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<title>
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Entry
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- *191041 - TROPONIN T1, SKELETAL, SLOW; TNNT1
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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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<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 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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<a href="/history"> Search History </a>
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</form>
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<p />
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</div>
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*191041</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li 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/191041">Table View</a>
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</li>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></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 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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|
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000105048;t=ENST00000588981" 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=7138" 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=191041" 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=ENSG00000105048;t=ENST00000588981" 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_001126132,NM_001126133,NM_001291774,NM_003283,XM_011527246,XM_017027186,XM_017027187" 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_003283" 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=191041" 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=01841&isoform_id=01841_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/TNNT1" 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/339781,339783,546021,546023,1174800,4056562,4056563,4056564,4261678,15012113,21706667,33870023,54696128,59803494,59803496,78070766,116283308,119592742,119592743,119592744,119592745,158256140,187173288,187173290,187173292,619534207,768010732,1034609152,1034609154,2462567207,2462567209,2462567211" 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/P13805" 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=7138" 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=ENSG00000105048;t=ENST00000588981" 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=TNNT1" 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=TNNT1" 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+7138" 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/TNNT1" 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:7138" 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/7138" 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=ENST00000588981.6&hgg_start=55132698&hgg_end=55149206&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:11948" 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:11948" 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=191041[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=191041[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://gnomad.broadinstitute.org/gene/ENSG00000105048" 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=TNNT1" 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=TNNT1" 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=TNNT1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/TNNT1" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TNNT1&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/PA36637" 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:11948" 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/FBgn0004169.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:1333868" 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/TNNT1#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:1333868" 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/7138/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002285/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=7138" 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=WBGene00003495;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00003495 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006587;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006587 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006588;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006588 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006589;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006589 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-080723-27" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:191041" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7138" 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=TNNT1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1197155007<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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191041
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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 T1, SKELETAL, SLOW; TNNT1
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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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TROPONIN T
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TNNT1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TNNT1</a></em></strong>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:55132698-55149206&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'})">19:55,132,698-55,149,206</a> </span>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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<strong>Gene-Phenotype Relationships</strong>
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Phenotype
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View Clinical Synopses
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Phenotype <br /> MIM number
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Inheritance
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<a href="/geneMap/19/1155?start=-3&limit=10&highlight=1155">
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19q13.42
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Nemaline myopathy 5A, autosomal recessive, severe infantile
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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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Nemaline myopathy 5B, autosomal recessive, childhood-onset
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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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Nemaline myopathy 5C, autosomal dominant
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<a href="/entry/620389"> 620389 </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/191041" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/191041" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Description</strong>
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<p>The TNNT1 gene encodes the slow skeletal muscle troponin. The sarcomere, the contractile element in muscle, including the myocardium, is constituted by 7 major proteins and several minor ones organized into thin and thick filaments. Each tropomyosin dimer (TPM1, <a href="/entry/191010">191010</a>; TPM2, <a href="/entry/190990">190990</a>) interacts with 7 actins and is associated with a troponin complex. Each complex is composed of 1 molecule of each of the 3 troponins: T, C, and I. This tropomyosin-troponin complex is responsible for the calcium sensitivity of the contractile apparatus (<a href="#11" class="mim-tip-reference" title="Nadal-Ginard, B., Mahdavi, V. <strong>Molecular basis of cardiac performance: plasticity of the myocardium generated through protein isoform switches.</strong> J. Clin. Invest. 84: 1693-1700, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2687327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2687327</a>] [<a href="https://doi.org/10.1172/JCI114351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2687327">Nadal-Ginard and Mahdavi, 1989</a>), and thus plays an important role in linking excitation to contraction in skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2687327" 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>Cloning and Expression</strong>
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<p><a href="#18" class="mim-tip-reference" title="Samson, F., Mesnard, L., Mihovilovic, M., Potter, T. G., Mercadier, J.-J., Roses, A. D., Gilbert, J. R. <strong>A new human slow skeletal troponin T (TnTs) mRNA isoform derived from alternative splicing of a single gene.</strong> Biochem. Biophys. Res. Commun. 199: 841-847, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8135831/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8135831</a>] [<a href="https://doi.org/10.1006/bbrc.1994.1305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8135831">Samson et al. (1994)</a> concluded that there are 4 isoforms of human slow skeletal troponin-T mRNA and that these probably result from combinatorial alternative splicing of a single gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8135831" 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 PCR of adult human skeletal muscle total RNA, <a href="#1" 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> cloned full-length TNNT1 and identified 3 shorter splice variants. The full-length protein contains 278 amino acids. Northern blot analysis detected TNNT1 expression in adult skeletal muscle, but not in adult heart and liver or in fetal heart. <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>Alternative splicing of exon 5 of the TNNT1 gene generates a high molecular weight (HMW) isoform (with exon 5) and a low molecular weight isoform (LMW) isoform (without exon 5). LMW TNNT1 has a higher binding affinity for tropomyosin and generates more calcium-activated contractile force than the HMW isoform, which enables regulation and modulation of muscle contractility. Normal adult slow muscles express mainly the HMW isoform (summary by <a href="#5" class="mim-tip-reference" title="Holling, T., Lisfeld, J., Johannsen, J., Matschke, J., Song, F., Altmeppen, H. C., Kutsche, K. <strong>Autosomal dominantly inherited myopathy likely caused by the TNNT1 variant p.(Asp65Ala).</strong> Hum. Mutat. 43: 1224-1233, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35510366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35510366</a>] [<a href="https://doi.org/10.1002/humu.24397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35510366">Holling et al., 2022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35510366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="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 TNNT1 gene contains 14 exons and spans more than 16 kb. The first exon is noncoding. <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>
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<strong>Mapping</strong>
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<p><a href="#17" class="mim-tip-reference" title="Samson, F., Lee, J. E., Hung, W. Y., Potter, T. G., Herbstreith, M., Roses, A. D., Gilbert, J. R. <strong>Isolation and localisation of a slow troponin (TNT) gene on chromosome 19 by subtraction of a cDNA muscle library using myotonic muscle cDNA.</strong> J. Neurosci. Res. 27: 441-451, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1706783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1706783</a>] [<a href="https://doi.org/10.1002/jnr.490270403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1706783">Samson et al. (1990)</a> assigned the slow skeletal isoform of troponin T (TNNT1) to chromosome 19q13.3-q13.4 using a panel of somatic cell hybrids and a cDNA clone as probe. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1706783" 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>Novelli et al. (<a href="#13" class="mim-tip-reference" title="Novelli, G., Gennarelli, M., Zelano, G., Sangiuolo, F., Rocchi, M., Dallapiccola, B. <strong>Isolation and mapping of the slow skeletal troponin T using the polymerase chain reaction. (Abstract)</strong> Cytogenet. Cell Genet. 58: 2023, 1991."None>1991</a>, <a href="#12" class="mim-tip-reference" title="Novelli, G., Gennarelli, M., Rocchi, M., Dallapiccola, B. <strong>Assignment of the slow troponin T (TNNT1) gene to chromosome 19 using polymerase chain reaction.</strong> Hum. Genet. 88: 697-698, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1551677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1551677</a>] [<a href="https://doi.org/10.1007/BF02265301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1551677">1992</a>) confirmed the assignment of the TNNT1 gene to human chromosome 19 by showing the presence of a specific PCR product in hybrids retaining chromosome 19. The cardiac isoform of troponin-I (TNNI3; <a href="/entry/191044">191044</a>) maps to the same region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1551677" 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="Samson, F., Gilbert, J. R., Lee, J. E., Potter, T. G., Koza-Taylor, P., Speer, M. C., Bachinski, L. L., Siciliano, M. J., Roses, A. D. <strong>Isolation and localization of a human slow troponin T gene on chromosome 19q. (Abstract)</strong> Cytogenet. Cell Genet. 58: 2025, 1991."None>Samson et al. (1991)</a> achieved regional assignment to the 19q13.2-qter region by analysis of 7 somatic cell hybrids containing different portions of chromosome 19. They excluded TNNT1 as a candidate gene for myotonic dystrophy (DM1; <a href="/entry/160900">160900</a>) by the finding of obligate recombination events in family linkage studies.</p><p><a href="#15" class="mim-tip-reference" title="Samson, F., de Jong, P. J., Trask, B. J., Koza-Taylor, P., Speer, M. C., Potter, T., Roses, A. D., Gilbert, J. R. <strong>Assignment of the human slow skeletal troponin T gene to 19q13.4 using somatic cell hybrids and fluorescence in situ hybridization analysis.</strong> Genomics 13: 1374-1375, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1505979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1505979</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90077-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1505979">Samson et al. (1992)</a> mapped the TNNT1 gene to chromosome 19q13.4 by study of somatic cell hybrids and fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1505979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="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 TNNT1 gene 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>
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<p><strong><em>Autosomal Recessive Severe Infantile Nemaline Myopathy 5A</em></strong></p><p>
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In Amish patients with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; <a href="/entry/605355">605355</a>), <a href="#7" class="mim-tip-reference" title="Johnston, J. J., Kelley, R. I., Crawford, T. O., Morton, D. H., Agarwala, R., Koch, T., Schaffer, A. A., Francomano, C. A., Biesecker, L. G. <strong>A novel nemaline myopathy in the Amish caused by a mutation in troponin T1.</strong> Am. J. Hum. Genet. 67: 814-821, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10952871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10952871</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10952871[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/303089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10952871">Johnston et al. (2000)</a> identified homozygosity for a nonsense mutation in the TNNT1 gene (E180X; <a href="#0001">191041.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10952871" 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 Dutch boy with NEM5A, <a href="#21" class="mim-tip-reference" title="van der Pol, W. L., Leijenaar, J. F., Spliet, W. G. M., Lavrijsen, S. W., Jansen, N. J. G., Braun, K. P. J., Mulder, M., Timmers-Raaijmakers, B., Ratsma, K., Dooijes, D., van Haelst, M. M. <strong>Nemaline myopathy caused by TNNT1 mutations in a Dutch pedigree.</strong> Molec. Genet. Genomic Med. 2: 134-137, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24689076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24689076</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24689076[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/mgg3.52" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24689076">van der Pol et al. (2014)</a> identified compound heterozygous mutations in the TNNT1 gene: a splice site mutation (<a href="#0002">191041.0002</a>) and an intragenic deletion (ex14del; <a href="#0003">191041.0003</a>). The mutations were inherited from the unaffected parents. Homozygosity for the splice site mutation was identified in 2 paternal cousins with a similar disorder who died in childhood of respiratory insufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24689076" 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 3 unrelated patients with NEM5A, <a href="#3" class="mim-tip-reference" title="Geraud, J., Dieterich, K., Rendu, J., Uro Coste, E., Dobrzynski, M., Marcorelle, P., Ioos, C., Romero, N. B., Baudou, E., Brocard, J., Coville, A.-C., Faure, J., and 10 others. <strong>Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy.</strong> J. Med. Genet. 58: 602-608, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32994279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32994279</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32994279[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106714" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32994279">Geraud et al. (2021)</a> identified homozygous or compound heterozygous mutations in the TNNT1 gene (see, e.g., <a href="#0004">191041.0004</a>-<a href="#0006">191041.0006</a>). Western blot analysis of skeletal muscle from the patients showed absence of the TNNT1 protein. All died by 29 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32994279" 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>Autosomal Recessive Childhood-Onset Nemaline Myopathy 5B</em></strong></p><p>
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In 4 patients from 3 unrelated French Canadian families with autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B; <a href="/entry/620386">620386</a>), <a href="#14" class="mim-tip-reference" title="Pellerin, D., Aykanat, A., Ellezam, B., Troiano, E. C., Karamchandani, J., Dicaire, M.-J., Petitclerc, M., Robertson, R., Allard-Chamard, X., Brunet, D., Konersman, C. G., Mathieu, J., Warman Chardon, J., Gupta, V. A., Beggs, A. H., Brais, B., Chrestian, N. <strong>Novel recessive TNNT1 congenital core-rod myopathy in French Canadians.</strong> Ann. Neurol. 87: 568-583, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31970803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31970803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31970803[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.25685" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31970803">Pellerin et al. (2020)</a> identified a homozygous missense mutation in the TNNT1 gene (L96P; <a href="#0007">191041.0007</a>). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in 3 of the families who underwent testing. The mutation was unable to rescue the abnormal muscle phenotype in tnnt1-null zebrafish, suggesting that it causes a loss of function. The authors postulated that there was some residual activity or compensation by the low molecular weight TNNT1 isoform, resulting in a milder phenotype compared to patients with complete loss of TNNT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31970803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 brothers, born of unrelated Korean parents, with NEM5B, <a href="#9" class="mim-tip-reference" title="Lee, S., Eum, J., Park, S., Ki, S., Hwang, B. J., Kee, Y., Chae, J. H. <strong>TNNT1 myopathy with novel compound heterozygous mutations.</strong> Neuromusc. Disord. 32: 176-184, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35165004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35165004</a>] [<a href="https://doi.org/10.1016/j.nmd.2021.12.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35165004">Lee et al. (2022)</a> identified compound heterozygosity for a missense mutation (A242P; <a href="#0008">191041.0008</a>) and a splice site mutation (<a href="#0009">191041.0009</a>) in the TNNT1 gene. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were inherited from the unaffected parents. The splice site mutation was demonstrated to result in altered splicing and frameshifts, and the A242P mutation was unable to rescue the myopathic phenotype in tnnt1-null zebrafish, suggesting that both mutations caused a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35165004" 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 51-year-old man with NEM5B, <a href="#10" class="mim-tip-reference" title="Martin-Jimenez, P., Fuenmayor-Fernandez de la Hoz, C. P., Hernandez-Lain, A., Arteche-Lopez, A., Quesada-Espinosa, J. F., Voth, A. H., Vesperinas, A., Olive, M., Dominguez-Gonzalez, C. <strong>Adult-onset nemaline myopathy due to a novel homozygous variant in the TNNT1 gene.</strong> Muscle Nerve 66: E13-E15, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35833674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35833674</a>] [<a href="https://doi.org/10.1002/mus.27678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35833674">Martin-Jimenez et al. (2022)</a> detected homozygosity for a variant in the TNNT1 gene (c.551_552delinsCA) that resulted in an arg184-to-pro (R184P) substitution. The variant was absent from gnomAD. Segregation studies and functional studies were not performed. The patient presented at age 50 years with a respiratory infection followed by respiratory arrest requiring intubation. He subsequently developed muscle weakness in all limbs which was slowly progressive and resulted in difficulty climbing stairs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35833674" 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>Autosomal Dominant Nemaline Myopathy 5C</em></strong></p><p>
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In 8 affected members of a large consanguineous Ashkenazi Jewish family with autosomal dominant nemaline myopathy-5C (NEM5C; <a href="/entry/620389">620389</a>) originally reported by <a href="#19" class="mim-tip-reference" title="Spiro, A. J., Kennedy, C. <strong>Hereditary occurrence of nemaline myopathy.</strong> Arch. Neurol. 13: 155-159, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14315666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14315666</a>] [<a href="https://doi.org/10.1001/archneur.1965.00470020045006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14315666">Spiro and Kennedy (1965)</a> and <a href="#4" class="mim-tip-reference" title="Gonatas, N. K., Shy, G. M., Godfrey, E. H. <strong>Nemaline myopathy: the origin of nemaline structures.</strong> New Eng. J. Med. 274: 535-539, 1966.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5908457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5908457</a>] [<a href="https://doi.org/10.1056/NEJM196603102741002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5908457">Gonatas et al. (1966)</a>, <a href="#8" class="mim-tip-reference" title="Konersman, C. G., Freyermuth, F., Winder, T. L., Lawlor, M. W., Lagier-Tourenne, C., Patel, S. B. <strong>Novel autosomal dominant TNNT1 mutation causing nemaline myopathy.</strong> Molec. Genet. Genomic Med. 5: 678-691, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29178646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29178646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29178646[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/mgg3.325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29178646">Konersman et al. (2017)</a> identified a heterozygous missense mutation in the TNNT1 gene (E104V; <a href="#0010">191041.0010</a>). The mutation, which was found by Sanger sequencing of candidate genes, segregated with the disorder in the family. <a href="#5" class="mim-tip-reference" title="Holling, T., Lisfeld, J., Johannsen, J., Matschke, J., Song, F., Altmeppen, H. C., Kutsche, K. <strong>Autosomal dominantly inherited myopathy likely caused by the TNNT1 variant p.(Asp65Ala).</strong> Hum. Mutat. 43: 1224-1233, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35510366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35510366</a>] [<a href="https://doi.org/10.1002/humu.24397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35510366">Holling et al. (2022)</a> stated that the E104V mutation affects a residue just outside of the tropomyosin-binding site 1. In vitro studies in HEK293 cells transfected with the mutation showed normal expression of TNNT1 and effective binding to tropomyosin-3 (TPM3; <a href="/entry/191030">191030</a>), although binding of the mutant protein to TPM3 was reduced by 35% in the presence of calcium. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14315666+35510366+29178646+5908457" 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 mother and son with NEM5C, <a href="#5" class="mim-tip-reference" title="Holling, T., Lisfeld, J., Johannsen, J., Matschke, J., Song, F., Altmeppen, H. C., Kutsche, K. <strong>Autosomal dominantly inherited myopathy likely caused by the TNNT1 variant p.(Asp65Ala).</strong> Hum. Mutat. 43: 1224-1233, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35510366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35510366</a>] [<a href="https://doi.org/10.1002/humu.24397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35510366">Holling et al. (2022)</a> identified a heterozygous missense mutation in the TNNT1 gene (D65A; <a href="#0011">191041.0011</a>) that occurred within the tropomyosin-binding site 1 region. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. In vitro studies in HEK293 cells transfected with the mutation showed normal expression of TNNT1, whereas coimmunoprecipitation studies showed significantly increased binding of the D65A variant to TPM3 compared to controls, both in the presence and absence of calcium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35510366" 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="#2" class="mim-tip-reference" title="Fox, M. D., Carson, V. J., Feng, H.-Z., Lawlor, M. W., Gray, J. T., Brigatti, K. W., Jin, J.-P., Strauss, K. A. <strong>TNNT1 nemaline myopathy: natural history and therapeutic frontier.</strong> Hum. Molec. Genet. 27: 3272-3282, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29931346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29931346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29931346[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/10.1093/hmg/ddy233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29931346">Fox et al. (2018)</a> described muscle features in 2 mouse models of Tnnt1 deficiency: a targeted gene knockout (Tnnt1 -/-) model and a site-specific knock-in (Tnnt1 c.505G-T) model. Quadratus femoris muscle tissue showed absence of Tnnt1, atrophy/hypotrophy of small type 1 myofibers, hypertrophy of fast type 2 fibers, and the presence of nemaline rods in both mouse models. Both models also showed impaired muscle force generation and exercise recovery in soleus muscles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29931346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Pellerin, D., Aykanat, A., Ellezam, B., Troiano, E. C., Karamchandani, J., Dicaire, M.-J., Petitclerc, M., Robertson, R., Allard-Chamard, X., Brunet, D., Konersman, C. G., Mathieu, J., Warman Chardon, J., Gupta, V. A., Beggs, A. H., Brais, B., Chrestian, N. <strong>Novel recessive TNNT1 congenital core-rod myopathy in French Canadians.</strong> Ann. Neurol. 87: 568-583, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31970803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31970803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31970803[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.25685" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31970803">Pellerin et al. (2020)</a> found that morpholino knockout of the tnnt1 gene in zebrafish caused reduced muscle mass, reduced birefringence, and severe truncal curvature compared to controls. Myofibers were disorganized and showed corelike intramyofibrillar areas of sarcomeric disorganization and Z-line thickening. These defects could be rescued by expression of wildtype human TNNT1 mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31970803" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=191041[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 NEMALINE MYOPATHY 5A, AUTOSOMAL RECESSIVE, SEVERE INFANTILE</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> rs80358249 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80358249;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/rs80358249?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=rs80358249" 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=rs80358249" 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 individuals with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; <a href="/entry/605355">605355</a>), also known as Amish nemaline myopathy, <a href="#7" class="mim-tip-reference" title="Johnston, J. J., Kelley, R. I., Crawford, T. O., Morton, D. H., Agarwala, R., Koch, T., Schaffer, A. A., Francomano, C. A., Biesecker, L. G. <strong>A novel nemaline myopathy in the Amish caused by a mutation in troponin T1.</strong> Am. J. Hum. Genet. 67: 814-821, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10952871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10952871</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10952871[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/303089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10952871">Johnston et al. (2000)</a> identified a homozygous c.579G-T transversion in exon 11 of the TNNT1 gene, resulting in a stop codon at amino acid 180 (E180X) and loss of 83 C-terminal residues. <a href="#7" class="mim-tip-reference" title="Johnston, J. J., Kelley, R. I., Crawford, T. O., Morton, D. H., Agarwala, R., Koch, T., Schaffer, A. A., Francomano, C. A., Biesecker, L. G. <strong>A novel nemaline myopathy in the Amish caused by a mutation in troponin T1.</strong> Am. J. Hum. Genet. 67: 814-821, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10952871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10952871</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10952871[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/303089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10952871">Johnston et al. (2000)</a> had treated or obtained clinical information on 71 infants and young children from 33 nuclear Amish families with this form of nemaline myopathy. In the first months of life, affected infants had tremors with hypotonia and mild contractures of the shoulders and hips. Progressive worsening of the proximal contractures, weakness, and a pectus carinatum deformity developed before the children died of respiratory insufficiency, usually in the second year. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10952871" 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>Variant Function</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Jin, J.-P., Brotto, M. A., Hossain, M. M., Huang, Q.-Q., Brotto, L. S., Nosek, T. M., Morton, D. H., Crawford, T. O. <strong>Truncation by glu180 nonsense mutation results in complete loss of skeletal muscle troponin T in a lethal nemaline myopathy.</strong> J. Biol. Chem. 278: 26159-26165, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12732643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12732643</a>] [<a href="https://doi.org/10.1074/jbc.M303469200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12732643">Jin et al. (2003)</a> found complete loss of the TNNT1 protein in patients with the E180X mutation. The truncated protein results in elimination of the C-terminal T2 domain that interacts with troponin C (TNNC1; <a href="/entry/191040">191040</a>), I (TNNI2; <a href="/entry/191043">191043</a>), and tropomyosin (TPM1; <a href="/entry/191010">191010</a>), but was predicted to retain a central tropomyosin-binding site that participates in the anchoring of troponin complex to the thin actin filament. If residual truncated protein was produced, this could potentially result in a dominant-negative effect. The significant muscle atrophy observed in the disorder was consistent with the slow Tnt isoform being involved in muscle development and growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12732643" 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 patient with Amish nemaline myopathy due to the E180X mutation, <a href="#22" class="mim-tip-reference" title="Wang, X., Huang, Q.-Q., Breckenridge, M. T., Chen, A., Crawford, T. O., Morton, D. H., Jin, J.-P. <strong>Cellular fate of truncated slow skeletal muscle troponin T produced by glu180 nonsense mutation in Amish nemaline myopathy.</strong> J. Biol. Chem. 280: 13241-13249, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15665378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15665378</a>] [<a href="https://doi.org/10.1074/jbc.M413696200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15665378">Wang et al. (2005)</a> detected residual mutant TNNT1 mRNA in muscle tissue but no corresponding translated mutant TNNT1 protein. In vitro functional expression studies in nonmuscle cells showed that E180X-mutant protein could be produced but was not detectable when expressed in muscle cells in vitro. The findings suggested rapid degradation of E180X-mutant protein in muscle cells, rather than a loss of nonsense mRNA to explain the absence of a dominant effect. <a href="#22" class="mim-tip-reference" title="Wang, X., Huang, Q.-Q., Breckenridge, M. T., Chen, A., Crawford, T. O., Morton, D. H., Jin, J.-P. <strong>Cellular fate of truncated slow skeletal muscle troponin T produced by glu180 nonsense mutation in Amish nemaline myopathy.</strong> J. Biol. Chem. 280: 13241-13249, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15665378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15665378</a>] [<a href="https://doi.org/10.1074/jbc.M413696200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15665378">Wang et al. (2005)</a> postulated that inefficient incorporation of mutant TNNT1 into myofilaments results in its degradation by the muscle cell as a protective mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15665378" 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>.0002 NEMALINE MYOPATHY 5A, AUTOSOMAL RECESSIVE, SEVERE INFANTILE</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> rs149559898 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs149559898;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/rs149559898?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=rs149559898" 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=rs149559898" 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=RCV001529807 OR RCV003230283" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001529807, RCV003230283" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001529807...</a>
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<p>In a Dutch boy with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; <a href="/entry/605355">605355</a>), <a href="#21" class="mim-tip-reference" title="van der Pol, W. L., Leijenaar, J. F., Spliet, W. G. M., Lavrijsen, S. W., Jansen, N. J. G., Braun, K. P. J., Mulder, M., Timmers-Raaijmakers, B., Ratsma, K., Dooijes, D., van Haelst, M. M. <strong>Nemaline myopathy caused by TNNT1 mutations in a Dutch pedigree.</strong> Molec. Genet. Genomic Med. 2: 134-137, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24689076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24689076</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24689076[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/mgg3.52" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24689076">van der Pol et al. (2014)</a> identified compound heterozygous mutations in the TNNT1 gene: a G-to-A transition in intron 8 (c.309+1G-A, NM_003283.4) inherited from the unaffected father, and an exon 14 deletion (ex14del; <a href="#0003">191041.0003</a>) inherited from the unaffected mother. Homozygosity for the c.309+1G-A mutation was identified in 2 paternal cousins with a similar disorder who died in childhood of respiratory insufficiency. The splicing defect resulted in the skipping of exon 8 with an in-frame deletion of 39 functionally important residues from the TNNT1 troponin domain (Asp65_Ile103del). The mutations were predicted to result in a loss of function, although the authors noted that the predicted transcripts could be translated into shortened proteins with some residual activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24689076" 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>For discussion of the exon 14 deletion (ex14del, NM_003283.4) in the TNNT1 gene that was found in compound heterozygous state in a patient with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; <a href="/entry/605355">605355</a>) by <a href="#21" class="mim-tip-reference" title="van der Pol, W. L., Leijenaar, J. F., Spliet, W. G. M., Lavrijsen, S. W., Jansen, N. J. G., Braun, K. P. J., Mulder, M., Timmers-Raaijmakers, B., Ratsma, K., Dooijes, D., van Haelst, M. M. <strong>Nemaline myopathy caused by TNNT1 mutations in a Dutch pedigree.</strong> Molec. Genet. Genomic Med. 2: 134-137, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24689076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24689076</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24689076[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/mgg3.52" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24689076">van der Pol et al. (2014)</a>, see <a href="#0002">191041.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24689076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 NEMALINE MYOPATHY 5A, AUTOSOMAL RECESSIVE, SEVERE INFANTILE</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003230311" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003230311" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003230311</a>
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<p>In a female infant (patient 2) with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; <a href="/entry/605355">605355</a>) resulting in death at 16 months of age, <a href="#3" class="mim-tip-reference" title="Geraud, J., Dieterich, K., Rendu, J., Uro Coste, E., Dobrzynski, M., Marcorelle, P., Ioos, C., Romero, N. B., Baudou, E., Brocard, J., Coville, A.-C., Faure, J., and 10 others. <strong>Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy.</strong> J. Med. Genet. 58: 602-608, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32994279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32994279</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32994279[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106714" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32994279">Geraud et al. (2021)</a> identified compound heterozygous mutations in the TNNT1 gene: a c.334G-T transversion (c.334G-T, NM_003283.5), resulting in a glu112-to-ter (E112X) substitution, and a C-to-A transversion in intron 4 (c.74-67C-A; <a href="#0005">191041.0005</a>), predicted to result in a splicing defect. Western blot analysis of skeletal muscle from the patient showed absence of the TNNT1 protein. She had a severe form of the disorder with tongue fasciculations, kyphosis, pectus carinatum, and hypotonia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32994279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 NEMALINE MYOPATHY 5A, AUTOSOMAL RECESSIVE, SEVERE INFANTILE</strong>
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TNNT1, IVS4AS, C-A, -67
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003226144" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003226144" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003226144</a>
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<p>For discussion of the c.74-67C-A mutation (c.74-67C-A, NM_003283.5) in intron 4 of the TNNT1 gene, resulting in a splicing defect, that was found in compound heterozygous state in a patient with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; <a href="/entry/605355">605355</a>) by <a href="#3" class="mim-tip-reference" title="Geraud, J., Dieterich, K., Rendu, J., Uro Coste, E., Dobrzynski, M., Marcorelle, P., Ioos, C., Romero, N. B., Baudou, E., Brocard, J., Coville, A.-C., Faure, J., and 10 others. <strong>Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy.</strong> J. Med. Genet. 58: 602-608, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32994279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32994279</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32994279[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106714" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32994279">Geraud et al. (2021)</a> see <a href="#0004">191041.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32994279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 NEMALINE MYOPATHY 5A, AUTOSOMAL RECESSIVE, SEVERE INFANTILE</strong>
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TNNT1, GLU6TER
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003230312" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003230312" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003230312</a>
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<p>In a patient (patient 3) with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; <a href="/entry/605355">605355</a>) resulting in death at 6 months of age, <a href="#3" class="mim-tip-reference" title="Geraud, J., Dieterich, K., Rendu, J., Uro Coste, E., Dobrzynski, M., Marcorelle, P., Ioos, C., Romero, N. B., Baudou, E., Brocard, J., Coville, A.-C., Faure, J., and 10 others. <strong>Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy.</strong> J. Med. Genet. 58: 602-608, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32994279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32994279</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32994279[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106714" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32994279">Geraud et al. (2021)</a> identified a homozygous c.16G-T transversion (cc.74-67C-A, NM_003283.5) in the TNNT1 gene, resulting in a glu6-to-ter (E6X) substitution. Western blot analysis of patient skeletal muscle showed absence of the TNNT1 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32994279" 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 NEMALINE MYOPATHY 5B, AUTOSOMAL RECESSIVE, CHILDHOOD-ONSET</strong>
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TNNT1, LEU96PRO
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003230314 OR RCV004757582" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003230314, RCV004757582" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003230314...</a>
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<p>In 4 patients from 3 unrelated French Canadian families with autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B; <a href="/entry/620386">620386</a>), <a href="#14" class="mim-tip-reference" title="Pellerin, D., Aykanat, A., Ellezam, B., Troiano, E. C., Karamchandani, J., Dicaire, M.-J., Petitclerc, M., Robertson, R., Allard-Chamard, X., Brunet, D., Konersman, C. G., Mathieu, J., Warman Chardon, J., Gupta, V. A., Beggs, A. H., Brais, B., Chrestian, N. <strong>Novel recessive TNNT1 congenital core-rod myopathy in French Canadians.</strong> Ann. Neurol. 87: 568-583, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31970803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31970803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31970803[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.25685" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31970803">Pellerin et al. (2020)</a> identified a homozygous c.287T-C transition (c.287T-C, NM_003283.6) in exon 8 of the TNNT1 gene, resulting in a leu96-to-pro (L96P) substitution at a conserved residue. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in 3 of the families who underwent testing. The mutation was predicted to disrupt the alpha-helical secondary structure of the tropomyosin-binding site 1 and impair binding affinity. The mutant protein was likely to be misincorporated into myofilaments and undergo partial degradation, as evidenced by lower levels of the high molecular weight troponin T isoform in patient muscle; low molecular weight isoforms were retained. The mutation was unable to rescue the abnormal muscle phenotype in tnnt1-null zebrafish, suggesting that it causes a loss of function. The authors postulated that there was some residual activity or compensation by the low molecular weight isoform, resulting in a milder phenotype compared to patients with complete loss of TNNT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31970803" 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>Variant Function</em></strong></p><p>
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<a href="#5" class="mim-tip-reference" title="Holling, T., Lisfeld, J., Johannsen, J., Matschke, J., Song, F., Altmeppen, H. C., Kutsche, K. <strong>Autosomal dominantly inherited myopathy likely caused by the TNNT1 variant p.(Asp65Ala).</strong> Hum. Mutat. 43: 1224-1233, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35510366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35510366</a>] [<a href="https://doi.org/10.1002/humu.24397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35510366">Holling et al. (2022)</a> found that expression of the L96P mutation was increased compared to controls when transfected into HEK293 cells. Coimmunoprecipitation studies showed significantly reduced interaction (by 88%) of the L96P mutant with tropomyosin-3 (TPM3; <a href="/entry/191030">191030</a>), and this interaction was abrogated in the presence of calcium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35510366" 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 NEMALINE MYOPATHY 5B, AUTOSOMAL RECESSIVE, CHILDHOOD-ONSET</strong>
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TNNT1, ALA242PRO
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003230315" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003230315" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003230315</a>
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<p>In 2 brothers, born of unrelated Korean parents, with autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B; <a href="/entry/620386">620386</a>), <a href="#9" class="mim-tip-reference" title="Lee, S., Eum, J., Park, S., Ki, S., Hwang, B. J., Kee, Y., Chae, J. H. <strong>TNNT1 myopathy with novel compound heterozygous mutations.</strong> Neuromusc. Disord. 32: 176-184, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35165004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35165004</a>] [<a href="https://doi.org/10.1016/j.nmd.2021.12.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35165004">Lee et al. (2022)</a> identified compound heterozygous mutations in the TNNT1 gene: a c.724G-C transversion (c.724G-C, NM_003283) in exon 12, resulting in an ala242-to-pro (A242P) substitution in the conserved troponin I-binding domain, and a G-to-A transition in intron 11 (c.611+1G-A; <a href="#0009">191041.0009</a>), resulting in a splicing defect and frameshifts. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were inherited from the unaffected parents. The splice site mutation was found once in the heterozygous state in a Korean individual in gnomAD (1 of 249,306 alleles, frequency of 4.01 x 10(-6)). The A242P mutation was unable to rescue the myopathic phenotype in tnnt1-null zebrafish, suggesting that this mutation causes a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35165004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<h4>
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<strong>.0009 NEMALINE MYOPATHY 5B, AUTOSOMAL RECESSIVE, CHILDHOOD-ONSET</strong>
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TNNT1, IVS11DS, G-A, +1
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003230313" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003230313" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003230313</a>
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<p>For discussion of the G-to-A transition in intron 11 of the TNNT1 gene (c.611+1G-A, NM_003283), resulting in a splicing defect and frameshifts, that was found in compound heterozygous state in 2 brothers with autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B; <a href="/entry/620386">620386</a>) by <a href="#9" class="mim-tip-reference" title="Lee, S., Eum, J., Park, S., Ki, S., Hwang, B. J., Kee, Y., Chae, J. H. <strong>TNNT1 myopathy with novel compound heterozygous mutations.</strong> Neuromusc. Disord. 32: 176-184, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35165004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35165004</a>] [<a href="https://doi.org/10.1016/j.nmd.2021.12.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35165004">Lee et al. (2022)</a>, see <a href="#0008">191041.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35165004" 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 NEMALINE MYOPATHY 5C, AUTOSOMAL DOMINANT</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">rs2085441049 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2085441049;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=rs2085441049" 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=rs2085441049" 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=RCV001209655 OR RCV003230280" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001209655, RCV003230280" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001209655...</a>
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<p>In 8 affected members of a large consanguineous Ashkenazi Jewish family with autosomal dominant nemaline myopathy-5C (NEM5C; <a href="/entry/620389">620389</a>) originally reported by <a href="#19" class="mim-tip-reference" title="Spiro, A. J., Kennedy, C. <strong>Hereditary occurrence of nemaline myopathy.</strong> Arch. Neurol. 13: 155-159, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14315666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14315666</a>] [<a href="https://doi.org/10.1001/archneur.1965.00470020045006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14315666">Spiro and Kennedy (1965)</a> and <a href="#4" class="mim-tip-reference" title="Gonatas, N. K., Shy, G. M., Godfrey, E. H. <strong>Nemaline myopathy: the origin of nemaline structures.</strong> New Eng. J. Med. 274: 535-539, 1966.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5908457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5908457</a>] [<a href="https://doi.org/10.1056/NEJM196603102741002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5908457">Gonatas et al. (1966)</a>, <a href="#8" class="mim-tip-reference" title="Konersman, C. G., Freyermuth, F., Winder, T. L., Lawlor, M. W., Lagier-Tourenne, C., Patel, S. B. <strong>Novel autosomal dominant TNNT1 mutation causing nemaline myopathy.</strong> Molec. Genet. Genomic Med. 5: 678-691, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29178646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29178646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29178646[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/mgg3.325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29178646">Konersman et al. (2017)</a> identified a heterozygous c.311A-T transversion (c.311A-T, NM_003283.4) in exon 9 of the TNNT1 gene, resulting in a glu104-to-val (E104V) substitution at a highly conserved residue in the tropomyosin-binding site 1 region. The mutation, which was found by Sanger sequencing of candidate genes, segregated with the disorder in the family. It was not present in public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Muscle samples from 2 patients showed normal levels of the TNNT1 protein, although low molecular weight (LMW) TNNT1 transcripts and protein levels were increased compared to controls, suggesting a compensatory mechanism. The authors postulated that the mutation could affect the affinity of TNNT1 for tropomyosin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14315666+29178646+5908457" 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>Variant Function</em></strong></p><p>
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<a href="#5" class="mim-tip-reference" title="Holling, T., Lisfeld, J., Johannsen, J., Matschke, J., Song, F., Altmeppen, H. C., Kutsche, K. <strong>Autosomal dominantly inherited myopathy likely caused by the TNNT1 variant p.(Asp65Ala).</strong> Hum. Mutat. 43: 1224-1233, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35510366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35510366</a>] [<a href="https://doi.org/10.1002/humu.24397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35510366">Holling et al. (2022)</a> stated that the E104V mutation affects a residue just outside of the tropomyosin-binding site 1. In vitro studies in HEK293 cells transfected with the mutation showed normal expression of TNNT1 and effective binding to tropomyosin-3 (TPM3; <a href="/entry/191030">191030</a>), although binding of the mutant protein to TPM3 was reduced by 35% in the presence of calcium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35510366" 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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TNNT1, ASP65ALA
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003230316" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003230316" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003230316</a>
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<p>In a mother and son with autosomal dominant nemaline myopathy-5C (NEM5C; <a href="/entry/620389">620389</a>), <a href="#5" class="mim-tip-reference" title="Holling, T., Lisfeld, J., Johannsen, J., Matschke, J., Song, F., Altmeppen, H. C., Kutsche, K. <strong>Autosomal dominantly inherited myopathy likely caused by the TNNT1 variant p.(Asp65Ala).</strong> Hum. Mutat. 43: 1224-1233, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35510366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35510366</a>] [<a href="https://doi.org/10.1002/humu.24397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35510366">Holling et al. (2022)</a> identified a heterozygous c.194A-C transversion (c.194A-C, NM_003283.6) in exon 8 of the TNNT1 gene, resulting in an asp65-to-ala (D65A) substitution in the tropomyosin-binding site 1 region. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Genetic studies of the mother's parents showed that the mutation occurred de novo in the mother. The total amount of TNNT1 protein in the mother's skeletal muscle was similar to controls. Muscle biopsy from the mother showed type 1 fiber hypotrophy, type 2 fiber hypertrophy, increased amounts of fast skeletal fiber myosin-2a (MYH2; <a href="/entry/160740">160740</a>), and increased actin levels, which may be compensatory mechanisms. In vitro studies in HEK293 cells transfected with the mutation showed normal expression of TNNT1, and coimmunoprecipitation studies showed significantly increased binding to tropomyosin-3 (TPM3; <a href="/entry/191030">191030</a>), both in the presence and absence of calcium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35510366" 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="#Trask1993" class="mim-tip-reference" title="Trask, B., Fertitta, A., Christensen, M., Youngblom, J., Bergmann, A., Copeland, A., de Jong, P., Mohrenweiser, H., Olsen, A., Carrano, A., Tynan, K. <strong>Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers.</strong> Genomics 15: 133-145, 1993.">Trask et al. (1993)</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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Fox, M. D., Carson, V. J., Feng, H.-Z., Lawlor, M. W., Gray, J. T., Brigatti, K. W., Jin, J.-P., Strauss, K. A.
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<strong>TNNT1 nemaline myopathy: natural history and therapeutic frontier.</strong>
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Hum. Molec. Genet. 27: 3272-3282, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29931346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29931346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29931346[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29931346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddy233" target="_blank">Full Text</a>]
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Geraud, J., Dieterich, K., Rendu, J., Uro Coste, E., Dobrzynski, M., Marcorelle, P., Ioos, C., Romero, N. B., Baudou, E., Brocard, J., Coville, A.-C., Faure, J., and 10 others.
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<strong>Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy.</strong>
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J. Med. Genet. 58: 602-608, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32994279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32994279</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32994279[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32994279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Gonatas, N. K., Shy, G. M., Godfrey, E. H.
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<strong>Nemaline myopathy: the origin of nemaline structures.</strong>
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New Eng. J. Med. 274: 535-539, 1966.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5908457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5908457</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5908457" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM196603102741002" target="_blank">Full Text</a>]
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<strong>Autosomal dominantly inherited myopathy likely caused by the TNNT1 variant p.(Asp65Ala).</strong>
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Hum. Mutat. 43: 1224-1233, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35510366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35510366</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35510366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.24397" target="_blank">Full Text</a>]
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Jin, J.-P., Brotto, M. A., Hossain, M. M., Huang, Q.-Q., Brotto, L. S., Nosek, T. M., Morton, D. H., Crawford, T. O.
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<strong>Truncation by glu180 nonsense mutation results in complete loss of skeletal muscle troponin T in a lethal nemaline myopathy.</strong>
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J. Biol. Chem. 278: 26159-26165, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12732643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12732643</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12732643" 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.M303469200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/303089" target="_blank">Full Text</a>]
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<strong>Novel autosomal dominant TNNT1 mutation causing nemaline myopathy.</strong>
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[<a href="https://doi.org/10.1002/mgg3.325" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2021.12.003" target="_blank">Full Text</a>]
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Martin-Jimenez, P., Fuenmayor-Fernandez de la Hoz, C. P., Hernandez-Lain, A., Arteche-Lopez, A., Quesada-Espinosa, J. F., Voth, A. H., Vesperinas, A., Olive, M., Dominguez-Gonzalez, C.
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[<a href="https://doi.org/10.1002/mus.27678" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI114351" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF02265301" target="_blank">Full Text</a>]
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Pellerin, D., Aykanat, A., Ellezam, B., Troiano, E. C., Karamchandani, J., Dicaire, M.-J., Petitclerc, M., Robertson, R., Allard-Chamard, X., Brunet, D., Konersman, C. G., Mathieu, J., Warman Chardon, J., Gupta, V. A., Beggs, A. H., Brais, B., Chrestian, N.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31970803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31970803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31970803[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31970803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.25685" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1505979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1505979</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1505979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(92)90077-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/jnr.490270403" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/bbrc.1994.1305" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1965.00470020045006" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1993.1021" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/mgg3.52" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15665378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15665378</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15665378" 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.M413696200" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 05/22/2023
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Hilary J. Vernon - updated : 11/18/2020<br>Patricia A. Hartz - updated : 1/30/2009<br>Cassandra L. Kniffin - updated : 12/2/2008<br>Victor A. McKusick - updated : 10/19/2000
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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 : 12/30/1989
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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alopez : 05/31/2023
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alopez : 05/30/2023<br>alopez : 05/30/2023<br>ckniffin : 05/22/2023<br>carol : 11/18/2020<br>carol : 02/20/2014<br>joanna : 8/2/2013<br>carol : 8/2/2013<br>mgross : 1/30/2009<br>wwang : 12/8/2008<br>ckniffin : 12/2/2008<br>ckniffin : 4/4/2005<br>carol : 10/20/2004<br>carol : 10/24/2000<br>terry : 10/19/2000<br>dkim : 9/9/1998<br>terry : 6/3/1998<br>mark : 7/3/1997<br>joanna : 2/11/1996<br>jason : 6/13/1994<br>carol : 5/12/1993<br>carol : 2/11/1993<br>carol : 10/7/1992<br>carol : 9/16/1992<br>carol : 5/11/1992
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<strong>*</strong> 191041
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TROPONIN T1, SKELETAL, SLOW; TNNT1
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<em>Alternative titles; symbols</em>
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TROPONIN T
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TNNT1</em></strong>
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<strong>SNOMEDCT:</strong> 1197155007;
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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> : 19:55,132,698-55,149,206 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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19q13.42
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<span class="mim-font">
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Nemaline myopathy 5A, autosomal recessive, severe infantile
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<span class="mim-font">
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605355
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Autosomal recessive
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<span class="mim-font">
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3
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Nemaline myopathy 5B, autosomal recessive, childhood-onset
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<span class="mim-font">
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620386
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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Nemaline myopathy 5C, autosomal dominant
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<span class="mim-font">
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620389
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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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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<strong>Description</strong>
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<span class="mim-text-font">
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<p>The TNNT1 gene encodes the slow skeletal muscle troponin. The sarcomere, the contractile element in muscle, including the myocardium, is constituted by 7 major proteins and several minor ones organized into thin and thick filaments. Each tropomyosin dimer (TPM1, 191010; TPM2, 190990) interacts with 7 actins and is associated with a troponin complex. Each complex is composed of 1 molecule of each of the 3 troponins: T, C, and I. This tropomyosin-troponin complex is responsible for the calcium sensitivity of the contractile apparatus (Nadal-Ginard and Mahdavi, 1989), and thus plays an important role in linking excitation to contraction in skeletal muscle. </p>
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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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<span class="mim-text-font">
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<p>Samson et al. (1994) concluded that there are 4 isoforms of human slow skeletal troponin-T mRNA and that these probably result from combinatorial alternative splicing of a single gene. </p><p>By PCR of adult human skeletal muscle total RNA, Barton et al. (1999) cloned full-length TNNT1 and identified 3 shorter splice variants. The full-length protein contains 278 amino acids. Northern blot analysis detected TNNT1 expression in adult skeletal muscle, but not in adult heart and liver or in fetal heart. </p><p>Alternative splicing of exon 5 of the TNNT1 gene generates a high molecular weight (HMW) isoform (with exon 5) and a low molecular weight isoform (LMW) isoform (without exon 5). LMW TNNT1 has a higher binding affinity for tropomyosin and generates more calcium-activated contractile force than the HMW isoform, which enables regulation and modulation of muscle contractility. Normal adult slow muscles express mainly the HMW isoform (summary by Holling et al., 2022). </p>
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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>Barton et al. (1999) determined that the TNNT1 gene contains 14 exons and spans more than 16 kb. The first exon is noncoding. </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>Samson et al. (1990) assigned the slow skeletal isoform of troponin T (TNNT1) to chromosome 19q13.3-q13.4 using a panel of somatic cell hybrids and a cDNA clone as probe. </p><p>Novelli et al. (1991, 1992) confirmed the assignment of the TNNT1 gene to human chromosome 19 by showing the presence of a specific PCR product in hybrids retaining chromosome 19. The cardiac isoform of troponin-I (TNNI3; 191044) maps to the same region. </p><p>Samson et al. (1991) achieved regional assignment to the 19q13.2-qter region by analysis of 7 somatic cell hybrids containing different portions of chromosome 19. They excluded TNNT1 as a candidate gene for myotonic dystrophy (DM1; 160900) by the finding of obligate recombination events in family linkage studies.</p><p>Samson et al. (1992) mapped the TNNT1 gene to chromosome 19q13.4 by study of somatic cell hybrids and fluorescence in situ hybridization. </p><p>Barton et al. (1999) determined that the TNNI3 gene and the TNNT1 gene are oriented head to tail, with the TNNI3 gene 2.6 kb upstream of exon 1 of the TNNT1 gene. </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>Autosomal Recessive Severe Infantile Nemaline Myopathy 5A</em></strong></p><p>
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In Amish patients with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355), Johnston et al. (2000) identified homozygosity for a nonsense mutation in the TNNT1 gene (E180X; 191041.0001). </p><p>In a Dutch boy with NEM5A, van der Pol et al. (2014) identified compound heterozygous mutations in the TNNT1 gene: a splice site mutation (191041.0002) and an intragenic deletion (ex14del; 191041.0003). The mutations were inherited from the unaffected parents. Homozygosity for the splice site mutation was identified in 2 paternal cousins with a similar disorder who died in childhood of respiratory insufficiency. </p><p>In 3 unrelated patients with NEM5A, Geraud et al. (2021) identified homozygous or compound heterozygous mutations in the TNNT1 gene (see, e.g., 191041.0004-191041.0006). Western blot analysis of skeletal muscle from the patients showed absence of the TNNT1 protein. All died by 29 months of age. </p><p><strong><em>Autosomal Recessive Childhood-Onset Nemaline Myopathy 5B</em></strong></p><p>
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In 4 patients from 3 unrelated French Canadian families with autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B; 620386), Pellerin et al. (2020) identified a homozygous missense mutation in the TNNT1 gene (L96P; 191041.0007). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in 3 of the families who underwent testing. The mutation was unable to rescue the abnormal muscle phenotype in tnnt1-null zebrafish, suggesting that it causes a loss of function. The authors postulated that there was some residual activity or compensation by the low molecular weight TNNT1 isoform, resulting in a milder phenotype compared to patients with complete loss of TNNT1. </p><p>In 2 brothers, born of unrelated Korean parents, with NEM5B, Lee et al. (2022) identified compound heterozygosity for a missense mutation (A242P; 191041.0008) and a splice site mutation (191041.0009) in the TNNT1 gene. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were inherited from the unaffected parents. The splice site mutation was demonstrated to result in altered splicing and frameshifts, and the A242P mutation was unable to rescue the myopathic phenotype in tnnt1-null zebrafish, suggesting that both mutations caused a loss of function. </p><p>In a 51-year-old man with NEM5B, Martin-Jimenez et al. (2022) detected homozygosity for a variant in the TNNT1 gene (c.551_552delinsCA) that resulted in an arg184-to-pro (R184P) substitution. The variant was absent from gnomAD. Segregation studies and functional studies were not performed. The patient presented at age 50 years with a respiratory infection followed by respiratory arrest requiring intubation. He subsequently developed muscle weakness in all limbs which was slowly progressive and resulted in difficulty climbing stairs. </p><p><strong><em>Autosomal Dominant Nemaline Myopathy 5C</em></strong></p><p>
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In 8 affected members of a large consanguineous Ashkenazi Jewish family with autosomal dominant nemaline myopathy-5C (NEM5C; 620389) originally reported by Spiro and Kennedy (1965) and Gonatas et al. (1966), Konersman et al. (2017) identified a heterozygous missense mutation in the TNNT1 gene (E104V; 191041.0010). The mutation, which was found by Sanger sequencing of candidate genes, segregated with the disorder in the family. Holling et al. (2022) stated that the E104V mutation affects a residue just outside of the tropomyosin-binding site 1. In vitro studies in HEK293 cells transfected with the mutation showed normal expression of TNNT1 and effective binding to tropomyosin-3 (TPM3; 191030), although binding of the mutant protein to TPM3 was reduced by 35% in the presence of calcium. </p><p>In a mother and son with NEM5C, Holling et al. (2022) identified a heterozygous missense mutation in the TNNT1 gene (D65A; 191041.0011) that occurred within the tropomyosin-binding site 1 region. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. In vitro studies in HEK293 cells transfected with the mutation showed normal expression of TNNT1, whereas coimmunoprecipitation studies showed significantly increased binding of the D65A variant to TPM3 compared to controls, both in the presence and absence of calcium. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<span class="mim-text-font">
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<p>Fox et al. (2018) described muscle features in 2 mouse models of Tnnt1 deficiency: a targeted gene knockout (Tnnt1 -/-) model and a site-specific knock-in (Tnnt1 c.505G-T) model. Quadratus femoris muscle tissue showed absence of Tnnt1, atrophy/hypotrophy of small type 1 myofibers, hypertrophy of fast type 2 fibers, and the presence of nemaline rods in both mouse models. Both models also showed impaired muscle force generation and exercise recovery in soleus muscles. </p><p>Pellerin et al. (2020) found that morpholino knockout of the tnnt1 gene in zebrafish caused reduced muscle mass, reduced birefringence, and severe truncal curvature compared to controls. Myofibers were disorganized and showed corelike intramyofibrillar areas of sarcomeric disorganization and Z-line thickening. These defects could be rescued by expression of wildtype human TNNT1 mRNA. </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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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>11 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 NEMALINE MYOPATHY 5A, AUTOSOMAL RECESSIVE, SEVERE INFANTILE</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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TNNT1, GLU180TER
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<br />
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SNP: rs80358249,
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gnomAD: rs80358249,
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ClinVar: RCV000020554, RCV000024549
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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 individuals with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355), also known as Amish nemaline myopathy, Johnston et al. (2000) identified a homozygous c.579G-T transversion in exon 11 of the TNNT1 gene, resulting in a stop codon at amino acid 180 (E180X) and loss of 83 C-terminal residues. Johnston et al. (2000) had treated or obtained clinical information on 71 infants and young children from 33 nuclear Amish families with this form of nemaline myopathy. In the first months of life, affected infants had tremors with hypotonia and mild contractures of the shoulders and hips. Progressive worsening of the proximal contractures, weakness, and a pectus carinatum deformity developed before the children died of respiratory insufficiency, usually in the second year. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Jin et al. (2003) found complete loss of the TNNT1 protein in patients with the E180X mutation. The truncated protein results in elimination of the C-terminal T2 domain that interacts with troponin C (TNNC1; 191040), I (TNNI2; 191043), and tropomyosin (TPM1; 191010), but was predicted to retain a central tropomyosin-binding site that participates in the anchoring of troponin complex to the thin actin filament. If residual truncated protein was produced, this could potentially result in a dominant-negative effect. The significant muscle atrophy observed in the disorder was consistent with the slow Tnt isoform being involved in muscle development and growth. </p><p>In a patient with Amish nemaline myopathy due to the E180X mutation, Wang et al. (2005) detected residual mutant TNNT1 mRNA in muscle tissue but no corresponding translated mutant TNNT1 protein. In vitro functional expression studies in nonmuscle cells showed that E180X-mutant protein could be produced but was not detectable when expressed in muscle cells in vitro. The findings suggested rapid degradation of E180X-mutant protein in muscle cells, rather than a loss of nonsense mRNA to explain the absence of a dominant effect. Wang et al. (2005) postulated that inefficient incorporation of mutant TNNT1 into myofilaments results in its degradation by the muscle cell as a protective mechanism. </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 NEMALINE MYOPATHY 5A, AUTOSOMAL RECESSIVE, SEVERE INFANTILE</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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TNNT1, IVS8DS, G-A, +1
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<br />
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SNP: rs149559898,
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gnomAD: rs149559898,
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ClinVar: RCV001529807, RCV003230283
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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 Dutch boy with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355), van der Pol et al. (2014) identified compound heterozygous mutations in the TNNT1 gene: a G-to-A transition in intron 8 (c.309+1G-A, NM_003283.4) inherited from the unaffected father, and an exon 14 deletion (ex14del; 191041.0003) inherited from the unaffected mother. Homozygosity for the c.309+1G-A mutation was identified in 2 paternal cousins with a similar disorder who died in childhood of respiratory insufficiency. The splicing defect resulted in the skipping of exon 8 with an in-frame deletion of 39 functionally important residues from the TNNT1 troponin domain (Asp65_Ile103del). The mutations were predicted to result in a loss of function, although the authors noted that the predicted transcripts could be translated into shortened proteins with some residual activity. </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 NEMALINE MYOPATHY 5A, AUTOSOMAL RECESSIVE, SEVERE INFANTILE</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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TNNT1, EX14 DEL
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<br />
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ClinVar: RCV003230310
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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>For discussion of the exon 14 deletion (ex14del, NM_003283.4) in the TNNT1 gene that was found in compound heterozygous state in a patient with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355) by van der Pol et al. (2014), see 191041.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 NEMALINE MYOPATHY 5A, AUTOSOMAL RECESSIVE, SEVERE INFANTILE</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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TNNT1, GLU112TER
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<br />
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ClinVar: RCV003230311
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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 female infant (patient 2) with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355) resulting in death at 16 months of age, Geraud et al. (2021) identified compound heterozygous mutations in the TNNT1 gene: a c.334G-T transversion (c.334G-T, NM_003283.5), resulting in a glu112-to-ter (E112X) substitution, and a C-to-A transversion in intron 4 (c.74-67C-A; 191041.0005), predicted to result in a splicing defect. Western blot analysis of skeletal muscle from the patient showed absence of the TNNT1 protein. She had a severe form of the disorder with tongue fasciculations, kyphosis, pectus carinatum, and hypotonia. </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 NEMALINE MYOPATHY 5A, AUTOSOMAL RECESSIVE, SEVERE INFANTILE</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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TNNT1, IVS4AS, C-A, -67
|
|
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<br />
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|
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ClinVar: RCV003226144
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.74-67C-A mutation (c.74-67C-A, NM_003283.5) in intron 4 of the TNNT1 gene, resulting in a splicing defect, that was found in compound heterozygous state in a patient with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355) by Geraud et al. (2021) see 191041.0004. </p>
|
|
</span>
|
|
</div>
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|
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<div>
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|
<br />
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</div>
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 NEMALINE MYOPATHY 5A, AUTOSOMAL RECESSIVE, SEVERE INFANTILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT1, GLU6TER
|
|
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|
|
|
<br />
|
|
|
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|
|
|
|
ClinVar: RCV003230312
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (patient 3) with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355) resulting in death at 6 months of age, Geraud et al. (2021) identified a homozygous c.16G-T transversion (cc.74-67C-A, NM_003283.5) in the TNNT1 gene, resulting in a glu6-to-ter (E6X) substitution. Western blot analysis of patient skeletal muscle showed absence of the TNNT1 protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 NEMALINE MYOPATHY 5B, AUTOSOMAL RECESSIVE, CHILDHOOD-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT1, LEU96PRO
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV003230314, RCV004757582
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 patients from 3 unrelated French Canadian families with autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B; 620386), Pellerin et al. (2020) identified a homozygous c.287T-C transition (c.287T-C, NM_003283.6) in exon 8 of the TNNT1 gene, resulting in a leu96-to-pro (L96P) substitution at a conserved residue. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in 3 of the families who underwent testing. The mutation was predicted to disrupt the alpha-helical secondary structure of the tropomyosin-binding site 1 and impair binding affinity. The mutant protein was likely to be misincorporated into myofilaments and undergo partial degradation, as evidenced by lower levels of the high molecular weight troponin T isoform in patient muscle; low molecular weight isoforms were retained. The mutation was unable to rescue the abnormal muscle phenotype in tnnt1-null zebrafish, suggesting that it causes a loss of function. The authors postulated that there was some residual activity or compensation by the low molecular weight isoform, resulting in a milder phenotype compared to patients with complete loss of TNNT1. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Holling et al. (2022) found that expression of the L96P mutation was increased compared to controls when transfected into HEK293 cells. Coimmunoprecipitation studies showed significantly reduced interaction (by 88%) of the L96P mutant with tropomyosin-3 (TPM3; 191030), and this interaction was abrogated in the presence of calcium. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 NEMALINE MYOPATHY 5B, AUTOSOMAL RECESSIVE, CHILDHOOD-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT1, ALA242PRO
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV003230315
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers, born of unrelated Korean parents, with autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B; 620386), Lee et al. (2022) identified compound heterozygous mutations in the TNNT1 gene: a c.724G-C transversion (c.724G-C, NM_003283) in exon 12, resulting in an ala242-to-pro (A242P) substitution in the conserved troponin I-binding domain, and a G-to-A transition in intron 11 (c.611+1G-A; 191041.0009), resulting in a splicing defect and frameshifts. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were inherited from the unaffected parents. The splice site mutation was found once in the heterozygous state in a Korean individual in gnomAD (1 of 249,306 alleles, frequency of 4.01 x 10(-6)). The A242P mutation was unable to rescue the myopathic phenotype in tnnt1-null zebrafish, suggesting that this mutation causes a loss of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 NEMALINE MYOPATHY 5B, AUTOSOMAL RECESSIVE, CHILDHOOD-ONSET</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT1, IVS11DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV003230313
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the G-to-A transition in intron 11 of the TNNT1 gene (c.611+1G-A, NM_003283), resulting in a splicing defect and frameshifts, that was found in compound heterozygous state in 2 brothers with autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B; 620386) by Lee et al. (2022), see 191041.0008. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 NEMALINE MYOPATHY 5C, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT1, GLU104VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2085441049,
|
|
|
|
|
|
|
|
ClinVar: RCV001209655, RCV003230280
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 8 affected members of a large consanguineous Ashkenazi Jewish family with autosomal dominant nemaline myopathy-5C (NEM5C; 620389) originally reported by Spiro and Kennedy (1965) and Gonatas et al. (1966), Konersman et al. (2017) identified a heterozygous c.311A-T transversion (c.311A-T, NM_003283.4) in exon 9 of the TNNT1 gene, resulting in a glu104-to-val (E104V) substitution at a highly conserved residue in the tropomyosin-binding site 1 region. The mutation, which was found by Sanger sequencing of candidate genes, segregated with the disorder in the family. It was not present in public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Muscle samples from 2 patients showed normal levels of the TNNT1 protein, although low molecular weight (LMW) TNNT1 transcripts and protein levels were increased compared to controls, suggesting a compensatory mechanism. The authors postulated that the mutation could affect the affinity of TNNT1 for tropomyosin. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Holling et al. (2022) stated that the E104V mutation affects a residue just outside of the tropomyosin-binding site 1. In vitro studies in HEK293 cells transfected with the mutation showed normal expression of TNNT1 and effective binding to tropomyosin-3 (TPM3; 191030), although binding of the mutant protein to TPM3 was reduced by 35% in the presence of calcium. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 NEMALINE MYOPATHY 5C, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TNNT1, ASP65ALA
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV003230316
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and son with autosomal dominant nemaline myopathy-5C (NEM5C; 620389), Holling et al. (2022) identified a heterozygous c.194A-C transversion (c.194A-C, NM_003283.6) in exon 8 of the TNNT1 gene, resulting in an asp65-to-ala (D65A) substitution in the tropomyosin-binding site 1 region. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Genetic studies of the mother's parents showed that the mutation occurred de novo in the mother. The total amount of TNNT1 protein in the mother's skeletal muscle was similar to controls. Muscle biopsy from the mother showed type 1 fiber hypotrophy, type 2 fiber hypertrophy, increased amounts of fast skeletal fiber myosin-2a (MYH2; 160740), and increased actin levels, which may be compensatory mechanisms. In vitro studies in HEK293 cells transfected with the mutation showed normal expression of TNNT1, and coimmunoprecipitation studies showed significantly increased binding to tropomyosin-3 (TPM3; 191030), both in the presence and absence of calcium. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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</div>
|
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|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Trask et al. (1993)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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|
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|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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: 10191089]
|
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|
|
[Full Text: https://doi.org/10.1006/geno.1998.5702]
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</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fox, M. D., Carson, V. J., Feng, H.-Z., Lawlor, M. W., Gray, J. T., Brigatti, K. W., Jin, J.-P., Strauss, K. A.
|
|
<strong>TNNT1 nemaline myopathy: natural history and therapeutic frontier.</strong>
|
|
Hum. Molec. Genet. 27: 3272-3282, 2018.
|
|
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|
|
[PubMed: 29931346]
|
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddy233]
|
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|
</p>
|
|
</li>
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</body>
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</html>
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