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<title>
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Entry
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- *190990 - TROPOMYOSIN 2; TPM2
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- OMIM
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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="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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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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Advanced Search
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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 style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </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">*190990</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="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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</li>
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<li role="presentation">
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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/190990">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000198467;t=ENST00000645482" 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=7169" 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=190990" 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=ENSG00000198467;t=ENST00000645482" 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_001301226,NM_001301227,NM_003289,NM_213674,XM_017015088,XM_047423827" 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_003289" 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=190990" 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=11768&isoform_id=11768_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/TPM2" 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/37249,136090,339731,339952,339969,339975,463070,6573280,15079982,42476296,47519616,62898077,119578758,119578759,156255416,194377570,194388338,194390512,209402746,669033275,669033277,1034671179,2217378468,2462626239" 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/P07951" 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=7169" 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=ENSG00000198467;t=ENST00000645482" 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=TPM2" 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=TPM2" 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+7169" 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/TPM2" 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:7169" 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/7169" 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=chr9&hgg_gene=ENST00000645482.3&hgg_start=35681993&hgg_end=35690056&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:12011" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/tpm2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=190990[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=190990[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/TPM2/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000198467" 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=TPM2" 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=TPM2" 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=TPM2" 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/TPM2" 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=TPM2&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/PA36691" 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:12011" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0003721.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:98810" 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/TPM2#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:98810" 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/7169/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=7169" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00002978;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040625-114" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7169" 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=TPM2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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190990
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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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TROPOMYOSIN 2; TPM2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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TROPOMYOSIN, SKELETAL MUSCLE BETA; TMSB
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TPM2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TPM2</a></em></strong>
|
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/9/172?start=-3&limit=10&highlight=172">9p13.3</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:35681993-35690056&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'})">9:35,681,993-35,690,056</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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<a href="/geneMap/9/172?start=-3&limit=10&highlight=172">
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9p13.3
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Arthrogryposis, distal, type 1A
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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Arthrogryposis, distal, type 2B4
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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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Congenital myopathy 23
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<a href="/entry/609285"> 609285 </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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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/190990" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/190990" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<h4>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The TPM2 gene encodes beta-tropomyosin, an isoform of tropomyosin that is mainly expressed in slow, type 1 muscle fibers, and, to some extent, in fast muscle fibers and cardiac muscle (summary by <a href="#19" class="mim-tip-reference" title="Tajsharghi, H., Ohlsson, M., Lindberg, C., Oldfors, A. <strong>Congenital myopathy with nemaline rods and cap structures caused by a mutation in the beta-tropomyosin gene (TPM2).</strong> Arch. Neurol. 64: 1334-1338, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17846275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17846275</a>] [<a href="https://doi.org/10.1001/archneur.64.9.1334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17846275">Tajsharghi et al., 2007</a>). See also TPM1 (<a href="/entry/191010">191010</a>), TPM3 (<a href="/entry/191030">191030</a>), and TPM4 (<a href="/entry/600317">600317</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17846275" 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="#21" class="mim-tip-reference" title="Widada, J. S., Ferraz, C., Capony, J.-P., Liautard, J.-P. <strong>Complete nucleotide sequence of the adult skeletal isoform of human skeletal muscle beta-tropomyosin.</strong> Nucleic Acids Res. 16: 3109 only, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3368322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3368322</a>] [<a href="https://doi.org/10.1093/nar/16.7.3109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3368322">Widada et al. (1988)</a> reported the complete nucleotide sequence of the mRNA encoding the human skeletal muscle isoform of beta-tropomyosin. Comparison of this sequence with that of the human fibroblast isoform confirmed that alternative splicing occurs on exons 6 and 9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3368322" 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="#8" class="mim-tip-reference" title="Laing, N. G., Wilton, S. D., Akkari, P. A., Dorosz, S., Boundy, K., Kneebone, C., Blumbergs, P., White, S., Watkins, H., Love, D. R., Haan, E. <strong>A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy.</strong> Nature Genet. 9: 75-79, 1995. Note: Erratum: Nature Genet. 10: 249 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7704029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7704029</a>] [<a href="https://doi.org/10.1038/ng0195-75" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7704029">Laing et al. (1995)</a> referred to unpublished observations indicating that the TPM2 gene maps to 9p13. <a href="#5" class="mim-tip-reference" title="Hunt, C. C. J., Eyre, H. J., Akkari, P. A., Meredith, C., Dorosz, S. M., Wilton, S. D., Callen, D. F., Laing, N. G., Baker, E. <strong>Assignment of the human beta tropomyosin gene (TPM2) to band 9p13 by fluorescence in situ hybridization.</strong> Cytogenet. Cell Genet. 71: 94-95, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7606936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7606936</a>] [<a href="https://doi.org/10.1159/000134070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7606936">Hunt et al. (1995)</a> developed a sequence tagged site (STS) for the TPM2 gene and used it to amplify DNA from somatic cell hybrids to localize the gene to human chromosome 9. The genomic clones isolated with the STS product were in turn used in fluorescence in situ hybridization to metaphase chromosome spreads to refine the localization of TPM2 to 9p13. <a href="#20" class="mim-tip-reference" title="Tiso, N., Rampoldi, L., Pallavicini, A., Zimbello, R., Pandolfo, D., Valle, G., Lanfranchi, G., Danieli, G. A. <strong>Fine mapping of five human skeletal muscle genes: alpha-tropomyosin, beta-tropomyosin, troponin-I slow-twitch, troponin-I fast-twitch, and troponin-C fast.</strong> Biochem. Biophys. Res. Commun. 230: 347-350, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9016781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9016781</a>] [<a href="https://doi.org/10.1006/bbrc.1996.5958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9016781">Tiso et al. (1997)</a> further refined the mapping of the TPM2 gene to 9p13.2-p13.1 using PCR of radiation hybrids. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9016781+7606936+7704029" 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="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 06/17/2022."None>Stumpf (2022)</a> mapped the TPM2 gene to chromosome 9p13.3 based on an alignment of the TPM2 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC011776" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC011776</a>) with the genomic sequence (GRCh38).</p>
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<strong>Gene Function</strong>
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<p>Tropomyosin, together with actin (ACTA1; <a href="/entry/102610">102610</a>) and troponin (see, e.g., TNNT1; <a href="/entry/191041">191041</a>), constitutes the basic thin filament structural and calcium-regulatory machinery that interacts with myosin when muscle contracts. Tropomyosin polymerizes head-to-tail with other tropomyosin molecules into long strands spanning the whole thin filament length, and binds to different actin monomers. The key function of tropomyosin is in cooperatively switching the location of the actin-tropomyosin interface between active and relaxed states under the control of troponin, calcium, and myosin heads. <a href="#11" class="mim-tip-reference" title="Marston, S., Memo, M., Messer, A., Papadaki, M., Nowak, K., McNamara, E., Ong, R., El-Mezgueldi, M., Li, X., Lehman, W. <strong>Mutations in repeating motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients.</strong> Hum. Molec. Genet. 22: 4978-4987, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23886664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23886664</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23886664[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/ddt345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23886664">Marston et al. (2013)</a> noted that the actin-binding interface motifs in tropomyosin are repeated motifs common to all tropomyosin molecules, and include K6-K7, K48-K49, R90-R91, and R167-K168, which interact with D25 in actin, and 3 additional tropomyosin motifs, E139, E181, and E218, which interact with a cluster of actin motifs at K326, K328, and R147. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23886664" 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>Distal Arthrogryposis Type 1A1</em></strong></p><p>
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In affected members of a large multigenerational family (family K5) with distal arthrogryposis type 1A1 (DA1A; <a href="/entry/108120">108120</a>), originally reported as family F by <a href="#1" class="mim-tip-reference" title="Bamshad, M., Watkins, W. S., Zenger, R. K., Bohnsack, J. F., Carey, J. C., Otterud, B., Krakowiak, P. A., Robertson, M., Jorde, L. B. <strong>A gene for distal arthrogryposis type I maps to the pericentromeric region of chromosome 9.</strong> Am. J. Hum. Genet. 55: 1153-1158, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7977374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7977374</a>]" pmid="7977374">Bamshad et al. (1994)</a> and linked to the pericentromeric region of chromosome 9, <a href="#17" class="mim-tip-reference" title="Sung, S. S., Brassington, A.-M. E., Grannatt, K., Rutherford, A., Whitby, F. G., Krakowiak, P. A., Jorde, L. B., Carey, J. C., Bamshad, M. <strong>Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes.</strong> Am. J. Hum. Genet. 72: 681-690, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12592607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12592607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12592607[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/10.1086/368294" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12592607">Sung et al. (2003)</a> identified a heterozygous missense mutation in the TPM2 gene (R91G; <a href="#0001">190990.0001</a>). The findings indicated that this form of distal arthrogryposis has a myopathic origin, specifically in the contractile apparatus of fast-twitch myofibers. Functional studies of the variant and studies of patient cells were not performed. TPM2 mutations were not found in 13 additional probands with a similar disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7977374+12592607" 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 in vitro studies, <a href="#15" class="mim-tip-reference" title="Robinson, P., Lipscomb, S., Preston, L. C., Altin, E., Watkins, H., Ashley, C. C., Redwood, C. S. <strong>Mutations in fast skeletal troponin I, troponin T, and beta-tropomyosin that cause distal arthrogryposis all increase contractile function.</strong> FASEB J. 21: 896-905, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17194691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17194691</a>] [<a href="https://doi.org/10.1096/fj.06-6899com" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17194691">Robinson et al. (2007)</a> demonstrated that the TPM2 R91G mutation resulted in a gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility. <a href="#15" class="mim-tip-reference" title="Robinson, P., Lipscomb, S., Preston, L. C., Altin, E., Watkins, H., Ashley, C. C., Redwood, C. S. <strong>Mutations in fast skeletal troponin I, troponin T, and beta-tropomyosin that cause distal arthrogryposis all increase contractile function.</strong> FASEB J. 21: 896-905, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17194691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17194691</a>] [<a href="https://doi.org/10.1096/fj.06-6899com" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17194691">Robinson et al. (2007)</a> concluded that the mutation would cause increased tension in developing muscles, thus resulting in contractures and limb deformities via an active process rather than a passive process. These findings implicated disturbed muscle function as the pathogenic mechanism underlying DA1A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17194691" 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>Distal Arthrogryposis Type 2B4</em></strong></p><p>
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In a mother and daughter with a form of distal arthrogryposis most consistent with type 2B (DA2B4; see <a href="/entry/108120">108120</a>), <a href="#18" class="mim-tip-reference" title="Tajsharghi, H., Kimber, E., Holmgren, D., Tulinius, M., Oldfors, A. <strong>Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation.</strong> Neurology 68: 772-775, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17339586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17339586</a>] [<a href="https://doi.org/10.1212/01.wnl.0000256339.40667.fb" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17339586">Tajsharghi et al. (2007)</a> identified a heterozygous mutation in the TPM2 gene (R133W; <a href="#0004">190990.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17339586" 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 Korean mother and daughter with distal arthrogryposis type 2, <a href="#7" class="mim-tip-reference" title="Ko, J. M., Choi, I.-H., Baek, G.-H., Kim, K.-w. <strong>First Korean family with a mutation in TPM2 associated with Sheldon-Hall syndrome.</strong> J. Korean Med. Sci. 28: 780-783, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23678273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23678273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23678273[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/10.3346/jkms.2013.28.5.780" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23678273">Ko et al. (2013)</a> identified the same R133W mutation in the TPM2 gene that had previously been identified in an affected mother and daughter (<a href="#0004">190990.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23678273" 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 female infant, born to unrelated parents, with congenital distal arthrogryposis, dysmorphic facial features, and myopathy, <a href="#13" class="mim-tip-reference" title="Mroczek, M., Kabzinska, D., Chrzanowska, K. H., Pronicki, M., Kochanski, A. <strong>A novel TPM2 gene splice-site mutation causes severe congenital myopathy with arthrogryposis and dysmorphic features.</strong> J. Appl. Genet. 58: 199-203, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27726070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27726070</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27726070[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/10.1007/s13353-016-0368-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27726070">Mroczek et al. (2017)</a> identified a de novo heterozygous splice site mutation in the TPM2 gene (<a href="#0011">190990.0011</a>). The mutation was not present in the parents or in 100 healthy controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27726070" 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 affected members of a Chinese family (family 1) segregating DA2B4, <a href="#10" class="mim-tip-reference" title="Li, S., You, Y., Gao, J., Mao, B., Cao, Y., Zhao, X., Zhang, X. <strong>Novel mutations in TPM2 and PIEZO2 are responsible for distal arthrogryposis (DA) and mild DA in two Chinese families.</strong> BMC Med. Genet. 19: 179 only, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30285720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30285720</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30285720[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/10.1186/s12881-018-0692-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30285720">Li et al. (2018)</a> identified heterozygosity for a missense mutation (Q103R; <a href="#0010">190990.0010</a>) in the TPM2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30285720" 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>Congenital Myopathy 23</em></strong></p><p>
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In 2 unrelated patients with congenital myopathy-23 (CMYO23; <a href="/entry/609285">609285</a>), a woman with a mild form of the disease and the son of an affected mother, <a href="#4" class="mim-tip-reference" title="Donner, K., Ollikainen, M., Ridanpaa, M., Christen, H.-J., Goebel, H. H., de Visser, M., Pelin, K., Wallgren-Pettersson, C. <strong>Mutations in the beta-tropomyosin (TPM2) gene--a rare cause of nemaline myopathy.</strong> Neuromusc. Disord. 12: 151-158, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11738357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11738357</a>] [<a href="https://doi.org/10.1016/s0960-8966(01)00252-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11738357">Donner et al. (2002)</a> identified 2 different heterozygous missense mutations in the TPM2 gene (Q147P, <a href="#0002">190990.0002</a> and E117K, <a href="#0003">190990.0003</a>, respectively). The affected mother was found to carry the same mutation as her son. Functional studies of the variants were not performed, but the authors speculated that the mutation affects the actin-binding properties of TPM2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11738357" 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 36-year-old man with CMYO23 since childhood, <a href="#9" class="mim-tip-reference" title="Lehtokari, V.-L., Ceuterick-de Groote, C., de Jonghe, P., Marttila, M., Laing, N. G., Pelin, K., Wallgren-Pettersson, C. <strong>Cap disease caused by heterozygous deletion of the beta-tropomyosin gene TPM2.</strong> Neuromusc. Disord. 17: 433-442, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17434307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17434307</a>] [<a href="https://doi.org/10.1016/j.nmd.2007.02.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17434307">Lehtokari et al. (2007)</a> identified a heterozygous 3-bp in-frame deletion (415delGAG; <a href="#0006">190990.0006</a>) of the TPM2 gene, resulting in the removal of glu139 and predicted to disrupt the 7-amino acid repeat essential for making a coiled-coil motif and to impair tropomyosin-actin interaction. <a href="#2" class="mim-tip-reference" title="Clarke, N. F., Domazetovska, A., Waddell, L., Kornberg, A., McLean, C., North, K. N. <strong>Cap disease due to mutation of the beta-tropomyosin gene (TPM2).</strong> Neuromusc. Disord. 19: 348-351, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19345583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19345583</a>] [<a href="https://doi.org/10.1016/j.nmd.2009.03.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19345583">Clarke et al. (2009)</a> identified the E139del mutation in a girl with cap myopathy. Protein studies showed that the mutant TPM2 protein interacted with the wildtype protein and was incorporated into the sarcomere. The authors postulated that the mutation probably weakened the interaction with other proteins within skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19345583+17434307" 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="Ohlsson, M., Quijano-Roy, S., Darin, N., Brochier, G., Lacene, E., Avila-Smirnow, D., Fardeau, M., Oldfors, A., Tajsharghi, H. <strong>New morphologic and genetic findings in cap disease associated with beta-tropomyosin (TPM2) mutations.</strong> Neurology 71: 1896-1901, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19047562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19047562</a>] [<a href="https://doi.org/10.1212/01.wnl.0000336654.44814.b8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19047562">Ohlsson et al. (2008)</a> identified 3 different heterozygous TPM2 mutations (see, e.g., <a href="#0007">190990.0007</a> and <a href="#0008">190990.0008</a>) in 3 unrelated patients with CMYO23. One of the mutations deleted residue K49 (<a href="#0007">190990.0007</a>). Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19047562" 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 8 patients from 5 unrelated families with CMYO23, <a href="#12" class="mim-tip-reference" title="Mokbel, N., Ilkovski, B., Kreissl, M., Memo, M., Jeffries, C. M., Marttila, M., Lehtokari, V.-L., Lemola, E., Gronholm, M., Yang, N., Menard, D., Marcorelles, P., and 14 others. <strong>K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity.</strong> Brain 136: 494-507, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23378224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23378224</a>] [<a href="https://doi.org/10.1093/brain/aws348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23378224">Mokbel et al. (2013)</a> identified the same 3-bp deletion in the TPM2 gene (lys7del, K7del; <a href="#0009">190990.0009</a>). The transmission pattern in 2 families was consistent with autosomal dominant inheritance; the mutation was suspected to have occurred de novo in 3 other families. Studies of patient muscle and differentiated myotubes transfected with the mutation suggested that the mutant protein incorporates poorly into sarcomeres and likely accumulates in nemaline bodies, and interferes with wildtype in a dominant-negative manner. Patient myofibers had normal force generation, but increased sensitivity to calcium in motility assays. The mutant protein also showed reduced binding affinity for actin and a decreased ability to polymerize into long tropomyosin filaments. <a href="#12" class="mim-tip-reference" title="Mokbel, N., Ilkovski, B., Kreissl, M., Memo, M., Jeffries, C. M., Marttila, M., Lehtokari, V.-L., Lemola, E., Gronholm, M., Yang, N., Menard, D., Marcorelles, P., and 14 others. <strong>K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity.</strong> Brain 136: 494-507, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23378224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23378224</a>] [<a href="https://doi.org/10.1093/brain/aws348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23378224">Mokbel et al. (2013)</a> noted that the presence of joint contractures was the most prominent clinical feature in these patients and that 1 patient had hypertonicity. These findings suggested that the joint contractures may result from impaired muscle relaxation and a tendency for muscles to slowly shorten. Progressive muscle weakness in adulthood may result from a combination of muscle degeneration and apoptosis due to cellular stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23378224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Davidson, A. E., Siddiqui, F. M., Lopez, M. A., Lunt, P., Carlson, H. A., Moore, B. E., Love, S., Born, D. E., Roper, H., Majumdar, A., Jayadev, S., Underhill, H. R., and 14 others. <strong>Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies.</strong> Brain 136: 508-521, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23413262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23413262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23413262[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/brain/aws344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23413262">Davidson et al. (2013)</a> identified a heterozygous K7del mutation in affected members of 4 families with CMYO23 associated with distal arthrogryposis and limited jaw opening. The mutation in 1 family was found by whole-exome sequencing and confirmed by Sanger sequencing to segregate with the disorder; the mutation in the other families was found by candidate gene testing. Molecular modeling predicted that the mutation would alter protein-protein binding between TPM2 and other proteins as well as disturb the head-to-tail polymerization of TPM2 dimers. Expression of the mutation in developing zebrafish showed that the mutant protein did not localize properly within the thin filament compartment and altered sarcomere length, suggesting that it impaired sarcomeric structure. Areas of perimembranous accumulations of alpha-actinin were observed in mutant myofibers, consistent with findings in nemaline myopathy. These findings unified the phenotype of congenital myopathy with distal arthrogryposis (DA1A; <a href="/entry/108120">108120</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23413262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In in vitro studies, <a href="#11" class="mim-tip-reference" title="Marston, S., Memo, M., Messer, A., Papadaki, M., Nowak, K., McNamara, E., Ong, R., El-Mezgueldi, M., Li, X., Lehman, W. <strong>Mutations in repeating motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients.</strong> Hum. Molec. Genet. 22: 4978-4987, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23886664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23886664</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23886664[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/ddt345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23886664">Marston et al. (2013)</a> found that certain TPM2 mutations affecting the actin binding sites, K49del (<a href="/entry/190090#0007">190090.0007</a>), R91G (<a href="/entry/190090#0001">190090.0001</a>), E139del (<a href="/entry/190090#0006">190090.0006</a>), E181K, and K168E, resulted in higher calcium sensitivity, higher filament sliding speeds, and a gain-of-function effect. In contrast, the E41K (<a href="/entry/190090#0005">190090.0005</a>) and E117K (<a href="/entry/190090#0003">190090.0003</a>) mutations showed lower calcium sensitivity, slower sliding speeds, and a hypocontractile phenotype. <a href="#11" class="mim-tip-reference" title="Marston, S., Memo, M., Messer, A., Papadaki, M., Nowak, K., McNamara, E., Ong, R., El-Mezgueldi, M., Li, X., Lehman, W. <strong>Mutations in repeating motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients.</strong> Hum. Molec. Genet. 22: 4978-4987, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23886664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23886664</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23886664[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/ddt345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23886664">Marston et al. (2013)</a> noted the range of muscle biopsy findings identified in patients with these mutations and suggested that consideration of the effects of the mutations on muscle contractility would be more predictive of the phenotype. Specifically, patients with gain-of-function mutations tended to have hypercontractility associated with arthrogryposis. A mutation at one of the tropomyosin binding sites in the actin molecule (K328N; <a href="/entry/102610#0016">102610.0016</a>) resulted in a similar phenotype characterized by hypercontractility (<a href="#6" class="mim-tip-reference" title="Jain, R. K., Jayawant, S., Squier, W., Muntoni, F., Sewry, C. A., Manzur, A., Quinlivan, R., Lillis, S., Jungbluth, H., Sparrow, J. C., Ravenscroft, G., Nowak, K. J., Memo, M., Marston, S. B., Laing, N. G. <strong>Nemaline myopathy with stiffness and hypertonia associated with an ACTA1 mutation.</strong> Neurology 78: 1100-1103, 2012. Note: Erratum: Neurology 78: 1704 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22442437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22442437</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31824e8ebe" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22442437">Jain et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22442437+23886664" 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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<strong>11 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=190990[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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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894127 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894127;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=rs104894127" 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=rs104894127" 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=RCV000013276 OR RCV000128679" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013276, RCV000128679" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013276...</a>
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<p>In affected members of a large multigenerational family with distal arthrogryposis type 1 (DA1; <a href="/entry/108120">108120</a>) originally reported by <a href="#1" class="mim-tip-reference" title="Bamshad, M., Watkins, W. S., Zenger, R. K., Bohnsack, J. F., Carey, J. C., Otterud, B., Krakowiak, P. A., Robertson, M., Jorde, L. B. <strong>A gene for distal arthrogryposis type I maps to the pericentromeric region of chromosome 9.</strong> Am. J. Hum. Genet. 55: 1153-1158, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7977374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7977374</a>]" pmid="7977374">Bamshad et al. (1994)</a> and linked to the pericentromeric region of chromosome 9, <a href="#17" class="mim-tip-reference" title="Sung, S. S., Brassington, A.-M. E., Grannatt, K., Rutherford, A., Whitby, F. G., Krakowiak, P. A., Jorde, L. B., Carey, J. C., Bamshad, M. <strong>Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes.</strong> Am. J. Hum. Genet. 72: 681-690, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12592607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12592607</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12592607[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/10.1086/368294" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12592607">Sung et al. (2003)</a> identified a heterozygous c.271C-G transversion in exon 3 of the TPM2 gene, resulting in an arg91-to-gly (R91G) substitution at a highly conserved residue. The findings indicated that this form of distal arthrogryposis has a myopathic origin, specifically in the contractile apparatus of fast-twitch myofibers. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7977374+12592607" 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 in vitro studies, <a href="#15" class="mim-tip-reference" title="Robinson, P., Lipscomb, S., Preston, L. C., Altin, E., Watkins, H., Ashley, C. C., Redwood, C. S. <strong>Mutations in fast skeletal troponin I, troponin T, and beta-tropomyosin that cause distal arthrogryposis all increase contractile function.</strong> FASEB J. 21: 896-905, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17194691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17194691</a>] [<a href="https://doi.org/10.1096/fj.06-6899com" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17194691">Robinson et al. (2007)</a> demonstrated that the R91G mutation resulted in a gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility. Structurally, the R91G mutation disrupted both actin binding and coiled-coil stability. <a href="#15" class="mim-tip-reference" title="Robinson, P., Lipscomb, S., Preston, L. C., Altin, E., Watkins, H., Ashley, C. C., Redwood, C. S. <strong>Mutations in fast skeletal troponin I, troponin T, and beta-tropomyosin that cause distal arthrogryposis all increase contractile function.</strong> FASEB J. 21: 896-905, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17194691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17194691</a>] [<a href="https://doi.org/10.1096/fj.06-6899com" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17194691">Robinson et al. (2007)</a> concluded that in patients the mutation would cause increased tension in developing muscles, thus resulting in contractures and limb defects via an active process rather than a passive process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17194691" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894128 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894128;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=rs104894128" 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=rs104894128" 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=RCV000013277 OR RCV000128685 OR RCV002513007" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013277, RCV000128685, RCV002513007" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013277...</a>
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<p>In 1 of 66 unrelated patients with congenital myopathy-23 (CMYO23; <a href="/entry/609285">609285</a>), <a href="#4" class="mim-tip-reference" title="Donner, K., Ollikainen, M., Ridanpaa, M., Christen, H.-J., Goebel, H. H., de Visser, M., Pelin, K., Wallgren-Pettersson, C. <strong>Mutations in the beta-tropomyosin (TPM2) gene--a rare cause of nemaline myopathy.</strong> Neuromusc. Disord. 12: 151-158, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11738357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11738357</a>] [<a href="https://doi.org/10.1016/s0960-8966(01)00252-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11738357">Donner et al. (2002)</a> identified a heterozygous A-to-C transversion in exon 4 of the TPM2 gene, resulting in a gln147-to-pro (Q147P) substitution. The affected Dutch woman had a mild form of the disorder, presenting at age 12 years with difficulty walking. Muscle biopsy showed type 1 fiber predominance and aggregates of rods. There was no family history of the disorder. The mutation was not identified in 100 control individuals. <a href="#4" class="mim-tip-reference" title="Donner, K., Ollikainen, M., Ridanpaa, M., Christen, H.-J., Goebel, H. H., de Visser, M., Pelin, K., Wallgren-Pettersson, C. <strong>Mutations in the beta-tropomyosin (TPM2) gene--a rare cause of nemaline myopathy.</strong> Neuromusc. Disord. 12: 151-158, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11738357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11738357</a>] [<a href="https://doi.org/10.1016/s0960-8966(01)00252-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11738357">Donner et al. (2002)</a> speculated that the mutation affects the actin-binding properties of beta-tropomyosin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11738357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013278 OR RCV000128681 OR RCV000531827" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013278, RCV000128681, RCV000531827" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013278...</a>
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<p>In a Bosnian mother and son with presumed congenital myopathy-23 (CMYO23; <a href="/entry/609285">609285</a>), <a href="#4" class="mim-tip-reference" title="Donner, K., Ollikainen, M., Ridanpaa, M., Christen, H.-J., Goebel, H. H., de Visser, M., Pelin, K., Wallgren-Pettersson, C. <strong>Mutations in the beta-tropomyosin (TPM2) gene--a rare cause of nemaline myopathy.</strong> Neuromusc. Disord. 12: 151-158, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11738357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11738357</a>] [<a href="https://doi.org/10.1016/s0960-8966(01)00252-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11738357">Donner et al. (2002)</a> identified a heterozygous G-to-A transition in exon 3 of the TPM2 gene, resulting in a glu117-to-lys (E117K) substitution. The boy presented with feeding difficulties and severe hypotonia at birth. He had delayed motor milestones, but achieved ambulation. His mother had never been able to run, had myopathic facies and a high-arched palate, and asymmetric limb involvement. One muscle biopsy from the son showed type 1 fiber predominance consistent with nemaline myopathy, but the finding of nemaline rods was equivocal; however, <a href="#4" class="mim-tip-reference" title="Donner, K., Ollikainen, M., Ridanpaa, M., Christen, H.-J., Goebel, H. H., de Visser, M., Pelin, K., Wallgren-Pettersson, C. <strong>Mutations in the beta-tropomyosin (TPM2) gene--a rare cause of nemaline myopathy.</strong> Neuromusc. Disord. 12: 151-158, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11738357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11738357</a>] [<a href="https://doi.org/10.1016/s0960-8966(01)00252-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11738357">Donner et al. (2002)</a> noted that the quantity of nemaline rods can vary substantially in affected patients. The mutation was not identified in 100 control individuals. The authors speculated that the mutation affects the actin-binding properties of beta-tropomyosin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11738357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853305 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853305;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=rs137853305" 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=rs137853305" 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=RCV000013279 OR RCV000128682 OR RCV001775067 OR RCV004532331 OR RCV004798725" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013279, RCV000128682, RCV001775067, RCV004532331, RCV004798725" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013279...</a>
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<p>In a mother and daughter with a form of distal arthrogryposis most consistent with type 2B (DA2B4; see <a href="/entry/108120">108120</a>), <a href="#18" class="mim-tip-reference" title="Tajsharghi, H., Kimber, E., Holmgren, D., Tulinius, M., Oldfors, A. <strong>Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation.</strong> Neurology 68: 772-775, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17339586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17339586</a>] [<a href="https://doi.org/10.1212/01.wnl.0000256339.40667.fb" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17339586">Tajsharghi et al. (2007)</a> identified a heterozygous 5396C-T transition in exon 4 of the TPM2 gene, resulting in an arg133-to-trp (R133W) substitution. At the time of the report, the mother and daughter were 65 and 28 years, respectively. Both had presented with distal joint contractures at birth. At the time of examination, both complained of muscle weakness in proximal and distal muscles, most prominent in the hands and feet. Other notable features in both patients included hearing impairment, high-arched palate, short neck, short stature, contractures in proximal joints, smooth palms, and scoliosis. Neither had cardiac involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17339586" 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 Korean mother and daughter with DA2B4, <a href="#7" class="mim-tip-reference" title="Ko, J. M., Choi, I.-H., Baek, G.-H., Kim, K.-w. <strong>First Korean family with a mutation in TPM2 associated with Sheldon-Hall syndrome.</strong> J. Korean Med. Sci. 28: 780-783, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23678273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23678273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23678273[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/10.3346/jkms.2013.28.5.780" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23678273">Ko et al. (2013)</a> identified heterozygosity for the R133W mutation in the TPM2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23678273" 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 CONGENITAL MYOPATHY 23</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">rs137853306 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853306;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=rs137853306" 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=rs137853306" 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=RCV000013280 OR RCV000128672 OR RCV001206319" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013280, RCV000128672, RCV001206319" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013280...</a>
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<p>In a mother and daughter with congenital myopathy-23 (CMYO23; <a href="/entry/609285">609285</a>), <a href="#19" class="mim-tip-reference" title="Tajsharghi, H., Ohlsson, M., Lindberg, C., Oldfors, A. <strong>Congenital myopathy with nemaline rods and cap structures caused by a mutation in the beta-tropomyosin gene (TPM2).</strong> Arch. Neurol. 64: 1334-1338, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17846275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17846275</a>] [<a href="https://doi.org/10.1001/archneur.64.9.1334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17846275">Tajsharghi et al. (2007)</a> identified a heterozygous 360G-A transition (c.360G-A, NM-213674) in exon 2 of the TPM2 gene, resulting in a glu41-to-lys (E41K) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17846275" 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 CONGENITAL MYOPATHY 23</strong>
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TPM2, 3-BP DEL, 415GAG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476153 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476153;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=rs199476153" 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=rs199476153" 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=RCV000128684 OR RCV000500415 OR RCV000532873 OR RCV004528107" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000128684, RCV000500415, RCV000532873, RCV004528107" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000128684...</a>
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<p>In a 36-year-old man with congenital myopathy-23 (CMYO23; <a href="/entry/609285">609285</a>) since childhood, <a href="#9" class="mim-tip-reference" title="Lehtokari, V.-L., Ceuterick-de Groote, C., de Jonghe, P., Marttila, M., Laing, N. G., Pelin, K., Wallgren-Pettersson, C. <strong>Cap disease caused by heterozygous deletion of the beta-tropomyosin gene TPM2.</strong> Neuromusc. Disord. 17: 433-442, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17434307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17434307</a>] [<a href="https://doi.org/10.1016/j.nmd.2007.02.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17434307">Lehtokari et al. (2007)</a> identified a heterozygous 3-bp in-frame deletion (c.415delGAG, ENST00000329305) in exon 4 of the TPM2 gene, resulting in the removal of glu139 and predicted to disrupt the 7-amino acid repeat essential for making a coiled-coil motif and to impair tropomyosin-actin interaction. The patient had delayed motor development, was never able to run, showed generalized muscle weakness, and had additional features, including hyperlordosis, ptosis, and high-arched palate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17434307" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Clarke, N. F., Domazetovska, A., Waddell, L., Kornberg, A., McLean, C., North, K. N. <strong>Cap disease due to mutation of the beta-tropomyosin gene (TPM2).</strong> Neuromusc. Disord. 19: 348-351, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19345583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19345583</a>] [<a href="https://doi.org/10.1016/j.nmd.2009.03.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19345583">Clarke et al. (2009)</a> reported a 14-year-old Australian girl with CMYO23 who was heterozygous for the 415delGAG deletion (c.415delGAG, NM_003289). She had a history of hypotonia since infancy, delayed motor development, and slow running. She had generalized muscle wasting and weakness, particularly in the proximal muscles, and hyporeflexia. Other features included mild facial weakness, nasal voice, high-arched palate, long thin face, and mild micrognathia. Cardiac examination showed decreased systolic function, with an ejection fraction of 42%, mild mitral valve prolapse, and borderline aortic root dilatation. She also had central hypoventilation and restrictive lung disease with decreased forced vital capacity, and developed thoracic scoliosis in her teens. Skeletal muscle biopsy at age 10 showed fiber type variability, and she received an initial diagnosis of congenital fiber-type disproportion, a diagnosis of exclusion. However, about 4% of fibers were later noted to have caps, leading to a final histologic diagnosis of cap myopathy. There was type 1 fiber predominance. Electron microscopy showed irregular and thickened Z-lines, and the caps contained disorganized thin filaments. No classic nemaline rods were observed. Protein studies showed that the mutant TPM2 protein interacted with the wildtype protein and was incorporated into the sarcomere. The authors postulated that the mutation probably weakened the interaction with other proteins within skeletal muscle. <a href="#2" class="mim-tip-reference" title="Clarke, N. F., Domazetovska, A., Waddell, L., Kornberg, A., McLean, C., North, K. N. <strong>Cap disease due to mutation of the beta-tropomyosin gene (TPM2).</strong> Neuromusc. Disord. 19: 348-351, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19345583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19345583</a>] [<a href="https://doi.org/10.1016/j.nmd.2009.03.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19345583">Clarke et al. (2009)</a> noted that the cardiac involvement in this patient was an unusual finding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19345583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476147 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476147;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=rs199476147" 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=rs199476147" 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=RCV000128673 OR RCV001379219 OR RCV003231100" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000128673, RCV001379219, RCV003231100" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000128673...</a>
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<p>In a 42-year-old man with congenital myopathy-23 (CMYO23; <a href="/entry/609285">609285</a>) and symptoms of muscle weakness since childhood, <a href="#14" class="mim-tip-reference" title="Ohlsson, M., Quijano-Roy, S., Darin, N., Brochier, G., Lacene, E., Avila-Smirnow, D., Fardeau, M., Oldfors, A., Tajsharghi, H. <strong>New morphologic and genetic findings in cap disease associated with beta-tropomyosin (TPM2) mutations.</strong> Neurology 71: 1896-1901, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19047562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19047562</a>] [<a href="https://doi.org/10.1212/01.wnl.0000336654.44814.b8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19047562">Ohlsson et al. (2008)</a> identified a de novo heterozygous in-frame 3-bp deletion (c.384delGAA, NM_003289) in exon 2 of the TPM2 gene, resulting in the deletion of lys49. By age 15 years, he required a wheelchair when outdoors, but the disorder was no longer progressive in adulthood. He had diffuse, symmetric muscle weakness and wasting, kyphoscoliosis, high-pitched voice, and decreased pulmonary vital capacity. Muscle biopsy showed uniformity of type 1 fibers, cap structures with disorganized myofibrils, and an irregular intermyofibrillar network. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19047562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853307 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853307;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=rs137853307" 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=rs137853307" 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=RCV000128687 OR RCV003231101" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000128687, RCV003231101" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000128687...</a>
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<p>In an 8-year-old girl with a severe form of congenital myopathy-23 (CMYO23; <a href="/entry/609285">609285</a>), <a href="#14" class="mim-tip-reference" title="Ohlsson, M., Quijano-Roy, S., Darin, N., Brochier, G., Lacene, E., Avila-Smirnow, D., Fardeau, M., Oldfors, A., Tajsharghi, H. <strong>New morphologic and genetic findings in cap disease associated with beta-tropomyosin (TPM2) mutations.</strong> Neurology 71: 1896-1901, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19047562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19047562</a>] [<a href="https://doi.org/10.1212/01.wnl.0000336654.44814.b8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19047562">Ohlsson et al. (2008)</a> identified a de novo heterozygous 845C-G transversion (c.845C-G, NM_003289) in the TPM2 gene, resulting in an asn202-to-lys (N202K) substitution in the putative troponin T-binding region. The patient had reduced fetal movements in utero and was hypotonic at birth. She had severe muscle weakness in the face and axial muscles and severe respiratory compromise necessitating mechanical ventilation. Muscle biopsy showed uniformity of type 1 fibers, cap structures, and a coarse intermyofibrillar network. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19047562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476146 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476146;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=rs199476146" 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=rs199476146" 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=RCV000128675 OR RCV000223947 OR RCV000795370" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000128675, RCV000223947, RCV000795370" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000128675...</a>
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<p>In 8 patients from 5 unrelated families with congenital myopathy-23 (CMYO23; <a href="/entry/609285">609285</a>), <a href="#12" class="mim-tip-reference" title="Mokbel, N., Ilkovski, B., Kreissl, M., Memo, M., Jeffries, C. M., Marttila, M., Lehtokari, V.-L., Lemola, E., Gronholm, M., Yang, N., Menard, D., Marcorelles, P., and 14 others. <strong>K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity.</strong> Brain 136: 494-507, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23378224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23378224</a>] [<a href="https://doi.org/10.1093/brain/aws348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23378224">Mokbel et al. (2013)</a> identified a heterozygous 3-bp deletion (c.19_21delAAG) in exon 1 of the TPM2 gene, resulting in the deletion of residue lys7 (K7del), which is 1 of 3 highly conserved lysine residues at the N terminus. The transmission pattern in 2 families was consistent with autosomal dominant inheritance; the mutation was suspected to have occurred de novo in 3 other families. The mutation was not found in the Exome Variant Server database. Studies of patient muscle and differentiated myotubes transfected with the mutation suggested that the mutant protein incorporates poorly into sarcomeres and likely accumulates in nemaline bodies, and interferes with wildtype protein in a dominant-negative manner. Patient myofibers had normal force generation, but increased sensitivity to calcium in motility assays. The mutant protein also showed reduced binding affinity for actin and a decreased ability to polymerize into long tropomyosin filaments. <a href="#12" class="mim-tip-reference" title="Mokbel, N., Ilkovski, B., Kreissl, M., Memo, M., Jeffries, C. M., Marttila, M., Lehtokari, V.-L., Lemola, E., Gronholm, M., Yang, N., Menard, D., Marcorelles, P., and 14 others. <strong>K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity.</strong> Brain 136: 494-507, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23378224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23378224</a>] [<a href="https://doi.org/10.1093/brain/aws348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23378224">Mokbel et al. (2013)</a> noted that the presence of joint contractures was the most prominent clinical feature in these patients and that 1 patient had hypertonicity. These findings suggested that the joint contractures may result from impaired muscle relaxation and a tendency for muscles to slowly shorten. Progressive muscle weakness in adulthood may result from a combination of muscle degeneration and apoptosis due to cellular stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23378224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Davidson, A. E., Siddiqui, F. M., Lopez, M. A., Lunt, P., Carlson, H. A., Moore, B. E., Love, S., Born, D. E., Roper, H., Majumdar, A., Jayadev, S., Underhill, H. R., and 14 others. <strong>Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies.</strong> Brain 136: 508-521, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23413262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23413262</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23413262[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/brain/aws344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23413262">Davidson et al. (2013)</a> identified a heterozygous K7del mutation, which they stated resulted from c.20_22del, in affected members of 4 families with a phenotype consistent with nemaline myopathy. Common clinical features in the families included muscle weakness and the presence of early distal extremity contractures combined with trismus. These findings unified the phenotype of congenital myopathy with distal arthrogryposis (DA1A; <a href="/entry/108120">108120</a>). The mutation in 1 family was found by whole-exome sequencing and confirmed by Sanger sequencing. It segregated with the disorder and was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in an in-house exome database. The mutation in the other families was found by candidate gene testing. Molecular modeling predicted that the mutation would alter protein-protein binding between TPM2 and other proteins as well as disturb the head-to-tail polymerization of TPM2 dimers. Expression of the mutation in developing zebrafish showed that the mutant protein did not localize properly within the thin filament compartment and altered sarcomere length, suggesting that it impaired sarcomeric structure. Areas of perimembranous accumulations of alpha-actinin were observed in mutant myofibers, consistent with findings in nemaline myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23413262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a Chinese family (family 1) segregating distal arthrogryposis type 2B4 (DA2B4; see <a href="/entry/108120">108120</a>), <a href="#10" class="mim-tip-reference" title="Li, S., You, Y., Gao, J., Mao, B., Cao, Y., Zhao, X., Zhang, X. <strong>Novel mutations in TPM2 and PIEZO2 are responsible for distal arthrogryposis (DA) and mild DA in two Chinese families.</strong> BMC Med. Genet. 19: 179 only, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30285720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30285720</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30285720[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/10.1186/s12881-018-0692-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30285720">Li et al. (2018)</a> identified heterozygosity for a c.308A-G transition in exon 3 of the TPM2 gene, resulting in a gln103-to-arg (Q103R) substitution at a highly conserved residue. The mutation, which was found by linkage analysis and Sanger sequencing, was not found in the ExAC, gnomAD, ESP6599, 1000 Genomes Project, and dbSNP databases. Molecular modeling indicated that the mutation may impair protein function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30285720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs113612402 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113612402;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=rs113612402" 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=rs113612402" 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=RCV000778066 OR RCV001784379" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000778066, RCV001784379" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000778066...</a>
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<p>In a female infant, born to unrelated parents, with congenital distal arthrogryposis, facial dysmorphism, and myopathy (DA2B4; see <a href="/entry/108120">108120</a>), <a href="#13" class="mim-tip-reference" title="Mroczek, M., Kabzinska, D., Chrzanowska, K. H., Pronicki, M., Kochanski, A. <strong>A novel TPM2 gene splice-site mutation causes severe congenital myopathy with arthrogryposis and dysmorphic features.</strong> J. Appl. Genet. 58: 199-203, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27726070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27726070</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27726070[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/10.1007/s13353-016-0368-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27726070">Mroczek et al. (2017)</a> identified a de novo heterozygous splice site mutation (c.374+2T-C) in the TPM2 gene. The mutation resulted in an aberrantly spliced transcript containing intron 3 and a frameshift mutation resulting in a premature stop codon. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the unaffected parents or in 100 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27726070" 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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Bamshad, M., Watkins, W. S., Zenger, R. K., Bohnsack, J. F., Carey, J. C., Otterud, B., Krakowiak, P. A., Robertson, M., Jorde, L. B.
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<strong>A gene for distal arthrogryposis type I maps to the pericentromeric region of chromosome 9.</strong>
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Am. J. Hum. Genet. 55: 1153-1158, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7977374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7977374</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7977374" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Clarke, N. F., Domazetovska, A., Waddell, L., Kornberg, A., McLean, C., North, K. N.
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<strong>Cap disease due to mutation of the beta-tropomyosin gene (TPM2).</strong>
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Neuromusc. Disord. 19: 348-351, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19345583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19345583</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19345583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Davidson, A. E., Siddiqui, F. M., Lopez, M. A., Lunt, P., Carlson, H. A., Moore, B. E., Love, S., Born, D. E., Roper, H., Majumdar, A., Jayadev, S., Underhill, H. R., and 14 others.
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<strong>Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies.</strong>
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Brain 136: 508-521, 2013.
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[<a href="https://doi.org/10.1093/brain/aws344" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0960-8966(01)00252-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000134070" target="_blank">Full Text</a>]
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<strong>Nemaline myopathy with stiffness and hypertonia associated with an ACTA1 mutation.</strong>
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[<a href="https://doi.org/10.1212/WNL.0b013e31824e8ebe" target="_blank">Full Text</a>]
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<strong>First Korean family with a mutation in TPM2 associated with Sheldon-Hall syndrome.</strong>
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[<a href="https://doi.org/10.3346/jkms.2013.28.5.780" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0195-75" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2007.02.015" target="_blank">Full Text</a>]
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<strong>Novel mutations in TPM2 and PIEZO2 are responsible for distal arthrogryposis (DA) and mild DA in two Chinese families.</strong>
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[<a href="https://doi.org/10.1186/s12881-018-0692-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddt345" target="_blank">Full Text</a>]
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<strong>K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity.</strong>
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[<a href="https://doi.org/10.1093/brain/aws348" target="_blank">Full Text</a>]
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<strong>A novel TPM2 gene splice-site mutation causes severe congenital myopathy with arthrogryposis and dysmorphic features.</strong>
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[<a href="https://doi.org/10.1007/s13353-016-0368-z" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000336654.44814.b8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1096/fj.06-6899com" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/368294" target="_blank">Full Text</a>]
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<a id="Tajsharghi2007" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1212/01.wnl.0000256339.40667.fb" target="_blank">Full Text</a>]
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<a id="Tajsharghi2007" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17846275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17846275</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17846275" 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/10.1001/archneur.64.9.1334" target="_blank">Full Text</a>]
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</p>
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<a id="20" class="mim-anchor"></a>
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<a id="Tiso1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tiso, N., Rampoldi, L., Pallavicini, A., Zimbello, R., Pandolfo, D., Valle, G., Lanfranchi, G., Danieli, G. A.
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<strong>Fine mapping of five human skeletal muscle genes: alpha-tropomyosin, beta-tropomyosin, troponin-I slow-twitch, troponin-I fast-twitch, and troponin-C fast.</strong>
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Biochem. Biophys. Res. Commun. 230: 347-350, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9016781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9016781</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9016781" 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/bbrc.1996.5958" target="_blank">Full Text</a>]
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</p>
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<a id="21" class="mim-anchor"></a>
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<a id="Widada1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Widada, J. S., Ferraz, C., Capony, J.-P., Liautard, J.-P.
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<strong>Complete nucleotide sequence of the adult skeletal isoform of human skeletal muscle beta-tropomyosin.</strong>
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Nucleic Acids Res. 16: 3109 only, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3368322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3368322</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3368322" 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/nar/16.7.3109" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 06/01/2023
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 06/17/2022<br>Carol A. Bocchini - updated : 05/17/2019<br>Marla J. F. O'Neill - updated : 05/16/2019<br>Cassandra L. Kniffin - updated : 3/13/2009<br>Cassandra L. Kniffin - updated : 5/22/2008<br>Cassandra L. Kniffin - updated : 3/31/2008<br>Cassandra L. Kniffin - updated : 11/29/2007<br>Cassandra L. Kniffin - updated : 1/21/2005<br>Victor A. McKusick - updated : 2/26/2003<br>Rebekah S. Rasooly - updated : 3/4/1998
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 5/24/1988
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 07/16/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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carol : 06/06/2023<br>carol : 06/05/2023<br>carol : 06/01/2023<br>alopez : 06/17/2022<br>carol : 05/21/2019<br>carol : 05/21/2019<br>joanna : 05/21/2019<br>carol : 05/17/2019<br>carol : 05/16/2019<br>carol : 02/28/2017<br>alopez : 06/02/2016<br>alopez : 6/2/2016<br>alopez : 6/1/2016<br>ckniffin : 4/28/2016<br>mcolton : 6/16/2014<br>carol : 8/5/2013<br>terry : 5/16/2012<br>wwang : 11/17/2009<br>wwang : 11/17/2009<br>ckniffin : 11/3/2009<br>ckniffin : 9/28/2009<br>wwang : 3/25/2009<br>ckniffin : 3/13/2009<br>wwang : 7/3/2008<br>wwang : 5/29/2008<br>ckniffin : 5/22/2008<br>wwang : 4/4/2008<br>ckniffin : 3/31/2008<br>wwang : 12/7/2007<br>ckniffin : 11/29/2007<br>carol : 4/7/2005<br>ckniffin : 4/4/2005<br>tkritzer : 1/26/2005<br>ckniffin : 1/21/2005<br>carol : 12/21/2004<br>alopez : 2/27/2003<br>terry : 2/26/2003<br>carol : 4/6/1999<br>alopez : 3/4/1998<br>terry : 6/13/1996<br>mark : 10/13/1995<br>carol : 1/20/1995<br>carol : 8/28/1992<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>supermim : 3/9/1990
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 190990
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</span>
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<div>
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<h3>
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<span class="mim-font">
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TROPOMYOSIN 2; TPM2
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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TROPOMYOSIN, SKELETAL MUSCLE BETA; TMSB
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</span>
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<div>
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<br />
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TPM2</em></strong>
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</span>
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<strong>
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<em>
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Cytogenetic location: 9p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:35,681,993-35,690,056 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<th>
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Location
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</th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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<tbody>
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<td rowspan="3">
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<span class="mim-font">
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9p13.3
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<td>
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<span class="mim-font">
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Arthrogryposis, distal, type 1A
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</span>
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</td>
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<td>
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<span class="mim-font">
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108120
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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<tr>
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<td>
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<span class="mim-font">
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Arthrogryposis, distal, type 2B4
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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108120
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Congenital myopathy 23
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</span>
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</td>
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<td>
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<span class="mim-font">
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609285
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The TPM2 gene encodes beta-tropomyosin, an isoform of tropomyosin that is mainly expressed in slow, type 1 muscle fibers, and, to some extent, in fast muscle fibers and cardiac muscle (summary by Tajsharghi et al., 2007). See also TPM1 (191010), TPM3 (191030), and TPM4 (600317). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Widada et al. (1988) reported the complete nucleotide sequence of the mRNA encoding the human skeletal muscle isoform of beta-tropomyosin. Comparison of this sequence with that of the human fibroblast isoform confirmed that alternative splicing occurs on exons 6 and 9. </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>Laing et al. (1995) referred to unpublished observations indicating that the TPM2 gene maps to 9p13. Hunt et al. (1995) developed a sequence tagged site (STS) for the TPM2 gene and used it to amplify DNA from somatic cell hybrids to localize the gene to human chromosome 9. The genomic clones isolated with the STS product were in turn used in fluorescence in situ hybridization to metaphase chromosome spreads to refine the localization of TPM2 to 9p13. Tiso et al. (1997) further refined the mapping of the TPM2 gene to 9p13.2-p13.1 using PCR of radiation hybrids. </p><p>Stumpf (2022) mapped the TPM2 gene to chromosome 9p13.3 based on an alignment of the TPM2 sequence (GenBank BC011776) with the genomic sequence (GRCh38).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Tropomyosin, together with actin (ACTA1; 102610) and troponin (see, e.g., TNNT1; 191041), constitutes the basic thin filament structural and calcium-regulatory machinery that interacts with myosin when muscle contracts. Tropomyosin polymerizes head-to-tail with other tropomyosin molecules into long strands spanning the whole thin filament length, and binds to different actin monomers. The key function of tropomyosin is in cooperatively switching the location of the actin-tropomyosin interface between active and relaxed states under the control of troponin, calcium, and myosin heads. Marston et al. (2013) noted that the actin-binding interface motifs in tropomyosin are repeated motifs common to all tropomyosin molecules, and include K6-K7, K48-K49, R90-R91, and R167-K168, which interact with D25 in actin, and 3 additional tropomyosin motifs, E139, E181, and E218, which interact with a cluster of actin motifs at K326, K328, and R147. </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>Distal Arthrogryposis Type 1A1</em></strong></p><p>
|
|
In affected members of a large multigenerational family (family K5) with distal arthrogryposis type 1A1 (DA1A; 108120), originally reported as family F by Bamshad et al. (1994) and linked to the pericentromeric region of chromosome 9, Sung et al. (2003) identified a heterozygous missense mutation in the TPM2 gene (R91G; 190990.0001). The findings indicated that this form of distal arthrogryposis has a myopathic origin, specifically in the contractile apparatus of fast-twitch myofibers. Functional studies of the variant and studies of patient cells were not performed. TPM2 mutations were not found in 13 additional probands with a similar disorder. </p><p>In in vitro studies, Robinson et al. (2007) demonstrated that the TPM2 R91G mutation resulted in a gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility. Robinson et al. (2007) concluded that the mutation would cause increased tension in developing muscles, thus resulting in contractures and limb deformities via an active process rather than a passive process. These findings implicated disturbed muscle function as the pathogenic mechanism underlying DA1A. </p><p><strong><em>Distal Arthrogryposis Type 2B4</em></strong></p><p>
|
|
In a mother and daughter with a form of distal arthrogryposis most consistent with type 2B (DA2B4; see 108120), Tajsharghi et al. (2007) identified a heterozygous mutation in the TPM2 gene (R133W; 190990.0004). </p><p>In a Korean mother and daughter with distal arthrogryposis type 2, Ko et al. (2013) identified the same R133W mutation in the TPM2 gene that had previously been identified in an affected mother and daughter (190990.0004). </p><p>In a female infant, born to unrelated parents, with congenital distal arthrogryposis, dysmorphic facial features, and myopathy, Mroczek et al. (2017) identified a de novo heterozygous splice site mutation in the TPM2 gene (190990.0011). The mutation was not present in the parents or in 100 healthy controls. </p><p>In affected members of a Chinese family (family 1) segregating DA2B4, Li et al. (2018) identified heterozygosity for a missense mutation (Q103R; 190990.0010) in the TPM2 gene. </p><p><strong><em>Congenital Myopathy 23</em></strong></p><p>
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In 2 unrelated patients with congenital myopathy-23 (CMYO23; 609285), a woman with a mild form of the disease and the son of an affected mother, Donner et al. (2002) identified 2 different heterozygous missense mutations in the TPM2 gene (Q147P, 190990.0002 and E117K, 190990.0003, respectively). The affected mother was found to carry the same mutation as her son. Functional studies of the variants were not performed, but the authors speculated that the mutation affects the actin-binding properties of TPM2. </p><p>In a 36-year-old man with CMYO23 since childhood, Lehtokari et al. (2007) identified a heterozygous 3-bp in-frame deletion (415delGAG; 190990.0006) of the TPM2 gene, resulting in the removal of glu139 and predicted to disrupt the 7-amino acid repeat essential for making a coiled-coil motif and to impair tropomyosin-actin interaction. Clarke et al. (2009) identified the E139del mutation in a girl with cap myopathy. Protein studies showed that the mutant TPM2 protein interacted with the wildtype protein and was incorporated into the sarcomere. The authors postulated that the mutation probably weakened the interaction with other proteins within skeletal muscle. </p><p>Ohlsson et al. (2008) identified 3 different heterozygous TPM2 mutations (see, e.g., 190990.0007 and 190990.0008) in 3 unrelated patients with CMYO23. One of the mutations deleted residue K49 (190990.0007). Functional studies of the variants were not performed. </p><p>In 8 patients from 5 unrelated families with CMYO23, Mokbel et al. (2013) identified the same 3-bp deletion in the TPM2 gene (lys7del, K7del; 190990.0009). The transmission pattern in 2 families was consistent with autosomal dominant inheritance; the mutation was suspected to have occurred de novo in 3 other families. Studies of patient muscle and differentiated myotubes transfected with the mutation suggested that the mutant protein incorporates poorly into sarcomeres and likely accumulates in nemaline bodies, and interferes with wildtype in a dominant-negative manner. Patient myofibers had normal force generation, but increased sensitivity to calcium in motility assays. The mutant protein also showed reduced binding affinity for actin and a decreased ability to polymerize into long tropomyosin filaments. Mokbel et al. (2013) noted that the presence of joint contractures was the most prominent clinical feature in these patients and that 1 patient had hypertonicity. These findings suggested that the joint contractures may result from impaired muscle relaxation and a tendency for muscles to slowly shorten. Progressive muscle weakness in adulthood may result from a combination of muscle degeneration and apoptosis due to cellular stress. </p><p>Davidson et al. (2013) identified a heterozygous K7del mutation in affected members of 4 families with CMYO23 associated with distal arthrogryposis and limited jaw opening. The mutation in 1 family was found by whole-exome sequencing and confirmed by Sanger sequencing to segregate with the disorder; the mutation in the other families was found by candidate gene testing. Molecular modeling predicted that the mutation would alter protein-protein binding between TPM2 and other proteins as well as disturb the head-to-tail polymerization of TPM2 dimers. Expression of the mutation in developing zebrafish showed that the mutant protein did not localize properly within the thin filament compartment and altered sarcomere length, suggesting that it impaired sarcomeric structure. Areas of perimembranous accumulations of alpha-actinin were observed in mutant myofibers, consistent with findings in nemaline myopathy. These findings unified the phenotype of congenital myopathy with distal arthrogryposis (DA1A; 108120). </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In in vitro studies, Marston et al. (2013) found that certain TPM2 mutations affecting the actin binding sites, K49del (190090.0007), R91G (190090.0001), E139del (190090.0006), E181K, and K168E, resulted in higher calcium sensitivity, higher filament sliding speeds, and a gain-of-function effect. In contrast, the E41K (190090.0005) and E117K (190090.0003) mutations showed lower calcium sensitivity, slower sliding speeds, and a hypocontractile phenotype. Marston et al. (2013) noted the range of muscle biopsy findings identified in patients with these mutations and suggested that consideration of the effects of the mutations on muscle contractility would be more predictive of the phenotype. Specifically, patients with gain-of-function mutations tended to have hypercontractility associated with arthrogryposis. A mutation at one of the tropomyosin binding sites in the actin molecule (K328N; 102610.0016) resulted in a similar phenotype characterized by hypercontractility (Jain et al., 2012). </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>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 ARTHROGRYPOSIS, DISTAL, TYPE 1A1</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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TPM2, ARG91GLY
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<br />
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SNP: rs104894127,
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ClinVar: RCV000013276, RCV000128679
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</span>
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</div>
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<span class="mim-text-font">
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<p>In affected members of a large multigenerational family with distal arthrogryposis type 1 (DA1; 108120) originally reported by Bamshad et al. (1994) and linked to the pericentromeric region of chromosome 9, Sung et al. (2003) identified a heterozygous c.271C-G transversion in exon 3 of the TPM2 gene, resulting in an arg91-to-gly (R91G) substitution at a highly conserved residue. The findings indicated that this form of distal arthrogryposis has a myopathic origin, specifically in the contractile apparatus of fast-twitch myofibers. Functional studies of the variant and studies of patient cells were not performed. </p><p>In in vitro studies, Robinson et al. (2007) demonstrated that the R91G mutation resulted in a gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility. Structurally, the R91G mutation disrupted both actin binding and coiled-coil stability. Robinson et al. (2007) concluded that in patients the mutation would cause increased tension in developing muscles, thus resulting in contractures and limb defects via an active process rather than a passive process. </p>
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</span>
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</div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CONGENITAL MYOPATHY 23</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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TPM2, GLN147PRO
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<br />
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SNP: rs104894128,
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ClinVar: RCV000013277, RCV000128685, RCV002513007
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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 1 of 66 unrelated patients with congenital myopathy-23 (CMYO23; 609285), Donner et al. (2002) identified a heterozygous A-to-C transversion in exon 4 of the TPM2 gene, resulting in a gln147-to-pro (Q147P) substitution. The affected Dutch woman had a mild form of the disorder, presenting at age 12 years with difficulty walking. Muscle biopsy showed type 1 fiber predominance and aggregates of rods. There was no family history of the disorder. The mutation was not identified in 100 control individuals. Donner et al. (2002) speculated that the mutation affects the actin-binding properties of beta-tropomyosin. </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 CONGENITAL MYOPATHY 23</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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TPM2, GLU117LYS
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<br />
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SNP: rs104894129,
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ClinVar: RCV000013278, RCV000128681, RCV000531827
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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 Bosnian mother and son with presumed congenital myopathy-23 (CMYO23; 609285), Donner et al. (2002) identified a heterozygous G-to-A transition in exon 3 of the TPM2 gene, resulting in a glu117-to-lys (E117K) substitution. The boy presented with feeding difficulties and severe hypotonia at birth. He had delayed motor milestones, but achieved ambulation. His mother had never been able to run, had myopathic facies and a high-arched palate, and asymmetric limb involvement. One muscle biopsy from the son showed type 1 fiber predominance consistent with nemaline myopathy, but the finding of nemaline rods was equivocal; however, Donner et al. (2002) noted that the quantity of nemaline rods can vary substantially in affected patients. The mutation was not identified in 100 control individuals. The authors speculated that the mutation affects the actin-binding properties of beta-tropomyosin. </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 ARTHROGRYPOSIS, DISTAL, TYPE 2B4</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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TPM2, ARG133TRP
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<br />
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SNP: rs137853305,
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ClinVar: RCV000013279, RCV000128682, RCV001775067, RCV004532331, RCV004798725
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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 mother and daughter with a form of distal arthrogryposis most consistent with type 2B (DA2B4; see 108120), Tajsharghi et al. (2007) identified a heterozygous 5396C-T transition in exon 4 of the TPM2 gene, resulting in an arg133-to-trp (R133W) substitution. At the time of the report, the mother and daughter were 65 and 28 years, respectively. Both had presented with distal joint contractures at birth. At the time of examination, both complained of muscle weakness in proximal and distal muscles, most prominent in the hands and feet. Other notable features in both patients included hearing impairment, high-arched palate, short neck, short stature, contractures in proximal joints, smooth palms, and scoliosis. Neither had cardiac involvement. </p><p>In a Korean mother and daughter with DA2B4, Ko et al. (2013) identified heterozygosity for the R133W mutation in the TPM2 gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 CONGENITAL MYOPATHY 23</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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TPM2, GLU41LYS
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<br />
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SNP: rs137853306,
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ClinVar: RCV000013280, RCV000128672, RCV001206319
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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 mother and daughter with congenital myopathy-23 (CMYO23; 609285), Tajsharghi et al. (2007) identified a heterozygous 360G-A transition (c.360G-A, NM-213674) in exon 2 of the TPM2 gene, resulting in a glu41-to-lys (E41K) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 CONGENITAL MYOPATHY 23</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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TPM2, 3-BP DEL, 415GAG
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<br />
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SNP: rs199476153,
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ClinVar: RCV000128684, RCV000500415, RCV000532873, RCV004528107
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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 36-year-old man with congenital myopathy-23 (CMYO23; 609285) since childhood, Lehtokari et al. (2007) identified a heterozygous 3-bp in-frame deletion (c.415delGAG, ENST00000329305) in exon 4 of the TPM2 gene, resulting in the removal of glu139 and predicted to disrupt the 7-amino acid repeat essential for making a coiled-coil motif and to impair tropomyosin-actin interaction. The patient had delayed motor development, was never able to run, showed generalized muscle weakness, and had additional features, including hyperlordosis, ptosis, and high-arched palate. </p><p>Clarke et al. (2009) reported a 14-year-old Australian girl with CMYO23 who was heterozygous for the 415delGAG deletion (c.415delGAG, NM_003289). She had a history of hypotonia since infancy, delayed motor development, and slow running. She had generalized muscle wasting and weakness, particularly in the proximal muscles, and hyporeflexia. Other features included mild facial weakness, nasal voice, high-arched palate, long thin face, and mild micrognathia. Cardiac examination showed decreased systolic function, with an ejection fraction of 42%, mild mitral valve prolapse, and borderline aortic root dilatation. She also had central hypoventilation and restrictive lung disease with decreased forced vital capacity, and developed thoracic scoliosis in her teens. Skeletal muscle biopsy at age 10 showed fiber type variability, and she received an initial diagnosis of congenital fiber-type disproportion, a diagnosis of exclusion. However, about 4% of fibers were later noted to have caps, leading to a final histologic diagnosis of cap myopathy. There was type 1 fiber predominance. Electron microscopy showed irregular and thickened Z-lines, and the caps contained disorganized thin filaments. No classic nemaline rods were observed. Protein studies showed that the mutant TPM2 protein interacted with the wildtype protein and was incorporated into the sarcomere. The authors postulated that the mutation probably weakened the interaction with other proteins within skeletal muscle. Clarke et al. (2009) noted that the cardiac involvement in this patient was an unusual finding. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 CONGENITAL MYOPATHY 23</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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TPM2, 3-BP DEL, 384GAA
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<br />
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SNP: rs199476147,
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ClinVar: RCV000128673, RCV001379219, RCV003231100
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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 42-year-old man with congenital myopathy-23 (CMYO23; 609285) and symptoms of muscle weakness since childhood, Ohlsson et al. (2008) identified a de novo heterozygous in-frame 3-bp deletion (c.384delGAA, NM_003289) in exon 2 of the TPM2 gene, resulting in the deletion of lys49. By age 15 years, he required a wheelchair when outdoors, but the disorder was no longer progressive in adulthood. He had diffuse, symmetric muscle weakness and wasting, kyphoscoliosis, high-pitched voice, and decreased pulmonary vital capacity. Muscle biopsy showed uniformity of type 1 fibers, cap structures with disorganized myofibrils, and an irregular intermyofibrillar network. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 CONGENITAL MYOPATHY 23</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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TPM2, ASN202LYS
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<br />
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SNP: rs137853307,
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ClinVar: RCV000128687, RCV003231101
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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 an 8-year-old girl with a severe form of congenital myopathy-23 (CMYO23; 609285), Ohlsson et al. (2008) identified a de novo heterozygous 845C-G transversion (c.845C-G, NM_003289) in the TPM2 gene, resulting in an asn202-to-lys (N202K) substitution in the putative troponin T-binding region. The patient had reduced fetal movements in utero and was hypotonic at birth. She had severe muscle weakness in the face and axial muscles and severe respiratory compromise necessitating mechanical ventilation. Muscle biopsy showed uniformity of type 1 fibers, cap structures, and a coarse intermyofibrillar network. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 CONGENITAL MYOPATHY 23</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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TPM2, 3-BP DEL, 19AAG
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<br />
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SNP: rs199476146,
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ClinVar: RCV000128675, RCV000223947, RCV000795370
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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 8 patients from 5 unrelated families with congenital myopathy-23 (CMYO23; 609285), Mokbel et al. (2013) identified a heterozygous 3-bp deletion (c.19_21delAAG) in exon 1 of the TPM2 gene, resulting in the deletion of residue lys7 (K7del), which is 1 of 3 highly conserved lysine residues at the N terminus. The transmission pattern in 2 families was consistent with autosomal dominant inheritance; the mutation was suspected to have occurred de novo in 3 other families. The mutation was not found in the Exome Variant Server database. Studies of patient muscle and differentiated myotubes transfected with the mutation suggested that the mutant protein incorporates poorly into sarcomeres and likely accumulates in nemaline bodies, and interferes with wildtype protein in a dominant-negative manner. Patient myofibers had normal force generation, but increased sensitivity to calcium in motility assays. The mutant protein also showed reduced binding affinity for actin and a decreased ability to polymerize into long tropomyosin filaments. Mokbel et al. (2013) noted that the presence of joint contractures was the most prominent clinical feature in these patients and that 1 patient had hypertonicity. These findings suggested that the joint contractures may result from impaired muscle relaxation and a tendency for muscles to slowly shorten. Progressive muscle weakness in adulthood may result from a combination of muscle degeneration and apoptosis due to cellular stress. </p><p>Davidson et al. (2013) identified a heterozygous K7del mutation, which they stated resulted from c.20_22del, in affected members of 4 families with a phenotype consistent with nemaline myopathy. Common clinical features in the families included muscle weakness and the presence of early distal extremity contractures combined with trismus. These findings unified the phenotype of congenital myopathy with distal arthrogryposis (DA1A; 108120). The mutation in 1 family was found by whole-exome sequencing and confirmed by Sanger sequencing. It segregated with the disorder and was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in an in-house exome database. The mutation in the other families was found by candidate gene testing. Molecular modeling predicted that the mutation would alter protein-protein binding between TPM2 and other proteins as well as disturb the head-to-tail polymerization of TPM2 dimers. Expression of the mutation in developing zebrafish showed that the mutant protein did not localize properly within the thin filament compartment and altered sarcomere length, suggesting that it impaired sarcomeric structure. Areas of perimembranous accumulations of alpha-actinin were observed in mutant myofibers, consistent with findings in nemaline myopathy. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0010 ARTHROGRYPOSIS, DISTAL, TYPE 2B4</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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TPM2, GLN103ARG
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<br />
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SNP: rs1563929383,
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ClinVar: RCV000778065
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Chinese family (family 1) segregating distal arthrogryposis type 2B4 (DA2B4; see 108120), Li et al. (2018) identified heterozygosity for a c.308A-G transition in exon 3 of the TPM2 gene, resulting in a gln103-to-arg (Q103R) substitution at a highly conserved residue. The mutation, which was found by linkage analysis and Sanger sequencing, was not found in the ExAC, gnomAD, ESP6599, 1000 Genomes Project, and dbSNP databases. Molecular modeling indicated that the mutation may impair protein function. </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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<h4>
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<span class="mim-font">
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<strong>.0011 ARTHROGRYPOSIS, DISTAL, TYPE 2B4</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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TPM2, c.374+2T-C
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<br />
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SNP: rs113612402,
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ClinVar: RCV000778066, RCV001784379
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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 female infant, born to unrelated parents, with congenital distal arthrogryposis, facial dysmorphism, and myopathy (DA2B4; see 108120), Mroczek et al. (2017) identified a de novo heterozygous splice site mutation (c.374+2T-C) in the TPM2 gene. The mutation resulted in an aberrantly spliced transcript containing intron 3 and a frameshift mutation resulting in a premature stop codon. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the unaffected parents or in 100 control individuals. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Bamshad, M., Watkins, W. S., Zenger, R. K., Bohnsack, J. F., Carey, J. C., Otterud, B., Krakowiak, P. A., Robertson, M., Jorde, L. B.
|
|
<strong>A gene for distal arthrogryposis type I maps to the pericentromeric region of chromosome 9.</strong>
|
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Am. J. Hum. Genet. 55: 1153-1158, 1994.
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[PubMed: 7977374]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Clarke, N. F., Domazetovska, A., Waddell, L., Kornberg, A., McLean, C., North, K. N.
|
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<strong>Cap disease due to mutation of the beta-tropomyosin gene (TPM2).</strong>
|
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Neuromusc. Disord. 19: 348-351, 2009.
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[PubMed: 19345583]
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[Full Text: https://doi.org/10.1016/j.nmd.2009.03.003]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Davidson, A. E., Siddiqui, F. M., Lopez, M. A., Lunt, P., Carlson, H. A., Moore, B. E., Love, S., Born, D. E., Roper, H., Majumdar, A., Jayadev, S., Underhill, H. R., and 14 others.
|
|
<strong>Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies.</strong>
|
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Brain 136: 508-521, 2013.
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[PubMed: 23413262]
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[Full Text: https://doi.org/10.1093/brain/aws344]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Donner, K., Ollikainen, M., Ridanpaa, M., Christen, H.-J., Goebel, H. H., de Visser, M., Pelin, K., Wallgren-Pettersson, C.
|
|
<strong>Mutations in the beta-tropomyosin (TPM2) gene--a rare cause of nemaline myopathy.</strong>
|
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Neuromusc. Disord. 12: 151-158, 2002.
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[PubMed: 11738357]
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[Full Text: https://doi.org/10.1016/s0960-8966(01)00252-8]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hunt, C. C. J., Eyre, H. J., Akkari, P. A., Meredith, C., Dorosz, S. M., Wilton, S. D., Callen, D. F., Laing, N. G., Baker, E.
|
|
<strong>Assignment of the human beta tropomyosin gene (TPM2) to band 9p13 by fluorescence in situ hybridization.</strong>
|
|
Cytogenet. Cell Genet. 71: 94-95, 1995.
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[PubMed: 7606936]
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[Full Text: https://doi.org/10.1159/000134070]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Jain, R. K., Jayawant, S., Squier, W., Muntoni, F., Sewry, C. A., Manzur, A., Quinlivan, R., Lillis, S., Jungbluth, H., Sparrow, J. C., Ravenscroft, G., Nowak, K. J., Memo, M., Marston, S. B., Laing, N. G.
|
|
<strong>Nemaline myopathy with stiffness and hypertonia associated with an ACTA1 mutation.</strong>
|
|
Neurology 78: 1100-1103, 2012. Note: Erratum: Neurology 78: 1704 only, 2012.
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|
|
[PubMed: 22442437]
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[Full Text: https://doi.org/10.1212/WNL.0b013e31824e8ebe]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ko, J. M., Choi, I.-H., Baek, G.-H., Kim, K.-w.
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<strong>First Korean family with a mutation in TPM2 associated with Sheldon-Hall syndrome.</strong>
|
|
J. Korean Med. Sci. 28: 780-783, 2013.
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[PubMed: 23678273]
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[Full Text: https://doi.org/10.3346/jkms.2013.28.5.780]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Laing, N. G., Wilton, S. D., Akkari, P. A., Dorosz, S., Boundy, K., Kneebone, C., Blumbergs, P., White, S., Watkins, H., Love, D. R., Haan, E.
|
|
<strong>A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy.</strong>
|
|
Nature Genet. 9: 75-79, 1995. Note: Erratum: Nature Genet. 10: 249 only, 1995.
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|
|
[PubMed: 7704029]
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[Full Text: https://doi.org/10.1038/ng0195-75]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lehtokari, V.-L., Ceuterick-de Groote, C., de Jonghe, P., Marttila, M., Laing, N. G., Pelin, K., Wallgren-Pettersson, C.
|
|
<strong>Cap disease caused by heterozygous deletion of the beta-tropomyosin gene TPM2.</strong>
|
|
Neuromusc. Disord. 17: 433-442, 2007.
|
|
|
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|
|
[PubMed: 17434307]
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[Full Text: https://doi.org/10.1016/j.nmd.2007.02.015]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Li, S., You, Y., Gao, J., Mao, B., Cao, Y., Zhao, X., Zhang, X.
|
|
<strong>Novel mutations in TPM2 and PIEZO2 are responsible for distal arthrogryposis (DA) and mild DA in two Chinese families.</strong>
|
|
BMC Med. Genet. 19: 179 only, 2018. Note: Electronic Article.
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|
|
[PubMed: 30285720]
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[Full Text: https://doi.org/10.1186/s12881-018-0692-8]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Marston, S., Memo, M., Messer, A., Papadaki, M., Nowak, K., McNamara, E., Ong, R., El-Mezgueldi, M., Li, X., Lehman, W.
|
|
<strong>Mutations in repeating motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients.</strong>
|
|
Hum. Molec. Genet. 22: 4978-4987, 2013.
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|
|
[PubMed: 23886664]
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[Full Text: https://doi.org/10.1093/hmg/ddt345]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Mokbel, N., Ilkovski, B., Kreissl, M., Memo, M., Jeffries, C. M., Marttila, M., Lehtokari, V.-L., Lemola, E., Gronholm, M., Yang, N., Menard, D., Marcorelles, P., and 14 others.
|
|
<strong>K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity.</strong>
|
|
Brain 136: 494-507, 2013.
|
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|
|
[PubMed: 23378224]
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|
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[Full Text: https://doi.org/10.1093/brain/aws348]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Mroczek, M., Kabzinska, D., Chrzanowska, K. H., Pronicki, M., Kochanski, A.
|
|
<strong>A novel TPM2 gene splice-site mutation causes severe congenital myopathy with arthrogryposis and dysmorphic features.</strong>
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J. Appl. Genet. 58: 199-203, 2017.
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[PubMed: 27726070]
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[Full Text: https://doi.org/10.1007/s13353-016-0368-z]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ohlsson, M., Quijano-Roy, S., Darin, N., Brochier, G., Lacene, E., Avila-Smirnow, D., Fardeau, M., Oldfors, A., Tajsharghi, H.
|
|
<strong>New morphologic and genetic findings in cap disease associated with beta-tropomyosin (TPM2) mutations.</strong>
|
|
Neurology 71: 1896-1901, 2008.
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|
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[PubMed: 19047562]
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[Full Text: https://doi.org/10.1212/01.wnl.0000336654.44814.b8]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Robinson, P., Lipscomb, S., Preston, L. C., Altin, E., Watkins, H., Ashley, C. C., Redwood, C. S.
|
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<strong>Mutations in fast skeletal troponin I, troponin T, and beta-tropomyosin that cause distal arthrogryposis all increase contractile function.</strong>
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FASEB J. 21: 896-905, 2007.
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[PubMed: 17194691]
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[Full Text: https://doi.org/10.1096/fj.06-6899com]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 06/17/2022.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Sung, S. S., Brassington, A.-M. E., Grannatt, K., Rutherford, A., Whitby, F. G., Krakowiak, P. A., Jorde, L. B., Carey, J. C., Bamshad, M.
|
|
<strong>Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes.</strong>
|
|
Am. J. Hum. Genet. 72: 681-690, 2003.
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[PubMed: 12592607]
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[Full Text: https://doi.org/10.1086/368294]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Tajsharghi, H., Kimber, E., Holmgren, D., Tulinius, M., Oldfors, A.
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<strong>Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation.</strong>
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|
Neurology 68: 772-775, 2007.
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[PubMed: 17339586]
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[Full Text: https://doi.org/10.1212/01.wnl.0000256339.40667.fb]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Tajsharghi, H., Ohlsson, M., Lindberg, C., Oldfors, A.
|
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<strong>Congenital myopathy with nemaline rods and cap structures caused by a mutation in the beta-tropomyosin gene (TPM2).</strong>
|
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Arch. Neurol. 64: 1334-1338, 2007.
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[PubMed: 17846275]
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[Full Text: https://doi.org/10.1001/archneur.64.9.1334]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Tiso, N., Rampoldi, L., Pallavicini, A., Zimbello, R., Pandolfo, D., Valle, G., Lanfranchi, G., Danieli, G. A.
|
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<strong>Fine mapping of five human skeletal muscle genes: alpha-tropomyosin, beta-tropomyosin, troponin-I slow-twitch, troponin-I fast-twitch, and troponin-C fast.</strong>
|
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Biochem. Biophys. Res. Commun. 230: 347-350, 1997.
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[PubMed: 9016781]
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[Full Text: https://doi.org/10.1006/bbrc.1996.5958]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Widada, J. S., Ferraz, C., Capony, J.-P., Liautard, J.-P.
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<strong>Complete nucleotide sequence of the adult skeletal isoform of human skeletal muscle beta-tropomyosin.</strong>
|
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Nucleic Acids Res. 16: 3109 only, 1988.
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[PubMed: 3368322]
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[Full Text: https://doi.org/10.1093/nar/16.7.3109]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 06/01/2023<br>Anne M. Stumpf - updated : 06/17/2022<br>Carol A. Bocchini - updated : 05/17/2019<br>Marla J. F. O'Neill - updated : 05/16/2019<br>Cassandra L. Kniffin - updated : 3/13/2009<br>Cassandra L. Kniffin - updated : 5/22/2008<br>Cassandra L. Kniffin - updated : 3/31/2008<br>Cassandra L. Kniffin - updated : 11/29/2007<br>Cassandra L. Kniffin - updated : 1/21/2005<br>Victor A. McKusick - updated : 2/26/2003<br>Rebekah S. Rasooly - updated : 3/4/1998
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</span>
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</div>
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</div>
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</div>
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<br />
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 5/24/1988
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</span>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Edit History:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 07/16/2024<br>carol : 06/06/2023<br>carol : 06/05/2023<br>carol : 06/01/2023<br>alopez : 06/17/2022<br>carol : 05/21/2019<br>carol : 05/21/2019<br>joanna : 05/21/2019<br>carol : 05/17/2019<br>carol : 05/16/2019<br>carol : 02/28/2017<br>alopez : 06/02/2016<br>alopez : 6/2/2016<br>alopez : 6/1/2016<br>ckniffin : 4/28/2016<br>mcolton : 6/16/2014<br>carol : 8/5/2013<br>terry : 5/16/2012<br>wwang : 11/17/2009<br>wwang : 11/17/2009<br>ckniffin : 11/3/2009<br>ckniffin : 9/28/2009<br>wwang : 3/25/2009<br>ckniffin : 3/13/2009<br>wwang : 7/3/2008<br>wwang : 5/29/2008<br>ckniffin : 5/22/2008<br>wwang : 4/4/2008<br>ckniffin : 3/31/2008<br>wwang : 12/7/2007<br>ckniffin : 11/29/2007<br>carol : 4/7/2005<br>ckniffin : 4/4/2005<br>tkritzer : 1/26/2005<br>ckniffin : 1/21/2005<br>carol : 12/21/2004<br>alopez : 2/27/2003<br>terry : 2/26/2003<br>carol : 4/6/1999<br>alopez : 3/4/1998<br>terry : 6/13/1996<br>mark : 10/13/1995<br>carol : 1/20/1995<br>carol : 8/28/1992<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>supermim : 3/9/1990
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