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Entry
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- *191030 - TROPOMYOSIN 3; TPM3
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- OMIM
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<p>
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<span class="h4">*191030</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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 role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/191030">Table View</a>
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</li>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li 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 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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<h4 class="panel-title">
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<div style="display: table-row">
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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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<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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<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=ENSG00000143549;t=ENST00000651641" 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=7170" 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=191030" 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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<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 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=ENSG00000143549;t=ENST00000651641" 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_001043351,NM_001043352,NM_001043353,NM_001278188,NM_001278189,NM_001278190,NM_001278191,NM_001349679,NM_001364679,NM_001364680,NM_001364681,NM_001364682,NM_001364683,NM_152263,NM_153649,NR_103460,NR_103461" 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_152263" 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=191030" 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=01840&isoform_id=01840_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/TPM3" 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/37430,553799,9508585,12653955,14250022,14250052,15929959,19072649,21104374,21438792,21751343,21751375,23961732,24119203,38541687,47938162,57997573,114155140,114155144,114155146,114155148,119573614,119573615,119573616,119573617,119573618,119573619,119573620,119573621,119573622,189054904,193787016,194377172,194384872,194739611,209402808,308219514,499137516,499137518,499137520,499137522,519668659,957950306,957950309,957950312,1167503335,1243361731,1409929381,1409931450,1409931471,1409931498,1409931609" 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/P06753" 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 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=7170" 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=ENSG00000143549;t=ENST00000651641" 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=TPM3" 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=TPM3" 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+7170" 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/TPM3" 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:7170" 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/7170" 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=chr1&hgg_gene=ENST00000651641.1&hgg_start=154155308&hgg_end=154192100&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:12012" 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/tpm3" 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=191030[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=191030[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/TPM3/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/ENSG00000143549" 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=TPM3" 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=TPM3" 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=TPM3" 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/TPM3" 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=TPM3&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/PA36692" 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:12012" 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:1890149" 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/TPM3#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:1890149" 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/7170/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=7170" 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-030826-16" 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:7170" 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=TPM3&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 240084007<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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191030
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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 3; TPM3
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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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ALPHA-TROPOMYOSIN 3<br />
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ALPHA-TROPOMYOSIN, SLOW SKELETAL
|
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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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<a id="includedTitles" 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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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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TRK ONCOGENE, INCLUDED
|
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</span>
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</div>
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<div>
|
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<span class="h4 mim-font">
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TPM3/NTRK1 FUSION GENE, INCLUDED
|
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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>
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</div>
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<div>
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TPM3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TPM3</a></em></strong>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:154155308-154192100&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'})">1:154,155,308-154,192,100</a> </span>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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Phenotype <br /> MIM number
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Congenital myopathy 4A, autosomal dominant
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<a href="/entry/255310"> 255310 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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Congenital myopathy 4B, autosomal recessive
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<a href="/entry/609284"> 609284 </a>
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/191030" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/191030" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<a id="description" class="mim-anchor"></a>
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Description</strong>
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<p>Tropomyosins are proteins that were first isolated from skeletal muscle, but later identified in many nonmuscle tissues. Vertebrates have at least 4 different tropomyosin genes: TPM1 (<a href="/entry/191010">191010</a>), TPM2 (<a href="/entry/190990">190990</a>), TPM3, and TPM4 (<a href="/entry/600317">600317</a>). Both muscle and nonmuscle forms of the protein are expressed by alternative splicing of each of the 4 genes (<a href="#22" class="mim-tip-reference" title="MacLeod, A. R., Houlker, C., Reinach, F. C., Smillie, L. B., Talbot, K., Modi, G., Walsh, F. S. <strong>A muscle-type tropomyosin in human fibroblasts: evidence for expression by an alternative RNA splicing mechanism.</strong> Proc. Nat. Acad. Sci. 82: 7835-7839, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3865200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3865200</a>] [<a href="https://doi.org/10.1073/pnas.82.23.7835" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3865200">MacLeod et al., 1985</a>; <a href="#19" 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>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3865200+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>
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Cloning and Expression</strong>
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<p><a href="#22" class="mim-tip-reference" title="MacLeod, A. R., Houlker, C., Reinach, F. C., Smillie, L. B., Talbot, K., Modi, G., Walsh, F. S. <strong>A muscle-type tropomyosin in human fibroblasts: evidence for expression by an alternative RNA splicing mechanism.</strong> Proc. Nat. Acad. Sci. 82: 7835-7839, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3865200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3865200</a>] [<a href="https://doi.org/10.1073/pnas.82.23.7835" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3865200">MacLeod et al. (1985)</a> isolated a cDNA corresponding to tropomyosin from a human fibroblast cDNA library. A 1.1-kb mRNA transcript encoded a 284-amino acid protein with similarity to chicken smooth muscle tropomyosin. A 2.5-kb mRNA transcript encoded a 247-amino acid cytoskeletal tropomyosin protein. The findings indicated that nonmuscle cells express both muscle and non-muscle types of tropomyosin. <a href="#22" class="mim-tip-reference" title="MacLeod, A. R., Houlker, C., Reinach, F. C., Smillie, L. B., Talbot, K., Modi, G., Walsh, F. S. <strong>A muscle-type tropomyosin in human fibroblasts: evidence for expression by an alternative RNA splicing mechanism.</strong> Proc. Nat. Acad. Sci. 82: 7835-7839, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3865200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3865200</a>] [<a href="https://doi.org/10.1073/pnas.82.23.7835" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3865200">MacLeod et al. (1985)</a> suggested that both cytoskeletal tropomyosin and skeletal muscle tropomyosin are derived from a common structural gene by alternative splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3865200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="MacLeod, A. R., Houlker, C., Reinach, F. C., Talbot, K. <strong>The mRNA and RNA-copy pseudogenes encoding TM30nm, a human cytoskeletal tropomyosin.</strong> Nucleic Acids Res. 14: 8413-8426, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3024106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3024106</a>] [<a href="https://doi.org/10.1093/nar/14.21.8413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3024106">MacLeod et al. (1986)</a> and <a href="#5" class="mim-tip-reference" title="Clayton, L., Reinach, F. C., Chumbley, G. M., MacLeod, A. R. <strong>Organization of the hTMnm gene: implications for the evolution of muscle and non-muscle tropomyosins.</strong> J. Molec. Biol. 201: 507-515, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3418707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3418707</a>] [<a href="https://doi.org/10.1016/0022-2836(88)90633-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3418707">Clayton et al. (1988)</a> isolated cDNAs corresponding to human tropomyosin-3. In non-muscle tissues, the gene produces a 2.5-kb mRNA encoding a 248-amino acid cytoskeletal protein with a molecular mass of approximately 30 kD. In muscle, alternative splicing of the gene produces a 1.3-kb mRNA encoding a 285-amino acid protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3418707+3024106" 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>TPM3/NTRK1 Fusion Gene</em></strong></p><p>
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<a href="#27" class="mim-tip-reference" title="Martin-Zanca, D., Mitra, G., Long, L. K., Barbacid, M. <strong>Molecular characterization of the human trk oncogene.</strong> Cold Spring Harbor Symp. Quant. Biol. 51: 983-992, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3472772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3472772</a>] [<a href="https://doi.org/10.1101/sqb.1986.051.01.112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3472772">Martin-Zanca et al. (1986)</a> identified a biologically active cDNA of a transforming gene in a human colon carcinoma cell line. The gene, referred to as TRK protooncogene, is a chimera containing sequences of both tropomyosin-3 and a tyrosine kinase. The TRK protooncogene was predicted to encode a 641-amino acid transmembrane tyrosine kinase expressed in neural tissues. The protein was identified by its ability to transform rodent cells in gene transfer assays. <a href="#27" class="mim-tip-reference" title="Martin-Zanca, D., Mitra, G., Long, L. K., Barbacid, M. <strong>Molecular characterization of the human trk oncogene.</strong> Cold Spring Harbor Symp. Quant. Biol. 51: 983-992, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3472772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3472772</a>] [<a href="https://doi.org/10.1101/sqb.1986.051.01.112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3472772">Martin-Zanca et al. (1986)</a> suggested that the chimeric gene was likely formed by a somatic rearrangement between the 2 genes, resulting in the replacement of the extracellular domain of the transmembrane receptor with the first 221 amino acids of the tropomyosin-3 molecule. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3472772" 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="#32" class="mim-tip-reference" title="Mitra, G., Martin-Zanca, D., Barbacid, M. <strong>Identification and biochemical characterization of p70(TRK), product of the human TRK oncogene.</strong> Proc. Nat. Acad. Sci. 84: 6707-6711, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3477801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3477801</a>] [<a href="https://doi.org/10.1073/pnas.84.19.6707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3477801">Mitra et al. (1987)</a> expressed the entire coding sequence of the TRK oncogene in E. coli. Antisera raised against these bacteria-synthesized TRK polypeptides were used to identify the gene product of the TRK oncogene as a 70-kD protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3477801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Clayton, L., Reinach, F. C., Chumbley, G. M., MacLeod, A. R. <strong>Organization of the hTMnm gene: implications for the evolution of muscle and non-muscle tropomyosins.</strong> J. Molec. Biol. 201: 507-515, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3418707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3418707</a>] [<a href="https://doi.org/10.1016/0022-2836(88)90633-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3418707">Clayton et al. (1988)</a> determined that the TPM3 gene spans 42 kb and contains 13 exons; only 5 exons are common to both the 2.5- and 1.3-kb mRNA transcripts. A comparison of the structure of exons encoding the amino-terminal sequences of the muscle and non-muscle isoforms suggested that the TPM3 gene evolved by a specific pattern of exon duplication with alternative splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3418707" 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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<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<p>By in situ hybridization and studies of somatic cell hybrids, <a href="#26" class="mim-tip-reference" title="Martin-Zanca, D., Hughes, S. H., Barbacid, M. <strong>A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences.</strong> Nature 319: 743-748, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2869410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2869410</a>] [<a href="https://doi.org/10.1038/319743a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2869410">Martin-Zanca et al. (1986)</a> mapped the TPM3 gene to chromosome 1q31-q41. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2869410" 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="#36" class="mim-tip-reference" title="Radice, P., Sozzi, G., Miozzo, M., De Benedetti, V., Cariani, T., Bongarzone, I., Spurr, N. K., Pierotti, M. A., Della Porta, G. <strong>The human tropomyosin gene involved in the generation of the TRK oncogene maps to chromosome 1q31.</strong> Oncogene 6: 2145-2148, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1834975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1834975</a>]" pmid="1834975">Radice et al. (1991)</a> assigned the TPM3 gene to 1q by Southern blot analysis of a panel of human-rodent somatic cell hybrids. Using the same probe, they localized the gene to 1q31 by in situ hybridization to human metaphase chromosomes. <a href="#42" class="mim-tip-reference" title="Wilton, S. D., Eyre, H., Akkari, P. A., Watkins, H. C., MacRae, C., Laing, N. G., Callen, D. C. <strong>Assignment of the human alpha-tropomyosin gene TPM3 to 1q22-q23 by fluorescence in situ hybridisation.</strong> Cytogenet. Cell Genet. 68: 122-124, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7956350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7956350</a>] [<a href="https://doi.org/10.1159/000133905" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7956350">Wilton et al. (1995)</a> reassigned the TPM3 gene to 1q22-q23 by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1834975+7956350" 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>Linkage findings in a family with nemaline myopathy caused by mutation in the TPM3 gene (CMYO4A; see <a href="/entry/255310">255310</a>) by <a href="#19" 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> placed TPM3 in close proximity to NTRK1 (<a href="/entry/191315">191315</a>), which had been reassigned to 1q23-q24 (<a href="#33" class="mim-tip-reference" title="Morris, C. M., Hao, Q. L., Heisterkamp, N., Fitzgerald, P. H., Groffen, J. <strong>Localization of the TRK proto-oncogene to human chromosome bands 1q23-1q24.</strong> Oncogene 6: 1093-1095, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1829807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1829807</a>]" pmid="1829807">Morris et al., 1991</a>), so that a gene fusion rearrangement involving these 2 genes would not be cytologically detectable. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7704029+1829807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a human cDNA fragment of the TPM3 gene and a mapping panel from a murine interspecific cross, <a href="#14" class="mim-tip-reference" title="Gariboldi, M., Manenti, G., Dragani, T. A., Pierotti, M. A. <strong>Chromosome mapping of nine tropomyosin-related sequences in mice.</strong> Mammalian Genome 6: 273-277, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7613033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7613033</a>] [<a href="https://doi.org/10.1007/BF00352415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7613033">Gariboldi et al. (1995)</a> mapped the mouse Tpm3 gene to chromosome 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7613033" 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>TPM3/NTRK1 Fusion Gene</em></strong></p><p>
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By a combination of study of somatic cell hybrids and in situ hybridization, <a href="#31" class="mim-tip-reference" title="Miozzo, M., Pierotti, M. A., Sozzi, G., Radice, P., Bongarzone, I., Spurr, N. K., Della Porta, G. <strong>Human TRK proto-oncogene maps to chromosome 1q32-q41.</strong> Oncogene 5: 1411-1414, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2216464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2216464</a>]" pmid="2216464">Miozzo et al. (1990)</a> mapped the TPM3/NTRK1 (TRK) fusion gene to 1q32-q41. <a href="#33" class="mim-tip-reference" title="Morris, C. M., Hao, Q. L., Heisterkamp, N., Fitzgerald, P. H., Groffen, J. <strong>Localization of the TRK proto-oncogene to human chromosome bands 1q23-1q24.</strong> Oncogene 6: 1093-1095, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1829807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1829807</a>]" pmid="1829807">Morris et al. (1991)</a> localized the TRK gene to a more proximal location, 1q23-q24, by in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2216464+1829807" 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 skeletal muscle, tropomyosin isoforms are components of the thin filaments of the sarcomere and mediate the effect of calcium on the actin-myosin interaction. TPM3 is expressed mostly in slow, type 1 muscle fibers. Two muscle-specific isoforms of tropomyosin, an alpha and a beta, form an alpha-helical dimer, bind head to tail, and lie in the major groove of filamentous actin with each tropomyosin molecule binding to 7 actin molecules (<a href="#19" 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>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=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>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="#25" 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><p><strong><em>Role in TRK Protooncogene</em></strong></p><p>
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<a href="#9" class="mim-tip-reference" title="Coulier, F., Martin-Zanca, D., Ernst, M., Barbacid, M. <strong>Mechanism of activation of the human TRK oncogene.</strong> Molec. Cell. Biol. 9: 15-23, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2538716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2538716</a>] [<a href="https://doi.org/10.1128/mcb.9.1.15-23.1989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2538716">Coulier et al. (1989)</a> found that the 221 amino-terminal residues of the TPM3 protein are substituted for the external domain of a putative tyrosine-kinase cell surface receptor to create the TRK oncogene. Since the 2 components giving rise to the TRK oncogene are close together on chromosome 1, no microscopically discernible chromosome abnormality was found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2538716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By transfection assay, <a href="#2" class="mim-tip-reference" title="Bongarzone, I., Pierotti, M. A., Monzini, N., Mondellini, P., Manenti, G., Donghi, R., Pilotti, S., Grieco, M., Santoro, M., Fusco, A., Vecchio, G., Della Porta, G. <strong>High frequency of activation of tyrosine kinase oncogenes in human papillary thyroid carcinoma.</strong> Oncogene 4: 1457-1462, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594368</a>]" pmid="2594368">Bongarzone et al. (1989)</a> found that TRK was activated in tumor cells, both primary tumor and/or metastasis, in 4 of 16 patients with papillary thyroid carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594368" 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="Hempstead, B. L., Martin-Zanca, D., Kaplan, D. R., Parada, L. F., Chao, M. V. <strong>High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor.</strong> Nature 350: 678-683, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1850821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1850821</a>] [<a href="https://doi.org/10.1038/350678a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1850821">Hempstead et al. (1991)</a> and <a href="#18" class="mim-tip-reference" title="Kaplan, D. R., Hempstead, B. L., Martin-Zanca, D., Chao, M. V., Parada, L. F. <strong>The trk proto-oncogene product: a signal transducing receptor for nerve growth factor.</strong> Science 252: 554-558, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1850549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1850549</a>] [<a href="https://doi.org/10.1126/science.1850549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1850549">Kaplan et al. (1991)</a> identified the TRK gene product as a nerve growth factor receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1850821+1850549" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Loeb, D. M., Maragos, J., Martin-Zanca, D., Chao, M. V., Parada, L. F., Greene, L. A. <strong>The trk proto-oncogene rescues NGF responsiveness in mutant NGF-nonresponsive PC12 cell lines.</strong> Cell 66: 961-966, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1653650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1653650</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90441-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1653650">Loeb et al. (1991)</a> presented results indicating that TRK was necessary for functional nerve growth factor signal transduction. <a href="#8" class="mim-tip-reference" title="Cordon-Cardo, C., Tapley, P., Jing, S., Nanduri, V., O'Rourke, E., Lamballe, F., Kovary, K., Klein, R., Jones, K. R., Reichardt, L. F., Barbacid, M. <strong>The trk tyrosine protein kinase mediates the mitogenic properties of nerve growth factor and neurotrophin-3.</strong> Cell 66: 173-183, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1649007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1649007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=1649007[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/10.1016/0092-8674(91)90149-s" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1649007">Cordon-Cardo et al. (1991)</a> presented evidence that the product of the TRK protooncogene was sufficient to mediate signal transduction processes induced by nerve growth factor and neurotrophin-3 (<a href="/entry/162660">162660</a>). <a href="#12" class="mim-tip-reference" title="Ehrhard, P. B., Ganter, U., Stalder, A., Bauer, J., Otten, U. <strong>Expression of functional trk protooncogene in human monocytes.</strong> Proc. Nat. Acad. Sci. 90: 5423-5427, 1993. Note: Erratum: Proc. Nat. Acad. Sci. 91: 1193 only, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8390664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8390664</a>] [<a href="https://doi.org/10.1073/pnas.90.12.5423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8390664">Ehrhard et al. (1993)</a> reported that TRK is expressed in monocytes; this finding as well as others suggested that nerve growth factor is an immunoregulatory cytokine acting on monocytes in addition to its neurotrophic function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1653650+1649007+8390664" 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>The TPM3 gene is involved with the neighboring gene for neurotrophic tyrosine kinase receptor type 1 (NTRK1; <a href="/entry/191315">191315</a>) in a somatic rearrangement that creates the chimeric TRK oncogene. In 3 of 8 papillary thyroid carcinomas, <a href="#3" class="mim-tip-reference" title="Butti, M. G., Bongarzone, I., Ferraresi, G., Mondellini, P., Borrello, M. G., Pierotti, M. A. <strong>A sequence analysis of the genomic regions involved in the rearrangements between TPM3 and NTRK1 genes producing TRK oncogenes in papillary thyroid carcinomas.</strong> Genomics 28: 15-24, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7590742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7590742</a>] [<a href="https://doi.org/10.1006/geno.1995.1100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7590742">Butti et al. (1995)</a> found that replacement of the extracellular domain of the NTRK1 gene by sequences coding for the 221 N-terminal residues of the TPM3 gene was responsible for the oncogenic NTRK1 activation. In all 3 tumors, the illegitimate recombination involved the 611-bp NTRK1 intron placed upstream of the transmembrane domain and the TPM3 intron located between exons 7 and 8. Therefore, due to the displacing mechanism, all of the TPM3/NTRK1 gene fusions encoded an invariable transcript and the same chimeric protein of 70 kD, which was constitutively phosphorylated on tyrosine. In 2 of the 3 tumors, the simultaneous presence of the reciprocal products of the TPM3/NTRK1 recombination (5-prime-TPM3/3-prime NTRK1 and 5-prime NTRK1/3-prime TPM3) and the previously demonstrated localization of both genes on 1q led <a href="#3" class="mim-tip-reference" title="Butti, M. G., Bongarzone, I., Ferraresi, G., Mondellini, P., Borrello, M. G., Pierotti, M. A. <strong>A sequence analysis of the genomic regions involved in the rearrangements between TPM3 and NTRK1 genes producing TRK oncogenes in papillary thyroid carcinomas.</strong> Genomics 28: 15-24, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7590742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7590742</a>] [<a href="https://doi.org/10.1006/geno.1995.1100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7590742">Butti et al. (1995)</a> to suggest that an intrachromosomal inversion was responsible for their recombination. To understand the molecular basis predisposing NTRK1 and TPM3 to being a recurrent target of illegitimate recombination, they determined the nucleotide sequence around the breakpoints of the recombination products in all 3 patients and in the corresponding regions from the normal genes. In these regions, they found some recombinogenic elements as well as palindromes, direct and inverted repeats, and Alu family sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7590742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Autosomal Dominant Congenital Myopathy 4A</em></strong></p><p>
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In affected members of a large family with autosomal dominant congenital myopathy-4A (CMYO4A; <a href="/entry/255310">255310</a>), <a href="#19" 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> identified a heterozygous mutation in the TPM3 gene (M9R; <a href="#0001">191030.0001</a>) that segregated with the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=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>In affected members of a French family with autosomal dominant CMYO4A, <a href="#35" class="mim-tip-reference" title="Penisson-Besnier, I., Monnier, N., Toutain, A., Dubas, F., Laing, N. <strong>A second pedigree with autosomal dominant nemaline myopathy caused by TPM3 mutation: a clinical and pathological study.</strong> Neuromusc. Disord. 17: 330-337, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17376686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17376686</a>] [<a href="https://doi.org/10.1016/j.nmd.2007.01.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17376686">Penisson-Besnier et al. (2007)</a> identified a heterozygous mutation in the TPM3 gene (R168H; <a href="#0005">191030.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17376686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Clarke, N. F., Kolski, H., Dye, D. E., Lim, E., Smith, R. L. L., Patel, R., Fahey, M. C., Bellance, R., Romero, N. B., Johnson, E. S., Labarre-Vila, A., Monnier, N., Laing, N. G., North, K. N. <strong>Mutations in TPM3 are a common cause of congenital fiber type disproportion.</strong> Ann. Neurol. 63: 329-337, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18300303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18300303</a>] [<a href="https://doi.org/10.1002/ana.21308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18300303">Clarke et al. (2008)</a> identified 5 different heterozygous TPM3 mutations (see, e.g., <a href="#0005">191030.0005</a>; <a href="#0007">191030.0007</a>; <a href="#0008">191030.0008</a>), in affected members of 6 unrelated families with CMYO4A and congenital fiber-type disproportion (CFTD) on skeletal muscle biopsy. The mutations were identified among 23 unrelated probands with CFTD, making mutations in the TPM3 gene the most common cause of CFTD to date. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18300303" 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 38-year-old woman with CMYO4A associated with cap structures on skeletal muscle biopsy who had previously been reported by <a href="#13" class="mim-tip-reference" title="Fidzianska, A. <strong>'Cap disease'--a failure in the correct muscle fibre formation.</strong> J. Neurol. Sci. 201: 27-31, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12163190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12163190</a>] [<a href="https://doi.org/10.1016/s0022-510x(02)00156-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12163190">Fidzianska (2002)</a>, <a href="#34" class="mim-tip-reference" title="Ohlsson, M., Fidzianska, A., Tajsharghi, H., Oldfors, A. <strong>TPM3 mutation in one of the original cases of cap disease.</strong> Neurology 72: 1961-1963, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19487656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19487656</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181a82659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19487656">Ohlsson et al. (2009)</a> identified a heterozygous mutation in the TPM3 gene (R168C; <a href="#0009">191030.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12163190+19487656" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="De Paula, A. M., Franques, J., Fernandez, C., Monnier, N., Lunardi, J., Pellissier, J.-F., Figarella-Branger, D., Pouget, J. <strong>A TPM3 mutation causing cap myopathy.</strong> Neuromusc. Disord. 19: 685-688, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19553118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19553118</a>] [<a href="https://doi.org/10.1016/j.nmd.2009.06.365" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19553118">De Paula et al. (2009)</a> reported a 42-year-old man with cap myopathy associated with a heterozygous de novo mutation in the TPM3 gene (R168H; <a href="#0005">191030.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19553118" 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="#40" class="mim-tip-reference" title="Waddell, L. B., Kreissl, M., Kornberg, A., Kennedy, P., McLean, C., Labarre-Vila, A., Monnier, N., North, K. N., Clarke, N. F. <strong>Evidence for a dominant negative disease mechanism in cap myopathy due to TPM3.</strong> Neuromusc. Disord. 20: 464-466, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20554445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20554445</a>] [<a href="https://doi.org/10.1016/j.nmd.2010.05.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20554445">Waddell et al. (2010)</a> reported a man with CMYO4A and cap myopathy on skeletal muscle biopsy that was associated with a de novo heterozygous R168C mutation in the TPM3 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20554445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Malfatti, E., Schaeffer, U., Chapon, F., Yang, Y., Eymard, B., Xu, R., Laporte, J., Romero, N. B. <strong>Combined cap disease and nemaline myopathy in the same patient caused by an autosomal dominant mutation in the TPM3 gene.</strong> Neuromusc. Disord. 23: 992-997, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24095155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24095155</a>] [<a href="https://doi.org/10.1016/j.nmd.2013.07.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24095155">Malfatti et al. (2013)</a> reported a man of French Canadian origin with early-onset myopathy and a de novo heterozygous R168C mutation in the TPM3 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24095155" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 affected members of a family with autosomal dominant CMYO4A, <a href="#37" class="mim-tip-reference" title="Schreckenbach, T., Schroder, J. M., Voit, T., Abicht, A., Neuen-Jacob, E., Roos, A., Bulst, S., Kuhl, C., Schulz, J. B., Weis, J., Claeys, K. G. <strong>Novel TPM3 mutation in a family with cap myopathy and review of the literature.</strong> Neuromusc. Disord. 24: 117-124, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24239060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24239060</a>] [<a href="https://doi.org/10.1016/j.nmd.2013.10.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24239060">Schreckenbach et al. (2014)</a> identified a heterozygous missense mutation in the TPM3 gene (L149I; <a href="#0012">191030.0012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24239060" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Marttila, M., Lehtokari, V.-L., Marston, S., Nyman, T. A., Barnerias, C., Beggs, A. H., Bertini, E., Ceyhan-Birsoy, O., Cintas, P., Gerard, M., Gilbert-Dussardier, B., Hogue, J. S., and 29 others. <strong>Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies.</strong> Hum. Mutat. 35: 779-790, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24692096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24692096</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24692096[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22554" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24692096">Marttila et al. (2014)</a> reported 11 unrelated families with CMYO4A due to heterozygous missense mutations in the TPM3 gene. Six novel heterozygous mutations and several recurrent mutations affecting codon 168 (R168C, R168H) were identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24692096" 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="#43" class="mim-tip-reference" title="Xu, H., Liu, H., Chen, T., Song, B., Zhu, J., Liu, X., Li, M., Luo, C. <strong>The R168G heterozygous mutation of tropomyosin 3 (TPM3) was identified in three family members and has manifestations ranging from asymptotic to serve scoliosis and respiratory complications.</strong> Genes Dis. 8: 715-720, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34291143/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34291143</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34291143[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/10.1016/j.gendis.2020.01.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34291143">Xu et al. (2021)</a> reported a 10-year-old Chinese girl with CMYO4A associated with a heterozygous R168G mutation in the TPM3 gene (R168G; <a href="#0008">191030.0008</a>) that was inherited from her clinically unaffected father. Her brother, who also carried the mutation, had a milder phenotype. The authors noted the intrafamilial variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34291143" 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 47-year-old man with CMYO4A, <a href="#1" class="mim-tip-reference" title="Bevilacqua, J. A., Contreras, J. P., Trangulao, A., Hernandez, U., Brochier, G., Diaz, J., Hughes, R., Campero, M., Romero, N. B. <strong>Novel autosomal dominant TPM3 mutation causes a combined congenital fibre type disproportion-cap disease histological pattern.</strong> Neuromusc. Disord. 32: 687-691, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35688744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35688744</a>] [<a href="https://doi.org/10.1016/j.nmd.2022.05.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35688744">Bevilacqua et al. (2022)</a> identified a heterozygous mutation in the TPM3 gene (E237K; <a href="#0013">191030.0013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35688744" 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>Among 25 Brazilian families with a clinical diagnosis of nemaline myopathy, <a href="#15" class="mim-tip-reference" title="Gurgel-Giannetti, J., Souza, L. S., Yamamoto, G. L., Belisario, M., Lazar, M., Campos, W., Pavanello, R. C. M., Zatz, M., Reed, U., Zanoteli, E., Oliveira, A. B., Lehtokari, V.-L., Casella, E. B., Machado-Costa, M. C., Wallgren-Pettersson, C., Laing, N. G., Nigro, V., Vainzof, M. <strong>Nemaline myopathy in Brazilian patients: molecular and clinical characterization.</strong> Int. J. Molec. Sci. 23: 11995, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36233295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36233295</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36233295[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/10.3390/ijms231911995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36233295">Gurgel-Giannetti et al. (2022)</a> found 1 (4%) who carried a heterozygous missense mutation in the TPM3 gene (R168C). The mutation was present in a father and son (family 7) with congenital myopathy, scoliosis, and nocturnal hypoventilation; both were ambulatory. The findings suggested that mutations in the TPM3 gene are not a common cause of nemaline myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36233295" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated children with CMYO4A characterized by muscle stiffness, hypercontractility, and arthrogryposis multiplex congenita, <a href="#11" class="mim-tip-reference" title="Donkervoort, S., Papadaki, M., de Winter, J. M., Neu, M. B., Kirschner, J., Bolduc, V., Yang, M. L., Gibbons, M. A., Hu, Y., Dastgir, J., Leach, M. E., Rutkowski, A., and 11 others. <strong>TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype.</strong> Ann. Neurol. 78: 982-994, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26418456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26418456</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26418456[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26418456">Donkervoort et al. (2015)</a> identified 2 different de novo heterozygous in-frame deletions in the TPM3 gene (E218del, <a href="#0010">191030.0010</a> and E224del, <a href="#0011">191030.0011</a>). In vitro studies showed that both mutations resulted in increased calcium sensitivity, increased active interaction of actin and the myosin complex, and increased filament sliding motility, consistent with a gain of function. The findings conformed to the predictions made by <a href="#25" 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> in in vitro studies. 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="#17" 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=26418456+23886664+22442437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Autosomal Recessive Congenital Myopathy 4B</em></strong></p><p>
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In an Iranian patient, born of consanguineous parents, with severe autosomal recessive congenital myopathy-4B (CMYO4B; <a href="/entry/609284">609284</a>), resulting in death at 21 months of age, <a href="#39" class="mim-tip-reference" title="Tan, P., Briner, J., Boltshauser, E., Davis, M. R., Wilton, S. D., North, K., Wallgren-Pettersson, C., Laing, N. G. <strong>Homozygosity for a nonsense mutation in the alpha-tropomyosin slow gene TPM3 in a patient with severe infantile nemaline myopathy.</strong> Neuromusc. Disord. 9: 573-579, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10619715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10619715</a>] [<a href="https://doi.org/10.1016/s0960-8966(99)00053-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10619715">Tan et al. (1999)</a> identified a homozygous nonsense mutation in the TPM3 gene (Q32X; <a href="#0004">191030.0004</a>). Each mutation was inherited from an unaffected parent. The authors hypothesized that the patient had no functional TPM3. The patient was identified from a study of 40 unrelated patients diagnosed with congenital myopathy associated with nemaline rods on skeletal muscle biopsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10619715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with CMYO4B, <a href="#41" class="mim-tip-reference" title="Wattanasirichaigoon, D., Swoboda, K. J., Takada, F., Tong, H.-Q., Lip, V., Iannaccone, S. T., Wallgren-Pettersson, C., Laing, N. G., Beggs, A. H. <strong>Mutations of the slow muscle alpha-tropomyosin gene, TPM3, are a rare cause of nemaline myopathy.</strong> Neurology 59: 613-617, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12196661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12196661</a>] [<a href="https://doi.org/10.1212/wnl.59.4.613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12196661">Wattanasirichaigoon et al. (2002)</a> identified compound heterozygous mutations in the TPM3 gene (<a href="#0002">191030.0002</a> and <a href="#0003">191030.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12196661" 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 2 Turkish families with CMYO4B, <a href="#20" class="mim-tip-reference" title="Lehtokari, V.-L., Pelin, K., Donner, K., Voit, T., Rudnik-Schoneborn, S., Stoetter, M., Talim, B., Topaloglu, H., Laing, N. G., Wallgren-Pettersson, C. <strong>Identification of a founder mutation in TPM3 in nemaline myopathy patients of Turkish origin.</strong> Europ. J. Hum. Genet. 16: 1055-1061, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18382475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18382475</a>] [<a href="https://doi.org/10.1038/ejhg.2008.60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18382475">Lehtokari et al. (2008)</a> identified a homozygous mutation in the TPM3 gene (<a href="#0006">191030.0006</a>). Haplotype analysis suggested a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18382475" 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>Based on molecular modeling, <a href="#25" 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> predicted that mutations affecting certain TPM3 residues involved in the actin binding sites would result in higher calcium sensitivity, higher filament sliding speeds, and a gain-of-function effect. In contrast, in vitro studies showed that mutations affecting other regions, including R167H (<a href="#0005">191030.0005</a>), resulted in lower calcium sensitivity, slower sliding speeds, and a hypocontractile phenotype. <a href="#25" 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> suggested that consideration of the effects of the mutations on muscle contractility would be more predictive of the phenotype than histopathology studies. <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><a href="#7" class="mim-tip-reference" title="Corbett, M. A., Robinson, C. S., Dunglison, G. F., Yang, N., Joya, J. E., Stewart, A. W., Schnell, C., Gunning, P. W., North, K. N., Hardeman, E. C. <strong>A mutation in alpha-tropomyosin(slow) affects muscle strength, maturation and hypertrophy in a mouse model for nemaline myopathy.</strong> Hum. Molec. Genet. 10: 317-328, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157795</a>] [<a href="https://doi.org/10.1093/hmg/10.4.317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157795">Corbett et al. (2001)</a> generated a transgenic mouse model expressing an autosomal dominant mutant of TPM3 (M9R; <a href="#0001">191030.0001</a>) previously identified in a human patient with nemaline myopathy. Rods were found in all muscles, but to varying extents which did not correlate with the amount of mutant protein present. In addition, a pathologic feature not commonly associated with this disorder, cytoplasmic bodies, was found in the mouse and subsequently identified in human samples. Hypertrophy of fast, type 2B (glycolytic) fibers was apparent at 2 months of age. Muscle weakness was apparent in mice at 5 to 6 months of age, mimicking the late onset observed in humans with this mutation. The onset of weakness correlated with an age-related decrease in fiber diameter and suggested that early onset may be prevented by hypertrophy of fast, glycolytic fibers. The authors suggested that the clinical phenotype may be precipitated by a failure of the hypertrophy to persist and therefore compensate for muscle weakness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11157795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80358247 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80358247;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80358247?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80358247" 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=rs80358247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a large family with autosomal dominant congenital myopathy-4A (CMYO4A; <a href="/entry/255310">255310</a>), <a href="#19" 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> identified a heterozygous T-to-G transversion in exon 1 of the TPM3 gene, resulting in a met9-to-arg (M9R) substitution in a highly conserved residue located at the N-terminal end of the protein. The region may be important for head-to-tail association of tropomyosin molecules and may be crucial to actin binding. <a href="#19" 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> noted that actin binding was completely inhibited by removal of the N-terminal 9 amino acid residues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=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><strong><em>Variant Function</em></strong></p><p>
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<a href="#30" class="mim-tip-reference" title="Michele, D. E., Albayya, F. P., Metzger, J. M. <strong>A nemaline myopathy mutation in alpha-tropomyosin causes defective regulation of striated muscle force production.</strong> J. Clin. Invest. 104: 1575-1581, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10587521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10587521</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10587521[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI7842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10587521">Michele et al. (1999)</a> used adenoviral gene transfer to fully differentiated rat adult myocytes in vitro to determine the effects of nemaline myopathy mutant human tropomyosin expression on striated muscle sarcomeric structure and contractile function. The mutant tropomyosin was expressed and incorporated correctly into sarcomeres of adult muscle cells. The primary defect caused by expression of the mutant tropomyosin was a decrease in the sensitivity of contraction to activating Ca(2+), which could help explain the hypotonia seen in nemaline myopathy. The M9R mutant tropomyosin expression did not directly result in nemaline rod formation, which suggested that rod formation is secondary to contractile dysfunction and that load-dependent processes are likely involved in nemaline rod formation in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10587521" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Corbett, M. A., Akkari, P. A., Domazetovska, A., Cooper, S. T., North, K. N., Laing, N. G., Gunning, P. W., Hardeman, E. C. <strong>An alpha-tropomyosin mutation alters dimer preference in nemaline myopathy.</strong> Ann. Neurol. 57: 42-49, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15562513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15562513</a>] [<a href="https://doi.org/10.1002/ana.20305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15562513">Corbett et al. (2005)</a> found that skeletal muscle from both transgenic mice and human patients with the TPM3 M9R mutation had decreased levels of beta-tropomyosin (TPM2; <a href="/entry/190990">190990</a>), and that the timing of increased levels of the mutant TPM3 protein in muscle coincided with a decrease in TPM2 levels. In vertebrates, the preferred pairing of tropomyosin dimers is an alpha/beta heterodimer; however, Western blot analysis of the tropomyosin filament dimers from tissue with the M9R mutant protein showed a decrease in the TPM3/TPM2 heterodimer, with a shift to mutant TPM3 homodimers. The M9R mutation lies within the region of overlap for head-to-tail interactions between dimer pairs. <a href="#6" class="mim-tip-reference" title="Corbett, M. A., Akkari, P. A., Domazetovska, A., Cooper, S. T., North, K. N., Laing, N. G., Gunning, P. W., Hardeman, E. C. <strong>An alpha-tropomyosin mutation alters dimer preference in nemaline myopathy.</strong> Ann. Neurol. 57: 42-49, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15562513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15562513</a>] [<a href="https://doi.org/10.1002/ana.20305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15562513">Corbett et al. (2005)</a> suggested that the M9R mutant TPM3 protein changes the composition of sarcomeric thin filaments and the regulation of muscle contraction, resulting in disease manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15562513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199474720 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199474720;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199474720?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199474720" 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=rs199474720" 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=RCV000013260 OR RCV000128708 OR RCV000707046" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013260, RCV000128708, RCV000707046" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013260...</a>
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<p>In a patient with autosomal recessive congenital myopathy-4B (CMYO4B; <a href="/entry/609284">609284</a>), <a href="#41" class="mim-tip-reference" title="Wattanasirichaigoon, D., Swoboda, K. J., Takada, F., Tong, H.-Q., Lip, V., Iannaccone, S. T., Wallgren-Pettersson, C., Laing, N. G., Beggs, A. H. <strong>Mutations of the slow muscle alpha-tropomyosin gene, TPM3, are a rare cause of nemaline myopathy.</strong> Neurology 59: 613-617, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12196661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12196661</a>] [<a href="https://doi.org/10.1212/wnl.59.4.613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12196661">Wattanasirichaigoon et al. (2002)</a> identified compound heterozygous mutations in the TPM3 gene: a c.857A-C transversion (designated 915A-C in the article, based on a GenBank reference sequence) in exon 9sk, resulting in a TER285SER substitution and the addition of 57 amino acids; and a mutation at the acceptor splice site of the same exon, resulting in exon skipping (<a href="#0003">191030.0003</a>). Based on numbering from the first met codon (<a href="#4" class="mim-tip-reference" title="Clarke, N. F., Kolski, H., Dye, D. E., Lim, E., Smith, R. L. L., Patel, R., Fahey, M. C., Bellance, R., Romero, N. B., Johnson, E. S., Labarre-Vila, A., Monnier, N., Laing, N. G., North, K. N. <strong>Mutations in TPM3 are a common cause of congenital fiber type disproportion.</strong> Ann. Neurol. 63: 329-337, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18300303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18300303</a>] [<a href="https://doi.org/10.1002/ana.21308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18300303">Clarke et al. (2008)</a>), this mutation is designated TER286SER (X286S). The patient's asymptomatic father was heterozygous for the X286S mutation, and his asymptomatic mother was heterozygous for the splice site mutation. The patient was identified from a study of 40 unrelated patients with nemaline myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18300303+12196661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs113605263 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113605263;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs113605263?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs113605263" 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=rs113605263" 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=RCV000013261 OR RCV000128706 OR RCV000689419" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013261, RCV000128706, RCV000689419" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013261...</a>
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<p>For discussion of the IVS9-1G-A mutation in the TPM3 gene that was found in compound heterozygous state in a patient with congenital myopathy-4B (CMYO4B; <a href="/entry/609284">609284</a>) by <a href="#41" class="mim-tip-reference" title="Wattanasirichaigoon, D., Swoboda, K. J., Takada, F., Tong, H.-Q., Lip, V., Iannaccone, S. T., Wallgren-Pettersson, C., Laing, N. G., Beggs, A. H. <strong>Mutations of the slow muscle alpha-tropomyosin gene, TPM3, are a rare cause of nemaline myopathy.</strong> Neurology 59: 613-617, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12196661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12196661</a>] [<a href="https://doi.org/10.1212/wnl.59.4.613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12196661">Wattanasirichaigoon et al. (2002)</a>, see <a href="#0002">191030.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12196661" 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">rs80358248 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80358248;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=rs80358248" 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=rs80358248" 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=RCV000013262 OR RCV000128709 OR RCV003764563 OR RCV004562204" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013262, RCV000128709, RCV003764563, RCV004562204" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013262...</a>
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<p>In an Iranian patient, born of consanguineous parents, with congenital myopathy-4B (CMYO4B; <a href="/entry/609284">609284</a>), <a href="#39" class="mim-tip-reference" title="Tan, P., Briner, J., Boltshauser, E., Davis, M. R., Wilton, S. D., North, K., Wallgren-Pettersson, C., Laing, N. G. <strong>Homozygosity for a nonsense mutation in the alpha-tropomyosin slow gene TPM3 in a patient with severe infantile nemaline myopathy.</strong> Neuromusc. Disord. 9: 573-579, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10619715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10619715</a>] [<a href="https://doi.org/10.1016/s0960-8966(99)00053-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10619715">Tan et al. (1999)</a> identified a homozygous C-to-T transition in exon 1 of the TPM3 gene, resulting in a GLN31TER substitution. Based on numbering from the first met codon (<a href="#4" class="mim-tip-reference" title="Clarke, N. F., Kolski, H., Dye, D. E., Lim, E., Smith, R. L. L., Patel, R., Fahey, M. C., Bellance, R., Romero, N. B., Johnson, E. S., Labarre-Vila, A., Monnier, N., Laing, N. G., North, K. N. <strong>Mutations in TPM3 are a common cause of congenital fiber type disproportion.</strong> Ann. Neurol. 63: 329-337, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18300303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18300303</a>] [<a href="https://doi.org/10.1002/ana.21308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18300303">Clarke et al. (2008)</a>), this mutation is designated GLN32TER (Q32X). Although no neonatal problems were reported, the infant showed extremely delayed motor development and died at age 21 months due to respiratory insufficiency resulting from an infectious illness. Muscle biopsy showed type 1 fiber hypotrophy and atrophy, with a mild predominance of type 2 fibers. Nemaline bodies were present in type 1 fibers only. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10619715+18300303" 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">rs121964852 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964852;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=rs121964852" 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=rs121964852" 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=RCV000013263 OR RCV000054415 OR RCV000128701 OR RCV000537032 OR RCV001420249" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013263, RCV000054415, RCV000128701, RCV000537032, RCV001420249" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013263...</a>
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<p>In 4 affected members of a French family with autosomal dominant congenital myopathy-4A (CMYO4A; <a href="/entry/255310">255310</a>), <a href="#35" class="mim-tip-reference" title="Penisson-Besnier, I., Monnier, N., Toutain, A., Dubas, F., Laing, N. <strong>A second pedigree with autosomal dominant nemaline myopathy caused by TPM3 mutation: a clinical and pathological study.</strong> Neuromusc. Disord. 17: 330-337, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17376686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17376686</a>] [<a href="https://doi.org/10.1016/j.nmd.2007.01.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17376686">Penisson-Besnier et al. (2007)</a> identified a heterozygous c.503G-A transition in exon 5 of the TPM3 gene, resulting in an ARG167HIS substitution. Although most patients had symptoms in childhood, all remained ambulatory as adults. <a href="#4" class="mim-tip-reference" title="Clarke, N. F., Kolski, H., Dye, D. E., Lim, E., Smith, R. L. L., Patel, R., Fahey, M. C., Bellance, R., Romero, N. B., Johnson, E. S., Labarre-Vila, A., Monnier, N., Laing, N. G., North, K. N. <strong>Mutations in TPM3 are a common cause of congenital fiber type disproportion.</strong> Ann. Neurol. 63: 329-337, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18300303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18300303</a>] [<a href="https://doi.org/10.1002/ana.21308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18300303">Clarke et al. (2008)</a> noted that based on numbering from the first met codon this mutation is designated ARG168HIS (R168H). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17376686+18300303" 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 father and daughter with congenital myopathy, <a href="#4" class="mim-tip-reference" title="Clarke, N. F., Kolski, H., Dye, D. E., Lim, E., Smith, R. L. L., Patel, R., Fahey, M. C., Bellance, R., Romero, N. B., Johnson, E. S., Labarre-Vila, A., Monnier, N., Laing, N. G., North, K. N. <strong>Mutations in TPM3 are a common cause of congenital fiber type disproportion.</strong> Ann. Neurol. 63: 329-337, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18300303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18300303</a>] [<a href="https://doi.org/10.1002/ana.21308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18300303">Clarke et al. (2008)</a> identified the R168H mutation in the TPM3 gene. Both patients had onset of hypotonia in infancy and were able to run in late adolescence. At age 60, the father could walk, had impaired nocturnal ventilation, showed distal more than proximal weakness, and had scoliosis with lumbar lordosis. Skeletal muscle biopsy was consistent with nemaline myopathy. At age 20, the daughter was able to run, had decreased forced vital capacity, mild proximal weakness, and mild scoliosis. Skeletal muscle biopsy showed fiber-type disproportion (CFTD) The findings of both nemaline myopathy and CFTD in patients with the same mutation showed that TPM3 mutations can cause a range of histologic changes, and suggested that there is a close relation between nemaline myopathy and CFTD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18300303" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="De Paula, A. M., Franques, J., Fernandez, C., Monnier, N., Lunardi, J., Pellissier, J.-F., Figarella-Branger, D., Pouget, J. <strong>A TPM3 mutation causing cap myopathy.</strong> Neuromusc. Disord. 19: 685-688, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19553118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19553118</a>] [<a href="https://doi.org/10.1016/j.nmd.2009.06.365" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19553118">De Paula et al. (2009)</a> reported a 42-year-old man with the R168H mutation who showed cap myopathy on skeletal muscle biopsy. He had hypotonia in the first months of life, delayed motor development, and distal weakness of the lower limbs with frequent falls in childhood. At age 7 years, he had flat feet in valgus, long narrow face, high-arched palate, and mild lumbar hyperlordosis. Tendon reflexes were absent. The clinical course was stable until presentation at age 42 with inability to run, difficulty climbing stairs, and predominant distal muscle weakness. Skeletal muscle biopsy at age 7 years showed type 1 fiber hypotrophy. Biopsy at age 42 years showed only type 1 fibers, irregularity of fiber size, occasional central nuclei, and peripheral eosinophilic-basophilic densely stained substances consistent with 'caps.' The caps were present in about 10 to 15% of muscle fibers, were negative for ATPase staining, were present just beneath the sarcolemma, and consisted of abnormally arranged myofibrils. Z-lines were thickened with some rod-like structures. The authors noted that this case had first been reported as a congenital myopathy with selective hypotrophy of type 1 fibers (<a href="#38" class="mim-tip-reference" title="Serratrice, G., Pellissier, J. F., Gastaut, J. L., Pouget, J. <strong>Congenital myopathy with selective hypotrophy of type I fibers.</strong> Rev. Neurol. (Paris) 131: 813-816, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1221488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1221488</a>]" pmid="1221488">Serratrice et al., 1975</a>), and that the biopsy results discussed in that report would have been consistent with CFTD. The findings suggested a relationship between nemaline myopathy, CFTD, and cap myopathy, and indicated that cap structures may develop over time. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19553118+1221488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199474719 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199474719;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199474719?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199474719" 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=rs199474719" 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=RCV000013266 OR RCV000128707" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013266, RCV000128707" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013266...</a>
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<p>In 4 patients from 2 presumably unrelated Turkish families with autosomal recessive congenital myopathy-4B (CMYO4B; <a href="/entry/609284">609284</a>), <a href="#20" class="mim-tip-reference" title="Lehtokari, V.-L., Pelin, K., Donner, K., Voit, T., Rudnik-Schoneborn, S., Stoetter, M., Talim, B., Topaloglu, H., Laing, N. G., Wallgren-Pettersson, C. <strong>Identification of a founder mutation in TPM3 in nemaline myopathy patients of Turkish origin.</strong> Europ. J. Hum. Genet. 16: 1055-1061, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18382475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18382475</a>] [<a href="https://doi.org/10.1038/ejhg.2008.60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18382475">Lehtokari et al. (2008)</a> identified a homozygous 1-bp deletion (c.913delA, NM_152263) in exon 9b of the TPM3 gene, at the last nucleotide before the stop codon. The mutation was predicted to result in elongation of the protein by 73 residues, which would disrupt the coiled-coil polymer and render the protein nonfunctional. A shared haplotype between the 2 families suggested a founder effect. The phenotype was moderate to severe, with early-onset, restrictive respiratory vital capacity, and chest deformities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18382475" 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">rs121964853 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964853;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=rs121964853" 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=rs121964853" 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=RCV000013267 OR RCV000128697 OR RCV003151724" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013267, RCV000128697, RCV003151724" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013267...</a>
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<p>In 5 affected individuals from an Australian family with autosomal dominant congenital myopathy-4A (CMYO4A; <a href="/entry/255310">255310</a>), <a href="#4" class="mim-tip-reference" title="Clarke, N. F., Kolski, H., Dye, D. E., Lim, E., Smith, R. L. L., Patel, R., Fahey, M. C., Bellance, R., Romero, N. B., Johnson, E. S., Labarre-Vila, A., Monnier, N., Laing, N. G., North, K. N. <strong>Mutations in TPM3 are a common cause of congenital fiber type disproportion.</strong> Ann. Neurol. 63: 329-337, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18300303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18300303</a>] [<a href="https://doi.org/10.1002/ana.21308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18300303">Clarke et al. (2008)</a> identified a heterozygous c.298C-A transversion (c.298C-A, NM_152263.2) in exon 3 of the TPM3 gene, resulting in a leu100-to-met (L100M) substitution in a highly conserved residue in the alpha-helix domain. Four of the patients presented before age 1 year with hypotonia or decreased activity levels. Two had delayed walking, and all were able to run in the teenage years. The fifth patient presented at age 32 with respiratory failure. Three patients in their forties showed slow walking, impaired nocturnal ventilation, moderate proximal weakness, scapular winging, and ptosis. Two patients had scoliosis. Histologic examination of skeletal muscle showed that type 1 fibers were smaller than type 2 fibers by 50 to 65%, with internal nuclei and no other abnormalities; these findings were consistent with a diagnosis of congenital myopathy with fiber-type disproportion (CFTD). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18300303" 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">rs121964854 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964854;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=rs121964854" 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=rs121964854" 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=RCV000013268 OR RCV000128699 OR RCV000226212 OR RCV001382225 OR RCV003151725 OR RCV004585998" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013268, RCV000128699, RCV000226212, RCV001382225, RCV003151725, RCV004585998" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013268...</a>
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<p>In a patient with congenital myopathy-4A (CMYO4A; <a href="/entry/255310">255310</a>), <a href="#4" class="mim-tip-reference" title="Clarke, N. F., Kolski, H., Dye, D. E., Lim, E., Smith, R. L. L., Patel, R., Fahey, M. C., Bellance, R., Romero, N. B., Johnson, E. S., Labarre-Vila, A., Monnier, N., Laing, N. G., North, K. N. <strong>Mutations in TPM3 are a common cause of congenital fiber type disproportion.</strong> Ann. Neurol. 63: 329-337, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18300303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18300303</a>] [<a href="https://doi.org/10.1002/ana.21308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18300303">Clarke et al. (2008)</a> identified a heterozygous c.502C-G transversion (c.502C-G, NM_152263.2) in exon 5 of the TPM3 gene, resulting in an arg168-to-gly (R168G) substitution in the alpha-helix domain. At age 9 years, the patient showed slow running, decreased forced vital capacity, mild proximal muscle weakness, mild ptosis, and lumbar lordosis. Muscle biopsy showed fiber-type disproportion (CFTD). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18300303" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 CONGENITAL MYOPATHY 4A, AUTOSOMAL DOMINANT</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121964854 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964854;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=rs121964854" 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=rs121964854" 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=RCV000013269 OR RCV000054416 OR RCV000128700 OR RCV000624745 OR RCV000637291 OR RCV004585999" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013269, RCV000054416, RCV000128700, RCV000624745, RCV000637291, RCV004585999" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013269...</a>
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<p>In a woman with congenital myopathy-4A (CMYO4A; <a href="/entry/609284">609284</a>), <a href="#4" class="mim-tip-reference" title="Clarke, N. F., Kolski, H., Dye, D. E., Lim, E., Smith, R. L. L., Patel, R., Fahey, M. C., Bellance, R., Romero, N. B., Johnson, E. S., Labarre-Vila, A., Monnier, N., Laing, N. G., North, K. N. <strong>Mutations in TPM3 are a common cause of congenital fiber type disproportion.</strong> Ann. Neurol. 63: 329-337, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18300303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18300303</a>] [<a href="https://doi.org/10.1002/ana.21308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18300303">Clarke et al. (2008)</a> identified a heterozygous c.502C-T transition (c.502C-T, NM_152263.2) in exon 5 of the TPM3 gene, resulting in an arg168-to-cys (R168C) substitution in the alpha-helix domain. The patient had poor head control before 1 year of age, but normal walking at age 9 months, and could run in childhood. At age 32, she could walk stairs with difficulty and had impaired nocturnal ventilation, moderate proximal weakness, ptosis, and severe kyphoscoliosis. Skeletal muscle biopsy showed fiber-type disproportion (CFTD). The authors noted that several other mutations had been identified in this codon (see, e.g., R168G, <a href="#0008">191030.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18300303" 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="#34" class="mim-tip-reference" title="Ohlsson, M., Fidzianska, A., Tajsharghi, H., Oldfors, A. <strong>TPM3 mutation in one of the original cases of cap disease.</strong> Neurology 72: 1961-1963, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19487656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19487656</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181a82659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19487656">Ohlsson et al. (2009)</a> identified a heterozygous R168C mutation in a 38-year-old woman with CMYO4A associated with cap structures on skeletal muscle biopsy. She had previously been reported by <a href="#13" class="mim-tip-reference" title="Fidzianska, A. <strong>'Cap disease'--a failure in the correct muscle fibre formation.</strong> J. Neurol. Sci. 201: 27-31, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12163190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12163190</a>] [<a href="https://doi.org/10.1016/s0022-510x(02)00156-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12163190">Fidzianska (2002)</a>. She had slowly progressive muscle weakness and scoliosis since childhood, but was not examined until age 18 years. At that time, she had long narrow face, high-arched palate, chest deformity, and thin underdeveloped muscles. Other features included impaired nocturnal ventilation. Skeletal muscle biopsy showed that 20 to 30% of muscle fibers had granular cap structures devoid of ATPase activities. Myofibrils forming the caps were clearly demarcated from the remaining fibers and had an abnormal sarcomere pattern. Nemaline rods and fiber-type disproportion were not observed. The findings illustrated the phenotypic and histologic variability associated with TPM3 mutations, and suggested that cap disease is related to nemaline myopathy and CFTD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12163190+19487656" 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="#40" class="mim-tip-reference" title="Waddell, L. B., Kreissl, M., Kornberg, A., Kennedy, P., McLean, C., Labarre-Vila, A., Monnier, N., North, K. N., Clarke, N. F. <strong>Evidence for a dominant negative disease mechanism in cap myopathy due to TPM3.</strong> Neuromusc. Disord. 20: 464-466, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20554445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20554445</a>] [<a href="https://doi.org/10.1016/j.nmd.2010.05.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20554445">Waddell et al. (2010)</a> reported a young man with CMYO4A due to a de novo heterozygous R168C mutation. He had mildly delayed motor development in early childhood, generalized hypotonia, and muscle weakness, particularly of the proximal lower limbs, ankle dorsiflexors, and neck. He had a long myopathic face with open mouth, high-arched palate, retrognathia, narrow chest, and mild scoliosis. At age 20 years, his pulmonary vital capacity was 37% of that predicted. Muscle biopsy taken at age 3 years showed increased variation in fiber size and subsarcolemmal protein inclusions in 25% of fibers, typical of caps. There was also type 1 fiber predominance. Caps stained strongly for several proteins, including tropomyosin, and electron microscopy showed disorganized thin filament structures containing Z-band remnants. Nemaline rods were not present. Two-dimensional gel electrophoresis showed that the mutant protein accounted for about 50% of the TPM3 protein in sarcomeres, and <a href="#40" class="mim-tip-reference" title="Waddell, L. B., Kreissl, M., Kornberg, A., Kennedy, P., McLean, C., Labarre-Vila, A., Monnier, N., North, K. N., Clarke, N. F. <strong>Evidence for a dominant negative disease mechanism in cap myopathy due to TPM3.</strong> Neuromusc. Disord. 20: 464-466, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20554445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20554445</a>] [<a href="https://doi.org/10.1016/j.nmd.2010.05.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20554445">Waddell et al. (2010)</a> postulated a dominant-negative effect, perhaps resulting from altered protein-protein interactions. These findings indicated that the fiber type distribution pattern as well as the pattern of protein inclusions can vary widely even among patients with the same TPM3 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20554445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Malfatti, E., Schaeffer, U., Chapon, F., Yang, Y., Eymard, B., Xu, R., Laporte, J., Romero, N. B. <strong>Combined cap disease and nemaline myopathy in the same patient caused by an autosomal dominant mutation in the TPM3 gene.</strong> Neuromusc. Disord. 23: 992-997, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24095155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24095155</a>] [<a href="https://doi.org/10.1016/j.nmd.2013.07.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24095155">Malfatti et al. (2013)</a> reported a man of French Canadian origin, with early-onset myopathy and a de novo heterozygous R168C mutation in the TPM3 gene. He had typical clinical features of the disorder, with mildly delayed motor milestones, generalized hypotonia, proximal and distal muscle weakness, impaired respiratory function, long, narrow face, and high-arched palate. Muscle biopsy showed type 1 fiber uniformity, subsarcolemmal caps in about 20% of fibers, typical nemaline rods in about 10% of fibers, and both caps and rods in about 5% of fibers. Electron microscopy demonstrated that the cap structures were composed of disorganized myofibrils and thickened Z-bands; the nemaline rods had longitudinal and transverse striations and were surrounded by thin filaments. Some of the caps contained structures resembling small rods, and the intermyofibrillary network adjacent to caps or nemaline rods was irregular with jagged Z lines. <a href="#24" class="mim-tip-reference" title="Malfatti, E., Schaeffer, U., Chapon, F., Yang, Y., Eymard, B., Xu, R., Laporte, J., Romero, N. B. <strong>Combined cap disease and nemaline myopathy in the same patient caused by an autosomal dominant mutation in the TPM3 gene.</strong> Neuromusc. Disord. 23: 992-997, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24095155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24095155</a>] [<a href="https://doi.org/10.1016/j.nmd.2013.07.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24095155">Malfatti et al. (2013)</a> emphasized that the combination of rods and caps had not previously been reported in the same patient, which suggested that the 2 patterns are pathogenetically related. The findings confirmed that nemaline myopathy and cap myopathy resulting from TPM3 mutations are part of a disease spectrum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24095155" 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">rs876661406 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs876661406;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=rs876661406" 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=rs876661406" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 5-year-old boy with congenital myopathy-4A (CMYO4A; <a href="/entry/609284">609284</a>) characterized by muscle stiffness, hypercontractility, and arthrogryposis multiplex congenita, <a href="#11" class="mim-tip-reference" title="Donkervoort, S., Papadaki, M., de Winter, J. M., Neu, M. B., Kirschner, J., Bolduc, V., Yang, M. L., Gibbons, M. A., Hu, Y., Dastgir, J., Leach, M. E., Rutkowski, A., and 11 others. <strong>TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype.</strong> Ann. Neurol. 78: 982-994, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26418456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26418456</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26418456[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26418456">Donkervoort et al. (2015)</a> identified a de novo heterozygous 3-bp deletion (c.673_675delGAA, NM_152263.3) in exon 6A of the TPM3 gene, resulting in the deletion of residue glu224 (E224del) in a highly conserved region. The mutation, which was found by whole-exome sequencing, was not found in the dbSNP, Exome Variant Server, or ExAC databases. In vitro studies showed that the mutations resulted in increased calcium sensitivity, increased interaction of actin and the myosin complex, and increased filament sliding motility, consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26418456" 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">rs876661407 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs876661407;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=rs876661407" 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=rs876661407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 3-year-old girl with congenital myopathy-4A (CMYO4A; <a href="/entry/609284">609284</a>) characterized by muscle stiffness, hypercontractility, and arthrogryposis multiplex congenita, <a href="#11" class="mim-tip-reference" title="Donkervoort, S., Papadaki, M., de Winter, J. M., Neu, M. B., Kirschner, J., Bolduc, V., Yang, M. L., Gibbons, M. A., Hu, Y., Dastgir, J., Leach, M. E., Rutkowski, A., and 11 others. <strong>TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype.</strong> Ann. Neurol. 78: 982-994, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26418456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26418456</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26418456[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26418456">Donkervoort et al. (2015)</a> identified a de novo heterozygous 3-bp deletion (c.657_659delAGA, NM_152263.3) in exon 6A of the TPM3 gene, resulting in the deletion of residue glu218 (E218del) in a highly conserved region. The mutation was not found in the dbSNP, Exome Variant Server, or ExAC databases. In vitro studies showed that the mutations resulted in increased calcium sensitivity, increased interaction of actin and the myosin complex, and increased filament sliding motility, consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26418456" 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=RCV003152550" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003152550" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003152550</a>
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<p>In a woman and her son with autosomal dominant congenital myopathy-4A (CMYO4A; <a href="/entry/255310">255310</a>), <a href="#37" class="mim-tip-reference" title="Schreckenbach, T., Schroder, J. M., Voit, T., Abicht, A., Neuen-Jacob, E., Roos, A., Bulst, S., Kuhl, C., Schulz, J. B., Weis, J., Claeys, K. G. <strong>Novel TPM3 mutation in a family with cap myopathy and review of the literature.</strong> Neuromusc. Disord. 24: 117-124, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24239060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24239060</a>] [<a href="https://doi.org/10.1016/j.nmd.2013.10.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24239060">Schreckenbach et al. (2014)</a> identified a heterozygous c.445C-A transversion (c.445C-A, NM_152263.2) in exon 4 of the TPM3 gene, resulting in a leu149-to-ile (L149I) substitution. The woman's deceased mother had similar features, but genetic analysis was not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24239060" 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">rs1661445206 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1661445206;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=rs1661445206" 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=rs1661445206" 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=RCV001312798 OR RCV003223719" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001312798, RCV003223719" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001312798...</a>
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<p>In a 47-year-old man with congenital myopathy-4A (CMYO4A; <a href="/entry/255310">255310</a>), <a href="#1" class="mim-tip-reference" title="Bevilacqua, J. A., Contreras, J. P., Trangulao, A., Hernandez, U., Brochier, G., Diaz, J., Hughes, R., Campero, M., Romero, N. B. <strong>Novel autosomal dominant TPM3 mutation causes a combined congenital fibre type disproportion-cap disease histological pattern.</strong> Neuromusc. Disord. 32: 687-691, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35688744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35688744</a>] [<a href="https://doi.org/10.1016/j.nmd.2022.05.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35688744">Bevilacqua et al. (2022)</a> identified a heterozygous c.709G-A transition in exon 8 of the TPM3 gene, resulting in a glu237-to-lys (E237K) substitution. He had a history of delayed motor development with gait impairment and poor exercise tolerance since childhood. He had no family history of a similar disorder, suggesting that the mutation may have occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35688744" 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="#Martin-Zanca1989" class="mim-tip-reference" title="Martin-Zanca, D., Oskam, R., Mitra, G., Copeland, T., Barbacid, M. <strong>Molecular and biochemical characterization of the human TRK proto-oncogene.</strong> Molec. Cell. Biol. 9: 24-33, 1989.">Martin-Zanca et al. (1989)</a>
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Bevilacqua, J. A., Contreras, J. P., Trangulao, A., Hernandez, U., Brochier, G., Diaz, J., Hughes, R., Campero, M., Romero, N. B.
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<strong>Novel autosomal dominant TPM3 mutation causes a combined congenital fibre type disproportion-cap disease histological pattern.</strong>
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Neuromusc. Disord. 32: 687-691, 2022.
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<div class="">
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<p class="mim-text-font">
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Ohlsson, M., Fidzianska, A., Tajsharghi, H., Oldfors, A.
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<strong>TPM3 mutation in one of the original cases of cap disease.</strong>
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Neurology 72: 1961-1963, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19487656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19487656</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19487656" 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/10.1212/WNL.0b013e3181a82659" target="_blank">Full Text</a>]
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<a id="35" class="mim-anchor"></a>
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<a id="Penisson-Besnier2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Penisson-Besnier, I., Monnier, N., Toutain, A., Dubas, F., Laing, N.
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<strong>A second pedigree with autosomal dominant nemaline myopathy caused by TPM3 mutation: a clinical and pathological study.</strong>
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Neuromusc. Disord. 17: 330-337, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17376686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17376686</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17376686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2007.01.017" target="_blank">Full Text</a>]
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<a id="Radice1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Radice, P., Sozzi, G., Miozzo, M., De Benedetti, V., Cariani, T., Bongarzone, I., Spurr, N. K., Pierotti, M. A., Della Porta, G.
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<strong>The human tropomyosin gene involved in the generation of the TRK oncogene maps to chromosome 1q31.</strong>
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Oncogene 6: 2145-2148, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1834975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1834975</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1834975" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="37" class="mim-anchor"></a>
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<a id="Schreckenbach2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Schreckenbach, T., Schroder, J. M., Voit, T., Abicht, A., Neuen-Jacob, E., Roos, A., Bulst, S., Kuhl, C., Schulz, J. B., Weis, J., Claeys, K. G.
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<strong>Novel TPM3 mutation in a family with cap myopathy and review of the literature.</strong>
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Neuromusc. Disord. 24: 117-124, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24239060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24239060</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24239060" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2013.10.002" target="_blank">Full Text</a>]
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<a id="38" class="mim-anchor"></a>
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<a id="Serratrice1975" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Serratrice, G., Pellissier, J. F., Gastaut, J. L., Pouget, J.
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<strong>Congenital myopathy with selective hypotrophy of type I fibers.</strong>
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Rev. Neurol. (Paris) 131: 813-816, 1975.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1221488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1221488</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1221488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Tan1999" class="mim-anchor"></a>
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Tan, P., Briner, J., Boltshauser, E., Davis, M. R., Wilton, S. D., North, K., Wallgren-Pettersson, C., Laing, N. G.
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<strong>Homozygosity for a nonsense mutation in the alpha-tropomyosin slow gene TPM3 in a patient with severe infantile nemaline myopathy.</strong>
|
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Neuromusc. Disord. 9: 573-579, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10619715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10619715</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10619715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0960-8966(99)00053-x" target="_blank">Full Text</a>]
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<a id="Waddell2010" class="mim-anchor"></a>
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<p class="mim-text-font">
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Waddell, L. B., Kreissl, M., Kornberg, A., Kennedy, P., McLean, C., Labarre-Vila, A., Monnier, N., North, K. N., Clarke, N. F.
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<strong>Evidence for a dominant negative disease mechanism in cap myopathy due to TPM3.</strong>
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Neuromusc. Disord. 20: 464-466, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20554445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20554445</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20554445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2010.05.012" target="_blank">Full Text</a>]
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<a id="41" class="mim-anchor"></a>
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<a id="Wattanasirichaigoon2002" class="mim-anchor"></a>
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Wattanasirichaigoon, D., Swoboda, K. J., Takada, F., Tong, H.-Q., Lip, V., Iannaccone, S. T., Wallgren-Pettersson, C., Laing, N. G., Beggs, A. H.
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<strong>Mutations of the slow muscle alpha-tropomyosin gene, TPM3, are a rare cause of nemaline myopathy.</strong>
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Neurology 59: 613-617, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12196661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12196661</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12196661" 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/10.1212/wnl.59.4.613" target="_blank">Full Text</a>]
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<a id="Wilton1995" class="mim-anchor"></a>
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Wilton, S. D., Eyre, H., Akkari, P. A., Watkins, H. C., MacRae, C., Laing, N. G., Callen, D. C.
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<strong>Assignment of the human alpha-tropomyosin gene TPM3 to 1q22-q23 by fluorescence in situ hybridisation.</strong>
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Cytogenet. Cell Genet. 68: 122-124, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7956350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7956350</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7956350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1159/000133905" target="_blank">Full Text</a>]
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<a id="43" class="mim-anchor"></a>
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<a id="Xu2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xu, H., Liu, H., Chen, T., Song, B., Zhu, J., Liu, X., Li, M., Luo, C.
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<strong>The R168G heterozygous mutation of tropomyosin 3 (TPM3) was identified in three family members and has manifestations ranging from asymptotic to serve scoliosis and respiratory complications.</strong>
|
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Genes Dis. 8: 715-720, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34291143/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34291143</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34291143[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34291143" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.gendis.2020.01.010" target="_blank">Full Text</a>]
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<br />
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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 : 03/05/2023
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 4/28/2016<br>Cassandra L. Kniffin - updated : 2/4/2014<br>Cassandra L. Kniffin - updated : 11/3/2009<br>Cassandra L. Kniffin - updated : 9/28/2009<br>Cassandra L. Kniffin - updated : 1/8/2009<br>Cassandra L. Kniffin - updated : 8/14/2008<br>Cassandra L. Kniffin - updated : 2/8/2008<br>Cassandra L. Kniffin - reorganized : 4/20/2006<br>Cassandra L. Kniffin - updated : 5/10/2005<br>Cassandra L. Kniffin - updated : 11/6/2002<br>George E. Tiller - updated : 5/1/2001<br>George E. Tiller - updated : 4/23/2001<br>Victor A. McKusick - updated : 12/20/1999
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</span>
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 6/25/1986
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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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alopez : 07/16/2024
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carol : 06/06/2023<br>carol : 06/05/2023<br>alopez : 03/06/2023<br>ckniffin : 03/05/2023<br>alopez : 06/02/2016<br>ckniffin : 4/28/2016<br>carol : 2/6/2015<br>mcolton : 2/5/2015<br>carol : 1/5/2015<br>carol : 1/5/2015<br>mcolton : 2/19/2014<br>ckniffin : 2/4/2014<br>carol : 8/5/2013<br>terry : 11/13/2012<br>terry : 5/16/2012<br>wwang : 11/17/2009<br>ckniffin : 11/3/2009<br>wwang : 10/14/2009<br>ckniffin : 9/28/2009<br>wwang : 1/20/2009<br>ckniffin : 1/8/2009<br>carol : 8/20/2008<br>ckniffin : 8/14/2008<br>wwang : 2/20/2008<br>ckniffin : 2/8/2008<br>carol : 4/20/2006<br>ckniffin : 5/10/2005<br>carol : 4/7/2005<br>ckniffin : 4/4/2005<br>carol : 12/3/2002<br>carol : 12/3/2002<br>ckniffin : 11/6/2002<br>cwells : 5/11/2001<br>cwells : 5/1/2001<br>cwells : 4/23/2001<br>carol : 1/5/2000<br>mcapotos : 1/5/2000<br>mcapotos : 12/29/1999<br>terry : 12/20/1999<br>terry : 11/5/1997<br>terry : 10/30/1997<br>terry : 6/13/1996<br>mark : 8/16/1995<br>carol : 7/9/1995<br>terry : 3/27/1995<br>carol : 11/30/1993<br>carol : 8/28/1992<br>supermim : 3/16/1992
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 191030
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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TROPOMYOSIN 3; TPM3
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</span>
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</div>
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<br />
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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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</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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ALPHA-TROPOMYOSIN 3<br />
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ALPHA-TROPOMYOSIN, SLOW SKELETAL
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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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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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TRK ONCOGENE, INCLUDED
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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TPM3/NTRK1 FUSION GENE, INCLUDED
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</span>
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</div>
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<div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TPM3</em></strong>
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</span>
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</p>
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</div>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 240084007;
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Cytogenetic location: 1q21.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:154,155,308-154,192,100 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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1q21.3
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Congenital myopathy 4A, autosomal dominant
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255310
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Autosomal dominant
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3
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Congenital myopathy 4B, autosomal recessive
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609284
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Autosomal recessive
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Tropomyosins are proteins that were first isolated from skeletal muscle, but later identified in many nonmuscle tissues. Vertebrates have at least 4 different tropomyosin genes: TPM1 (191010), TPM2 (190990), TPM3, and TPM4 (600317). Both muscle and nonmuscle forms of the protein are expressed by alternative splicing of each of the 4 genes (MacLeod et al., 1985; Laing et al., 1995). </p>
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<strong>Cloning and Expression</strong>
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<p>MacLeod et al. (1985) isolated a cDNA corresponding to tropomyosin from a human fibroblast cDNA library. A 1.1-kb mRNA transcript encoded a 284-amino acid protein with similarity to chicken smooth muscle tropomyosin. A 2.5-kb mRNA transcript encoded a 247-amino acid cytoskeletal tropomyosin protein. The findings indicated that nonmuscle cells express both muscle and non-muscle types of tropomyosin. MacLeod et al. (1985) suggested that both cytoskeletal tropomyosin and skeletal muscle tropomyosin are derived from a common structural gene by alternative splicing. </p><p>MacLeod et al. (1986) and Clayton et al. (1988) isolated cDNAs corresponding to human tropomyosin-3. In non-muscle tissues, the gene produces a 2.5-kb mRNA encoding a 248-amino acid cytoskeletal protein with a molecular mass of approximately 30 kD. In muscle, alternative splicing of the gene produces a 1.3-kb mRNA encoding a 285-amino acid protein. </p><p><strong><em>TPM3/NTRK1 Fusion Gene</em></strong></p><p>
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Martin-Zanca et al. (1986) identified a biologically active cDNA of a transforming gene in a human colon carcinoma cell line. The gene, referred to as TRK protooncogene, is a chimera containing sequences of both tropomyosin-3 and a tyrosine kinase. The TRK protooncogene was predicted to encode a 641-amino acid transmembrane tyrosine kinase expressed in neural tissues. The protein was identified by its ability to transform rodent cells in gene transfer assays. Martin-Zanca et al. (1986) suggested that the chimeric gene was likely formed by a somatic rearrangement between the 2 genes, resulting in the replacement of the extracellular domain of the transmembrane receptor with the first 221 amino acids of the tropomyosin-3 molecule. </p><p>Mitra et al. (1987) expressed the entire coding sequence of the TRK oncogene in E. coli. Antisera raised against these bacteria-synthesized TRK polypeptides were used to identify the gene product of the TRK oncogene as a 70-kD protein. </p>
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<strong>Gene Structure</strong>
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<p>Clayton et al. (1988) determined that the TPM3 gene spans 42 kb and contains 13 exons; only 5 exons are common to both the 2.5- and 1.3-kb mRNA transcripts. A comparison of the structure of exons encoding the amino-terminal sequences of the muscle and non-muscle isoforms suggested that the TPM3 gene evolved by a specific pattern of exon duplication with alternative splicing. </p>
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<strong>Mapping</strong>
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<p>By in situ hybridization and studies of somatic cell hybrids, Martin-Zanca et al. (1986) mapped the TPM3 gene to chromosome 1q31-q41. </p><p>Radice et al. (1991) assigned the TPM3 gene to 1q by Southern blot analysis of a panel of human-rodent somatic cell hybrids. Using the same probe, they localized the gene to 1q31 by in situ hybridization to human metaphase chromosomes. Wilton et al. (1995) reassigned the TPM3 gene to 1q22-q23 by fluorescence in situ hybridization. </p><p>Linkage findings in a family with nemaline myopathy caused by mutation in the TPM3 gene (CMYO4A; see 255310) by Laing et al. (1995) placed TPM3 in close proximity to NTRK1 (191315), which had been reassigned to 1q23-q24 (Morris et al., 1991), so that a gene fusion rearrangement involving these 2 genes would not be cytologically detectable. </p><p>Using a human cDNA fragment of the TPM3 gene and a mapping panel from a murine interspecific cross, Gariboldi et al. (1995) mapped the mouse Tpm3 gene to chromosome 3. </p><p><strong><em>TPM3/NTRK1 Fusion Gene</em></strong></p><p>
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By a combination of study of somatic cell hybrids and in situ hybridization, Miozzo et al. (1990) mapped the TPM3/NTRK1 (TRK) fusion gene to 1q32-q41. Morris et al. (1991) localized the TRK gene to a more proximal location, 1q23-q24, by in situ hybridization. </p>
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<strong>Gene Function</strong>
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<p>In skeletal muscle, tropomyosin isoforms are components of the thin filaments of the sarcomere and mediate the effect of calcium on the actin-myosin interaction. TPM3 is expressed mostly in slow, type 1 muscle fibers. Two muscle-specific isoforms of tropomyosin, an alpha and a beta, form an alpha-helical dimer, bind head to tail, and lie in the major groove of filamentous actin with each tropomyosin molecule binding to 7 actin molecules (Laing et al., 1995). </p><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><p><strong><em>Role in TRK Protooncogene</em></strong></p><p>
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Coulier et al. (1989) found that the 221 amino-terminal residues of the TPM3 protein are substituted for the external domain of a putative tyrosine-kinase cell surface receptor to create the TRK oncogene. Since the 2 components giving rise to the TRK oncogene are close together on chromosome 1, no microscopically discernible chromosome abnormality was found. </p><p>By transfection assay, Bongarzone et al. (1989) found that TRK was activated in tumor cells, both primary tumor and/or metastasis, in 4 of 16 patients with papillary thyroid carcinoma. </p><p>Hempstead et al. (1991) and Kaplan et al. (1991) identified the TRK gene product as a nerve growth factor receptor. </p><p>Loeb et al. (1991) presented results indicating that TRK was necessary for functional nerve growth factor signal transduction. Cordon-Cardo et al. (1991) presented evidence that the product of the TRK protooncogene was sufficient to mediate signal transduction processes induced by nerve growth factor and neurotrophin-3 (162660). Ehrhard et al. (1993) reported that TRK is expressed in monocytes; this finding as well as others suggested that nerve growth factor is an immunoregulatory cytokine acting on monocytes in addition to its neurotrophic function. </p><p>The TPM3 gene is involved with the neighboring gene for neurotrophic tyrosine kinase receptor type 1 (NTRK1; 191315) in a somatic rearrangement that creates the chimeric TRK oncogene. In 3 of 8 papillary thyroid carcinomas, Butti et al. (1995) found that replacement of the extracellular domain of the NTRK1 gene by sequences coding for the 221 N-terminal residues of the TPM3 gene was responsible for the oncogenic NTRK1 activation. In all 3 tumors, the illegitimate recombination involved the 611-bp NTRK1 intron placed upstream of the transmembrane domain and the TPM3 intron located between exons 7 and 8. Therefore, due to the displacing mechanism, all of the TPM3/NTRK1 gene fusions encoded an invariable transcript and the same chimeric protein of 70 kD, which was constitutively phosphorylated on tyrosine. In 2 of the 3 tumors, the simultaneous presence of the reciprocal products of the TPM3/NTRK1 recombination (5-prime-TPM3/3-prime NTRK1 and 5-prime NTRK1/3-prime TPM3) and the previously demonstrated localization of both genes on 1q led Butti et al. (1995) to suggest that an intrachromosomal inversion was responsible for their recombination. To understand the molecular basis predisposing NTRK1 and TPM3 to being a recurrent target of illegitimate recombination, they determined the nucleotide sequence around the breakpoints of the recombination products in all 3 patients and in the corresponding regions from the normal genes. In these regions, they found some recombinogenic elements as well as palindromes, direct and inverted repeats, and Alu family sequences. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Autosomal Dominant Congenital Myopathy 4A</em></strong></p><p>
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In affected members of a large family with autosomal dominant congenital myopathy-4A (CMYO4A; 255310), Laing et al. (1995) identified a heterozygous mutation in the TPM3 gene (M9R; 191030.0001) that segregated with the disorder. </p><p>In affected members of a French family with autosomal dominant CMYO4A, Penisson-Besnier et al. (2007) identified a heterozygous mutation in the TPM3 gene (R168H; 191030.0005). </p><p>Clarke et al. (2008) identified 5 different heterozygous TPM3 mutations (see, e.g., 191030.0005; 191030.0007; 191030.0008), in affected members of 6 unrelated families with CMYO4A and congenital fiber-type disproportion (CFTD) on skeletal muscle biopsy. The mutations were identified among 23 unrelated probands with CFTD, making mutations in the TPM3 gene the most common cause of CFTD to date. </p><p>In a 38-year-old woman with CMYO4A associated with cap structures on skeletal muscle biopsy who had previously been reported by Fidzianska (2002), Ohlsson et al. (2009) identified a heterozygous mutation in the TPM3 gene (R168C; 191030.0009). </p><p>De Paula et al. (2009) reported a 42-year-old man with cap myopathy associated with a heterozygous de novo mutation in the TPM3 gene (R168H; 191030.0005). </p><p>Waddell et al. (2010) reported a man with CMYO4A and cap myopathy on skeletal muscle biopsy that was associated with a de novo heterozygous R168C mutation in the TPM3 gene. </p><p>Malfatti et al. (2013) reported a man of French Canadian origin with early-onset myopathy and a de novo heterozygous R168C mutation in the TPM3 gene. </p><p>In 2 affected members of a family with autosomal dominant CMYO4A, Schreckenbach et al. (2014) identified a heterozygous missense mutation in the TPM3 gene (L149I; 191030.0012). </p><p>Marttila et al. (2014) reported 11 unrelated families with CMYO4A due to heterozygous missense mutations in the TPM3 gene. Six novel heterozygous mutations and several recurrent mutations affecting codon 168 (R168C, R168H) were identified. </p><p>Xu et al. (2021) reported a 10-year-old Chinese girl with CMYO4A associated with a heterozygous R168G mutation in the TPM3 gene (R168G; 191030.0008) that was inherited from her clinically unaffected father. Her brother, who also carried the mutation, had a milder phenotype. The authors noted the intrafamilial variability. </p><p>In a 47-year-old man with CMYO4A, Bevilacqua et al. (2022) identified a heterozygous mutation in the TPM3 gene (E237K; 191030.0013). </p><p>Among 25 Brazilian families with a clinical diagnosis of nemaline myopathy, Gurgel-Giannetti et al. (2022) found 1 (4%) who carried a heterozygous missense mutation in the TPM3 gene (R168C). The mutation was present in a father and son (family 7) with congenital myopathy, scoliosis, and nocturnal hypoventilation; both were ambulatory. The findings suggested that mutations in the TPM3 gene are not a common cause of nemaline myopathy. </p><p>In 2 unrelated children with CMYO4A characterized by muscle stiffness, hypercontractility, and arthrogryposis multiplex congenita, Donkervoort et al. (2015) identified 2 different de novo heterozygous in-frame deletions in the TPM3 gene (E218del, 191030.0010 and E224del, 191030.0011). In vitro studies showed that both mutations resulted in increased calcium sensitivity, increased active interaction of actin and the myosin complex, and increased filament sliding motility, consistent with a gain of function. The findings conformed to the predictions made by Marston et al. (2013) in in vitro studies. 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><p><strong><em>Autosomal Recessive Congenital Myopathy 4B</em></strong></p><p>
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In an Iranian patient, born of consanguineous parents, with severe autosomal recessive congenital myopathy-4B (CMYO4B; 609284), resulting in death at 21 months of age, Tan et al. (1999) identified a homozygous nonsense mutation in the TPM3 gene (Q32X; 191030.0004). Each mutation was inherited from an unaffected parent. The authors hypothesized that the patient had no functional TPM3. The patient was identified from a study of 40 unrelated patients diagnosed with congenital myopathy associated with nemaline rods on skeletal muscle biopsy. </p><p>In a patient with CMYO4B, Wattanasirichaigoon et al. (2002) identified compound heterozygous mutations in the TPM3 gene (191030.0002 and 191030.0003). </p><p>In affected members of 2 Turkish families with CMYO4B, Lehtokari et al. (2008) identified a homozygous mutation in the TPM3 gene (191030.0006). Haplotype analysis suggested a founder effect. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Based on molecular modeling, Marston et al. (2013) predicted that mutations affecting certain TPM3 residues involved in the actin binding sites would result in higher calcium sensitivity, higher filament sliding speeds, and a gain-of-function effect. In contrast, in vitro studies showed that mutations affecting other regions, including R167H (191030.0005), resulted in lower calcium sensitivity, slower sliding speeds, and a hypocontractile phenotype. Marston et al. (2013) suggested that consideration of the effects of the mutations on muscle contractility would be more predictive of the phenotype than histopathology studies. </p>
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<strong>Animal Model</strong>
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<p>Corbett et al. (2001) generated a transgenic mouse model expressing an autosomal dominant mutant of TPM3 (M9R; 191030.0001) previously identified in a human patient with nemaline myopathy. Rods were found in all muscles, but to varying extents which did not correlate with the amount of mutant protein present. In addition, a pathologic feature not commonly associated with this disorder, cytoplasmic bodies, was found in the mouse and subsequently identified in human samples. Hypertrophy of fast, type 2B (glycolytic) fibers was apparent at 2 months of age. Muscle weakness was apparent in mice at 5 to 6 months of age, mimicking the late onset observed in humans with this mutation. The onset of weakness correlated with an age-related decrease in fiber diameter and suggested that early onset may be prevented by hypertrophy of fast, glycolytic fibers. The authors suggested that the clinical phenotype may be precipitated by a failure of the hypertrophy to persist and therefore compensate for muscle weakness. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>13 Selected Examples):</strong>
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<strong>.0001 CONGENITAL MYOPATHY 4A, AUTOSOMAL DOMINANT</strong>
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TPM3, MET9ARG
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SNP: rs80358247,
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gnomAD: rs80358247,
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ClinVar: RCV000013259, RCV000128695, RCV003151723
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<p>In affected members of a large family with autosomal dominant congenital myopathy-4A (CMYO4A; 255310), Laing et al. (1995) identified a heterozygous T-to-G transversion in exon 1 of the TPM3 gene, resulting in a met9-to-arg (M9R) substitution in a highly conserved residue located at the N-terminal end of the protein. The region may be important for head-to-tail association of tropomyosin molecules and may be crucial to actin binding. Laing et al. (1995) noted that actin binding was completely inhibited by removal of the N-terminal 9 amino acid residues. </p><p><strong><em>Variant Function</em></strong></p><p>
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Michele et al. (1999) used adenoviral gene transfer to fully differentiated rat adult myocytes in vitro to determine the effects of nemaline myopathy mutant human tropomyosin expression on striated muscle sarcomeric structure and contractile function. The mutant tropomyosin was expressed and incorporated correctly into sarcomeres of adult muscle cells. The primary defect caused by expression of the mutant tropomyosin was a decrease in the sensitivity of contraction to activating Ca(2+), which could help explain the hypotonia seen in nemaline myopathy. The M9R mutant tropomyosin expression did not directly result in nemaline rod formation, which suggested that rod formation is secondary to contractile dysfunction and that load-dependent processes are likely involved in nemaline rod formation in vivo. </p><p>Corbett et al. (2005) found that skeletal muscle from both transgenic mice and human patients with the TPM3 M9R mutation had decreased levels of beta-tropomyosin (TPM2; 190990), and that the timing of increased levels of the mutant TPM3 protein in muscle coincided with a decrease in TPM2 levels. In vertebrates, the preferred pairing of tropomyosin dimers is an alpha/beta heterodimer; however, Western blot analysis of the tropomyosin filament dimers from tissue with the M9R mutant protein showed a decrease in the TPM3/TPM2 heterodimer, with a shift to mutant TPM3 homodimers. The M9R mutation lies within the region of overlap for head-to-tail interactions between dimer pairs. Corbett et al. (2005) suggested that the M9R mutant TPM3 protein changes the composition of sarcomeric thin filaments and the regulation of muscle contraction, resulting in disease manifestations. </p>
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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 4B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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TPM3, TER286SER
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<br />
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SNP: rs199474720,
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gnomAD: rs199474720,
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ClinVar: RCV000013260, RCV000128708, RCV000707046
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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 patient with autosomal recessive congenital myopathy-4B (CMYO4B; 609284), Wattanasirichaigoon et al. (2002) identified compound heterozygous mutations in the TPM3 gene: a c.857A-C transversion (designated 915A-C in the article, based on a GenBank reference sequence) in exon 9sk, resulting in a TER285SER substitution and the addition of 57 amino acids; and a mutation at the acceptor splice site of the same exon, resulting in exon skipping (191030.0003). Based on numbering from the first met codon (Clarke et al. (2008)), this mutation is designated TER286SER (X286S). The patient's asymptomatic father was heterozygous for the X286S mutation, and his asymptomatic mother was heterozygous for the splice site mutation. The patient was identified from a study of 40 unrelated patients with 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>.0003 CONGENITAL MYOPATHY 4B, AUTOSOMAL RECESSIVE</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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TPM3, IVS9AS, G-A, -1
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<br />
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SNP: rs113605263,
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gnomAD: rs113605263,
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ClinVar: RCV000013261, RCV000128706, RCV000689419
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the IVS9-1G-A mutation in the TPM3 gene that was found in compound heterozygous state in a patient with congenital myopathy-4B (CMYO4B; 609284) by Wattanasirichaigoon et al. (2002), see 191030.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 CONGENITAL MYOPATHY 4B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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TPM3, GLN32TER
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<br />
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SNP: rs80358248,
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ClinVar: RCV000013262, RCV000128709, RCV003764563, RCV004562204
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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 Iranian patient, born of consanguineous parents, with congenital myopathy-4B (CMYO4B; 609284), Tan et al. (1999) identified a homozygous C-to-T transition in exon 1 of the TPM3 gene, resulting in a GLN31TER substitution. Based on numbering from the first met codon (Clarke et al. (2008)), this mutation is designated GLN32TER (Q32X). Although no neonatal problems were reported, the infant showed extremely delayed motor development and died at age 21 months due to respiratory insufficiency resulting from an infectious illness. Muscle biopsy showed type 1 fiber hypotrophy and atrophy, with a mild predominance of type 2 fibers. Nemaline bodies were present in type 1 fibers only. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CONGENITAL MYOPATHY 4A, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TPM3, ARG168HIS
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<br />
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SNP: rs121964852,
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|
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ClinVar: RCV000013263, RCV000054415, RCV000128701, RCV000537032, RCV001420249
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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 4 affected members of a French family with autosomal dominant congenital myopathy-4A (CMYO4A; 255310), Penisson-Besnier et al. (2007) identified a heterozygous c.503G-A transition in exon 5 of the TPM3 gene, resulting in an ARG167HIS substitution. Although most patients had symptoms in childhood, all remained ambulatory as adults. Clarke et al. (2008) noted that based on numbering from the first met codon this mutation is designated ARG168HIS (R168H). </p><p>In a father and daughter with congenital myopathy, Clarke et al. (2008) identified the R168H mutation in the TPM3 gene. Both patients had onset of hypotonia in infancy and were able to run in late adolescence. At age 60, the father could walk, had impaired nocturnal ventilation, showed distal more than proximal weakness, and had scoliosis with lumbar lordosis. Skeletal muscle biopsy was consistent with nemaline myopathy. At age 20, the daughter was able to run, had decreased forced vital capacity, mild proximal weakness, and mild scoliosis. Skeletal muscle biopsy showed fiber-type disproportion (CFTD) The findings of both nemaline myopathy and CFTD in patients with the same mutation showed that TPM3 mutations can cause a range of histologic changes, and suggested that there is a close relation between nemaline myopathy and CFTD. </p><p>De Paula et al. (2009) reported a 42-year-old man with the R168H mutation who showed cap myopathy on skeletal muscle biopsy. He had hypotonia in the first months of life, delayed motor development, and distal weakness of the lower limbs with frequent falls in childhood. At age 7 years, he had flat feet in valgus, long narrow face, high-arched palate, and mild lumbar hyperlordosis. Tendon reflexes were absent. The clinical course was stable until presentation at age 42 with inability to run, difficulty climbing stairs, and predominant distal muscle weakness. Skeletal muscle biopsy at age 7 years showed type 1 fiber hypotrophy. Biopsy at age 42 years showed only type 1 fibers, irregularity of fiber size, occasional central nuclei, and peripheral eosinophilic-basophilic densely stained substances consistent with 'caps.' The caps were present in about 10 to 15% of muscle fibers, were negative for ATPase staining, were present just beneath the sarcolemma, and consisted of abnormally arranged myofibrils. Z-lines were thickened with some rod-like structures. The authors noted that this case had first been reported as a congenital myopathy with selective hypotrophy of type 1 fibers (Serratrice et al., 1975), and that the biopsy results discussed in that report would have been consistent with CFTD. The findings suggested a relationship between nemaline myopathy, CFTD, and cap myopathy, and indicated that cap structures may develop over time. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
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|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CONGENITAL MYOPATHY 4B, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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TPM3, 1-BP DEL, 913A
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<br />
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|
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SNP: rs199474719,
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|
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gnomAD: rs199474719,
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|
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|
|
ClinVar: RCV000013266, RCV000128707
|
|
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|
|
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</span>
|
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</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In 4 patients from 2 presumably unrelated Turkish families with autosomal recessive congenital myopathy-4B (CMYO4B; 609284), Lehtokari et al. (2008) identified a homozygous 1-bp deletion (c.913delA, NM_152263) in exon 9b of the TPM3 gene, at the last nucleotide before the stop codon. The mutation was predicted to result in elongation of the protein by 73 residues, which would disrupt the coiled-coil polymer and render the protein nonfunctional. A shared haplotype between the 2 families suggested a founder effect. The phenotype was moderate to severe, with early-onset, restrictive respiratory vital capacity, and chest deformities. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CONGENITAL MYOPATHY 4A, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
TPM3, LEU100MET
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<br />
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|
|
SNP: rs121964853,
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|
|
ClinVar: RCV000013267, RCV000128697, RCV003151724
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 affected individuals from an Australian family with autosomal dominant congenital myopathy-4A (CMYO4A; 255310), Clarke et al. (2008) identified a heterozygous c.298C-A transversion (c.298C-A, NM_152263.2) in exon 3 of the TPM3 gene, resulting in a leu100-to-met (L100M) substitution in a highly conserved residue in the alpha-helix domain. Four of the patients presented before age 1 year with hypotonia or decreased activity levels. Two had delayed walking, and all were able to run in the teenage years. The fifth patient presented at age 32 with respiratory failure. Three patients in their forties showed slow walking, impaired nocturnal ventilation, moderate proximal weakness, scapular winging, and ptosis. Two patients had scoliosis. Histologic examination of skeletal muscle showed that type 1 fibers were smaller than type 2 fibers by 50 to 65%, with internal nuclei and no other abnormalities; these findings were consistent with a diagnosis of congenital myopathy with fiber-type disproportion (CFTD). </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CONGENITAL MYOPATHY 4A, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TPM3, ARG168GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121964854,
|
|
|
|
|
|
|
|
ClinVar: RCV000013268, RCV000128699, RCV000226212, RCV001382225, RCV003151725, RCV004585998
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with congenital myopathy-4A (CMYO4A; 255310), Clarke et al. (2008) identified a heterozygous c.502C-G transversion (c.502C-G, NM_152263.2) in exon 5 of the TPM3 gene, resulting in an arg168-to-gly (R168G) substitution in the alpha-helix domain. At age 9 years, the patient showed slow running, decreased forced vital capacity, mild proximal muscle weakness, mild ptosis, and lumbar lordosis. Muscle biopsy showed fiber-type disproportion (CFTD). </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
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</div>
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CONGENITAL MYOPATHY 4A, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TPM3, ARG168CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121964854,
|
|
|
|
|
|
|
|
ClinVar: RCV000013269, RCV000054416, RCV000128700, RCV000624745, RCV000637291, RCV004585999
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman with congenital myopathy-4A (CMYO4A; 609284), Clarke et al. (2008) identified a heterozygous c.502C-T transition (c.502C-T, NM_152263.2) in exon 5 of the TPM3 gene, resulting in an arg168-to-cys (R168C) substitution in the alpha-helix domain. The patient had poor head control before 1 year of age, but normal walking at age 9 months, and could run in childhood. At age 32, she could walk stairs with difficulty and had impaired nocturnal ventilation, moderate proximal weakness, ptosis, and severe kyphoscoliosis. Skeletal muscle biopsy showed fiber-type disproportion (CFTD). The authors noted that several other mutations had been identified in this codon (see, e.g., R168G, 191030.0008). </p><p>Ohlsson et al. (2009) identified a heterozygous R168C mutation in a 38-year-old woman with CMYO4A associated with cap structures on skeletal muscle biopsy. She had previously been reported by Fidzianska (2002). She had slowly progressive muscle weakness and scoliosis since childhood, but was not examined until age 18 years. At that time, she had long narrow face, high-arched palate, chest deformity, and thin underdeveloped muscles. Other features included impaired nocturnal ventilation. Skeletal muscle biopsy showed that 20 to 30% of muscle fibers had granular cap structures devoid of ATPase activities. Myofibrils forming the caps were clearly demarcated from the remaining fibers and had an abnormal sarcomere pattern. Nemaline rods and fiber-type disproportion were not observed. The findings illustrated the phenotypic and histologic variability associated with TPM3 mutations, and suggested that cap disease is related to nemaline myopathy and CFTD. </p><p>Waddell et al. (2010) reported a young man with CMYO4A due to a de novo heterozygous R168C mutation. He had mildly delayed motor development in early childhood, generalized hypotonia, and muscle weakness, particularly of the proximal lower limbs, ankle dorsiflexors, and neck. He had a long myopathic face with open mouth, high-arched palate, retrognathia, narrow chest, and mild scoliosis. At age 20 years, his pulmonary vital capacity was 37% of that predicted. Muscle biopsy taken at age 3 years showed increased variation in fiber size and subsarcolemmal protein inclusions in 25% of fibers, typical of caps. There was also type 1 fiber predominance. Caps stained strongly for several proteins, including tropomyosin, and electron microscopy showed disorganized thin filament structures containing Z-band remnants. Nemaline rods were not present. Two-dimensional gel electrophoresis showed that the mutant protein accounted for about 50% of the TPM3 protein in sarcomeres, and Waddell et al. (2010) postulated a dominant-negative effect, perhaps resulting from altered protein-protein interactions. These findings indicated that the fiber type distribution pattern as well as the pattern of protein inclusions can vary widely even among patients with the same TPM3 mutation. </p><p>Malfatti et al. (2013) reported a man of French Canadian origin, with early-onset myopathy and a de novo heterozygous R168C mutation in the TPM3 gene. He had typical clinical features of the disorder, with mildly delayed motor milestones, generalized hypotonia, proximal and distal muscle weakness, impaired respiratory function, long, narrow face, and high-arched palate. Muscle biopsy showed type 1 fiber uniformity, subsarcolemmal caps in about 20% of fibers, typical nemaline rods in about 10% of fibers, and both caps and rods in about 5% of fibers. Electron microscopy demonstrated that the cap structures were composed of disorganized myofibrils and thickened Z-bands; the nemaline rods had longitudinal and transverse striations and were surrounded by thin filaments. Some of the caps contained structures resembling small rods, and the intermyofibrillary network adjacent to caps or nemaline rods was irregular with jagged Z lines. Malfatti et al. (2013) emphasized that the combination of rods and caps had not previously been reported in the same patient, which suggested that the 2 patterns are pathogenetically related. The findings confirmed that nemaline myopathy and cap myopathy resulting from TPM3 mutations are part of a disease spectrum. </p>
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CONGENITAL MYOPATHY 4A, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TPM3, 3-BP DEL, 673GAA
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|
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|
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<br />
|
|
|
|
SNP: rs876661406,
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|
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|
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|
|
ClinVar: RCV003151757
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|
|
|
|
|
</span>
|
|
</div>
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|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 5-year-old boy with congenital myopathy-4A (CMYO4A; 609284) characterized by muscle stiffness, hypercontractility, and arthrogryposis multiplex congenita, Donkervoort et al. (2015) identified a de novo heterozygous 3-bp deletion (c.673_675delGAA, NM_152263.3) in exon 6A of the TPM3 gene, resulting in the deletion of residue glu224 (E224del) in a highly conserved region. The mutation, which was found by whole-exome sequencing, was not found in the dbSNP, Exome Variant Server, or ExAC databases. In vitro studies showed that the mutations resulted in increased calcium sensitivity, increased interaction of actin and the myosin complex, and increased filament sliding motility, consistent with a gain of 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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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CONGENITAL MYOPATHY 4A, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
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<span class="mim-text-font">
|
|
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|
TPM3, 3-BP DEL, 657AGA
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|
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|
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<br />
|
|
|
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SNP: rs876661407,
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ClinVar: RCV003151758
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|
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|
|
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</span>
|
|
</div>
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-year-old girl with congenital myopathy-4A (CMYO4A; 609284) characterized by muscle stiffness, hypercontractility, and arthrogryposis multiplex congenita, Donkervoort et al. (2015) identified a de novo heterozygous 3-bp deletion (c.657_659delAGA, NM_152263.3) in exon 6A of the TPM3 gene, resulting in the deletion of residue glu218 (E218del) in a highly conserved region. The mutation was not found in the dbSNP, Exome Variant Server, or ExAC databases. In vitro studies showed that the mutations resulted in increased calcium sensitivity, increased interaction of actin and the myosin complex, and increased filament sliding motility, consistent with a gain of function. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 CONGENITAL MYOPATHY 4A, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
TPM3, LEU149ILE
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<br />
|
|
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|
|
ClinVar: RCV003152550
|
|
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|
|
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</span>
|
|
</div>
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|
|
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<div>
|
|
<span class="mim-text-font">
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<p>In a woman and her son with autosomal dominant congenital myopathy-4A (CMYO4A; 255310), Schreckenbach et al. (2014) identified a heterozygous c.445C-A transversion (c.445C-A, NM_152263.2) in exon 4 of the TPM3 gene, resulting in a leu149-to-ile (L149I) substitution. The woman's deceased mother had similar features, but genetic analysis was not performed. </p>
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</span>
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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>.0013 CONGENITAL MYOPATHY 4A, AUTOSOMAL DOMINANT</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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TPM3, GLU237LYS
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<br />
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SNP: rs1661445206,
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ClinVar: RCV001312798, RCV003223719
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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 47-year-old man with congenital myopathy-4A (CMYO4A; 255310), Bevilacqua et al. (2022) identified a heterozygous c.709G-A transition in exon 8 of the TPM3 gene, resulting in a glu237-to-lys (E237K) substitution. He had a history of delayed motor development with gait impairment and poor exercise tolerance since childhood. He had no family history of a similar disorder, suggesting that the mutation may have occurred de novo. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Martin-Zanca et al. (1989)
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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<strong>Novel autosomal dominant TPM3 mutation causes a combined congenital fibre type disproportion-cap disease histological pattern.</strong>
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Wilton, S. D., Eyre, H., Akkari, P. A., Watkins, H. C., MacRae, C., Laing, N. G., Callen, D. C.
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Xu, H., Liu, H., Chen, T., Song, B., Zhu, J., Liu, X., Li, M., Luo, C.
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<strong>The R168G heterozygous mutation of tropomyosin 3 (TPM3) was identified in three family members and has manifestations ranging from asymptotic to serve scoliosis and respiratory complications.</strong>
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