 2-hybrid analysis and protein pull-down assays, Canaider et al. (2006) showed that DSCR1L2 (RCAN3; 605860) and a DSCR1L2 isoform, DSCR1L2-E2E5, bound TNNI3 via an N-terminal domain. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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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Takeda et al. (2003) presented the crystal structure of the core domains (relative molecular mass of 46,000 and 52,000) of human cardiac troponin in the calcium-saturated form. Analysis of the 4-molecule structures revealed that the core domain is further divided into structurally distinct subdomains that are connected by flexible linkers, making the entire molecule highly flexible. The alpha-helical coiled-coil formed between TnT and TnI is integrated in a rigid and asymmetric structure about 80 angstroms long, the IT arm, which bridges putative tropomyosin (see 191010)-anchoring regions. The structures of the troponin ternary complex imply that calcium binding to the regulatory site of TnC removes the carboxy-terminal portion of TnI from actin, thereby altering the mobility and/or flexibility of troponin and tropomyosin on the actin filament. </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>Reviews</em></strong></p><p>
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Chien (2003) reviewed the molecular defects linked to human cardiomyopathies. </p><p>Huang and Du (2004) reviewed the role of TNNI3 in cardiac function, the diastolic dysfunction that results from TNNI3 deficiency, and TNNI3 mutation in restrictive cardiomyopathy. </p><p><strong><em>Hypertrophic Cardiomyopathy 7</em></strong></p><p>
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Kimura et al. (1997) analyzed the TNNI3 gene in 184 unrelated patients with hypertrophic cardiomyopathy (CMH7; 613690) and identified 6 heterozygous mutations in 6 probands, respectively (see, e.g., 191044.0001 and 191044.0002). Although apical HCM had been associated particularly with CMH4 (115197), Kimura et al. (1997) found that 3 of 36 (8.3%) patients with apical HCM had mutations in the TNNI3 gene. In addition, all 3 individuals with G203S mutation in the TNNI3 gene (191044.0014) exhibited Wolff-Parkinson-White ventricular preexcitation (WPW; 194200); Kimura et al. (1997) noted that although a locus for 'CMH with WPW' had been mapped to chromosome 7q3 (CMH6; 600858), their findings indicated that more than 1 form of CMH is associated with WPW syndrome. </p><p><strong><em>Restrictive Cardiomyopathy 1</em></strong></p><p>
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Mogensen et al. (2003) studied a family segregating both hypertrophic cardiomyopathy and restrictive cardiomyopathy (RCM1; 115210). Linkage analysis of recognized CMH genes identified TNNI3 as the likely disease gene. Mutation analysis of TNNI3 by direct sequencing identified an asp190-to-gly substitution (D190G; 191044.0005), which was incorrectly reported as an asp190-to-his substitution, that segregated with the disease in the family (maximum 2-point lod score = 4.8). Analysis of TNNI3 was performed in an additional 9 unrelated patients with idiopathic RCM, 6 of whom were shown to carry TNNI3 mutations (e.g., 191044.0006-191044.0008). </p><p><strong><em>Dilated Cardiomyopathy 2A</em></strong></p><p>
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Using a candidate gene approach, Murphy et al. (2004) analyzed the TNNI3 gene in 235 consecutive patients with dilated cardiomyopathy (CMD; see CMD2A, 611880) and identified homozygosity for a missense mutation (A2V; 191044.0009) in a man who had undergone cardiac transplantation at 28 years of age. His affected sister was also homozygous for the mutation; the unaffected parents and an unaffected sister were heterozygotes. Functional studies of the A2V mutant cTnI showed impairment of troponin interactions. </p><p><strong><em>Dilated Cardiomyopathy 1FF</em></strong></p><p>
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Carballo et al. (2009) analyzed the TNNI3 gene in 96 probands with dilated cardiomyopathy in whom screening for mutations in 6 more commonly implicated CMD genes was negative and identified heterozygosity for respective missense mutations (191044.0012-191044.0013) in the TNNI3 gene in 2 probands with severe, early-onset CMD (CMD1FF; 613286). Functional analysis revealed that troponin reconstituted with either mutant had lower maximum ATPase rates and reduced Ca(2+) sensitivity compared to wildtype; in addition, mutant thin filaments had lower Ca(2+) affinity than normal. </p><p>Vikhorev et al. (2017) compared contractility and passive stiffness of cardiac myofibril samples from 3 unrelated patients with dilated cardiomyopathy (DCM) and 2 different truncation mutations in titin (TTN; 188840), 3 unrelated DCM patients with mutations in different contractile proteins (lys36 to gln in TNNI3 (191044.0012), gly159 to asp in TNNC1 (191040.0001)), and glu1426 to lys in MYH7 (160760), and controls. All 3 contractile protein mutations, but not the titin mutations, had faster relaxation kinetics than controls. Myofibril passive stiffness was reduced by about 38% in all DCM samples compared with controls, but there was no change in maximum force or titin N2BA/N2B isoform ratio, and there was no titin haploinsufficiency. The authors concluded that decreased myofibril passive stiffness, a common feature in all DCM samples, may be a causative of DCM. </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 actomyosin ATPase assays, Gomes et al. (2005) showed that wildtype human cTnI inhibited ATPase activity in a concentration-dependent manner. However, cTnI with any of 5 mutations associated with restrictive cardiomyopathy (RCM1; 115210), leu144 to gln (L144Q; 191044.0011), ala171 to thr (A171T; 191044.0010), arg192 to his (R192H; 191044.0006), lys178 to glu (K178E; 191044.0007), and arg145 to trp (R145W; 191044.0008), showed reduced ability to inhibit ATPase activity in the absence of Ca(2+). Mixing wildtype and mutant cTnIs in actomyosin ATPase assays in the absence of Ca(2+) revealed that L144Q, A171T, and R192H were dominant over wildtype cTnI, whereas K178E was equivalent to wildtype cTnI, and R145W was weaker than wildtype cTnI. The L144Q, R145W, and K178E mutants were unable to fully relax contraction in porcine skinned fibers in the absence of Ca(2+). The 2 mutants that showed the greatest inability to inhibit ATPase activity, L144Q and R145W, also showed the worst ability to inhibit force development in porcine fibers at basal Ca(2+) levels. All 5 mutants showed an increase in the Ca(2+) sensitivity of force development compared with wildtype cTnI. The 2 mutants associated with the worst clinical phenotype, K178E and R192H, showed large increases in Ca(2+) sensitivity. Gomes et al. (2005) concluded that mutations in cTnI associated with restrictive cardiomyopathy result in increased Ca(2+) sensitivity of force development and also affect basal and maximal force and basal and maximal actomyosin ATPase activity. </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>Evolution</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>Joyce et al. (2024) determined that the 32-amino acid N-terminal extension of cardiac Tnni3 was lost during evolution in shrew and mole lineages due to exon-3 inactivation. An exception was Pyrenean desman, as exon 3 was intact and had the potential to encode ser23 and ser24. However, despite being intact, exon 3 was not present in Tnni3 mRNA in desmans, likely because desman exon 3 evolved under purifying selection and may be alternatively spliced out and skipped. The Tnni3 N-terminal extension was also intact in bats, a family related to shrew and mole lineages with exceptionally high heart rates. However, cardiac Tnni3 exon 3 was alternatively spliced and skipped in bats. As a results, exon 3 was not translated in bats, and the variant isoform was incorporated into cardiac myofibrils, supporting possible alternative splicing of exon 3 in desmans. These results suggested that skipping exon 3 during evolution to mimic ser23 and ser24 phosphorylation in cardiac Tnni3 without adrenergic stimulation might be a mechanism to improve diastolic filling and facilitate evolution of exceptionally high resting heart rates. </p>
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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>16 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, 7</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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TNNI3, ARG145GLY
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<br />
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SNP: rs104894724,
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gnomAD: rs104894724,
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ClinVar: RCV000013231, RCV000251781, RCV000441050, RCV000557688, RCV001798003
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a large multigenerational Korean family with hypertrophic cardiomyopathy-7 (CMH7; 613690), Kimura et al. (1997) identified a CGG-to-GGG nucleotide change in the TNNI3 gene, resulting in an arg145-to-gly (R145G) substitution at a conserved residue. </p><p>Lang et al. (2002) showed that the R145G mutation impairs force development and relaxation. These intrinsic contractile changes would likely result in diastolic dysfunction in vivo. Hypertrophy could arise as a compensatory mechanism. </p><p>Wen et al. (2008) found that skinned papillary fibers from transgenic mice expressing human cTnI with the R145G mutation (Tg-R145G mice) developed significantly decreased maximal Ca(2+)-activated force without changes in maximal ATPase activity compared with transgenic mice expressing wildtype human cTnI (Tg-WT mice). Tg-R145G fibers showed increased Ca(2+) sensitivity in both ATPase and force development compared with Tg-WT fibers. Energy cost calculations demonstrated higher energy consumption in Tg-R145G fibers compared with Tg-WT fibers. Use of a myosin ATPase inhibitor showed that R145G impaired the ability of the cardiac troponin complex to fully inhibit cross-bridge attachment under relaxing conditions. Furthermore, electrical stimulation caused prolonged force and intracellular Ca(2+) concentration transients in intact Tg-R145G papillary muscles compared with Tg-WT papillary muscles. Wen et al. (2008) concluded that hypertrophic cardiomyopathy due to the R145G mutation is likely caused by compensatory changes activated by higher energy cost of cross-bridge formation, slowed rate of fiber relaxation, and the inability of cardiac fibers to completely relax in the absence of Ca(2+). </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, 7</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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TNNI3, LYS206GLN
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<br />
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SNP: rs104894725,
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ClinVar: RCV000013232
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Japanese male patient with sporadic hypertrophic cardiomyopathy (CMH7; 613690), Kimura et al. (1997) identified heterozygosity for an A-C transversion in exon 8 of the TNNI3 gene, resulting in a lys206-to-gln (K206Q) substitution at a highly conserved residue. The mutation was not found in the unaffected parents. </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, 7, MODIFIER OF</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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TNNI3, PRO82SER
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<br />
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SNP: rs77615401,
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gnomAD: rs77615401,
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ClinVar: RCV000013233, RCV000036277, RCV000224174, RCV000229361, RCV000238609, RCV000252511, RCV000271700, RCV000277490, RCV000367372, RCV000852767, RCV001133540, RCV001135028, RCV002482859
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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>Niimura et al. (2002) reported an individual with late-onset hypertrophic cardiomyopathy (CMH7; 613690) in whom they found a missense mutation in the TNNI3 gene. The individual concerned had no family history of hypertrophic cardiomyopathy. The mutation, a C-to-T transition in exon 5, replaced proline with serine at amino acid position 82 (P82S). Proline-82 is highly conserved in mammalian, avian, and amphibian troponin I molecules. </p><p>In a 32-year-old African American woman with severe hypertrophic cardiomyopathy and a family history of CMH and sudden cardiac death, Frazier et al. (2008) identified a heterozygous P82S mutation in the TNNI3 gene and a heterozygous missense mutation in the MYH7 gene (160760.0043). Her affected 8-year-old daughter carried only the heterozygous MYH7 mutation, whereas her as yet unaffected 13-year-old son carried only the TNNI3 P82S variant. Frazier et al. (2008) suggested that the P82S variant, which they found in 3% of healthy African Americans, is a disease-modifying mutation in severely affected individuals, and that carriers of the variant might be at increased risk of late-onset cardiac hypertrophy. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7</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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TNNI3, ASP196ASN
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<br />
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SNP: rs104894727,
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gnomAD: rs104894727,
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ClinVar: RCV000013234, RCV000148897, RCV000159246, RCV000461416, RCV000777480, RCV002354157, RCV002496340
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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>Niimura et al. (2002) reported an individual with late-onset hypertrophic cardiomyopathy (CMH7; 613690) in whom a missense mutation in TNNI3 was found. The individual concerned had no family history of hypertrophic cardiomyopathy. The mutation, a G-to-A transition in exon 8, replaced aspartic acid with asparagine at amino acid position 196 (D196R). Aspartic acid-196 is highly conserved in mammalian, avian, and amphibian troponin I molecules. </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>.0005 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 1, INCLUDED
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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TNNI3, ASP190GLY
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<br />
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|
|
SNP: rs104894728,
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ClinVar: RCV000013235, RCV000013236
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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 family with both hypertrophic cardiomyopathy-7 (CMH7; 613690) and restrictive cardiomyopathy-1 (RCM1; 115210), Mogensen et al. (2003) identified an 87A-G nucleotide transition in exon 8 of the TNNI3 gene, resulting in an asp190-to-gly substitution (D190G), that segregated with the disease (maximum 2-point lod score = 4.8). (Mogensen et al. (2003) originally referred to the mutation as asp190 to his, which they later corrected in an erratum.) The mutation was not found in 200 chromosomes from Caucasian control individuals. There were a significant number of premature sudden deaths in the family, suggesting that the R190G substitution is associated with an adverse phenotype. Asp190 is found in the conserved C-terminal region, which is required for normal inhibitory function of troponin I (Perry, 1999). </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>.0006 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 1</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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|
TNNI3, ARG192HIS
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<br />
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|
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SNP: rs104894729,
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|
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ClinVar: RCV000013237, RCV000154212, RCV000157534, RCV000159242, RCV000619328, RCV000629012, RCV000852483, RCV003147282, RCV003388566
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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 an individual with restrictive cardiomyopathy (RCM1; 115210), Mogensen et al. (2003) identified a de novo 93G-A transition in exon 8 of the TNNI3 gene, resulting in an arg192-to-his (R92H) substitution. (Mogensen et al. (2003) originally referred to the transition as 92C-A, which they later corrected in an erratum.) Arg192 is found in the conserved C-terminal region, which is required for normal inhibitory function of troponin (Perry, 1999). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0007 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TNNI3, LYS178GLU
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<br />
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SNP: rs104894730,
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ClinVar: RCV000013238, RCV001331172
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a young individual with idiopathic restrictive cardiomyopathy (RCM1;115210), Mogensen et al. (2003) identified a de novo 886A-G transition in exon 7 of the TNNI3 gene, resulting in a lys178-to-glu (K178E) substitution. Amino acids 173-181 bind to actin and increase the inhibitory effect of troponin I (Perry, 1999). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0008 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TNNI3, ARG145TRP
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<br />
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SNP: rs104894724,
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gnomAD: rs104894724,
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ClinVar: RCV000013239, RCV000159222, RCV000498333, RCV001170617, RCV001254730, RCV001787387, RCV004549357, RCV004795401
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In 2 unrelated individuals with typical features of restrictive cardiomyopathy (RCM1; 115210) diagnosed in their late fifties, Mogensen et al. (2003) identified a 799C-T transition in the TNNI3 gene, resulting in an arg145-to-trp (R145W) substitution. The sequence required for inhibition of human cardiac troponin I actomyosin ATPase activity consists of 21 amino acid residues (137-148) (Perry, 1999). Haplotype analysis with respect to the TNNI3 locus on chromosome 19 did not suggest a common founder effect. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0009 CARDIOMYOPATHY, DILATED, 2A (1 family)</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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TNNI3, A2V
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<br />
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SNP: rs397516359,
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gnomAD: rs397516359,
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ClinVar: RCV000013240, RCV000036309, RCV000769534, RCV001753445, RCV002513379, RCV004760353, RCV004991983
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a brother and sister from a family with dilated cardiomyopathy (CMD2A; 611880), Murphy et al. (2004) identified homozygosity for a 4C-T transition in exon 1 of the TNNI3 gene, resulting in an ala2-to-val (A2V) substitution. The unaffected parents and an unaffected sister were heterozygous for the mutation. The parents were unaware of any familial relationship, but analysis of microsatellite markers around the TNNI3 locus showed that they shared the same haplotype of the mutated allele, indicating remote consanguinity. Functional studies showed significant impairment of mutant TNNI3 and wildtype TNNT2 protein interaction. </p><p>Carballo et al. (2009) stated that in their analysis of the effect of the A2V mutation on ATPase regulation, troponin function was not significantly altered. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TNNI3, LEU144GLN
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<br />
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SNP: rs121917760,
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ClinVar: RCV000013241
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a woman with restrictive cardiomyopathy (RCM1; 115210), Mogensen et al. (2003) identified a T-to-A transversion at nucleotide 797 in exon 7 of the TNNI3 gene, resulting in a leu144-to-gln (L144Q) substitution. The patient developed symptoms of heart failure at the age of 17 years, and she died of heart failure at the age of 31 years awaiting cardiac transplantation. Several members of her family had died suddenly, but were not available for investigation. </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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<div>
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<h4>
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<span class="mim-font">
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<strong>.0011 CARDIOMYOPATHY, FAMILIAL RESTRICTIVE, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TNNI3, ALA171THR
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<br />
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SNP: rs121917761,
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ClinVar: RCV000013242, RCV000817897, RCV001804728
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a man with restrictive cardiomyopathy (RCM1; 115210), Mogensen et al. (2003) identified a G-to-A transition at nucleotide 856 in exon 7 of the TNNI3 gene, resulting in an ala171-to-thr (A171T) substitution. The patient was diagnosed in his late fifties following an embolic stroke. He was an only child, and no clinical data or DNA was available on his deceased parents. Subsequent mutation analysis of his children did not reveal further carriers. </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>.0012 CARDIOMYOPATHY, DILATED, 1FF</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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TNNI3, LYS36GLN
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<br />
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SNP: rs267607130,
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ClinVar: RCV000013243
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a father and 2 sons with dilated cardiomyopathy (CMD1FF; 613286), Carballo et al. (2009) identified heterozygosity for a 106A-C transversion in exon 3 of the TNNI3 gene, resulting in a lys36-to-gln (K36Q) substitution at a highly conserved residue. Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase by troponin showed that troponin reconstituted with K36Q had lower maximum ATPase rates and reduced Ca(2+) sensitivity compared to wildtype; in addition, mutant thin filaments had lower Ca(2+) affinity than normal. The father and 1 son had rapidly progressive disease, requiring cardiac transplantation soon after diagnosis at ages 15 years and 6 years, respectively; screening of the other mutation-positive son revealed mild CMD with mildly reduced systolic contractility. The mutation was not found in 280 chromosomes from ethnically matched controls or in the patient's asymptomatic mother and 3 brothers; ECG and echocardiography in the mother and 1 brother confirmed normal cardiac function. Haplotype analysis indicated that the proband inherited the mutation from his father, who died in a traffic accident at age 50 years with no known cardiac disease. </p><p>Vikhorev et al. (2017) compared contractility and passive stiffness of cardiac myofibril samples from 3 unrelated patients with dilated cardiomyopathy (DCM) and 2 different truncation mutations in titin (TTN; 188840), 3 unrelated DCM patients with mutations in different contractile proteins, including K36Q in TNNI3, and controls. All 3 contractile protein mutations, but not the titin mutations, had faster relaxation kinetics than controls. Myofibril passive stiffness was reduced by about 38% in all DCM samples compared with controls, but there was no change in maximum force or titin N2BA/N2B isoform ratio, and there was no titin haploinsufficiency. The authors concluded that decreased myofibril passive stiffness, a common feature in all DCM samples, may be a causative of DCM. </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>.0013 CARDIOMYOPATHY, DILATED, 1FF</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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TNNI3, ASN185LYS
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<br />
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SNP: rs267607129,
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ClinVar: RCV000013244
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a man who was diagnosed at age 24 years with severe dilated cardiomyopathy (CMD1FF; 613286), requiring implantation of a left ventricular assist device within 2 months and undergoing cardiac transplantation 13 months later, Carballo et al. (2009) identified heterozygosity for a 555C-G transversion in exon 7 of the TNNI3 gene, resulting in an asn185-to-lys (N185K) substitution at a highly conserved residue. Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase by troponin showed that troponin reconstituted with N185K had lower maximum ATPase rates and reduced Ca(2+) sensitivity compared to wildtype; in addition, mutant thin filaments had lower Ca(2+) affinity than normal. The mutation was not found in 280 chromosomes from ethnically matched controls or in the patient's asymptomatic mother and brother, who had normal ECGs and echocardiograms. However, it was detected in a stored DNA sample from his father, who was diagnosed with CMD at 50 years of age and died 4 years later from complications related to cardiac resynchronization therapy. </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>.0014 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TNNI3, GLY203SER
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<br />
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SNP: rs267607127,
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ClinVar: RCV000013245
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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 Japanese mother and her son and daughter with hypertrophic cardiomyopathy (CMH7; 613690), Kimura et al. (1997) identified heterozygosity for a G-A transition in exon 8 of the TNNI3 gene, resulting in a gly203-to-ser (G203S) substitution at a highly conserved residue. The affected individuals in this family had cardiac hypertrophy only at the apex (apical CMH), and all 3 also exhibited Wolff-Parkinson-White ventricular preexcitation (WPW; 194200). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
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TNNI3, 3-BP DEL, LYS183
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<br />
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|
|
SNP: rs2147283135,
|
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|
|
ClinVar: RCV000013246
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese father and son with hypertrophic cardiomyopathy (CMH7; 613690), Kimura et al. (1997) identified heterozygosity for a 3-bp deletion (delAAG) in exon 7 of the TNNI3 gene, resulting in deletion of a lys residue at codon 183 (L183). The father had cardiac hypertrophy only at the apex (apical CMH), whereas the son had ventricular hypertrophy typical of CMH. </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNI3, ARG21CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607128,
|
|
|
|
|
|
|
|
ClinVar: RCV000013247, RCV001851817, RCV002354158
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a proband who was found to have apical hypertrophy (CMH7; 613690) after presenting with atrial fibrillation, Arad et al. (2005) identified a heterozygous arg21-to-cys (R21C) mutation in the TNNI3 gene. The proband's father, 3 sibs, and her 18-year-old daughter all had sudden cardiac death. Clinical evaluation of 3 other mutation carriers in the family revealed that 1 had asymmetric septal hypertrophy, another had isolated left atrial enlargement, and the third had normal cardiac dimensions despite an abnormal electrocardiogram. Arad et al. (2005) stated that they also identified the R21C mutation in another CMH family, in which 4 patients had subaortic asymmetric hypertrophy and 1 mutation carrier with normal cardiac dimensions was resuscitated from sudden cardiac death. </p>
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</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</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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<ol>
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<li>
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<p class="mim-text-font">
|
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Arad, M., Penas-Lado, M., Monserrat, L., Maron, B. J., Sherrid, M., Ho, C. Y., Barr, S., Karim, A., Olson, T. M., Kamisago, M., Seidman, J. G., Seidman, C. E.
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<strong>Gene mutations in apical hypertrophic cardiomyopathy.</strong>
|
|
Circulation 112: 2805-2811, 2005.
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[PubMed: 16267253]
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[Full Text: https://doi.org/10.1161/CIRCULATIONAHA.105.547448]
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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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Barton, P. J. R., Cullen, M. E., Townsend, P. J., Brand, N. J., Mullen, A. J., Norman, D. A. M., Bhavsar, P. K., Yacoub, M. H.
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<strong>Close physical linkage of human troponin genes: organization, sequence, and expression of the locus encoding cardiac troponin I and slow skeletal troponin T.</strong>
|
|
Genomics 57: 102-109, 1999.
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[PubMed: 10191089]
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[Full Text: https://doi.org/10.1006/geno.1998.5702]
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</li>
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<li>
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<p class="mim-text-font">
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|
Bermingham, N., Hernandez, D., Balfour, A., Gilmour, F., Martin, J. E., Fisher, E. M. C.
|
|
<strong>Mapping TNNC1, the gene that encodes cardiac troponin I in the human and mouse.</strong>
|
|
Genomics 30: 620-622, 1995.
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[PubMed: 8825654]
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[Full Text: https://doi.org/10.1006/geno.1995.1288]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Bhavsar, P. K., Brand, N. J., Yacoub, M. H., Barton, P. J. R.
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<strong>Isolation and characterization of the human cardiac troponin I gene (TNNI3).</strong>
|
|
Genomics 35: 11-23, 1996.
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[PubMed: 8661099]
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[Full Text: https://doi.org/10.1006/geno.1996.0317]
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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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Canaider, S., Facchin, F., Griffoni, C., Casadei, R., Vitale, L., Lenzi, L., Frabetti, F., D'Addabbo, P., Carinci, P., Zannotti, M., Strippoli, P.
|
|
<strong>Proteins encoded by human Down syndrome critical region gene 1-like 2 (DSCR1L2) mRNA and by a novel DSCR1L2 mRNA isoform interact with cardiac troponin I (TNNI3).</strong>
|
|
Gene 372: 128-136, 2006.
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[PubMed: 16516408]
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[Full Text: https://doi.org/10.1016/j.gene.2005.12.029]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Carballo, S., Robinson, P., Otway, R., Fatkin, D., Jongbloed, J. D. H., de Jonge, N., Blair, E., van tintelen, J. P., Redwood, C., Watkins, H.
|
|
<strong>Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.</strong>
|
|
Circ. Res. 105: 375-382, 2009.
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[PubMed: 19590045]
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[Full Text: https://doi.org/10.1161/CIRCRESAHA.109.196055]
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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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Chien, K. R.
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<strong>Genotype, phenotype: upstairs, downstairs in the family of cardiomyopathies.</strong>
|
|
J. Clin. Invest. 111: 175-178, 2003. Note: Erratum: J. Clin. Invest. 11: 1433 only, 2003.
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[PubMed: 12531871]
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[Full Text: https://doi.org/10.1172/JCI17612]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Frazier, A., Judge, D. P., Schulman, S. P., Johnson, N., Holmes, K. W., Murphy, A. M.
|
|
<strong>Familial hypertrophic cardiomyopathy associated with cardiac beta-myosin heavy chain and troponin I mutations.</strong>
|
|
Pediat. Cardiol. 29: 846-850, 2008.
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|
|
[PubMed: 18175163]
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|
|
[Full Text: https://doi.org/10.1007/s00246-007-9177-9]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Gomes, A. V., Liang, J., Potter, J. D.
|
|
<strong>Mutations in human cardiac troponin I that are associated with restrictive cardiomyopathy affect basal ATPase activity and the calcium sensitivity of force development.</strong>
|
|
J. Biol. Chem. 280: 30909-30915, 2005.
|
|
|
|
|
|
[PubMed: 15961398]
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|
|
[Full Text: https://doi.org/10.1074/jbc.M500287200]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Guenet, J.-L., Simon-Chazottes, D., Gravel, M., Hastings, K. E. M., Schiaffino, S.
|
|
<strong>Cardiac and skeletal muscle troponin I isoforms are encoded by a dispersed gene family on mouse chromosomes 1 and 7.</strong>
|
|
Mammalian Genome 7: 13-15, 1996.
|
|
|
|
|
|
[PubMed: 8903721]
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|
|
|
|
[Full Text: https://doi.org/10.1007/s003359900004]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Horwich, T. B., Patel, J., MacLellan, W. R., Fonarow, G. C.
|
|
<strong>Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure.</strong>
|
|
Circulation 108: 833-838, 2003.
|
|
|
|
|
|
[PubMed: 12912820]
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|
|
[Full Text: https://doi.org/10.1161/01.CIR.0000084543.79097.34]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Huang, X., Du, J.
|
|
<strong>Troponin I, cardiac diastolic dysfunction and restrictive cardiomyopathy.</strong>
|
|
Acta Pharm. Sin. 25: 1569-1575, 2004.
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|
|
[PubMed: 15569399]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Joyce, W., He, K., Zhang, M., Ogunsola, S., Wu, X., Joseph, K. T., Bogomolny, D., Yu, W., Springer, M. S., Xie, J., Signore, A. V., Campbell, K. L.
|
|
<strong>Genetic excision of the regulatory cardiac troponin I extension in high-heart rate mammal clades.</strong>
|
|
Science 385: 1466-1471, 2024.
|
|
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