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Entry
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- *102610 - ACTIN, ALPHA-1, SKELETAL MUSCLE; ACTA1
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- OMIM
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</ul>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="row">
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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</li>
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<li role="separator" class="divider"></li>
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<li>
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<a href="/history"> Search History </a>
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</ul>
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</div>
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</div>
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<div class="autocomplete" id="mimEntrySearchAutocomplete"></div>
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<span class="small">
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</form>
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<div class="row">
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<p />
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</div>
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<!-- <div id="mimSearch"> -->
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<div id="mimAlertBanner">
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*102610</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
|
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</li>
|
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<li role="presentation" style="margin-left: 1em">
|
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<a href="/allelicVariants/102610">Table View</a>
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</li>
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<li role="presentation">
|
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
|
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<h4 class="panel-title">
|
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
|
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<div style="display: table-row">
|
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
|
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</div>
|
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</a>
|
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</h4>
|
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</div>
|
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
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<div class="panel-body small mim-panel-body">
|
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000143632;t=ENST00000366684" 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=58" 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=102610" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
|
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</span>
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</span>
|
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000143632;t=ENST00000366684" 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_001100" 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_001100" 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=102610" 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=00030&isoform_id=00030_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/ACTA1" 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/178029,337746,4501881,6049633,15214923,30908859,49168518,49456549,61218043,119590304,193788501,221043300" 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/P68133" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
|
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</div>
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</a>
|
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</span>
|
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=58" 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=ENSG00000143632;t=ENST00000366684" 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=ACTA1" 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=ACTA1" 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+58" 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/ACTA1" 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:58" 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/58" 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=ENST00000366684.7&hgg_start=229431245&hgg_end=229434094&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:129" 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/acta1" 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=102610[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=102610[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/ACTA1/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/ENSG00000143632" 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=ACTA1" 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=ACTA1" 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=ACTA1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://acta1.waimr.uwa.edu.au/home.php?select_db=ACTA1" title="Laing Laboratory Skeletal muscle alpha-actin (ACTA1)" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Laing Laboratory Skeletal …</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/ACTA1" title="Leiden Muscular Dystrophy pages" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Leiden Muscular Dystrophy …</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ACTA1&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/PA24455" 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:129" 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://www.mousephenotype.org/data/genes/MGI:87902" 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/ACTA1#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:87902" 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/58/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=58" 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://zfin.org/ZDB-GENE-030131-55" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:102610" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:58" 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=ACTA1&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> 1217226000, 702349003<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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102610
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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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ACTIN, ALPHA-1, SKELETAL MUSCLE; ACTA1
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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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ASMA
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ACTA1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ACTA1</a></em></strong>
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<span class="mim-text-font">
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<strong>
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Cytogenetic location: <a href="/geneMap/1/1785?start=-3&limit=10&highlight=1785">1q42.13</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:229431245-229434094&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'})">1:229,431,245-229,434,094</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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Location
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
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<a href="/clinicalSynopsis/table?mimNumber=616852,161800,620265,620278" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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View Clinical Synopses
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</a>
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</th>
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<th>
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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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<tbody>
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<tr>
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<span class="mim-font">
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<a href="/geneMap/1/1785?start=-3&limit=10&highlight=1785">
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1q42.13
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</a>
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</td>
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<span class="mim-font">
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?Myopathy, scapulohumeroperoneal
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
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<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
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</span>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/616852"> 616852 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<tr>
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<span class="mim-font">
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Congenital myopathy 2A, typical, autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/161800"> 161800 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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<tr>
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<span class="mim-font">
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Congenital myopathy 2B, severe infantile, autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/620265"> 620265 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<span class="mim-font">
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Congenital myopathy 2C, severe infantile, autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/620278"> 620278 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/102610" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/102610" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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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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</div>
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<div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>The ACTA1 gene encodes skeletal muscle alpha-actin, the principal actin isoform in adult skeletal muscle, which forms the core of the thin filament of the sarcomere where it interacts with a variety of proteins to produce the force for muscle contraction (<a href="#26" class="mim-tip-reference" title="Laing, N. G., Dye, D. E., Wallgren-Pettersson, C., Richard, G., Monnier, N., Lillis, S., Winder, T. L., Lochmuller, H., Graziano, C., Mitrani-Rosenbaum, S., Twomey, D., Sparrow, J. C., Beggs, A. H., Nowak, K. J. <strong>Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1).</strong> Hum. Mutat. 30: 1267-1277, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562689</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562689[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.21059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562689">Laing et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19562689" 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>
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<div>
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<br />
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<div>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>Using chick beta-actin cDNA as probe, <a href="#15" class="mim-tip-reference" title="Gunning, P., Ponte, P., Okayama, H., Engel, J., Blau, H., Kedes, L. <strong>Isolation and characterization of full-length cDNA clones for human alpha-, beta-, and gamma-actin mRNAs: skeletal but not cytoplasmic actins have an amino-terminal cysteine that is subsequently removed.</strong> Molec. Cell. Biol. 3: 787-795, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6865942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6865942</a>] [<a href="https://doi.org/10.1128/mcb.3.5.787-795.1983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6865942">Gunning et al. (1983)</a> cloned alpha-actin from a human muscle cDNA library. They also cloned beta-actin (ACTB; <a href="/entry/102630">102630</a>) and gamma-actin (ACTG1; <a href="/entry/102560">102560</a>) from a fibroblast cDNA library. Sequence analysis of the 5-prime ends revealed that alpha-actin starts with both a methionine and a cysteine not found in the mature protein. They concluded that, since no known actin proteins start with a cysteine, there must be posttranslational removal of cysteine in addition to methionine in alpha-actin synthesis, but not in beta- or gamma-actin synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6865942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Hanauer, A., Levin, M., Heilig, R., Daegelen, D., Kahn, A., Mandel, J. L. <strong>Isolation and characterization of cDNA clones for human skeletal muscle alpha actin.</strong> Nucleic Acids Res. 11: 3503-3516, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6190133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6190133</a>] [<a href="https://doi.org/10.1093/nar/11.11.3503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6190133">Hanauer et al. (1983)</a> cloned alpha-actin from a cDNA library developed from quadriceps muscle mRNA using mouse skeletal alpha-actin cDNA as probe. The sequence is characterized by a high GC content (61.6%). <a href="#17" class="mim-tip-reference" title="Hanauer, A., Levin, M., Heilig, R., Daegelen, D., Kahn, A., Mandel, J. L. <strong>Isolation and characterization of cDNA clones for human skeletal muscle alpha actin.</strong> Nucleic Acids Res. 11: 3503-3516, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6190133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6190133</a>] [<a href="https://doi.org/10.1093/nar/11.11.3503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6190133">Hanauer et al. (1983)</a> noted conservation of the amino acid sequence between human and rat actins, and a comparison of the coding sequences revealed 61% silent changes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6190133" 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="#38" class="mim-tip-reference" title="Taylor, A., Erba, H. P., Muscat, G. E. O., Kedes, L. <strong>Nucleotide sequence and expression of the human skeletal alpha-actin gene: evolution of functional regulatory domains.</strong> Genomics 3: 323-336, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2907503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2907503</a>] [<a href="https://doi.org/10.1016/0888-7543(88)90123-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2907503">Taylor et al. (1988)</a> cloned alpha-actin and determined that the primary transcript encodes a 377-amino acid protein, including the first 2 residues, which are absent from the mature protein. They noted that the same 2 codons precede the codon specifying the N-terminal amino acid in the homologous genes of rat, mouse, chicken, Drosophila, and sea urchin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2907503" 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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<br />
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<a id="geneStructure" class="mim-anchor"></a>
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<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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<div id="mimGeneStructureFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#38" class="mim-tip-reference" title="Taylor, A., Erba, H. P., Muscat, G. E. O., Kedes, L. <strong>Nucleotide sequence and expression of the human skeletal alpha-actin gene: evolution of functional regulatory domains.</strong> Genomics 3: 323-336, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2907503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2907503</a>] [<a href="https://doi.org/10.1016/0888-7543(88)90123-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2907503">Taylor et al. (1988)</a> determined that the alpha-actin gene contains 7 exons. There is a large intron in the 5-prime untranslated region that is characteristic of actins and many muscle-specific genes. The promoter contains a TATA box and 3 conserved CArG boxes; <a href="#38" class="mim-tip-reference" title="Taylor, A., Erba, H. P., Muscat, G. E. O., Kedes, L. <strong>Nucleotide sequence and expression of the human skeletal alpha-actin gene: evolution of functional regulatory domains.</strong> Genomics 3: 323-336, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2907503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2907503</a>] [<a href="https://doi.org/10.1016/0888-7543(88)90123-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2907503">Taylor et al. (1988)</a> showed that these were activated by muscle cell differentiation in a rat myogenic cell line. The 3-prime untranslated region contains a GC-rich region as well as a putative poly(A) addition signal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2907503" 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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<br />
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<div>
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<a id="mapping" class="mim-anchor"></a>
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<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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<div id="mimMappingFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>By use of a cDNA probe in somatic cell hybrids, <a href="#16" class="mim-tip-reference" title="Hanauer, A., Heilig, R., Levin, M., Moisan, J. P., Grzeschik, K. H., Mandel, J. L. <strong>The actin gene family in man: assignment of the gene for skeletal muscle alpha-actin to chromosome 1, and presence of actin sequences on autosomes 2 and 3, and on the X and Y chromosomes. (Abstract)</strong> Cytogenet. Cell Genet. 37: 487-488, 1984."None>Hanauer et al. (1984)</a> assigned the gene for the alpha chain of skeletal muscle actin to chromosome 1. Actin sequences were found at high stringency also at 2p23-qter and 3pter-q21. Under conditions of low or medium stringency, actin sequences were demonstrated on the X (p11-p12) and Y chromosomes. The actin genes assigned to the X and Y chromosomes (<a href="#18" class="mim-tip-reference" title="Heilig, R., Hanauer, A., Grzeschik, K.-H., Hors-Cayla, M. C., Mandel, J. L. <strong>Actin-like sequences are present on the X and Y chromosomes.</strong> EMBO J. 3: 1803-1807, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6592095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6592095</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1984.tb02049.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6592095">Heilig et al., 1984</a>; <a href="#24" class="mim-tip-reference" title="Koenig, M., Moisan, J. P., Heilig, R., Andre, G., Mandel, J. L. <strong>Homologies between the X and Y chromosomes analyzed with DNA probes. (Abstract)</strong> Cytogenet. Cell Genet. 40: 670-671, 1985."None>Koenig et al., 1985</a>) appear to be intronless pseudogenes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6592095" 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 cDNA copy of the 3-prime untranslated region of the human skeletal alpha-actin gene, <a href="#36" class="mim-tip-reference" title="Shows, T., Eddy, R. L., Haley, L., Byers, M., Henry, M., Gunning, P., Ponte, P., Kedes, L. <strong>The coexpressed genes for human alpha (ACTA) and cardiac actin (ACTC) are on chromosomes 1 and 15, respectively. (Abstract)</strong> Cytogenet. Cell Genet. 37: 583 only, 1984."None>Shows et al. (1984)</a> mapped the gene to 1p12-qter. This gene and that for cardiac alpha-actin (ACTC; <a href="/entry/102540">102540</a>) are coexpressed in both human skeletal muscle and heart. Coexpression is not a function of linkage; the loci are on separate chromosomes: 1p21-qter and 15q11-qter, respectively (<a href="#14" class="mim-tip-reference" title="Gunning, P., Ponte, P., Kedes, L., Eddy, R., Shows, T. <strong>Chromosomal location of the co-expressed human skeletal and cardiac actin genes.</strong> Proc. Nat. Acad. Sci. 81: 1813-1817, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6584914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6584914</a>] [<a href="https://doi.org/10.1073/pnas.81.6.1813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6584914">Gunning et al., 1984</a>). Using a panel of somatic cell hybrids, <a href="#4" class="mim-tip-reference" title="Alonso, S., Montagutelli, X., Simon-Chazottes, D., Guenet, J.-L., Buckingham, M. <strong>Re-localization of Actsk-1 to mouse chromosome 8, a new region of homology with human chromosome 1.</strong> Mammalian Genome 4: 15-20, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8422497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8422497</a>] [<a href="https://doi.org/10.1007/BF00364657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8422497">Alonso et al. (1993)</a> confirmed the localization of the ACTA1 gene on human chromosome 1. <a href="#3" class="mim-tip-reference" title="Akkari, P. A., Eyre, H. J., Wilton, S. D., Callen, D. F., Lane, S. A., Meredith, C., Kedes, L., Laing, N. G. <strong>Assignment of the human skeletal muscle alpha actin gene (ACTA1) to 1q42 by fluorescence in situ hybridisation.</strong> Cytogenet. Cell Genet. 65: 265-267, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8258301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8258301</a>] [<a href="https://doi.org/10.1159/000133644" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8258301">Akkari et al. (1994)</a> narrowed the assignment of the ACTA1 gene to 1q42 by fluorescence in situ hybridization. Also by fluorescence in situ hybridization, <a href="#39" class="mim-tip-reference" title="Ueyama, H., Inazawa, J., Ariyama, T., Nishino, H., Ochiai, Y., Ohkubo, I., Miwa, T. <strong>Reexamination of chromosomal loci of human muscle actin genes by fluorescence in situ hybridization.</strong> Jpn. J. Hum. Genet. 40: 145-148, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7780165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7780165</a>] [<a href="https://doi.org/10.1007/BF01874078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7780165">Ueyama et al. (1995)</a> mapped the gene to 1q42.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7780165+8422497+6584914+8258301" 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>On the basis of analysis of mouse/hamster somatic cell hybrids segregating mouse chromosomes, <a href="#8" class="mim-tip-reference" title="Czosnek, H., Nudel, U., Shani, M., Barker, P. E., Pravtcheva, D. D., Ruddle, F. H., Yaffe, D. <strong>The genes coding for the muscle contractile proteins, myosin heavy chain, myosin light chain 2, and skeletal muscle actin are located on three different mouse chromosomes.</strong> EMBO J. 1: 1299-1305, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6897916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6897916</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1982.tb01314.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6897916">Czosnek et al. (1982)</a> concluded that the skeletal actin gene is located on mouse chromosome 3. However, <a href="#4" class="mim-tip-reference" title="Alonso, S., Montagutelli, X., Simon-Chazottes, D., Guenet, J.-L., Buckingham, M. <strong>Re-localization of Actsk-1 to mouse chromosome 8, a new region of homology with human chromosome 1.</strong> Mammalian Genome 4: 15-20, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8422497/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8422497</a>] [<a href="https://doi.org/10.1007/BF00364657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8422497">Alonso et al. (1993)</a> found by PCR analysis of a microsatellite in an interspecific backcross that the alpha-actin gene is closely linked to tyrosine aminotransferase and adenine phosphoribosyltransferase on mouse chromosome 8. The Acta1 gene is situated between Tat and Aprt; the human homologs TAT (<a href="/entry/613018">613018</a>) and APRT (<a href="/entry/102600">102600</a>) are on human chromosome 16. <a href="#1" class="mim-tip-reference" title="Abonia, J. P., Abel, K. J., Eddy, R. L., Elliott, R. W., Chapman, V. M., Shows, T. B., Gross, K. W. <strong>Linkage of Agt and Actsk-1 to distal mouse chromosome 8 loci: a new conserved linkage.</strong> Mammalian Genome 4: 25-32, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8093670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8093670</a>] [<a href="https://doi.org/10.1007/BF00364659" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8093670">Abonia et al. (1993)</a> likewise mapped the Acta1 gene to mouse chromosome 8 by segregation of RFLVs in 2 interspecific backcross sets and in 4 recombinant inbred mouse sets. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8422497+8093670+6897916" 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>Actin makes up 10 to 20% of cellular protein and has vital roles in cell integrity, structure, and motility. It is highly conserved throughout evolution. Its function depends on the balance between monomeric (globular) G-actin (42 kD) and (filamentous) F-actin, a linear polymer of G-actin subunits. Among the cytosolic actin-binding proteins, 3 appear to be of primary importance in limiting polymerization: profilin (<a href="/entry/176590">176590</a>, <a href="/entry/176610">176610</a>), thymosin beta-4 (<a href="/entry/300159">300159</a>), and gelsolin (GSN; <a href="/entry/137350">137350</a>). The existence of intracellular actin-binding proteins allows the concentration of G-actin to be maintained substantially above the threshold at which polymerization and the formation of filaments would normally occur. When released into the extracellular space, actin, which otherwise is known to have a pathologic effect, is bound by gelsolin and by the Gc protein (GC; <a href="/entry/139200">139200</a>). This is the so-called extracellular actin-scavenger system (<a href="#27" class="mim-tip-reference" title="Lee, W. M., Galbraith, R. M. <strong>The extracellular actin-scavenger system and actin toxicity.</strong> New Eng. J. Med. 326: 1335-1341, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1314333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1314333</a>] [<a href="https://doi.org/10.1056/NEJM199205143262006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1314333">Lee and Galbraith, 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1314333" 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="#33" class="mim-tip-reference" title="Oda, T., Iwasa, M., Aihara, T., Maeda, Y., Narita, A. <strong>The nature of the globular-to-fibrous-actin transition.</strong> Nature 457: 441-445, 2009. Note: Erratum: Nature 461: 550 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19158791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19158791</a>] [<a href="https://doi.org/10.1038/nature07685" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19158791">Oda et al. (2009)</a> created a model of F-actin using x-ray fiber diffraction intensities obtained from well oriented sols of rabbit skeletal muscle F-actin to 3.3 angstroms in the radial direction and 5.6 angstroms along the equator. The authors showed that the G- to F-actin conformational transition is a simple relative rotation of the 2 major domains by about 20 degrees. As a result of the domain rotation, the actin molecule in the filament is flat. The flat form is essential for the formation of stable, helical F-actin. <a href="#33" class="mim-tip-reference" title="Oda, T., Iwasa, M., Aihara, T., Maeda, Y., Narita, A. <strong>The nature of the globular-to-fibrous-actin transition.</strong> Nature 457: 441-445, 2009. Note: Erratum: Nature 461: 550 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19158791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19158791</a>] [<a href="https://doi.org/10.1038/nature07685" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19158791">Oda et al. (2009)</a> concluded that their F-actin structure model provided a basis for understanding actin polymerization as well as its molecular interactions with actin-binding proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19158791" 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>Mutations in the ACTA1 gene cause congenital myopathy that varies clinically, ranging from death in infancy to adult survival. Most patients (90%) carry heterozygous mutations, the majority of which occur de novo and encode missense variants that likely act in a dominant-negative manner and cause typical congenital myopathy-2A (CMYO2A; <a href="/entry/161800">161800</a>). Most patients with a heterozygous mutation have a typical presentation, but some have severe infantile congenital myopathy-2C (CMYO2C; <a href="/entry/620278">620278</a>). Rare families who demonstrate autosomal dominant transmission of the disorder are less severely affected, since affected individuals survive to reproductive age. Patients with biallelic ACTA1 mutations (10%) showing autosomal recessive inheritance (CMYO2B; <a href="/entry/620265">620265</a>) have a severe phenotype, often with loss of expression of the ACTA1 protein due to frameshift or nonsense mutations. These likely act as loss-of-function alleles since carrier parents are unaffected (review by <a href="#37" class="mim-tip-reference" title="Sparrow, J. C., Nowak, K. J., Durling, H. J., Beggs, A. H., Wallgren-Pettersson, C., Romero, N., Nonaka, I., Laing, N. G. <strong>Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1).</strong> Neuromusc. Disord. 13: 519-531, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12921789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12921789</a>] [<a href="https://doi.org/10.1016/s0960-8966(03)00101-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12921789">Sparrow et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12921789" 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 immunoblot analysis, <a href="#21" class="mim-tip-reference" title="Ilkovski, B., Nowak, K. J., Domazetovska, A., Maxwell, A. L., Clement, S., Davies, K. E., Laing, N. G., North, K. N., Cooper, S. T. <strong>Evidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by abnormal folding, aggregation and altered polymerization of mutant actin isoforms.</strong> Hum. Molec. Genet. 13: 1727-1743, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15198992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15198992</a>] [<a href="https://doi.org/10.1093/hmg/ddh185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15198992">Ilkovski et al. (2004)</a> showed that muscle from patients with ACTA1 mutations had increased levels of gamma-filamin (FLNC; <a href="/entry/102565">102565</a>), myotilin (TTID; <a href="/entry/604103">604103</a>), desmin (DES; <a href="/entry/125660">125660</a>), and alpha-actinin (ACTN1; <a href="/entry/102575">102575</a>), consistent with accumulation of Z line-derived nemaline bodies. Intranuclear aggregates were observed upon transfecting myoblasts with V163L (<a href="#0004">102610.0004</a>)-null-, V163L (<a href="#0024">102610.0024</a>)-null-, V163M (<a href="#0014">102610.0014</a>)-null-, and R183G-null-acting transgene constructs, and modeling showed these residues to be adjacent to the nuclear export signal of actin. Transfection studies further showed significant alterations in the ability of V136L and R183G actin mutants to polymerize and contribute to insoluble acting filaments. In vitro studies suggested that abnormal folding, altered polymerization, and aggregation of mutant actin isoforms may be common properties of NM ACTA1 mutants. A combination of these effects may contribute to the common pathologic hallmarks of NM, namely intranuclear and cytoplasmic rod formation, accumulation of thin filaments, and myofibrillar disorganization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15198992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Laing, N. G., Dye, D. E., Wallgren-Pettersson, C., Richard, G., Monnier, N., Lillis, S., Winder, T. L., Lochmuller, H., Graziano, C., Mitrani-Rosenbaum, S., Twomey, D., Sparrow, J. C., Beggs, A. H., Nowak, K. J. <strong>Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1).</strong> Hum. Mutat. 30: 1267-1277, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562689</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562689[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.21059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562689">Laing et al. (2009)</a> provided a review of mutations and polymorphisms in the ACTA1 gene and described 85 novel mutations. Mutations are spread throughout the 6 coding exons, and there are no mutation hotspots. Irrespective of the pathology, ACTA1 mutations usually result in a clinically severe myopathy, with many patients dying in the first years of life. Most mutations are dominant, and most of these are de novo. About 10% mutations are recessive and functionally null. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19562689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Congenital Myopathy 2A, Typical, Autosomal Dominant</em></strong></p><p>
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In 2 unrelated patients (P7 and P10) with autosomal dominant typical congenital myopathy-2A (CMYO2A; <a href="/entry/161800">161800</a>), <a href="#31" class="mim-tip-reference" title="Nowak, K. J., Wattanasirichaigoon, D., Goebel, H. H., Wilce, M., Pelin, K., Donner, K., Jacob, R. L., Hubner, C., Oexle, K., Anderson, J. R., Verity, C. M., North, K. N., and 13 others. <strong>Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.</strong> Nature Genet. 23: 208-212, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508519</a>] [<a href="https://doi.org/10.1038/13837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508519">Nowak et al. (1999)</a> identified heterozygous missense mutations in the ACTA1 gene (M132V and G182D). Clinical details were limited, but these patients were classified as having a milder disease; they were alive at 3 and 39 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508519" 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 patients (P3 and P4) with a typical form of CMYO2A, <a href="#20" class="mim-tip-reference" title="Ilkovski, B., Cooper, S. T., Nowak, K., Ryan, M. M., Yang, N., Schnell, C., Durling, H. J., Roddick, L. G., Wilkinson, I., Kornberg, A. J., Collins, K. J., Wallace, G., Gunning, P., Hardeman, E. C., Laing, N. G., North, K. N. <strong>Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene.</strong> Am. J. Hum. Genet. 68: 1333-1343, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11333380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11333380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11333380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11333380">Ilkovski et al. (2001)</a> identified 2 different heterozygous missense mutations in the ACTA1 gene: P3 carried a de novo G286C mutation (<a href="#0007">102610.0007</a>), whereas P4 carried a heterozygous I136M mutation (<a href="#0008">102610.0008</a>) that likely occurred de novo since he had no family history of a similar disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11333380" 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 Japanese boy with CMYO2A who died of cardiomyopathy at age 9.5 years, <a href="#12" class="mim-tip-reference" title="Gatayama, R., Ueno, K., Nakamura, H., Yanagi, S., Ueda, H., Yamagishi, H., Yasui, S. <strong>Nemaline myopathy with dilated cardiomyopathy in childhood.</strong> Pediatrics 131: e1986-1990, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23650303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23650303</a>] [<a href="https://doi.org/10.1542/peds.2012-1139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23650303">Gatayama et al. (2013)</a> identified a heterozygous missense mutation in the ACTA1 gene (W358C; <a href="#0017">102610.0017</a>). <a href="#12" class="mim-tip-reference" title="Gatayama, R., Ueno, K., Nakamura, H., Yanagi, S., Ueda, H., Yamagishi, H., Yasui, S. <strong>Nemaline myopathy with dilated cardiomyopathy in childhood.</strong> Pediatrics 131: e1986-1990, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23650303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23650303</a>] [<a href="https://doi.org/10.1542/peds.2012-1139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23650303">Gatayama et al. (2013)</a> noted that childhood-onset dilated cardiomyopathy is rare in patients with ACTA1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23650303" 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 families with CMYO2A manifest as 'core only' myopathy, <a href="#23" class="mim-tip-reference" title="Kaindl, A. M., Ruschendorf, F., Krause, S., Goebel, H.-H., Koehler, K., Becker, C., Pongratz, D., Muller-Hocker, J., Nurnberg, P., Stoltenburg-Didinger, G., Lochmuller, H., Huebner, A. <strong>Missense mutations of ACTA1 cause dominant congenital myopathy with cores.</strong> J. Med. Genet. 41: 842-848, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520409</a>] [<a href="https://doi.org/10.1136/jmg.2004.020271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520409">Kaindl et al. (2004)</a> identified heterozygous missense mutations in the ACTA1 gene (<a href="#0009">102610.0009</a>-<a href="#0010">102610.0010</a>). Patients of both families showed a mild and nonprogressive course of skeletal muscle weakness. The myopathy was accompanied by adult-onset hypertrophic cardiomyopathy and respiratory failure in 1 family. Histologically, cores were detected in the muscle fibers of at least 1 patient in each family, whereas nemaline bodies or rods and actin filament accumulation were absent. <a href="#23" class="mim-tip-reference" title="Kaindl, A. M., Ruschendorf, F., Krause, S., Goebel, H.-H., Koehler, K., Becker, C., Pongratz, D., Muller-Hocker, J., Nurnberg, P., Stoltenburg-Didinger, G., Lochmuller, H., Huebner, A. <strong>Missense mutations of ACTA1 cause dominant congenital myopathy with cores.</strong> J. Med. Genet. 41: 842-848, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520409</a>] [<a href="https://doi.org/10.1136/jmg.2004.020271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520409">Kaindl et al. (2004)</a> concluded that their findings established mutation in the ACTA1 gene as a cause of dominant congenital myopathy with cores and delineated another clinicopathologic phenotype for ACTA1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15520409" 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 4 patients from a 3-generation family with autosomal dominant CMYO2A, <a href="#19" class="mim-tip-reference" title="Hutchinson, D. O., Charlton, A., Laing, N. G., Ilkovski, B., North, K. N. <strong>Autosomal dominant nemaline myopathy with intranuclear rods due to mutation of the skeletal muscle ACTA1 gene: clinical and pathological variability within a kindred.</strong> Neuromusc. Disord. 16: 113-121, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16427282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16427282</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.11.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16427282">Hutchinson et al. (2006)</a> identified a heterozygous mutation in the ACTA1 gene (V163M; <a href="#0014">102610.0014</a>) that segregated with the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16427282" 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="#37" class="mim-tip-reference" title="Sparrow, J. C., Nowak, K. J., Durling, H. J., Beggs, A. H., Wallgren-Pettersson, C., Romero, N., Nonaka, I., Laing, N. G. <strong>Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1).</strong> Neuromusc. Disord. 13: 519-531, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12921789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12921789</a>] [<a href="https://doi.org/10.1016/s0960-8966(03)00101-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12921789">Sparrow et al. (2003)</a> reported a 42-year-old patient classified as having a 'typical' form of CMYO2A who carried a heterozygous H40Y mutation (see <a href="#0026">102610.0026</a>). He had no family history of the disorder. Further clinical details were not provided. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12921789" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Congenital Myopathy 2C, Severe Infantile, Autosomal Dominant</em></strong></p><p>
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In 3 patients with severe infantile autosomal dominant congenital myopathy-2C (CMYO2C; <a href="/entry/620278">620278</a>) reported by <a href="#13" class="mim-tip-reference" title="Goebel, H. H., Anderson, J. R., Hubner, C., Oexle, K., Warlo, I. <strong>Congenital myopathy with excess of thin myofilaments.</strong> Neuromusc. Disord. 7: 160-168, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9185179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9185179</a>] [<a href="https://doi.org/10.1016/s0960-8966(97)00441-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9185179">Goebel et al. (1997)</a>, <a href="#31" class="mim-tip-reference" title="Nowak, K. J., Wattanasirichaigoon, D., Goebel, H. H., Wilce, M., Pelin, K., Donner, K., Jacob, R. L., Hubner, C., Oexle, K., Anderson, J. R., Verity, C. M., North, K. N., and 13 others. <strong>Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.</strong> Nature Genet. 23: 208-212, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508519</a>] [<a href="https://doi.org/10.1038/13837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508519">Nowak et al. (1999)</a> identified heterozygous missense mutations in the ACTA1 gene (<a href="#0003">102610.0003</a>; <a href="#0004">102610.0004</a>; <a href="#0024">102610.0024</a>). The mutations were demonstrated to occur de novo in patients 1 and 2; parental DNA from patient 3 was not available. <a href="#31" class="mim-tip-reference" title="Nowak, K. J., Wattanasirichaigoon, D., Goebel, H. H., Wilce, M., Pelin, K., Donner, K., Jacob, R. L., Hubner, C., Oexle, K., Anderson, J. R., Verity, C. M., North, K. N., and 13 others. <strong>Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.</strong> Nature Genet. 23: 208-212, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508519</a>] [<a href="https://doi.org/10.1038/13837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508519">Nowak et al. (1999)</a> also identified heterozygous, mostly de novo, missense mutations in the ACTA1 gene (see, e.g., <a href="#0025">102610.0025</a> and <a href="#0026">102610.0026</a>), in 7 additional patients with severe congenital myopathy. Clinical details were limited, but most of the patients died in infancy. One patient (P10) classified as severe was still alive at 10 years of age. The missense mutations in ACTA1 were distributed throughout all 6 coding exons and some involved known functional domains of actin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9185179+10508519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated patients with severe infantile CMYO2C, <a href="#25" class="mim-tip-reference" title="Laing, N. G., Clarke, N. F., Dye, D. E., Liyanage, K., Walker, K. R., Kobayashi, Y., Shimakawa, S., Hagiwara, T., Ouvrier, R., Sparrow, J. C., Nishino, I., North, K. N., Nonaka, I. <strong>Actin mutations are one cause of congenital fibre type disproportion.</strong> Ann. Neurol. 56: 689-694, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15468086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15468086</a>] [<a href="https://doi.org/10.1002/ana.20260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15468086">Laing et al. (2004)</a> identified 3 different heterozygous missense mutations in the ACTA1 gene (<a href="#0011">102610.0011</a>-<a href="#0013">102610.0013</a>). Parental DNA was not available for any of the cases, but there was no family history of myopathy, suggesting that the mutations occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15468086" 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 male infant (25-1) with severe infantile CMYO2C, <a href="#2" class="mim-tip-reference" title="Agrawal, P. B., Strickland, C. D., Midgett, C., Morales, A., Newburger, D. E., Poulos, M. A., Tomczak, K. K., Ryan, M. M., Iannaccone, S. T., Crawford, T. O., Laing, N. G., Beggs, A. H. <strong>Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations.</strong> Ann. Neurol. 56: 86-96, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15236405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15236405</a>] [<a href="https://doi.org/10.1002/ana.20157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15236405">Agrawal et al. (2004)</a> identified a heterozygous missense mutation in the ACTA1 gene (D286G; <a href="#0025">102610.0025</a>). There was no family history of the disease, and this was an isolated case, likely due to a de novo mutation (parental DNA was not available for study). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15236405" 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 male infant with severe infantile CMYO2C, <a href="#11" class="mim-tip-reference" title="Garcia-Angarita, N., Kirschner, J., Heiliger, M., Thirion, C., Walter, M. C., Schnittfeld-Acarlioglu, S., Albrecht, M., Muller, K., Wieczorek, D., Lochmuller, H., Krause, S. <strong>Severe nemaline myopathy associated with consecutive mutations E74D and H75Y on a single ACTA1 allele.</strong> Neuromusc. Disord. 19: 481-484, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19553116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19553116</a>] [<a href="https://doi.org/10.1016/j.nmd.2009.05.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19553116">Garcia-Angarita et al. (2009)</a> identified heterozygosity for an allele carrying 2 de novo mutations in cis affecting adjacent nucleotides in the ACTA1 gene (E74D and H75Y; <a href="#0015">102610.0015</a>). Neither unaffected parent carried either of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19553116" 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 severe infantile CMYO2C, <a href="#22" 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> identified a de novo heterozygous activating mutation in the ACTA1 gene (K328N; <a href="#0016">102610.0016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=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>Congenital Myopathy 2B, Autosomal Recessive</em></strong></p><p>
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In 2 infant sibs (family 5) with autosomal recessive congenital myopathy-2B (CMYO2B; <a href="/entry/620265">620265</a>) leading to death at 5 and 19 days of age, <a href="#31" class="mim-tip-reference" title="Nowak, K. J., Wattanasirichaigoon, D., Goebel, H. H., Wilce, M., Pelin, K., Donner, K., Jacob, R. L., Hubner, C., Oexle, K., Anderson, J. R., Verity, C. M., North, K. N., and 13 others. <strong>Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.</strong> Nature Genet. 23: 208-212, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508519</a>] [<a href="https://doi.org/10.1038/13837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508519">Nowak et al. (1999)</a> identified compound heterozygous missense mutations in the ACTA1 gene (L94P; <a href="#0001">102610.0001</a> and E259V; <a href="#0005">102610.0005</a>). Each of the mutations was inherited from an unaffected parent, consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 5 patients from 3 unrelated families with CMYO2B resulting in death in infancy, <a href="#37" class="mim-tip-reference" title="Sparrow, J. C., Nowak, K. J., Durling, H. J., Beggs, A. H., Wallgren-Pettersson, C., Romero, N., Nonaka, I., Laing, N. G. <strong>Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1).</strong> Neuromusc. Disord. 13: 519-531, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12921789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12921789</a>] [<a href="https://doi.org/10.1016/s0960-8966(03)00101-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12921789">Sparrow et al. (2003)</a> identified homozygous or compound heterozygous mutations in the ACTA1 gene (<a href="#0005">102610.0005</a>; <a href="#0019">102610.0019</a>-<a href="#0021">102610.0021</a>). All patients carried at least 1 nonsense or frameshift mutation. In 1 family, the unaffected parents were heterozygous for the mutation. Functional studies of the variants were not performed, but all were predicted to have a loss-of-function effect. Biallelic ACTA1 mutations were present in only a minority of the large patient cohort studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12921789" 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 7 patients from 6 unrelated consanguineous families with CMYO2B, <a href="#30" class="mim-tip-reference" title="Nowak, K. J., Sewry, C. A., Navarro, C., Squier, W., Reina, C., Ricoy, J. R., Jayawant, S. S., Childs, A. M., Dobbie, J. A., Appleton, R. E., Mountford, R. C., Walker, K. R., Clement, S., Barois, A., Muntoni, F., Romero, N. B., Laing, N. G. <strong>Nemaline myopathy caused by absence of alpha-skeletal muscle actin.</strong> Ann. Neurol. 61: 175-184, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17187373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17187373</a>] [<a href="https://doi.org/10.1002/ana.21035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17187373">Nowak et al. (2007)</a> identified homozygous frameshift mutations in the ACTA1 gene (see, e.g., c.541delG, <a href="#0022">102610.0022</a>). In cases where DNA was available, the unaffected parents were heterozygous for the mutation. One of the patients had previously been reported by <a href="#37" class="mim-tip-reference" title="Sparrow, J. C., Nowak, K. J., Durling, H. J., Beggs, A. H., Wallgren-Pettersson, C., Romero, N., Nonaka, I., Laing, N. G. <strong>Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1).</strong> Neuromusc. Disord. 13: 519-531, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12921789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12921789</a>] [<a href="https://doi.org/10.1016/s0960-8966(03)00101-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12921789">Sparrow et al. (2003)</a>. Four families were of Pakistani and Indian British origin, and haplotype analysis was consistent with a founder effect for the c.541delG mutation. Five of the children died of respiratory failure in infancy, whereas 1 was alive at 4.5 years of age and another at 2.5 years of age. Skeletal muscle biopsy from some of the patients showed absence of the ACTA1 protein with increased expression of cardiac alpha-actin (ACTC1; <a href="/entry/102540">102540</a>), likely reflecting a compensatory mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12921789+17187373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 brothers, born of consanguineous Sri Lankan parents, with CMYO2B, <a href="#32" class="mim-tip-reference" title="O'Grady, G. L., Best, H. A., Oates, E. C., Kaur, S., Charlton, A., Brammah, S., Punetha, J., Kesari, A., North, K. N., Ilkovski, B., Hoffman, E. P., Clarke, N. F. <strong>Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine.</strong> Europ. J. Hum. Genet. 23: 883-886, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25182138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25182138</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25182138[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2014.169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25182138">O'Grady et al. (2015)</a> identified a homozygous missense mutation in the ACTA1 gene (V154L; <a href="#0023">102610.0023</a>). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The heterozygous parents were unaffected. Functional studies of the variant were not performed, but it was predicted to be deleterious. Immunostaining and Western blot analysis of patient muscle showed normal levels of skeletal muscle ACTA1 and upregulated expression of cardiac alpha-actin (ACTC1; <a href="/entry/102540">102540</a>). <a href="#32" class="mim-tip-reference" title="O'Grady, G. L., Best, H. A., Oates, E. C., Kaur, S., Charlton, A., Brammah, S., Punetha, J., Kesari, A., North, K. N., Ilkovski, B., Hoffman, E. P., Clarke, N. F. <strong>Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine.</strong> Europ. J. Hum. Genet. 23: 883-886, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25182138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25182138</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25182138[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2014.169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25182138">O'Grady et al. (2015)</a> noted that previously reported patients with biallelic ACTA1 mutations had functional 'null' variants and made no ACTA1 protein. Survival after birth was attributed to persistence of cardiac ACTC1 in the skeletal muscle of these children. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25182138" 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>Scapulohumeroperoneal Myopathy</em></strong></p><p>
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In affected members of a large family with scapulohumeroperoneal myopathy (SHPM; <a href="/entry/616852">616852</a>), <a href="#41" class="mim-tip-reference" title="Zukosky, K., Meilleur, K., Traynor, B. J., Dastgir, J., Medne, L., Devoto, M., Collins, J., Rooney, J., Zou, Y., Yang, M. L., Gibbs, J. R., Meier, M., and 11 others. <strong>Association of a novel ACTA1 mutation with a dominant progressive scapuloperoneal myopathy in an extended family.</strong> JAMA Neurol. 72: 689-698, 2015. Note: Erratum: JAMA Neurol. 72: 950 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25938801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25938801</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25938801[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/10.1001/jamaneurol.2015.37" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25938801">Zukosky et al. (2015)</a> identified a heterozygous missense mutation in the ACTA1 gene (E197D; <a href="#0018">102610.0018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25938801" 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="#20" class="mim-tip-reference" title="Ilkovski, B., Cooper, S. T., Nowak, K., Ryan, M. M., Yang, N., Schnell, C., Durling, H. J., Roddick, L. G., Wilkinson, I., Kornberg, A. J., Collins, K. J., Wallace, G., Gunning, P., Hardeman, E. C., Laing, N. G., North, K. N. <strong>Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene.</strong> Am. J. Hum. Genet. 68: 1333-1343, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11333380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11333380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11333380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11333380">Ilkovski et al. (2001)</a> evaluated a new series of 35 patients with nemaline myopathy. They identified 5 unrelated patients with a missense mutation in the ACTA1 gene (see, e.g., <a href="#0002">102610.0002</a>; <a href="#0006">102610.0006</a>-<a href="#0008">102610.0008</a>), which suggested that mutations in this gene account for the disease in approximately 15% of patients. All 5 mutations were novel, de novo dominant mutations. One proband subsequently had 2 affected children, a result consistent with autosomal dominant transmission. The 7 patients exhibited marked clinical variability, ranging from severe congenital weakness, with death from respiratory failure during the first year of life, to a mild childhood-onset myopathy with survival into adulthood. There was marked variation in both age at onset and clinical severity in the 3 affected members of 1 family. Pathologic features shared by the patients included abnormal fiber-type differentiation, glycogen accumulation, myofibrillar disruption, and 'whorling' of actin thin filaments. The percentage of fibers with rods did not correlate with clinical severity; however, the severe, lethal phenotype was associated with both severe, generalized disorganization of sarcomeric structure and abnormal localization of sarcomeric actin. The marked variability in clinical phenotype among patients with different mutations in ACTA1 suggested that both the site of the mutation and the nature of the amino acid change have differential effects on thin-filament formation and protein-protein interactions. The intrafamilial variability suggested that alpha-actin genotype is not the sole determinant of phenotype, however. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11333380" 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 report of the 2002 conference on nemaline myopathy, <a href="#40" class="mim-tip-reference" title="Wallgren-Pettersson, C., Laing, N. G. <strong>109th ENMC International Workshop: 5th workshop on nemaline myopathy, 11th-13th October 2002, Naarden, The Netherlands.</strong> Neuromusc. Disord. 13: 501-507, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12899878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12899878</a>] [<a href="https://doi.org/10.1016/s0960-8966(03)00007-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12899878">Wallgren-Pettersson and Laing (2003)</a> stated that 59 mutations in the ACTA1 gene had been identified. Ninety percent of families had a diagnosis of nemaline myopathy, 11% had a diagnosis of actin myopathy, and 11% had a diagnosis of intranuclear rod myopathy. The findings underscored the phenotypic variability caused by mutations in the ACTA1 gene. Among the patients with nemaline myopathy, the severe form was the most common, but mild and typical forms were also represented, and some patients had unusual associated features. Most cases were sporadic, but there were examples of both autosomal dominant and autosomal recessive inheritance. No obvious genotype/phenotype correlations were observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12899878" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Agrawal, P. B., Strickland, C. D., Midgett, C., Morales, A., Newburger, D. E., Poulos, M. A., Tomczak, K. K., Ryan, M. M., Iannaccone, S. T., Crawford, T. O., Laing, N. G., Beggs, A. H. <strong>Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations.</strong> Ann. Neurol. 56: 86-96, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15236405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15236405</a>] [<a href="https://doi.org/10.1002/ana.20157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15236405">Agrawal et al. (2004)</a> found 29 ACTA1 mutations in 28 of 109 (approximately 25%) patients with nemaline myopathy. Of the whole group, ACTA1 mutations were responsible for 14 of 25 (56%) of the severe congenital cases. Ten patients with ACTA1 mutations had 'typical disease,' defined as onset in infancy or childhood with delayed milestones and survival into adulthood, and 1 patient had adult onset. Four of the families with ACTA1 mutations showed autosomal dominant inheritance; 1 family showed autosomal recessive inheritance; 2 families suggested incomplete penetrance; the remaining 21 patients had sporadic disease with heterozygous mutations. Muscle biopsy at 5 weeks of age from the patient with biallelic ACTA1 mutations with severe disease showed intense staining for cardiac alpha-actin. <a href="#2" class="mim-tip-reference" title="Agrawal, P. B., Strickland, C. D., Midgett, C., Morales, A., Newburger, D. E., Poulos, M. A., Tomczak, K. K., Ryan, M. M., Iannaccone, S. T., Crawford, T. O., Laing, N. G., Beggs, A. H. <strong>Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations.</strong> Ann. Neurol. 56: 86-96, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15236405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15236405</a>] [<a href="https://doi.org/10.1002/ana.20157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15236405">Agrawal et al. (2004)</a> emphasized the phenotypic heterogeneity among patients with ACTA1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15236405" 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="Feng, J.-J., Marston, S. <strong>Genotype-phenotype correlations in ACTA1 mutations that cause congenital myopathies.</strong> Neuromusc. Disord. 19: 6-16, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18976909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18976909</a>] [<a href="https://doi.org/10.1016/j.nmd.2008.09.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18976909">Feng and Marston (2009)</a> provided a review of ACTA1 mutations and concluded that there are no obvious functional or biochemical patterns seen in mutations that result in the same pathology. Although some mutations are predicted or have been shown to interfere with N-terminal processing, posttranslational folding, polymerization, or interaction with other proteins, there is often disagreement in studies between the structure and function of mutant proteins. There are no clear genotype/phenotype correlations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18976909" 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>By homologous recombination, <a href="#7" class="mim-tip-reference" title="Crawford, K., Flick, R., Close, L., Shelly, D., Paul, R., Bove, K., Kumar, A., Lessard, J. <strong>Mice lacking skeletal muscle actin show reduced muscle strength and growth deficits and die during the neonatal period.</strong> Molec. Cell. Biol. 22: 5887-5896, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12138199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12138199</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12138199[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/10.1128/MCB.22.16.5887-5896.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12138199">Crawford et al. (2002)</a> disrupted the skeletal actin gene in mice. Newborn skeletal muscles from null mice were similar to those of wildtype mice in size, fiber type, and ultrastructural organization. Both hemizygous and homozygous null animals showed an increase in cardiac and vascular actin (<a href="/entry/102620">102620</a>) mRNA in skeletal muscle, with no skeletal actin mRNA present in null mice. The null animals appeared normal at birth and could breathe, walk, and suckle. However, the compensation provided by expression of vascular and cardiac actins was insufficient to support adequate skeletal muscle growth and/or function. Within 4 days, all null mice showed a markedly lower body weight than normal littermates, and some developed scoliosis. All mice lacking skeletal actin died in the early neonatal period. They showed a loss of glycogen and reduced brown fat, consistent with malnutrition leading to death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12138199" 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="Ravenscroft, G., Jackaman, C., Bringans, S., Papadimitriou, J. M., Griffiths, L. M., McNamara, E., Bakker, A. J., Davies, K. E., Laing, N. G., Nowak, K. J. <strong>Mouse models of dominant ACTA1 disease recapitulate human disease and provide insight into therapies.</strong> Brain 134: 1101-1115, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21303860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21303860</a>] [<a href="https://doi.org/10.1093/brain/awr004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21303860">Ravenscroft et al. (2011)</a> and <a href="#35" class="mim-tip-reference" title="Ravenscroft, G., Jackaman, C., Sewry, C. A., McNamara, E., Squire, S. E., Potter, A. C., Papadimitriou, J., Griffiths, L. M., Bakker, A. J., Davies, K. E., Laing, N. G., Nowak, K. J. <strong>Actin nemaline myopathy mouse reproduces disease, suggests other actin disease phenotypes and provides cautionary note on muscle transgene expression.</strong> PLoS One 6: e28699, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22174871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22174871</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22174871[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/10.1371/journal.pone.0028699" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22174871">Ravenscroft et al. (2011)</a> generated mutant mice harboring a D286G mutation in the ACTA1 gene (<a href="#0025">102610.0025</a>). Mice expressing the mutant protein at 25% of the total alpha-actin pool were less active than controls, but had a normal life span. Mice expressing the mutant protein at 45% of the alpha-actin pool had severe muscle weakness leading to early death. Skeletal muscle showed extensive structural abnormalities similar to those observed in humans with the disorder. The findings suggested a correlation between mutant ACTA1 protein load and disease severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22174871+21303860" 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="#28" class="mim-tip-reference" title="Nguyen, M. A., Joya, J. E., Kee, A. J., Domazetovska, A., Yang, N., Hook, J. W., Lemckert, F. A., Kettle, E., Valova, V. A., Robinson, P. J., North, K. N., Gunning, P. W., Mitchell, C. A., Hardeman, E. C. <strong>Hypertrophy and dietary tyrosine ameliorate the phenotypes of a mouse model of severe nemaline myopathy.</strong> Brain 134: 3516-3529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22067542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22067542</a>] [<a href="https://doi.org/10.1093/brain/awr274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22067542">Nguyen et al. (2011)</a> generated mutant mice carrying the ACTA1 H40Y mutation (<a href="#0026">102610.0026</a>) and found that they developed clinical features of severe congenital myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22067542" 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="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>26 Selected Examples</a>):</strong>
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<a href="/allelicVariants/102610" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=102610[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, AUTOSOMAL RECESSIVE</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">rs121909519 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909519;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=rs121909519" 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=rs121909519" 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=RCV000019941 OR RCV001731311 OR RCV003151730" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019941, RCV001731311, RCV003151730" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019941...</a>
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<p>In 2 infant sibs (family 5) with autosomal recessive congenital myopathy-2B (CMYO2B; <a href="/entry/620265">620265</a>) leading to death at 5 and 19 days of age, <a href="#31" class="mim-tip-reference" title="Nowak, K. J., Wattanasirichaigoon, D., Goebel, H. H., Wilce, M., Pelin, K., Donner, K., Jacob, R. L., Hubner, C., Oexle, K., Anderson, J. R., Verity, C. M., North, K. N., and 13 others. <strong>Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.</strong> Nature Genet. 23: 208-212, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508519</a>] [<a href="https://doi.org/10.1038/13837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508519">Nowak et al. (1999)</a> identified compound heterozygous missense mutations in the ACTA1 gene: a T-to-C transition in exon 3, resulting in a leu94-to-pro (L94P) substitution, inherited from the unaffected father, and an A-to-G transition in exon 5, resulting in a glu259-to-val (E259V; <a href="#0005">102610.0005</a>) substitution, inherited from the unaffected mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508519" 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="#37" class="mim-tip-reference" title="Sparrow, J. C., Nowak, K. J., Durling, H. J., Beggs, A. H., Wallgren-Pettersson, C., Romero, N., Nonaka, I., Laing, N. G. <strong>Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1).</strong> Neuromusc. Disord. 13: 519-531, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12921789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12921789</a>] [<a href="https://doi.org/10.1016/s0960-8966(03)00101-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12921789">Sparrow et al. (2003)</a> noted that both the L94P and E259V mutations are buried residues that likely affect the internal packing of actin and may thus disrupt the structure of the protein. These mutant proteins may be so significantly impaired that they did not cause a dominant-negative effect in the carrier parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12921789" 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">rs121909520 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909520;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=rs121909520" 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=rs121909520" 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=RCV000019942 OR RCV001090700" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019942, RCV001090700" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019942...</a>
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<p>In a mother and her 2 children (family 6) with autosomal dominant congenital myopathy-2A (CMYO2A; <a href="/entry/161800">161800</a>), <a href="#31" class="mim-tip-reference" title="Nowak, K. J., Wattanasirichaigoon, D., Goebel, H. H., Wilce, M., Pelin, K., Donner, K., Jacob, R. L., Hubner, C., Oexle, K., Anderson, J. R., Verity, C. M., North, K. N., and 13 others. <strong>Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.</strong> Nature Genet. 23: 208-212, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508519</a>] [<a href="https://doi.org/10.1038/13837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508519">Nowak et al. (1999)</a> identified a heterozygous A-to-G transition in exon 3 of the ACTA1 gene, resulting in an asn115-to-ser (N115S) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508519" 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="#20" class="mim-tip-reference" title="Ilkovski, B., Cooper, S. T., Nowak, K., Ryan, M. M., Yang, N., Schnell, C., Durling, H. J., Roddick, L. G., Wilkinson, I., Kornberg, A. J., Collins, K. J., Wallace, G., Gunning, P., Hardeman, E. C., Laing, N. G., North, K. N. <strong>Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene.</strong> Am. J. Hum. Genet. 68: 1333-1343, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11333380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11333380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11333380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11333380">Ilkovski et al. (2001)</a> reported a 35-year-old woman (family A, patient 5) with the N115S mutation. She had typical congenital myopathy with neonatal onset of feeding difficulties, respiratory tract infections, hypotonia, facial diplegia, and proximal muscle weakness in the first weeks of life. Her disease was very slowly progressive or nonprogressive. She had 2 affected children with the mutation, a daughter (patient 6) aged 19 years and a son (patient 7) aged 4 years at the time of the report. The daughter had onset of disease at age 6 years, with mild proximal weakness and frequent falls, and developed progressive scoliosis requiring surgery at age 14 years. The son had features of congenital myopathy in infancy and showed nonprogressive weakness with improvement of mild nocturnal hypoventilation over time. The intrafamilial variability observed suggested that the ACTA1 genotype is not the sole determinant of the phenotype and that modifying factors, both genetic and stochastic influence the clinical presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11333380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, AUTOSOMAL DOMINANT</strong>
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ACTA1, GLY15ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909521 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909521;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=rs121909521" 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=rs121909521" 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=RCV002510771 OR RCV003151731 OR RCV005016281" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002510771, RCV003151731, RCV005016281" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002510771...</a>
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<p>In a patient (P1) with severe infantile congenital myopathy-2C (CMYO2C; <a href="/entry/620278">620278</a>), previously reported as patient 2 by <a href="#13" class="mim-tip-reference" title="Goebel, H. H., Anderson, J. R., Hubner, C., Oexle, K., Warlo, I. <strong>Congenital myopathy with excess of thin myofilaments.</strong> Neuromusc. Disord. 7: 160-168, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9185179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9185179</a>] [<a href="https://doi.org/10.1016/s0960-8966(97)00441-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9185179">Goebel et al. (1997)</a>, <a href="#31" class="mim-tip-reference" title="Nowak, K. J., Wattanasirichaigoon, D., Goebel, H. H., Wilce, M., Pelin, K., Donner, K., Jacob, R. L., Hubner, C., Oexle, K., Anderson, J. R., Verity, C. M., North, K. N., and 13 others. <strong>Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.</strong> Nature Genet. 23: 208-212, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508519</a>] [<a href="https://doi.org/10.1038/13837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508519">Nowak et al. (1999)</a> identified a de novo heterozygous G-to-C transversion in exon 2 of the ACTA1 gene, resulting in a gly15-to-arg (G15R) substitution. The patient was delivered by emergency Cesarean section at 37 weeks' gestation due to maternal polyhydramnios, had severe hypotonia necessitating ventilatory support, and died at age 3 months. Postmortem examination excluded spinal muscular atrophy. Muscle biopsy showed large areas of sarcoplasm devoid of normal myofibrils and mitochondria, and replaced with dense masses of thin filaments that were immunoreactive to actin. Central cores, obvious rods, ragged-red fibers, and necrosis were absent. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9185179+10508519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, 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">rs121909522 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909522;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=rs121909522" 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=rs121909522" 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=RCV000019944 OR RCV003227607" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019944, RCV003227607" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019944...</a>
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<p>In a 7.5-year-old patient (P2) with severe infantile congenital myopathy-2C (CMYO2C; <a href="/entry/620278">620278</a>) originally reported as P1 by <a href="#13" class="mim-tip-reference" title="Goebel, H. H., Anderson, J. R., Hubner, C., Oexle, K., Warlo, I. <strong>Congenital myopathy with excess of thin myofilaments.</strong> Neuromusc. Disord. 7: 160-168, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9185179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9185179</a>] [<a href="https://doi.org/10.1016/s0960-8966(97)00441-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9185179">Goebel et al. (1997)</a>, <a href="#31" class="mim-tip-reference" title="Nowak, K. J., Wattanasirichaigoon, D., Goebel, H. H., Wilce, M., Pelin, K., Donner, K., Jacob, R. L., Hubner, C., Oexle, K., Anderson, J. R., Verity, C. M., North, K. N., and 13 others. <strong>Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.</strong> Nature Genet. 23: 208-212, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508519</a>] [<a href="https://doi.org/10.1038/13837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508519">Nowak et al. (1999)</a> identified a de novo heterozygous G-to-C transversion in exon 4 of the ACTA1 gene, resulting in a val163-to-leu (V163L) substitution. The patient was hypotonic from birth, had atrophy of the pelvic and shoulder girdle muscles, a high-arched palate, and cardiomyopathy. At 4.5 years, he could walk and sit unaided. Muscle biopsy showed subsarcolemmal regions that were devoid of oxidative activity and filled with actin-immunopositive densely packed thin filaments. Intranuclear nemaline rods were also present (<a href="#13" class="mim-tip-reference" title="Goebel, H. H., Anderson, J. R., Hubner, C., Oexle, K., Warlo, I. <strong>Congenital myopathy with excess of thin myofilaments.</strong> Neuromusc. Disord. 7: 160-168, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9185179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9185179</a>] [<a href="https://doi.org/10.1016/s0960-8966(97)00441-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9185179">Goebel et al., 1997</a>). The same amino acid substitution due to a different nucleotide change was observed in another patient with the disorder who died at 4 months of age (see <a href="#0024">102610.0024</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9185179+10508519" 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> rs121909523 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909523;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/rs121909523?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=rs121909523" 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=rs121909523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the glu259-to-val (E259V) mutation in the ACTA1 gene that was found in compound heterozygous state in 2 infant sibs with fatal autosomal recessive congenital myopathy-2B (CMYO2B; <a href="/entry/620265">620265</a>) by <a href="#31" class="mim-tip-reference" title="Nowak, K. J., Wattanasirichaigoon, D., Goebel, H. H., Wilce, M., Pelin, K., Donner, K., Jacob, R. L., Hubner, C., Oexle, K., Anderson, J. R., Verity, C. M., North, K. N., and 13 others. <strong>Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.</strong> Nature Genet. 23: 208-212, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508519</a>] [<a href="https://doi.org/10.1038/13837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508519">Nowak et al. (1999)</a>, see <a href="#0001">102610.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508519" 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 CMYO2B resulting in death at 2 months of age, <a href="#37" class="mim-tip-reference" title="Sparrow, J. C., Nowak, K. J., Durling, H. J., Beggs, A. H., Wallgren-Pettersson, C., Romero, N., Nonaka, I., Laing, N. G. <strong>Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1).</strong> Neuromusc. Disord. 13: 519-531, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12921789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12921789</a>] [<a href="https://doi.org/10.1016/s0960-8966(03)00101-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12921789">Sparrow et al. (2003)</a> identified compound heterozygous mutations in the ACTA1 gene: E259V and a 1-bp deletion (<a href="#0020">102610.0020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12921789" 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">rs121909524 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909524;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=rs121909524" 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=rs121909524" 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 patient (P1) with severe infantile congenital myopathy-2C (CMYO2C; <a href="/entry/620278">620278</a>), who died at the age of 6 months of respiratory failure, <a href="#20" class="mim-tip-reference" title="Ilkovski, B., Cooper, S. T., Nowak, K., Ryan, M. M., Yang, N., Schnell, C., Durling, H. J., Roddick, L. G., Wilkinson, I., Kornberg, A. J., Collins, K. J., Wallace, G., Gunning, P., Hardeman, E. C., Laing, N. G., North, K. N. <strong>Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene.</strong> Am. J. Hum. Genet. 68: 1333-1343, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11333380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11333380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11333380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11333380">Ilkovski et al. (2001)</a> identified a de novo heterozygous A-to-C transversion in the ACTA1 gene, resulting in an ile357-to-leu (I357L) substitution. This female infant was born with hypotonia, minimal spontaneous movements, and fractures of both femurs. She did not achieve motor milestones and required a feeding tube. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11333380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 CONGENITAL MYOPATHY 2A, TYPICAL, 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">rs121909525 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909525;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=rs121909525" 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=rs121909525" 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=RCV000019947" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019947" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019947</a>
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<p>In a 10-year-old boy (P3) with childhood onset of congenital myopathy-2A (CMYO2A1; <a href="/entry/161800">161800</a>), <a href="#20" class="mim-tip-reference" title="Ilkovski, B., Cooper, S. T., Nowak, K., Ryan, M. M., Yang, N., Schnell, C., Durling, H. J., Roddick, L. G., Wilkinson, I., Kornberg, A. J., Collins, K. J., Wallace, G., Gunning, P., Hardeman, E. C., Laing, N. G., North, K. N. <strong>Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene.</strong> Am. J. Hum. Genet. 68: 1333-1343, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11333380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11333380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11333380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11333380">Ilkovski et al. (2001)</a> identified a de novo heterozygous G-to-T transversion in the ACTA1 gene, resulting in a gly268-to-cys (G268C) substitution. The patient had no problems during the neonatal period, but presented at age 5 years with inability to run and frequent falls. He did not have feeding or respiratory difficulties. At age 10, he had slowly progressive weakness with involvement of proximal muscles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11333380" 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">rs121909526 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909526;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=rs121909526" 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=rs121909526" 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=RCV000019948 OR RCV004813045" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019948, RCV004813045" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019948...</a>
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<p>In a 45-year-old man (P4) with typical congenital myopathy-2A (CMYO2A; <a href="/entry/161800">161800</a>), <a href="#20" class="mim-tip-reference" title="Ilkovski, B., Cooper, S. T., Nowak, K., Ryan, M. M., Yang, N., Schnell, C., Durling, H. J., Roddick, L. G., Wilkinson, I., Kornberg, A. J., Collins, K. J., Wallace, G., Gunning, P., Hardeman, E. C., Laing, N. G., North, K. N. <strong>Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene.</strong> Am. J. Hum. Genet. 68: 1333-1343, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11333380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11333380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11333380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11333380">Ilkovski et al. (2001)</a> identified a de novo heterozygous C-to-G transversion in the ACTA1 gene, resulting in an ile136-to-met (I136M) substitution. Although he had infantile onset and delayed motor development, his weakness was nonprogressive, and he was physically active as an adult and regularly engaged in long-distance competitive cycling. He had a weak cough and frequent respiratory infections. Echocardiography was normal. <a href="#29" class="mim-tip-reference" title="Nowak, K. J., Ravenscroft, G., Laing, N. G. <strong>Skeletal muscle alpha-actin diseases (actinopathies): pathology and mechanisms.</strong> Acta Neuropath. 125: 19-32, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22825594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22825594</a>] [<a href="https://doi.org/10.1007/s00401-012-1019-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22825594">Nowak et al. (2013)</a> noted that the muscle fibers were hypertrophied in the patient reported by <a href="#20" class="mim-tip-reference" title="Ilkovski, B., Cooper, S. T., Nowak, K., Ryan, M. M., Yang, N., Schnell, C., Durling, H. J., Roddick, L. G., Wilkinson, I., Kornberg, A. J., Collins, K. J., Wallace, G., Gunning, P., Hardeman, E. C., Laing, N. G., North, K. N. <strong>Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene.</strong> Am. J. Hum. Genet. 68: 1333-1343, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11333380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11333380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11333380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11333380">Ilkovski et al. (2001)</a>, suggesting that both exercise and muscle fiber hypertrophy may be beneficial for patients with certain ACTA1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11333380+22825594" 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">rs121909527 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909527;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=rs121909527" 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=rs121909527" 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=RCV003148622" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003148622" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003148622</a>
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<p>In 11 affected members in 4 generations and 8 separate sibships of a German family with autosomal dominant congenital myopathy-2A (CMYO2A; <a href="/entry/161800">161800</a>), <a href="#23" class="mim-tip-reference" title="Kaindl, A. M., Ruschendorf, F., Krause, S., Goebel, H.-H., Koehler, K., Becker, C., Pongratz, D., Muller-Hocker, J., Nurnberg, P., Stoltenburg-Didinger, G., Lochmuller, H., Huebner, A. <strong>Missense mutations of ACTA1 cause dominant congenital myopathy with cores.</strong> J. Med. Genet. 41: 842-848, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520409</a>] [<a href="https://doi.org/10.1136/jmg.2004.020271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520409">Kaindl et al. (2004)</a> identified a heterozygous c.110G-T transversion in exon 2 of the ACTA1 gene, resulting in an asp1-to-tyr (D1Y) substitution at a highly conserved residue in the mature protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15520409" 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">rs121909528 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909528;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=rs121909528" 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=rs121909528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 5 affected members spanning 3 generations of a Chinese family with autosomal dominant congenital myopathy-2A (CMYO2A; <a href="/entry/161800">161800</a>), <a href="#23" class="mim-tip-reference" title="Kaindl, A. M., Ruschendorf, F., Krause, S., Goebel, H.-H., Koehler, K., Becker, C., Pongratz, D., Muller-Hocker, J., Nurnberg, P., Stoltenburg-Didinger, G., Lochmuller, H., Huebner, A. <strong>Missense mutations of ACTA1 cause dominant congenital myopathy with cores.</strong> J. Med. Genet. 41: 842-848, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520409</a>] [<a href="https://doi.org/10.1136/jmg.2004.020271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520409">Kaindl et al. (2004)</a> identified a heterozygous c.1110A-C transversion in the ACTA1 gene, resulting in a glu334-to-ala (E334A) substitution at a conserved residue. Two members of the family developed adult-onset hypertrophic cardiomyopathy and respiratory insufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15520409" 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">rs121909529 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909529;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=rs121909529" 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=rs121909529" 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=RCV000019951 OR RCV001028007 OR RCV003151734" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019951, RCV001028007, RCV003151734" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019951...</a>
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<p>In an Australian patient (P1) with severe infantile congenital myopathy-2C (CMYO2C; <a href="/entry/620278">620278</a>), <a href="#25" class="mim-tip-reference" title="Laing, N. G., Clarke, N. F., Dye, D. E., Liyanage, K., Walker, K. R., Kobayashi, Y., Shimakawa, S., Hagiwara, T., Ouvrier, R., Sparrow, J. C., Nishino, I., North, K. N., Nonaka, I. <strong>Actin mutations are one cause of congenital fibre type disproportion.</strong> Ann. Neurol. 56: 689-694, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15468086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15468086</a>] [<a href="https://doi.org/10.1002/ana.20260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15468086">Laing et al. (2004)</a> identified a heterozygous A-to-T transversion in exon 6 of the ACTA1 gene, resulting in an asp292-to-val (D292V) substitution in a region that forms part of the monomeric actin surface that would be exposed in the F-actin polymer. The mutation was not identified in more than 300 control chromosomes. There was no family history of the disorder and parental DNA was not available, but the authors hypothesized that the mutation occurred de novo. The patient died of respiratory failure at 3.5 years of age. Muscle biopsy showed congenital fiber-type disproportion (CFTD). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15468086" 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 mass spectrometry and gel electrophoresis to examine patient skeletal muscle, <a href="#6" class="mim-tip-reference" title="Clarke, N. F., Ilkovski, B., Cooper, S., Valova, V. A., Robinson, P. J., Nonaka, I., Feng, J.-J., Marston, S., North, K. <strong>The pathogenesis of ACTA1-related congenital fiber type disproportion.</strong> Ann. Neurol. 61: 552-561, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17387733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17387733</a>] [<a href="https://doi.org/10.1002/ana.21112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17387733">Clarke et al. (2007)</a> determined that D292V-actin accounted for 50% of total sarcomeric actin. In vitro assays showed that D292V-actin resulted in decreased motility due to abnormal interactions between actin and tropomyosin, with tropomyosin stabilized in the 'off' position. Cellular transfection studies demonstrated that the mutant protein incorporated into actin filaments and did not result in increased actin aggregation or disruption of the sarcomere. <a href="#6" class="mim-tip-reference" title="Clarke, N. F., Ilkovski, B., Cooper, S., Valova, V. A., Robinson, P. J., Nonaka, I., Feng, J.-J., Marston, S., North, K. <strong>The pathogenesis of ACTA1-related congenital fiber type disproportion.</strong> Ann. Neurol. 61: 552-561, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17387733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17387733</a>] [<a href="https://doi.org/10.1002/ana.21112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17387733">Clarke et al. (2007)</a> concluded that ACTA1 mutations resulting in congenital myopathy cause weakness by interfering with sarcomeric function rather than structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17387733" 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">rs121909530 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909530;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=rs121909530" 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=rs121909530" 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=RCV000019952 OR RCV001851954 OR RCV003151735" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019952, RCV001851954, RCV003151735" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019952...</a>
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<p>In a Japanese patient (P2) with severe infantile congenital myopathy-2C (CMYO2C; <a href="/entry/620278">620278</a>), <a href="#25" class="mim-tip-reference" title="Laing, N. G., Clarke, N. F., Dye, D. E., Liyanage, K., Walker, K. R., Kobayashi, Y., Shimakawa, S., Hagiwara, T., Ouvrier, R., Sparrow, J. C., Nishino, I., North, K. N., Nonaka, I. <strong>Actin mutations are one cause of congenital fibre type disproportion.</strong> Ann. Neurol. 56: 689-694, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15468086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15468086</a>] [<a href="https://doi.org/10.1002/ana.20260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15468086">Laing et al. (2004)</a> identified a heterozygous T-to-C transition in exon 5 of the ACTA1 gene, resulting in a leu221-to-pro (L221P) substitution in a region that forms part of the monomeric actin surface that would be exposed in the F-actin polymer. The mutation was not identified in more than 300 control chromosomes. There was no family history of the disorder and parental DNA was not available, but the authors hypothesized that the mutation occurred de novo. The patient required continuous ventilation and tube feeding; she died at 1.1 years of age. Muscle biopsy showed congenital fiber-type disproportion (CFTD). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15468086" 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>.0013 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, 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">rs121909531 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909531;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=rs121909531" 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=rs121909531" 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=RCV000019953 OR RCV002513127 OR RCV003151736 OR RCV004767013" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019953, RCV002513127, RCV003151736, RCV004767013" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019953...</a>
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<p>In a 3-year-old Japanese patient (P3) with severe infantile congenital myopathy-2C (CMYO2C; <a href="/entry/620278">620278</a>). <a href="#25" class="mim-tip-reference" title="Laing, N. G., Clarke, N. F., Dye, D. E., Liyanage, K., Walker, K. R., Kobayashi, Y., Shimakawa, S., Hagiwara, T., Ouvrier, R., Sparrow, J. C., Nishino, I., North, K. N., Nonaka, I. <strong>Actin mutations are one cause of congenital fibre type disproportion.</strong> Ann. Neurol. 56: 689-694, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15468086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15468086</a>] [<a href="https://doi.org/10.1002/ana.20260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15468086">Laing et al. (2004)</a> identified a heterozygous C-to-T transition in exon 7 of the ACTA1 gene, resulting in a pro332-to-ser (P332S) substitution in a region that forms part of the monomeric actin surface that would be exposed in the F-actin polymer. The mutation was not identified in more than 300 control chromosomes. There was no family history of the disorder and parental DNA was not available, but the authors hypothesized that the mutation occurred de novo. The patient had severe hypotonia with no head control and was bedridden with a feeding tube and continuous ventilation by tracheostomy. Muscle biopsy showed congenital fiber-type disproportion (CFTD). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15468086" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 CONGENITAL MYOPATHY 2A, TYPICAL, 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">rs121909522 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909522;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=rs121909522" 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=rs121909522" 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=RCV000019954 OR RCV001781286 OR RCV004813046" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019954, RCV001781286, RCV004813046" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019954...</a>
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<p>In affected members of a family with autosomal dominant typical congenital myopathy-2A (CMYO2A; <a href="/entry/161800">161800</a>), <a href="#19" class="mim-tip-reference" title="Hutchinson, D. O., Charlton, A., Laing, N. G., Ilkovski, B., North, K. N. <strong>Autosomal dominant nemaline myopathy with intranuclear rods due to mutation of the skeletal muscle ACTA1 gene: clinical and pathological variability within a kindred.</strong> Neuromusc. Disord. 16: 113-121, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16427282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16427282</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.11.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16427282">Hutchinson et al. (2006)</a> identified a heterozygous G-to-A transition in exon 4 of the ACTA1 gene, resulting in a val163-to-met (V163M) substitution. Other mutations have been reported in this codon (V163L; <a href="#0004">102610.0004</a> and <a href="#0024">102610.0024</a>). Clinical features included hypotonia early in life, limb muscle weakness and atrophy, tall thin face, and high-arched palate. Skeletal muscle biopsies varied but tended to show intranuclear rods within myofibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16427282" 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 electron microscopy of muscle samples from patients reported by <a href="#19" class="mim-tip-reference" title="Hutchinson, D. O., Charlton, A., Laing, N. G., Ilkovski, B., North, K. N. <strong>Autosomal dominant nemaline myopathy with intranuclear rods due to mutation of the skeletal muscle ACTA1 gene: clinical and pathological variability within a kindred.</strong> Neuromusc. Disord. 16: 113-121, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16427282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16427282</a>] [<a href="https://doi.org/10.1016/j.nmd.2005.11.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16427282">Hutchinson et al. (2006)</a>, <a href="#9" class="mim-tip-reference" title="Domazetovska, A., Ilkovski, B., Kumar, V., Valova, C. A., Vandebrouck, A., Hutchinson, D. O., Robinson, P. J., Cooper, S. T., Sparrow, J. C., Peckham, M., North, K. N. <strong>Intranuclear rod myopathy: molecular pathogenesis and mechanisms of weakness.</strong> Ann. Neurol. 62: 597-608, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17705262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17705262</a>] [<a href="https://doi.org/10.1002/ana.21200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17705262">Domazetovska et al. (2007)</a> found mostly normal sarcomere structure with small areas of sarcomeric disarray. Immunohistochemical studies showed that the V163M mutation resulted in sequestration of sarcomeric and Z line proteins into intranuclear aggregates. There was some evidence of muscle regeneration, suggesting a compensatory effect. Cell culture studies showed similar findings. Transgenic V161M-mutant Drosophila were flightless with sarcomeric disorganization and altered Z line structure in muscle. The findings provided a mechanism for muscle weakness. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17705262+16427282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, AUTOSOMAL DOMINANT</strong>
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ACTA1, GLU74ASP AND HIS75TYR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606626 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606626;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=rs267606626" 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=rs267606626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606627 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606627;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=rs267606627" 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=rs267606627" 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=RCV003151737" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003151737" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003151737</a>
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<p>In a male infant with severe infantile congenital myopathy-2C (CMYO2C; <a href="/entry/620278">620278</a>), <a href="#11" class="mim-tip-reference" title="Garcia-Angarita, N., Kirschner, J., Heiliger, M., Thirion, C., Walter, M. C., Schnittfeld-Acarlioglu, S., Albrecht, M., Muller, K., Wieczorek, D., Lochmuller, H., Krause, S. <strong>Severe nemaline myopathy associated with consecutive mutations E74D and H75Y on a single ACTA1 allele.</strong> Neuromusc. Disord. 19: 481-484, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19553116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19553116</a>] [<a href="https://doi.org/10.1016/j.nmd.2009.05.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19553116">Garcia-Angarita et al. (2009)</a> identified heterozygosity for an allele carrying 2 de novo mutations in cis affecting adjacent nucleotides in exon 3 of the ACTA1 gene: a c.222G-T transversion, resulting in a glu74-to-asp (E74D) substitution, and a c.223C-T transition, resulting in a his75-to-tyr (H75Y) substitution. Neither unaffected parent carried either of the mutations; germline mosaicism could not be ruled out. <a href="#11" class="mim-tip-reference" title="Garcia-Angarita, N., Kirschner, J., Heiliger, M., Thirion, C., Walter, M. C., Schnittfeld-Acarlioglu, S., Albrecht, M., Muller, K., Wieczorek, D., Lochmuller, H., Krause, S. <strong>Severe nemaline myopathy associated with consecutive mutations E74D and H75Y on a single ACTA1 allele.</strong> Neuromusc. Disord. 19: 481-484, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19553116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19553116</a>] [<a href="https://doi.org/10.1016/j.nmd.2009.05.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19553116">Garcia-Angarita et al. (2009)</a> noted that each mutation had previously been reported in isolation as causative for congenital myopathy, but had never been reported together on the same allele. The phenotype in their patient was severe, including decreased movements in utero, breech presentation, and congenital contractures. After birth, there was severe hypotonia, lack of spontaneous movements, and death from respiratory failure at age 2 months. Skeletal muscle biopsy showed myofibrillar disorganization and nemaline rods. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19553116" 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">rs398122936 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122936;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=rs398122936" 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=rs398122936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an infant with severe infantile congenital myopathy-2C (CMYO2C; <a href="/entry/620278">620278</a>) who presented with an atypical phenotype of stiffness and hypertonicity, <a href="#22" 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> identified a de novo heterozygous c.984G-C transversion in the ACTA1 gene, resulting in a lys328-to-asn (K328N) substitution (K326N in the mature protein). Patient biopsy showed nemaline bodies and 32% mutant actin. In vitro motility analysis of actin thin filaments derived from the patient's tissue showed increased sensitivity to calcium, indicating an activated state. Expression of the mutant in mouse muscle cells did not result in the formation of rod-like structures, suggesting a different mechanism of nemaline body formation. Medical treatment was ineffective, and the patient died at age 9 months in an asystolic episode. The report expanded the phenotypic spectrum associated with ACTA1 mutations to include stiffness, rigidity, and hypertonicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=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>
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<strong>.0017 CONGENITAL MYOPATHY 2A, TYPICAL, 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">rs587777354 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777354;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=rs587777354" 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=rs587777354" 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 9-year-old Japanese boy with congenital myopathy-2A (CMYO2A; <a href="/entry/161800">161800</a>) who developed fatal dilated cardiomyopathy, <a href="#12" class="mim-tip-reference" title="Gatayama, R., Ueno, K., Nakamura, H., Yanagi, S., Ueda, H., Yamagishi, H., Yasui, S. <strong>Nemaline myopathy with dilated cardiomyopathy in childhood.</strong> Pediatrics 131: e1986-1990, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23650303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23650303</a>] [<a href="https://doi.org/10.1542/peds.2012-1139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23650303">Gatayama et al. (2013)</a> identified a heterozygous c.1074G-T transversion in exon 7 of the ACTA1 gene, resulting in a trp358-to-cys (W358C) substitution. The parents were unaffected and the mutation was not found in 50 Japanese controls. Functional studies of the variant were not performed. The patient had normal motor development in early childhood, but showed mild nonprogressive skeletal muscle weakness, such as slowed running compared to his peers. Other features included hypotonia, myopathic facies, high-arched palate, and mild weakness of proximal and distal muscles. He presented at age 9 years with acute deterioration of cardiac function, and died of cardiac failure 6 months later. Postmortem examination of cardiac muscle showed variation in myocardial fiber size and a few electron-dense fine structures related to Z lines. Skeletal muscle biopsy had previously shown typical nemaline rods. <a href="#12" class="mim-tip-reference" title="Gatayama, R., Ueno, K., Nakamura, H., Yanagi, S., Ueda, H., Yamagishi, H., Yasui, S. <strong>Nemaline myopathy with dilated cardiomyopathy in childhood.</strong> Pediatrics 131: e1986-1990, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23650303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23650303</a>] [<a href="https://doi.org/10.1542/peds.2012-1139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23650303">Gatayama et al. (2013)</a> noted that childhood-onset dilated cardiomyopathy is rare in patients with ACTA1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23650303" 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>.0018 MYOPATHY, SCAPULOHUMEROPERONEAL (1 family)</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869312739 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869312739;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=rs869312739" 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=rs869312739" 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=RCV000210030 OR RCV000414423 OR RCV001853353" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000210030, RCV000414423, RCV001853353" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000210030...</a>
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<p>In affected members of a large family with scapulohumeroperoneal myopathy (SHPM; <a href="/entry/616852">616852</a>), originally reported by <a href="#5" class="mim-tip-reference" title="Armstrong, R. M., Fogelson, M. H., Silberberg, D. H. <strong>Familial proximal spinal muscular atrophy.</strong> Arch. Neurol. 14: 208-212, 1966.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4952447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4952447</a>] [<a href="https://doi.org/10.1001/archneur.1966.00470080092014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4952447">Armstrong et al. (1966)</a>, <a href="#41" class="mim-tip-reference" title="Zukosky, K., Meilleur, K., Traynor, B. J., Dastgir, J., Medne, L., Devoto, M., Collins, J., Rooney, J., Zou, Y., Yang, M. L., Gibbs, J. R., Meier, M., and 11 others. <strong>Association of a novel ACTA1 mutation with a dominant progressive scapuloperoneal myopathy in an extended family.</strong> JAMA Neurol. 72: 689-698, 2015. Note: Erratum: JAMA Neurol. 72: 950 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25938801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25938801</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25938801[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/10.1001/jamaneurol.2015.37" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25938801">Zukosky et al. (2015)</a> identified a heterozygous c.591C-A transversion in exon 4 of the ACTA1 gene, resulting in a glu197-to-asp (E197D) substitution. The mutation was found by a combination of linkage analysis and whole-exome sequencing and was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in the dbSNP or ExAC databases. Transfection of the mutation into COS-7 cells showed that the mutant protein had normal actin localization and did not form nemaline rods. Injection of the mutation into zebrafish embryos did not result in any morphologic abnormalities or abnormal muscle histology up to 6 days after fertilization. <a href="#41" class="mim-tip-reference" title="Zukosky, K., Meilleur, K., Traynor, B. J., Dastgir, J., Medne, L., Devoto, M., Collins, J., Rooney, J., Zou, Y., Yang, M. L., Gibbs, J. R., Meier, M., and 11 others. <strong>Association of a novel ACTA1 mutation with a dominant progressive scapuloperoneal myopathy in an extended family.</strong> JAMA Neurol. 72: 689-698, 2015. Note: Erratum: JAMA Neurol. 72: 950 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25938801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25938801</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25938801[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/10.1001/jamaneurol.2015.37" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25938801">Zukosky et al. (2015)</a> postulated that a fundamentally different pathogenic process than changes in actin cytoarchitecture or rod formation was responsible for the phenotype, such as changes in interaction or force generation, actin filament stability, or differences in the directionality of actin filament growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4952447+25938801" 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>.0019 CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, AUTOSOMAL RECESSIVE</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003152503" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003152503" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003152503</a>
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<p>In an infant with severe autosomal recessive congenital myopathy-2B (CMYO2B; <a href="/entry/620265">620265</a>) resulting in death from respiratory failure at 22 months of age, <a href="#37" class="mim-tip-reference" title="Sparrow, J. C., Nowak, K. J., Durling, H. J., Beggs, A. H., Wallgren-Pettersson, C., Romero, N., Nonaka, I., Laing, N. G. <strong>Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1).</strong> Neuromusc. Disord. 13: 519-531, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12921789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12921789</a>] [<a href="https://doi.org/10.1016/s0960-8966(03)00101-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12921789">Sparrow et al. (2003)</a> identified a homozygous mutation in exon 2 of the ACTA1 gene, resulting in an arg39-to-ter (R39X) substitution. <a href="#30" class="mim-tip-reference" title="Nowak, K. J., Sewry, C. A., Navarro, C., Squier, W., Reina, C., Ricoy, J. R., Jayawant, S. S., Childs, A. M., Dobbie, J. A., Appleton, R. E., Mountford, R. C., Walker, K. R., Clement, S., Barois, A., Muntoni, F., Romero, N. B., Laing, N. G. <strong>Nemaline myopathy caused by absence of alpha-skeletal muscle actin.</strong> Ann. Neurol. 61: 175-184, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17187373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17187373</a>] [<a href="https://doi.org/10.1002/ana.21035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17187373">Nowak et al. (2007)</a> also reported this patient, stating that he was born of consanguineous French Gypsy parents. The mutation was a c.121C-T transition, resulting in an arg41-to-ter (R41X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12921789+17187373" 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>.0020 CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1395648272 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1395648272;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/rs1395648272?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=rs1395648272" 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=rs1395648272" 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=RCV001959102 OR RCV002469442 OR RCV003228040" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001959102, RCV002469442, RCV003228040" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001959102...</a>
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<p>In a patient with severe autosomal recessive congenital myopathy-2B (CMYO2B; <a href="/entry/620265">620265</a>) resulting in death at 2 months of age, <a href="#37" class="mim-tip-reference" title="Sparrow, J. C., Nowak, K. J., Durling, H. J., Beggs, A. H., Wallgren-Pettersson, C., Romero, N., Nonaka, I., Laing, N. G. <strong>Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1).</strong> Neuromusc. Disord. 13: 519-531, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12921789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12921789</a>] [<a href="https://doi.org/10.1016/s0960-8966(03)00101-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12921789">Sparrow et al. (2003)</a> identified compound heterozygous mutations in the ACTA1 gene: a 1-bp deletion (g.2221delG), resulting in a frameshift at Ala144, and E259V (<a href="#0005">102610.0005</a>). Functional studies of the variants were not performed, but the frameshift mutation was predicted to result in a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12921789" 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 3 sibs with severe autosomal recessive congenital myopathy-2B (CMYO2B; <a href="/entry/620265">620265</a>) resulting in death in the first months of life, <a href="#37" class="mim-tip-reference" title="Sparrow, J. C., Nowak, K. J., Durling, H. J., Beggs, A. H., Wallgren-Pettersson, C., Romero, N., Nonaka, I., Laing, N. G. <strong>Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1).</strong> Neuromusc. Disord. 13: 519-531, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12921789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12921789</a>] [<a href="https://doi.org/10.1016/s0960-8966(03)00101-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12921789">Sparrow et al. (2003)</a> identified a homozygous G-to-T transversion (g.2891G-T) in the splice site junction of intron 5 and exon 6, predicted to result in a splicing abnormality and a loss of function. Each unaffected parent was heterozygous for the mutation. Functional studies of the variant were not performed, but it was predicted to have a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12921789" 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> rs759242559 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs759242559;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/rs759242559?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=rs759242559" 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=rs759242559" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 5 patients from 4 unrelated consanguineous families with autosomal recessive congenital myopathy-2B (CMYO2B; <a href="/entry/620265">620265</a>), <a href="#30" class="mim-tip-reference" title="Nowak, K. J., Sewry, C. A., Navarro, C., Squier, W., Reina, C., Ricoy, J. R., Jayawant, S. S., Childs, A. M., Dobbie, J. A., Appleton, R. E., Mountford, R. C., Walker, K. R., Clement, S., Barois, A., Muntoni, F., Romero, N. B., Laing, N. G. <strong>Nemaline myopathy caused by absence of alpha-skeletal muscle actin.</strong> Ann. Neurol. 61: 175-184, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17187373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17187373</a>] [<a href="https://doi.org/10.1002/ana.21035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17187373">Nowak et al. (2007)</a> identified a homozygous 1-bp deletion (c.541delG) in the ACTA1 gene, predicted to result in a frameshift and premature termination (Asp181fsTer10). In cases where DNA was available, the unaffected parents were heterozygous for the mutation. The families were of Pakistani and Indian British origin, and haplotype analysis was consistent with a founder effect. Skeletal muscle biopsy from some of the patients showed absence of the ACTA1 protein with increased expression of cardiac alpha-actin (ACTC1; <a href="/entry/102540">102540</a>), likely reflecting a compensatory mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17187373" 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>.0023 CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs768144106 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs768144106;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/rs768144106?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=rs768144106" 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=rs768144106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 brothers, born of consanguineous Sri Lankan parents, with autosomal recessive congenital myopathy-2B (CMYO2B; <a href="/entry/620265">620265</a>), <a href="#32" class="mim-tip-reference" title="O'Grady, G. L., Best, H. A., Oates, E. C., Kaur, S., Charlton, A., Brammah, S., Punetha, J., Kesari, A., North, K. N., Ilkovski, B., Hoffman, E. P., Clarke, N. F. <strong>Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine.</strong> Europ. J. Hum. Genet. 23: 883-886, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25182138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25182138</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25182138[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2014.169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25182138">O'Grady et al. (2015)</a> identified a homozygous c.460G-C transversion in the ACTA1 gene, resulting in a val154-to-leu (V154L) substitution in a residue near the ATP-binding pocket and hinge region. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The heterozygous parents were unaffected. Functional studies of the variant were not performed, but it was predicted to be deleterious. Immunostaining and Western blot analysis of patient muscle showed normal levels of skeletal muscle ACTA1 and upregulated expression of cardiac alpha-actin (ACTC1; <a href="/entry/102540">102540</a>). Of note, one of the brothers carried a heterozygous missense S388G variant in the SEPN1 gene. These sibs had a longer survival than most patients with recessive ACTA1 mutations: one died at age 6 years and the other was alive and ambulatory at age 34. <a href="#32" class="mim-tip-reference" title="O'Grady, G. L., Best, H. A., Oates, E. C., Kaur, S., Charlton, A., Brammah, S., Punetha, J., Kesari, A., North, K. N., Ilkovski, B., Hoffman, E. P., Clarke, N. F. <strong>Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine.</strong> Europ. J. Hum. Genet. 23: 883-886, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25182138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25182138</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25182138[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2014.169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25182138">O'Grady et al. (2015)</a> noted that previously reported patients with biallelic ACTA1 mutations had functional 'null' variants and made no ACTA1 protein. Survival after birth was attributed to persistence of cardiac ACTC1 in the skeletal muscle of these children. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25182138" 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>.0024 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, AUTOSOMAL DOMINANT</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019944 OR RCV003227607" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019944, RCV003227607" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019944...</a>
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<p>In a patient (P3) with severe infantile congenital myopathy-2C (CMYO2C; <a href="/entry/620278">620278</a>) originally reported as P3 by <a href="#13" class="mim-tip-reference" title="Goebel, H. H., Anderson, J. R., Hubner, C., Oexle, K., Warlo, I. <strong>Congenital myopathy with excess of thin myofilaments.</strong> Neuromusc. Disord. 7: 160-168, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9185179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9185179</a>] [<a href="https://doi.org/10.1016/s0960-8966(97)00441-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9185179">Goebel et al. (1997)</a>, <a href="#31" class="mim-tip-reference" title="Nowak, K. J., Wattanasirichaigoon, D., Goebel, H. H., Wilce, M., Pelin, K., Donner, K., Jacob, R. L., Hubner, C., Oexle, K., Anderson, J. R., Verity, C. M., North, K. N., and 13 others. <strong>Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.</strong> Nature Genet. 23: 208-212, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508519</a>] [<a href="https://doi.org/10.1038/13837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508519">Nowak et al. (1999)</a> identified a heterozygous G-to-T transversion in exon 4 of the ACTA1 gene, resulting in a val163-to-leu (V163L) substitution. This child was hypotonic from birth, had cardiomegaly, and died of cardiorespiratory insufficiency at age 4 months. Muscle biopsy showed a type-1 fiber predominance, subsarcolemmal masses of thin filaments, and intranuclear nemaline rods (<a href="#13" class="mim-tip-reference" title="Goebel, H. H., Anderson, J. R., Hubner, C., Oexle, K., Warlo, I. <strong>Congenital myopathy with excess of thin myofilaments.</strong> Neuromusc. Disord. 7: 160-168, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9185179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9185179</a>] [<a href="https://doi.org/10.1016/s0960-8966(97)00441-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9185179">Goebel et al., 1997</a>). The same amino acid substitution due to a different nucleotide change was observed in another patient with the disorder who was still alive at 7.5 years of age (see <a href="#0004">102610.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9185179+10508519" 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>.0025 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, AUTOSOMAL DOMINANT</strong>
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<p>In a patient (patient 17) with severe infantile congenital myopathy-2C (CMYO2C; <a href="/entry/620278">620278</a>), <a href="#31" class="mim-tip-reference" title="Nowak, K. J., Wattanasirichaigoon, D., Goebel, H. H., Wilce, M., Pelin, K., Donner, K., Jacob, R. L., Hubner, C., Oexle, K., Anderson, J. R., Verity, C. M., North, K. N., and 13 others. <strong>Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.</strong> Nature Genet. 23: 208-212, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508519</a>] [<a href="https://doi.org/10.1038/13837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508519">Nowak et al. (1999)</a> identified a heterozygous A-to-G transition in exon 6 of the ACTA1 gene, resulting in an asp286-to-gly (D286G) substitution. The patient died at 9 months of age. Parental DNA was not available for study, but the mutation likely occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508519" 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 male infant (25-1) with CMYO2C, <a href="#2" class="mim-tip-reference" title="Agrawal, P. B., Strickland, C. D., Midgett, C., Morales, A., Newburger, D. E., Poulos, M. A., Tomczak, K. K., Ryan, M. M., Iannaccone, S. T., Crawford, T. O., Laing, N. G., Beggs, A. H. <strong>Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations.</strong> Ann. Neurol. 56: 86-96, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15236405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15236405</a>] [<a href="https://doi.org/10.1002/ana.20157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15236405">Agrawal et al. (2004)</a> identified a heterozygous c.966A-G transition in the ACTA1 gene, resulting in a D286G substitution. There was no family history of the disease, and this was an isolated case, likely due to a de novo mutation (parental DNA was not available for study). The patient had hypotonia, joint contractures, femur fracture, no movement, and no respiratory effort at birth. He was tube-fed and required ventilatory support until his death at 6 days of age. Muscle biopsy showed marked fiber size variability, disruption of myofibrils, and nemaline bodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15236405" 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="Ravenscroft, G., Jackaman, C., Bringans, S., Papadimitriou, J. M., Griffiths, L. M., McNamara, E., Bakker, A. J., Davies, K. E., Laing, N. G., Nowak, K. J. <strong>Mouse models of dominant ACTA1 disease recapitulate human disease and provide insight into therapies.</strong> Brain 134: 1101-1115, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21303860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21303860</a>] [<a href="https://doi.org/10.1093/brain/awr004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21303860">Ravenscroft et al. (2011)</a> and <a href="#35" class="mim-tip-reference" title="Ravenscroft, G., Jackaman, C., Sewry, C. A., McNamara, E., Squire, S. E., Potter, A. C., Papadimitriou, J., Griffiths, L. M., Bakker, A. J., Davies, K. E., Laing, N. G., Nowak, K. J. <strong>Actin nemaline myopathy mouse reproduces disease, suggests other actin disease phenotypes and provides cautionary note on muscle transgene expression.</strong> PLoS One 6: e28699, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22174871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22174871</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22174871[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/10.1371/journal.pone.0028699" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22174871">Ravenscroft et al. (2011)</a> generated mutant mice harboring the D286G mutation. Mice expressing the mutant protein at 25% of the total alpha-actin pool were less active than controls, but had a normal life span. Mice expressing the mutant protein at 45% of the alpha-actin pool had severe muscle weakness leading to early death. Skeletal muscle showed extensive structural abnormalities similar to those observed in humans with the disorder. The findings suggested a correlation between mutant ACTA1 protein load and disease severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22174871+21303860" 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">rs2102736554 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2102736554;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=rs2102736554" 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=rs2102736554" 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=RCV002000054 OR RCV003228037 OR RCV004813198" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002000054, RCV003228037, RCV004813198" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002000054...</a>
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<p>In a patient (P4) with severe infantile congenital myopathy-2C (CMYO2C; <a href="/entry/620278">620278</a>) who died at 2 months of age, <a href="#31" class="mim-tip-reference" title="Nowak, K. J., Wattanasirichaigoon, D., Goebel, H. H., Wilce, M., Pelin, K., Donner, K., Jacob, R. L., Hubner, C., Oexle, K., Anderson, J. R., Verity, C. M., North, K. N., and 13 others. <strong>Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.</strong> Nature Genet. 23: 208-212, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508519</a>] [<a href="https://doi.org/10.1038/13837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508519">Nowak et al. (1999)</a> identified a de novo C-to-T transition in exon 2 of the ACTA1 gene, resulting in a his40-to-tyr (H40Y) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508519" 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="#28" class="mim-tip-reference" title="Nguyen, M. A., Joya, J. E., Kee, A. J., Domazetovska, A., Yang, N., Hook, J. W., Lemckert, F. A., Kettle, E., Valova, V. A., Robinson, P. J., North, K. N., Gunning, P. W., Mitchell, C. A., Hardeman, E. C. <strong>Hypertrophy and dietary tyrosine ameliorate the phenotypes of a mouse model of severe nemaline myopathy.</strong> Brain 134: 3516-3529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22067542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22067542</a>] [<a href="https://doi.org/10.1093/brain/awr274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22067542">Nguyen et al. (2011)</a> generated mutant mice carrying the ACTA1 H40Y mutation and found that they developed clinical features of severe congenital myopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22067542" 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://doi.org/10.1002/ana.20157" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000133644" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00364657" target="_blank">Full Text</a>]
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<strong>Familial proximal spinal muscular atrophy.</strong>
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[<a href="https://doi.org/10.1001/archneur.1966.00470080092014" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.21112" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/MCB.22.16.5887-5896.2002" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.21200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2008.09.005" target="_blank">Full Text</a>]
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Garcia-Angarita, N., Kirschner, J., Heiliger, M., Thirion, C., Walter, M. C., Schnittfeld-Acarlioglu, S., Albrecht, M., Muller, K., Wieczorek, D., Lochmuller, H., Krause, S.
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<strong>Severe nemaline myopathy associated with consecutive mutations E74D and H75Y on a single ACTA1 allele.</strong>
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[<a href="https://doi.org/10.1016/j.nmd.2009.05.001" target="_blank">Full Text</a>]
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Gatayama, R., Ueno, K., Nakamura, H., Yanagi, S., Ueda, H., Yamagishi, H., Yasui, S.
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<strong>Nemaline myopathy with dilated cardiomyopathy in childhood.</strong>
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[<a href="https://doi.org/10.1542/peds.2012-1139" target="_blank">Full Text</a>]
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Goebel, H. H., Anderson, J. R., Hubner, C., Oexle, K., Warlo, I.
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<strong>Congenital myopathy with excess of thin myofilaments.</strong>
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[<a href="https://doi.org/10.1016/s0960-8966(97)00441-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.81.6.1813" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/mcb.3.5.787-795.1983" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/nar/11.11.3503" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/j.1460-2075.1984.tb02049.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.nmd.2005.11.004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/320605" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddh185" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e31824e8ebe" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2004.020271" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20260" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.21059" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199205143262006" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awr274" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00401-012-1019-z" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17187373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17187373</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17187373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.21035" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/13837" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ejhg.2014.169" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature07685" target="_blank">Full Text</a>]
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Ravenscroft, G., Jackaman, C., Bringans, S., Papadimitriou, J. M., Griffiths, L. M., McNamara, E., Bakker, A. J., Davies, K. E., Laing, N. G., Nowak, K. J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21303860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21303860</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21303860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awr004" target="_blank">Full Text</a>]
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Ravenscroft, G., Jackaman, C., Sewry, C. A., McNamara, E., Squire, S. E., Potter, A. C., Papadimitriou, J., Griffiths, L. M., Bakker, A. J., Davies, K. E., Laing, N. G., Nowak, K. J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22174871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22174871</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22174871[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=22174871" 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/10.1371/journal.pone.0028699" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0960-8966(03)00101-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0888-7543(88)90123-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01874078" target="_blank">Full Text</a>]
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Wallgren-Pettersson, C., Laing, N. G.
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<strong>109th ENMC International Workshop: 5th workshop on nemaline myopathy, 11th-13th October 2002, Naarden, The Netherlands.</strong>
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Neuromusc. Disord. 13: 501-507, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12899878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12899878</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12899878" 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(03)00007-5" target="_blank">Full Text</a>]
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Zukosky, K., Meilleur, K., Traynor, B. J., Dastgir, J., Medne, L., Devoto, M., Collins, J., Rooney, J., Zou, Y., Yang, M. L., Gibbs, J. R., Meier, M., and 11 others.
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<strong>Association of a novel ACTA1 mutation with a dominant progressive scapuloperoneal myopathy in an extended family.</strong>
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JAMA Neurol. 72: 689-698, 2015. Note: Erratum: JAMA Neurol. 72: 950 only, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25938801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25938801</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25938801[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=25938801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/jamaneurol.2015.37" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 03/01/2023
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Cassandra L. Kniffin - updated : 3/11/2016<br>Cassandra L. Kniffin - updated : 4/30/2014<br>Cassandra L. Kniffin - updated : 5/6/2013<br>Cassandra L. Kniffin - updated : 11/23/2009<br>Cassandra L. Kniffin - updated : 10/12/2009<br>Ada Hamosh - updated : 3/4/2009<br>Cassandra L. Kniffin - updated : 3/21/2008<br>Cassandra L. Kniffin - updated : 12/28/2007<br>George E. Tiller - updated : 1/16/2007<br>Cassandra L. Kniffin - updated : 7/1/2005<br>Cassandra L. Kniffin - reorganized : 4/7/2005<br>Cassandra L. Kniffin - updated : 4/4/2005<br>Victor A. McKusick - updated : 1/18/2005<br>Cassandra L. Kniffin - updated : 12/10/2004<br>Patricia A. Hartz - updated : 11/5/2002<br>Victor A. McKusick - updated : 6/20/2001<br>Victor A. McKusick - updated : 9/28/1999
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carol : 03/10/2023<br>ckniffin : 03/08/2023<br>carol : 03/08/2023<br>carol : 03/06/2023<br>ckniffin : 03/01/2023<br>alopez : 02/20/2023<br>carol : 04/02/2021<br>carol : 03/11/2016<br>ckniffin : 3/11/2016<br>ckniffin : 3/11/2016<br>carol : 8/20/2015<br>mcolton : 8/19/2015<br>carol : 1/14/2015<br>carol : 6/18/2014<br>carol : 5/1/2014<br>ckniffin : 4/30/2014<br>alopez : 5/10/2013<br>ckniffin : 5/6/2013<br>mgross : 11/20/2012<br>terry : 10/26/2012<br>alopez : 12/11/2009<br>wwang : 12/10/2009<br>ckniffin : 11/23/2009<br>wwang : 11/23/2009<br>ckniffin : 10/12/2009<br>ckniffin : 9/28/2009<br>carol : 9/17/2009<br>alopez : 3/4/2009<br>terry : 3/4/2009<br>terry : 7/30/2008<br>terry : 7/30/2008<br>wwang : 3/31/2008<br>ckniffin : 3/21/2008<br>wwang : 1/14/2008<br>ckniffin : 12/28/2007<br>terry : 12/17/2007<br>carol : 9/5/2007<br>wwang : 1/26/2007<br>wwang : 1/23/2007<br>terry : 1/16/2007<br>ckniffin : 3/14/2006<br>carol : 7/13/2005<br>carol : 7/13/2005<br>ckniffin : 7/1/2005<br>carol : 4/8/2005<br>carol : 4/7/2005<br>ckniffin : 4/4/2005<br>tkritzer : 1/18/2005<br>tkritzer : 12/21/2004<br>ckniffin : 12/10/2004<br>ckniffin : 7/21/2004<br>joanna : 3/17/2004<br>carol : 7/9/2003<br>mgross : 11/5/2002<br>cwells : 7/2/2001<br>cwells : 6/25/2001<br>terry : 6/20/2001<br>carol : 8/9/2000<br>alopez : 11/15/1999<br>alopez : 11/5/1999<br>alopez : 10/11/1999<br>alopez : 10/11/1999<br>alopez : 9/30/1999<br>terry : 9/28/1999<br>dkim : 12/18/1998<br>mark : 3/20/1997<br>terry : 6/16/1995<br>carol : 5/27/1994<br>carol : 2/3/1993<br>carol : 5/28/1992<br>supermim : 3/16/1992<br>carol : 7/3/1991
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<h3>
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<span class="mim-font">
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<strong>*</strong> 102610
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</h3>
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<h3>
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<span class="mim-font">
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ACTIN, ALPHA-1, SKELETAL MUSCLE; ACTA1
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</span>
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</h3>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<h4>
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<span class="mim-font">
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ASMA
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</h4>
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</div>
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<div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ACTA1</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1217226000, 702349003;
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</span>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 1q42.13
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:229,431,245-229,434,094 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</thead>
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<tbody>
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<tr>
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<td rowspan="4">
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<span class="mim-font">
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1q42.13
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</span>
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</td>
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<td>
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<span class="mim-font">
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?Myopathy, scapulohumeroperoneal
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</span>
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</td>
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<td>
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<span class="mim-font">
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616852
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Congenital myopathy 2A, typical, autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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161800
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Congenital myopathy 2B, severe infantile, autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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620265
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<span class="mim-font">
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Congenital myopathy 2C, severe infantile, autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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620278
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</tr>
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</tbody>
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</table>
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</div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The ACTA1 gene encodes skeletal muscle alpha-actin, the principal actin isoform in adult skeletal muscle, which forms the core of the thin filament of the sarcomere where it interacts with a variety of proteins to produce the force for muscle contraction (Laing et al., 2009). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using chick beta-actin cDNA as probe, Gunning et al. (1983) cloned alpha-actin from a human muscle cDNA library. They also cloned beta-actin (ACTB; 102630) and gamma-actin (ACTG1; 102560) from a fibroblast cDNA library. Sequence analysis of the 5-prime ends revealed that alpha-actin starts with both a methionine and a cysteine not found in the mature protein. They concluded that, since no known actin proteins start with a cysteine, there must be posttranslational removal of cysteine in addition to methionine in alpha-actin synthesis, but not in beta- or gamma-actin synthesis. </p><p>Hanauer et al. (1983) cloned alpha-actin from a cDNA library developed from quadriceps muscle mRNA using mouse skeletal alpha-actin cDNA as probe. The sequence is characterized by a high GC content (61.6%). Hanauer et al. (1983) noted conservation of the amino acid sequence between human and rat actins, and a comparison of the coding sequences revealed 61% silent changes. </p><p>Taylor et al. (1988) cloned alpha-actin and determined that the primary transcript encodes a 377-amino acid protein, including the first 2 residues, which are absent from the mature protein. They noted that the same 2 codons precede the codon specifying the N-terminal amino acid in the homologous genes of rat, mouse, chicken, Drosophila, and sea urchin. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Taylor et al. (1988) determined that the alpha-actin gene contains 7 exons. There is a large intron in the 5-prime untranslated region that is characteristic of actins and many muscle-specific genes. The promoter contains a TATA box and 3 conserved CArG boxes; Taylor et al. (1988) showed that these were activated by muscle cell differentiation in a rat myogenic cell line. The 3-prime untranslated region contains a GC-rich region as well as a putative poly(A) addition signal. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By use of a cDNA probe in somatic cell hybrids, Hanauer et al. (1984) assigned the gene for the alpha chain of skeletal muscle actin to chromosome 1. Actin sequences were found at high stringency also at 2p23-qter and 3pter-q21. Under conditions of low or medium stringency, actin sequences were demonstrated on the X (p11-p12) and Y chromosomes. The actin genes assigned to the X and Y chromosomes (Heilig et al., 1984; Koenig et al., 1985) appear to be intronless pseudogenes. </p><p>Using a cDNA copy of the 3-prime untranslated region of the human skeletal alpha-actin gene, Shows et al. (1984) mapped the gene to 1p12-qter. This gene and that for cardiac alpha-actin (ACTC; 102540) are coexpressed in both human skeletal muscle and heart. Coexpression is not a function of linkage; the loci are on separate chromosomes: 1p21-qter and 15q11-qter, respectively (Gunning et al., 1984). Using a panel of somatic cell hybrids, Alonso et al. (1993) confirmed the localization of the ACTA1 gene on human chromosome 1. Akkari et al. (1994) narrowed the assignment of the ACTA1 gene to 1q42 by fluorescence in situ hybridization. Also by fluorescence in situ hybridization, Ueyama et al. (1995) mapped the gene to 1q42.1. </p><p>On the basis of analysis of mouse/hamster somatic cell hybrids segregating mouse chromosomes, Czosnek et al. (1982) concluded that the skeletal actin gene is located on mouse chromosome 3. However, Alonso et al. (1993) found by PCR analysis of a microsatellite in an interspecific backcross that the alpha-actin gene is closely linked to tyrosine aminotransferase and adenine phosphoribosyltransferase on mouse chromosome 8. The Acta1 gene is situated between Tat and Aprt; the human homologs TAT (613018) and APRT (102600) are on human chromosome 16. Abonia et al. (1993) likewise mapped the Acta1 gene to mouse chromosome 8 by segregation of RFLVs in 2 interspecific backcross sets and in 4 recombinant inbred mouse sets. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Actin makes up 10 to 20% of cellular protein and has vital roles in cell integrity, structure, and motility. It is highly conserved throughout evolution. Its function depends on the balance between monomeric (globular) G-actin (42 kD) and (filamentous) F-actin, a linear polymer of G-actin subunits. Among the cytosolic actin-binding proteins, 3 appear to be of primary importance in limiting polymerization: profilin (176590, 176610), thymosin beta-4 (300159), and gelsolin (GSN; 137350). The existence of intracellular actin-binding proteins allows the concentration of G-actin to be maintained substantially above the threshold at which polymerization and the formation of filaments would normally occur. When released into the extracellular space, actin, which otherwise is known to have a pathologic effect, is bound by gelsolin and by the Gc protein (GC; 139200). This is the so-called extracellular actin-scavenger system (Lee and Galbraith, 1992). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Oda et al. (2009) created a model of F-actin using x-ray fiber diffraction intensities obtained from well oriented sols of rabbit skeletal muscle F-actin to 3.3 angstroms in the radial direction and 5.6 angstroms along the equator. The authors showed that the G- to F-actin conformational transition is a simple relative rotation of the 2 major domains by about 20 degrees. As a result of the domain rotation, the actin molecule in the filament is flat. The flat form is essential for the formation of stable, helical F-actin. Oda et al. (2009) concluded that their F-actin structure model provided a basis for understanding actin polymerization as well as its molecular interactions with actin-binding proteins. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Mutations in the ACTA1 gene cause congenital myopathy that varies clinically, ranging from death in infancy to adult survival. Most patients (90%) carry heterozygous mutations, the majority of which occur de novo and encode missense variants that likely act in a dominant-negative manner and cause typical congenital myopathy-2A (CMYO2A; 161800). Most patients with a heterozygous mutation have a typical presentation, but some have severe infantile congenital myopathy-2C (CMYO2C; 620278). Rare families who demonstrate autosomal dominant transmission of the disorder are less severely affected, since affected individuals survive to reproductive age. Patients with biallelic ACTA1 mutations (10%) showing autosomal recessive inheritance (CMYO2B; 620265) have a severe phenotype, often with loss of expression of the ACTA1 protein due to frameshift or nonsense mutations. These likely act as loss-of-function alleles since carrier parents are unaffected (review by Sparrow et al., 2003). </p><p>By immunoblot analysis, Ilkovski et al. (2004) showed that muscle from patients with ACTA1 mutations had increased levels of gamma-filamin (FLNC; 102565), myotilin (TTID; 604103), desmin (DES; 125660), and alpha-actinin (ACTN1; 102575), consistent with accumulation of Z line-derived nemaline bodies. Intranuclear aggregates were observed upon transfecting myoblasts with V163L (102610.0004)-null-, V163L (102610.0024)-null-, V163M (102610.0014)-null-, and R183G-null-acting transgene constructs, and modeling showed these residues to be adjacent to the nuclear export signal of actin. Transfection studies further showed significant alterations in the ability of V136L and R183G actin mutants to polymerize and contribute to insoluble acting filaments. In vitro studies suggested that abnormal folding, altered polymerization, and aggregation of mutant actin isoforms may be common properties of NM ACTA1 mutants. A combination of these effects may contribute to the common pathologic hallmarks of NM, namely intranuclear and cytoplasmic rod formation, accumulation of thin filaments, and myofibrillar disorganization. </p><p>Laing et al. (2009) provided a review of mutations and polymorphisms in the ACTA1 gene and described 85 novel mutations. Mutations are spread throughout the 6 coding exons, and there are no mutation hotspots. Irrespective of the pathology, ACTA1 mutations usually result in a clinically severe myopathy, with many patients dying in the first years of life. Most mutations are dominant, and most of these are de novo. About 10% mutations are recessive and functionally null. </p><p><strong><em>Congenital Myopathy 2A, Typical, Autosomal Dominant</em></strong></p><p>
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In 2 unrelated patients (P7 and P10) with autosomal dominant typical congenital myopathy-2A (CMYO2A; 161800), Nowak et al. (1999) identified heterozygous missense mutations in the ACTA1 gene (M132V and G182D). Clinical details were limited, but these patients were classified as having a milder disease; they were alive at 3 and 39 years of age. </p><p>In 2 unrelated patients (P3 and P4) with a typical form of CMYO2A, Ilkovski et al. (2001) identified 2 different heterozygous missense mutations in the ACTA1 gene: P3 carried a de novo G286C mutation (102610.0007), whereas P4 carried a heterozygous I136M mutation (102610.0008) that likely occurred de novo since he had no family history of a similar disorder. </p><p>In a Japanese boy with CMYO2A who died of cardiomyopathy at age 9.5 years, Gatayama et al. (2013) identified a heterozygous missense mutation in the ACTA1 gene (W358C; 102610.0017). Gatayama et al. (2013) noted that childhood-onset dilated cardiomyopathy is rare in patients with ACTA1 mutations. </p><p>In affected members of 2 families with CMYO2A manifest as 'core only' myopathy, Kaindl et al. (2004) identified heterozygous missense mutations in the ACTA1 gene (102610.0009-102610.0010). Patients of both families showed a mild and nonprogressive course of skeletal muscle weakness. The myopathy was accompanied by adult-onset hypertrophic cardiomyopathy and respiratory failure in 1 family. Histologically, cores were detected in the muscle fibers of at least 1 patient in each family, whereas nemaline bodies or rods and actin filament accumulation were absent. Kaindl et al. (2004) concluded that their findings established mutation in the ACTA1 gene as a cause of dominant congenital myopathy with cores and delineated another clinicopathologic phenotype for ACTA1. </p><p>In 4 patients from a 3-generation family with autosomal dominant CMYO2A, Hutchinson et al. (2006) identified a heterozygous mutation in the ACTA1 gene (V163M; 102610.0014) that segregated with the disorder. </p><p>Sparrow et al. (2003) reported a 42-year-old patient classified as having a 'typical' form of CMYO2A who carried a heterozygous H40Y mutation (see 102610.0026). He had no family history of the disorder. Further clinical details were not provided. </p><p><strong><em>Congenital Myopathy 2C, Severe Infantile, Autosomal Dominant</em></strong></p><p>
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In 3 patients with severe infantile autosomal dominant congenital myopathy-2C (CMYO2C; 620278) reported by Goebel et al. (1997), Nowak et al. (1999) identified heterozygous missense mutations in the ACTA1 gene (102610.0003; 102610.0004; 102610.0024). The mutations were demonstrated to occur de novo in patients 1 and 2; parental DNA from patient 3 was not available. Nowak et al. (1999) also identified heterozygous, mostly de novo, missense mutations in the ACTA1 gene (see, e.g., 102610.0025 and 102610.0026), in 7 additional patients with severe congenital myopathy. Clinical details were limited, but most of the patients died in infancy. One patient (P10) classified as severe was still alive at 10 years of age. The missense mutations in ACTA1 were distributed throughout all 6 coding exons and some involved known functional domains of actin. </p><p>In 3 unrelated patients with severe infantile CMYO2C, Laing et al. (2004) identified 3 different heterozygous missense mutations in the ACTA1 gene (102610.0011-102610.0013). Parental DNA was not available for any of the cases, but there was no family history of myopathy, suggesting that the mutations occurred de novo. </p><p>In a male infant (25-1) with severe infantile CMYO2C, Agrawal et al. (2004) identified a heterozygous missense mutation in the ACTA1 gene (D286G; 102610.0025). There was no family history of the disease, and this was an isolated case, likely due to a de novo mutation (parental DNA was not available for study). </p><p>In a male infant with severe infantile CMYO2C, Garcia-Angarita et al. (2009) identified heterozygosity for an allele carrying 2 de novo mutations in cis affecting adjacent nucleotides in the ACTA1 gene (E74D and H75Y; 102610.0015). Neither unaffected parent carried either of the mutations. </p><p>In a patient with severe infantile CMYO2C, Jain et al. (2012) identified a de novo heterozygous activating mutation in the ACTA1 gene (K328N; 102610.0016). </p><p><strong><em>Congenital Myopathy 2B, Autosomal Recessive</em></strong></p><p>
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In 2 infant sibs (family 5) with autosomal recessive congenital myopathy-2B (CMYO2B; 620265) leading to death at 5 and 19 days of age, Nowak et al. (1999) identified compound heterozygous missense mutations in the ACTA1 gene (L94P; 102610.0001 and E259V; 102610.0005). Each of the mutations was inherited from an unaffected parent, consistent with autosomal recessive inheritance. </p><p>In 5 patients from 3 unrelated families with CMYO2B resulting in death in infancy, Sparrow et al. (2003) identified homozygous or compound heterozygous mutations in the ACTA1 gene (102610.0005; 102610.0019-102610.0021). All patients carried at least 1 nonsense or frameshift mutation. In 1 family, the unaffected parents were heterozygous for the mutation. Functional studies of the variants were not performed, but all were predicted to have a loss-of-function effect. Biallelic ACTA1 mutations were present in only a minority of the large patient cohort studied. </p><p>In 7 patients from 6 unrelated consanguineous families with CMYO2B, Nowak et al. (2007) identified homozygous frameshift mutations in the ACTA1 gene (see, e.g., c.541delG, 102610.0022). In cases where DNA was available, the unaffected parents were heterozygous for the mutation. One of the patients had previously been reported by Sparrow et al. (2003). Four families were of Pakistani and Indian British origin, and haplotype analysis was consistent with a founder effect for the c.541delG mutation. Five of the children died of respiratory failure in infancy, whereas 1 was alive at 4.5 years of age and another at 2.5 years of age. Skeletal muscle biopsy from some of the patients showed absence of the ACTA1 protein with increased expression of cardiac alpha-actin (ACTC1; 102540), likely reflecting a compensatory mechanism. </p><p>In 2 brothers, born of consanguineous Sri Lankan parents, with CMYO2B, O'Grady et al. (2015) identified a homozygous missense mutation in the ACTA1 gene (V154L; 102610.0023). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The heterozygous parents were unaffected. Functional studies of the variant were not performed, but it was predicted to be deleterious. Immunostaining and Western blot analysis of patient muscle showed normal levels of skeletal muscle ACTA1 and upregulated expression of cardiac alpha-actin (ACTC1; 102540). O'Grady et al. (2015) noted that previously reported patients with biallelic ACTA1 mutations had functional 'null' variants and made no ACTA1 protein. Survival after birth was attributed to persistence of cardiac ACTC1 in the skeletal muscle of these children. </p><p><strong><em>Scapulohumeroperoneal Myopathy</em></strong></p><p>
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In affected members of a large family with scapulohumeroperoneal myopathy (SHPM; 616852), Zukosky et al. (2015) identified a heterozygous missense mutation in the ACTA1 gene (E197D; 102610.0018). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ilkovski et al. (2001) evaluated a new series of 35 patients with nemaline myopathy. They identified 5 unrelated patients with a missense mutation in the ACTA1 gene (see, e.g., 102610.0002; 102610.0006-102610.0008), which suggested that mutations in this gene account for the disease in approximately 15% of patients. All 5 mutations were novel, de novo dominant mutations. One proband subsequently had 2 affected children, a result consistent with autosomal dominant transmission. The 7 patients exhibited marked clinical variability, ranging from severe congenital weakness, with death from respiratory failure during the first year of life, to a mild childhood-onset myopathy with survival into adulthood. There was marked variation in both age at onset and clinical severity in the 3 affected members of 1 family. Pathologic features shared by the patients included abnormal fiber-type differentiation, glycogen accumulation, myofibrillar disruption, and 'whorling' of actin thin filaments. The percentage of fibers with rods did not correlate with clinical severity; however, the severe, lethal phenotype was associated with both severe, generalized disorganization of sarcomeric structure and abnormal localization of sarcomeric actin. The marked variability in clinical phenotype among patients with different mutations in ACTA1 suggested that both the site of the mutation and the nature of the amino acid change have differential effects on thin-filament formation and protein-protein interactions. The intrafamilial variability suggested that alpha-actin genotype is not the sole determinant of phenotype, however. </p><p>In a report of the 2002 conference on nemaline myopathy, Wallgren-Pettersson and Laing (2003) stated that 59 mutations in the ACTA1 gene had been identified. Ninety percent of families had a diagnosis of nemaline myopathy, 11% had a diagnosis of actin myopathy, and 11% had a diagnosis of intranuclear rod myopathy. The findings underscored the phenotypic variability caused by mutations in the ACTA1 gene. Among the patients with nemaline myopathy, the severe form was the most common, but mild and typical forms were also represented, and some patients had unusual associated features. Most cases were sporadic, but there were examples of both autosomal dominant and autosomal recessive inheritance. No obvious genotype/phenotype correlations were observed. </p><p>Agrawal et al. (2004) found 29 ACTA1 mutations in 28 of 109 (approximately 25%) patients with nemaline myopathy. Of the whole group, ACTA1 mutations were responsible for 14 of 25 (56%) of the severe congenital cases. Ten patients with ACTA1 mutations had 'typical disease,' defined as onset in infancy or childhood with delayed milestones and survival into adulthood, and 1 patient had adult onset. Four of the families with ACTA1 mutations showed autosomal dominant inheritance; 1 family showed autosomal recessive inheritance; 2 families suggested incomplete penetrance; the remaining 21 patients had sporadic disease with heterozygous mutations. Muscle biopsy at 5 weeks of age from the patient with biallelic ACTA1 mutations with severe disease showed intense staining for cardiac alpha-actin. Agrawal et al. (2004) emphasized the phenotypic heterogeneity among patients with ACTA1 mutations. </p><p>Feng and Marston (2009) provided a review of ACTA1 mutations and concluded that there are no obvious functional or biochemical patterns seen in mutations that result in the same pathology. Although some mutations are predicted or have been shown to interfere with N-terminal processing, posttranslational folding, polymerization, or interaction with other proteins, there is often disagreement in studies between the structure and function of mutant proteins. There are no clear genotype/phenotype correlations. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By homologous recombination, Crawford et al. (2002) disrupted the skeletal actin gene in mice. Newborn skeletal muscles from null mice were similar to those of wildtype mice in size, fiber type, and ultrastructural organization. Both hemizygous and homozygous null animals showed an increase in cardiac and vascular actin (102620) mRNA in skeletal muscle, with no skeletal actin mRNA present in null mice. The null animals appeared normal at birth and could breathe, walk, and suckle. However, the compensation provided by expression of vascular and cardiac actins was insufficient to support adequate skeletal muscle growth and/or function. Within 4 days, all null mice showed a markedly lower body weight than normal littermates, and some developed scoliosis. All mice lacking skeletal actin died in the early neonatal period. They showed a loss of glycogen and reduced brown fat, consistent with malnutrition leading to death. </p><p>Ravenscroft et al. (2011) and Ravenscroft et al. (2011) generated mutant mice harboring a D286G mutation in the ACTA1 gene (102610.0025). Mice expressing the mutant protein at 25% of the total alpha-actin pool were less active than controls, but had a normal life span. Mice expressing the mutant protein at 45% of the alpha-actin pool had severe muscle weakness leading to early death. Skeletal muscle showed extensive structural abnormalities similar to those observed in humans with the disorder. The findings suggested a correlation between mutant ACTA1 protein load and disease severity. </p><p>Nguyen et al. (2011) generated mutant mice carrying the ACTA1 H40Y mutation (102610.0026) and found that they developed clinical features of severe congenital myopathy. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>26 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, 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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ACTA1, LEU94PRO
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<br />
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SNP: rs121909519,
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ClinVar: RCV000019941, RCV001731311, RCV003151730
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 infant sibs (family 5) with autosomal recessive congenital myopathy-2B (CMYO2B; 620265) leading to death at 5 and 19 days of age, Nowak et al. (1999) identified compound heterozygous missense mutations in the ACTA1 gene: a T-to-C transition in exon 3, resulting in a leu94-to-pro (L94P) substitution, inherited from the unaffected father, and an A-to-G transition in exon 5, resulting in a glu259-to-val (E259V; 102610.0005) substitution, inherited from the unaffected mother. </p><p>Sparrow et al. (2003) noted that both the L94P and E259V mutations are buried residues that likely affect the internal packing of actin and may thus disrupt the structure of the protein. These mutant proteins may be so significantly impaired that they did not cause a dominant-negative effect in the carrier parents. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0002 CONGENITAL MYOPATHY 2A, TYPICAL, 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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ACTA1, ASN115SER
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<br />
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SNP: rs121909520,
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ClinVar: RCV000019942, RCV001090700
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a mother and her 2 children (family 6) with autosomal dominant congenital myopathy-2A (CMYO2A; 161800), Nowak et al. (1999) identified a heterozygous A-to-G transition in exon 3 of the ACTA1 gene, resulting in an asn115-to-ser (N115S) substitution. </p><p>Ilkovski et al. (2001) reported a 35-year-old woman (family A, patient 5) with the N115S mutation. She had typical congenital myopathy with neonatal onset of feeding difficulties, respiratory tract infections, hypotonia, facial diplegia, and proximal muscle weakness in the first weeks of life. Her disease was very slowly progressive or nonprogressive. She had 2 affected children with the mutation, a daughter (patient 6) aged 19 years and a son (patient 7) aged 4 years at the time of the report. The daughter had onset of disease at age 6 years, with mild proximal weakness and frequent falls, and developed progressive scoliosis requiring surgery at age 14 years. The son had features of congenital myopathy in infancy and showed nonprogressive weakness with improvement of mild nocturnal hypoventilation over time. The intrafamilial variability observed suggested that the ACTA1 genotype is not the sole determinant of the phenotype and that modifying factors, both genetic and stochastic influence the clinical presentation. </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 2C, SEVERE INFANTILE, 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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ACTA1, GLY15ARG
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<br />
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SNP: rs121909521,
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ClinVar: RCV002510771, RCV003151731, RCV005016281
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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 (P1) with severe infantile congenital myopathy-2C (CMYO2C; 620278), previously reported as patient 2 by Goebel et al. (1997), Nowak et al. (1999) identified a de novo heterozygous G-to-C transversion in exon 2 of the ACTA1 gene, resulting in a gly15-to-arg (G15R) substitution. The patient was delivered by emergency Cesarean section at 37 weeks' gestation due to maternal polyhydramnios, had severe hypotonia necessitating ventilatory support, and died at age 3 months. Postmortem examination excluded spinal muscular atrophy. Muscle biopsy showed large areas of sarcoplasm devoid of normal myofibrils and mitochondria, and replaced with dense masses of thin filaments that were immunoreactive to actin. Central cores, obvious rods, ragged-red fibers, and necrosis were absent. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, 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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ACTA1, VAL163LEU, G-C
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<br />
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SNP: rs121909522,
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ClinVar: RCV000019944, RCV003227607
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 7.5-year-old patient (P2) with severe infantile congenital myopathy-2C (CMYO2C; 620278) originally reported as P1 by Goebel et al. (1997), Nowak et al. (1999) identified a de novo heterozygous G-to-C transversion in exon 4 of the ACTA1 gene, resulting in a val163-to-leu (V163L) substitution. The patient was hypotonic from birth, had atrophy of the pelvic and shoulder girdle muscles, a high-arched palate, and cardiomyopathy. At 4.5 years, he could walk and sit unaided. Muscle biopsy showed subsarcolemmal regions that were devoid of oxidative activity and filled with actin-immunopositive densely packed thin filaments. Intranuclear nemaline rods were also present (Goebel et al., 1997). The same amino acid substitution due to a different nucleotide change was observed in another patient with the disorder who died at 4 months of age (see 102610.0024). </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>.0005 CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
|
ACTA1, GLU259VAL
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<br />
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|
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SNP: rs121909523,
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gnomAD: rs121909523,
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ClinVar: RCV000019945, RCV001270724, RCV001804741, RCV002504811, RCV003151732
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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>For discussion of the glu259-to-val (E259V) mutation in the ACTA1 gene that was found in compound heterozygous state in 2 infant sibs with fatal autosomal recessive congenital myopathy-2B (CMYO2B; 620265) by Nowak et al. (1999), see 102610.0001. </p><p>In a patient with CMYO2B resulting in death at 2 months of age, Sparrow et al. (2003) identified compound heterozygous mutations in the ACTA1 gene: E259V and a 1-bp deletion (102610.0020). </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>.0006 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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ACTA1, ILE357LEU
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<br />
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|
|
SNP: rs121909524,
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ClinVar: RCV003151733
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient (P1) with severe infantile congenital myopathy-2C (CMYO2C; 620278), who died at the age of 6 months of respiratory failure, Ilkovski et al. (2001) identified a de novo heterozygous A-to-C transversion in the ACTA1 gene, resulting in an ile357-to-leu (I357L) substitution. This female infant was born with hypotonia, minimal spontaneous movements, and fractures of both femurs. She did not achieve motor milestones and required a feeding tube. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0007 CONGENITAL MYOPATHY 2A, TYPICAL, 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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ACTA1, GLY268CYS
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<br />
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SNP: rs121909525,
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ClinVar: RCV000019947
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 10-year-old boy (P3) with childhood onset of congenital myopathy-2A (CMYO2A1; 161800), Ilkovski et al. (2001) identified a de novo heterozygous G-to-T transversion in the ACTA1 gene, resulting in a gly268-to-cys (G268C) substitution. The patient had no problems during the neonatal period, but presented at age 5 years with inability to run and frequent falls. He did not have feeding or respiratory difficulties. At age 10, he had slowly progressive weakness with involvement of proximal muscles. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0008 CONGENITAL MYOPATHY 2A, TYPICAL, 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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ACTA1, ILE136MET
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<br />
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SNP: rs121909526,
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ClinVar: RCV000019948, RCV004813045
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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 45-year-old man (P4) with typical congenital myopathy-2A (CMYO2A; 161800), Ilkovski et al. (2001) identified a de novo heterozygous C-to-G transversion in the ACTA1 gene, resulting in an ile136-to-met (I136M) substitution. Although he had infantile onset and delayed motor development, his weakness was nonprogressive, and he was physically active as an adult and regularly engaged in long-distance competitive cycling. He had a weak cough and frequent respiratory infections. Echocardiography was normal. Nowak et al. (2013) noted that the muscle fibers were hypertrophied in the patient reported by Ilkovski et al. (2001), suggesting that both exercise and muscle fiber hypertrophy may be beneficial for patients with certain ACTA1 mutations. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0009 CONGENITAL MYOPATHY 2A, TYPICAL, 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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ACTA1, ASP1TYR
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<br />
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SNP: rs121909527,
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ClinVar: RCV003148622
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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 11 affected members in 4 generations and 8 separate sibships of a German family with autosomal dominant congenital myopathy-2A (CMYO2A; 161800), Kaindl et al. (2004) identified a heterozygous c.110G-T transversion in exon 2 of the ACTA1 gene, resulting in an asp1-to-tyr (D1Y) substitution at a highly conserved residue in the mature protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0010 CONGENITAL MYOPATHY 2A, TYPICAL, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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ACTA1, GLU334ALA
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|
<br />
|
|
|
|
SNP: rs121909528,
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|
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|
ClinVar: RCV003148623
|
|
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|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>In 5 affected members spanning 3 generations of a Chinese family with autosomal dominant congenital myopathy-2A (CMYO2A; 161800), Kaindl et al. (2004) identified a heterozygous c.1110A-C transversion in the ACTA1 gene, resulting in a glu334-to-ala (E334A) substitution at a conserved residue. Two members of the family developed adult-onset hypertrophic cardiomyopathy and respiratory insufficiency. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0011 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, 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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ACTA1, ASP292VAL
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<br />
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SNP: rs121909529,
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ClinVar: RCV000019951, RCV001028007, RCV003151734
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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 Australian patient (P1) with severe infantile congenital myopathy-2C (CMYO2C; 620278), Laing et al. (2004) identified a heterozygous A-to-T transversion in exon 6 of the ACTA1 gene, resulting in an asp292-to-val (D292V) substitution in a region that forms part of the monomeric actin surface that would be exposed in the F-actin polymer. The mutation was not identified in more than 300 control chromosomes. There was no family history of the disorder and parental DNA was not available, but the authors hypothesized that the mutation occurred de novo. The patient died of respiratory failure at 3.5 years of age. Muscle biopsy showed congenital fiber-type disproportion (CFTD). </p><p>Using mass spectrometry and gel electrophoresis to examine patient skeletal muscle, Clarke et al. (2007) determined that D292V-actin accounted for 50% of total sarcomeric actin. In vitro assays showed that D292V-actin resulted in decreased motility due to abnormal interactions between actin and tropomyosin, with tropomyosin stabilized in the 'off' position. Cellular transfection studies demonstrated that the mutant protein incorporated into actin filaments and did not result in increased actin aggregation or disruption of the sarcomere. Clarke et al. (2007) concluded that ACTA1 mutations resulting in congenital myopathy cause weakness by interfering with sarcomeric function rather than structure. </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 2C, SEVERE INFANTILE, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
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ACTA1, LEU221PRO
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<br />
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|
|
SNP: rs121909530,
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|
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|
|
ClinVar: RCV000019952, RCV001851954, RCV003151735
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In a Japanese patient (P2) with severe infantile congenital myopathy-2C (CMYO2C; 620278), Laing et al. (2004) identified a heterozygous T-to-C transition in exon 5 of the ACTA1 gene, resulting in a leu221-to-pro (L221P) substitution in a region that forms part of the monomeric actin surface that would be exposed in the F-actin polymer. The mutation was not identified in more than 300 control chromosomes. There was no family history of the disorder and parental DNA was not available, but the authors hypothesized that the mutation occurred de novo. The patient required continuous ventilation and tube feeding; she died at 1.1 years of age. Muscle biopsy showed congenital fiber-type disproportion (CFTD). </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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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
ACTA1, PRO332SER
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<br />
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|
|
SNP: rs121909531,
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|
|
ClinVar: RCV000019953, RCV002513127, RCV003151736, RCV004767013
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-year-old Japanese patient (P3) with severe infantile congenital myopathy-2C (CMYO2C; 620278). Laing et al. (2004) identified a heterozygous C-to-T transition in exon 7 of the ACTA1 gene, resulting in a pro332-to-ser (P332S) substitution in a region that forms part of the monomeric actin surface that would be exposed in the F-actin polymer. The mutation was not identified in more than 300 control chromosomes. There was no family history of the disorder and parental DNA was not available, but the authors hypothesized that the mutation occurred de novo. The patient had severe hypotonia with no head control and was bedridden with a feeding tube and continuous ventilation by tracheostomy. Muscle biopsy showed congenital fiber-type disproportion (CFTD). </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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|
</div>
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|
|
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|
|
<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 CONGENITAL MYOPATHY 2A, TYPICAL, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACTA1, VAL163MET, G-A
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs121909522,
|
|
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|
|
|
|
ClinVar: RCV000019954, RCV001781286, RCV004813046
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with autosomal dominant typical congenital myopathy-2A (CMYO2A; 161800), Hutchinson et al. (2006) identified a heterozygous G-to-A transition in exon 4 of the ACTA1 gene, resulting in a val163-to-met (V163M) substitution. Other mutations have been reported in this codon (V163L; 102610.0004 and 102610.0024). Clinical features included hypotonia early in life, limb muscle weakness and atrophy, tall thin face, and high-arched palate. Skeletal muscle biopsies varied but tended to show intranuclear rods within myofibers. </p><p>By electron microscopy of muscle samples from patients reported by Hutchinson et al. (2006), Domazetovska et al. (2007) found mostly normal sarcomere structure with small areas of sarcomeric disarray. Immunohistochemical studies showed that the V163M mutation resulted in sequestration of sarcomeric and Z line proteins into intranuclear aggregates. There was some evidence of muscle regeneration, suggesting a compensatory effect. Cell culture studies showed similar findings. Transgenic V161M-mutant Drosophila were flightless with sarcomeric disorganization and altered Z line structure in muscle. The findings provided a mechanism for muscle weakness. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACTA1, GLU74ASP AND HIS75TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606626, rs267606627,
|
|
|
|
|
|
|
|
ClinVar: RCV003151737
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male infant with severe infantile congenital myopathy-2C (CMYO2C; 620278), Garcia-Angarita et al. (2009) identified heterozygosity for an allele carrying 2 de novo mutations in cis affecting adjacent nucleotides in exon 3 of the ACTA1 gene: a c.222G-T transversion, resulting in a glu74-to-asp (E74D) substitution, and a c.223C-T transition, resulting in a his75-to-tyr (H75Y) substitution. Neither unaffected parent carried either of the mutations; germline mosaicism could not be ruled out. Garcia-Angarita et al. (2009) noted that each mutation had previously been reported in isolation as causative for congenital myopathy, but had never been reported together on the same allele. The phenotype in their patient was severe, including decreased movements in utero, breech presentation, and congenital contractures. After birth, there was severe hypotonia, lack of spontaneous movements, and death from respiratory failure at age 2 months. Skeletal muscle biopsy showed myofibrillar disorganization and nemaline rods. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACTA1, LYS328ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122936,
|
|
|
|
|
|
|
|
ClinVar: RCV003151741
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an infant with severe infantile congenital myopathy-2C (CMYO2C; 620278) who presented with an atypical phenotype of stiffness and hypertonicity, Jain et al. (2012) identified a de novo heterozygous c.984G-C transversion in the ACTA1 gene, resulting in a lys328-to-asn (K328N) substitution (K326N in the mature protein). Patient biopsy showed nemaline bodies and 32% mutant actin. In vitro motility analysis of actin thin filaments derived from the patient's tissue showed increased sensitivity to calcium, indicating an activated state. Expression of the mutant in mouse muscle cells did not result in the formation of rod-like structures, suggesting a different mechanism of nemaline body formation. Medical treatment was ineffective, and the patient died at age 9 months in an asystolic episode. The report expanded the phenotypic spectrum associated with ACTA1 mutations to include stiffness, rigidity, and hypertonicity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 CONGENITAL MYOPATHY 2A, TYPICAL, AUTOSOMAL DOMINANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACTA1, TRP358CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777354,
|
|
|
|
|
|
|
|
ClinVar: RCV000115017, RCV004813058
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 9-year-old Japanese boy with congenital myopathy-2A (CMYO2A; 161800) who developed fatal dilated cardiomyopathy, Gatayama et al. (2013) identified a heterozygous c.1074G-T transversion in exon 7 of the ACTA1 gene, resulting in a trp358-to-cys (W358C) substitution. The parents were unaffected and the mutation was not found in 50 Japanese controls. Functional studies of the variant were not performed. The patient had normal motor development in early childhood, but showed mild nonprogressive skeletal muscle weakness, such as slowed running compared to his peers. Other features included hypotonia, myopathic facies, high-arched palate, and mild weakness of proximal and distal muscles. He presented at age 9 years with acute deterioration of cardiac function, and died of cardiac failure 6 months later. Postmortem examination of cardiac muscle showed variation in myocardial fiber size and a few electron-dense fine structures related to Z lines. Skeletal muscle biopsy had previously shown typical nemaline rods. Gatayama et al. (2013) noted that childhood-onset dilated cardiomyopathy is rare in patients with ACTA1 mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 MYOPATHY, SCAPULOHUMEROPERONEAL (1 family)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACTA1, GLU197ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs869312739,
|
|
|
|
|
|
|
|
ClinVar: RCV000210030, RCV000414423, RCV001853353
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large family with scapulohumeroperoneal myopathy (SHPM; 616852), originally reported by Armstrong et al. (1966), Zukosky et al. (2015) identified a heterozygous c.591C-A transversion in exon 4 of the ACTA1 gene, resulting in a glu197-to-asp (E197D) substitution. The mutation was found by a combination of linkage analysis and whole-exome sequencing and was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in the dbSNP or ExAC databases. Transfection of the mutation into COS-7 cells showed that the mutant protein had normal actin localization and did not form nemaline rods. Injection of the mutation into zebrafish embryos did not result in any morphologic abnormalities or abnormal muscle histology up to 6 days after fertilization. Zukosky et al. (2015) postulated that a fundamentally different pathogenic process than changes in actin cytoarchitecture or rod formation was responsible for the phenotype, such as changes in interaction or force generation, actin filament stability, or differences in the directionality of actin filament growth. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACTA1, ARG39TER
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV003152503
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an infant with severe autosomal recessive congenital myopathy-2B (CMYO2B; 620265) resulting in death from respiratory failure at 22 months of age, Sparrow et al. (2003) identified a homozygous mutation in exon 2 of the ACTA1 gene, resulting in an arg39-to-ter (R39X) substitution. Nowak et al. (2007) also reported this patient, stating that he was born of consanguineous French Gypsy parents. The mutation was a c.121C-T transition, resulting in an arg41-to-ter (R41X) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACTA1, 1-BP DEL, G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1395648272,
|
|
|
|
|
|
gnomAD: rs1395648272,
|
|
|
|
|
|
ClinVar: RCV001959102, RCV002469442, RCV003228040
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe autosomal recessive congenital myopathy-2B (CMYO2B; 620265) resulting in death at 2 months of age, Sparrow et al. (2003) identified compound heterozygous mutations in the ACTA1 gene: a 1-bp deletion (g.2221delG), resulting in a frameshift at Ala144, and E259V (102610.0005). Functional studies of the variants were not performed, but the frameshift mutation was predicted to result in a loss-of-function effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACTA1, IVS5, G-T
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV003152505
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 sibs with severe autosomal recessive congenital myopathy-2B (CMYO2B; 620265) resulting in death in the first months of life, Sparrow et al. (2003) identified a homozygous G-to-T transversion (g.2891G-T) in the splice site junction of intron 5 and exon 6, predicted to result in a splicing abnormality and a loss of function. Each unaffected parent was heterozygous for the mutation. Functional studies of the variant were not performed, but it was predicted to have a loss-of-function effect. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0022 CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, 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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ACTA1, 1-BP DEL, 541G
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<br />
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SNP: rs759242559,
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gnomAD: rs759242559,
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ClinVar: RCV000479633, RCV001384035, RCV003223407, RCV004754450, RCV004813100
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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 5 patients from 4 unrelated consanguineous families with autosomal recessive congenital myopathy-2B (CMYO2B; 620265), Nowak et al. (2007) identified a homozygous 1-bp deletion (c.541delG) in the ACTA1 gene, predicted to result in a frameshift and premature termination (Asp181fsTer10). In cases where DNA was available, the unaffected parents were heterozygous for the mutation. The families were of Pakistani and Indian British origin, and haplotype analysis was consistent with a founder effect. Skeletal muscle biopsy from some of the patients showed absence of the ACTA1 protein with increased expression of cardiac alpha-actin (ACTC1; 102540), likely reflecting a compensatory mechanism. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0023 CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, 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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ACTA1, VAL154LEU
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<br />
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SNP: rs768144106,
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gnomAD: rs768144106,
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ClinVar: RCV000230128, RCV003221864
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 brothers, born of consanguineous Sri Lankan parents, with autosomal recessive congenital myopathy-2B (CMYO2B; 620265), O'Grady et al. (2015) identified a homozygous c.460G-C transversion in the ACTA1 gene, resulting in a val154-to-leu (V154L) substitution in a residue near the ATP-binding pocket and hinge region. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The heterozygous parents were unaffected. Functional studies of the variant were not performed, but it was predicted to be deleterious. Immunostaining and Western blot analysis of patient muscle showed normal levels of skeletal muscle ACTA1 and upregulated expression of cardiac alpha-actin (ACTC1; 102540). Of note, one of the brothers carried a heterozygous missense S388G variant in the SEPN1 gene. These sibs had a longer survival than most patients with recessive ACTA1 mutations: one died at age 6 years and the other was alive and ambulatory at age 34. O'Grady et al. (2015) noted that previously reported patients with biallelic ACTA1 mutations had functional 'null' variants and made no ACTA1 protein. Survival after birth was attributed to persistence of cardiac ACTC1 in the skeletal muscle of these children. </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>.0024 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, 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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ACTA1, VAL163LEU, G-T
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<br />
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ClinVar: RCV000019944, RCV003227607
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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 (P3) with severe infantile congenital myopathy-2C (CMYO2C; 620278) originally reported as P3 by Goebel et al. (1997), Nowak et al. (1999) identified a heterozygous G-to-T transversion in exon 4 of the ACTA1 gene, resulting in a val163-to-leu (V163L) substitution. This child was hypotonic from birth, had cardiomegaly, and died of cardiorespiratory insufficiency at age 4 months. Muscle biopsy showed a type-1 fiber predominance, subsarcolemmal masses of thin filaments, and intranuclear nemaline rods (Goebel et al., 1997). The same amino acid substitution due to a different nucleotide change was observed in another patient with the disorder who was still alive at 7.5 years of age (see 102610.0004). </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>.0025 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, 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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ACTA1, ASP286GLY
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<br />
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ClinVar: RCV003152501
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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 (patient 17) with severe infantile congenital myopathy-2C (CMYO2C; 620278), Nowak et al. (1999) identified a heterozygous A-to-G transition in exon 6 of the ACTA1 gene, resulting in an asp286-to-gly (D286G) substitution. The patient died at 9 months of age. Parental DNA was not available for study, but the mutation likely occurred de novo. </p><p>In a male infant (25-1) with CMYO2C, Agrawal et al. (2004) identified a heterozygous c.966A-G transition in the ACTA1 gene, resulting in a D286G substitution. There was no family history of the disease, and this was an isolated case, likely due to a de novo mutation (parental DNA was not available for study). The patient had hypotonia, joint contractures, femur fracture, no movement, and no respiratory effort at birth. He was tube-fed and required ventilatory support until his death at 6 days of age. Muscle biopsy showed marked fiber size variability, disruption of myofibrils, and nemaline bodies. </p><p>Ravenscroft et al. (2011) and Ravenscroft et al. (2011) generated mutant mice harboring the D286G mutation. Mice expressing the mutant protein at 25% of the total alpha-actin pool were less active than controls, but had a normal life span. Mice expressing the mutant protein at 45% of the alpha-actin pool had severe muscle weakness leading to early death. Skeletal muscle showed extensive structural abnormalities similar to those observed in humans with the disorder. The findings suggested a correlation between mutant ACTA1 protein load and disease severity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0026 CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, AUTOSOMAL DOMINANT</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACTA1, HIS40TYR
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<br />
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SNP: rs2102736554,
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ClinVar: RCV002000054, RCV003228037, RCV004813198
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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 (P4) with severe infantile congenital myopathy-2C (CMYO2C; 620278) who died at 2 months of age, Nowak et al. (1999) identified a de novo C-to-T transition in exon 2 of the ACTA1 gene, resulting in a his40-to-tyr (H40Y) substitution. </p><p>Nguyen et al. (2011) generated mutant mice carrying the ACTA1 H40Y mutation and found that they developed clinical features of severe congenital 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">
|
|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Abonia, J. P., Abel, K. J., Eddy, R. L., Elliott, R. W., Chapman, V. M., Shows, T. B., Gross, K. W.
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<strong>Linkage of Agt and Actsk-1 to distal mouse chromosome 8 loci: a new conserved linkage.</strong>
|
|
Mammalian Genome 4: 25-32, 1993.
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[PubMed: 8093670]
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[Full Text: https://doi.org/10.1007/BF00364659]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Agrawal, P. B., Strickland, C. D., Midgett, C., Morales, A., Newburger, D. E., Poulos, M. A., Tomczak, K. K., Ryan, M. M., Iannaccone, S. T., Crawford, T. O., Laing, N. G., Beggs, A. H.
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<strong>Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations.</strong>
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Ann. Neurol. 56: 86-96, 2004.
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<p class="mim-text-font">
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Akkari, P. A., Eyre, H. J., Wilton, S. D., Callen, D. F., Lane, S. A., Meredith, C., Kedes, L., Laing, N. G.
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<strong>Assignment of the human skeletal muscle alpha actin gene (ACTA1) to 1q42 by fluorescence in situ hybridisation.</strong>
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Cytogenet. Cell Genet. 65: 265-267, 1994.
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[PubMed: 8258301]
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[Full Text: https://doi.org/10.1159/000133644]
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<p class="mim-text-font">
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Alonso, S., Montagutelli, X., Simon-Chazottes, D., Guenet, J.-L., Buckingham, M.
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<strong>Re-localization of Actsk-1 to mouse chromosome 8, a new region of homology with human chromosome 1.</strong>
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Mammalian Genome 4: 15-20, 1993.
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[PubMed: 8422497]
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[Full Text: https://doi.org/10.1007/BF00364657]
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<p class="mim-text-font">
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Armstrong, R. M., Fogelson, M. H., Silberberg, D. H.
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<strong>Familial proximal spinal muscular atrophy.</strong>
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Arch. Neurol. 14: 208-212, 1966.
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[PubMed: 4952447]
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[Full Text: https://doi.org/10.1001/archneur.1966.00470080092014]
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<li>
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<p class="mim-text-font">
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Clarke, N. F., Ilkovski, B., Cooper, S., Valova, V. A., Robinson, P. J., Nonaka, I., Feng, J.-J., Marston, S., North, K.
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<strong>The pathogenesis of ACTA1-related congenital fiber type disproportion.</strong>
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Ann. Neurol. 61: 552-561, 2007.
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[PubMed: 17387733]
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[Full Text: https://doi.org/10.1002/ana.21112]
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<li>
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<p class="mim-text-font">
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Crawford, K., Flick, R., Close, L., Shelly, D., Paul, R., Bove, K., Kumar, A., Lessard, J.
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<strong>Mice lacking skeletal muscle actin show reduced muscle strength and growth deficits and die during the neonatal period.</strong>
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Molec. Cell. Biol. 22: 5887-5896, 2002.
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[PubMed: 12138199]
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[Full Text: https://doi.org/10.1128/MCB.22.16.5887-5896.2002]
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<li>
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<p class="mim-text-font">
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Czosnek, H., Nudel, U., Shani, M., Barker, P. E., Pravtcheva, D. D., Ruddle, F. H., Yaffe, D.
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<strong>The genes coding for the muscle contractile proteins, myosin heavy chain, myosin light chain 2, and skeletal muscle actin are located on three different mouse chromosomes.</strong>
|
|
EMBO J. 1: 1299-1305, 1982.
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[PubMed: 6897916]
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[Full Text: https://doi.org/10.1002/j.1460-2075.1982.tb01314.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Domazetovska, A., Ilkovski, B., Kumar, V., Valova, C. A., Vandebrouck, A., Hutchinson, D. O., Robinson, P. J., Cooper, S. T., Sparrow, J. C., Peckham, M., North, K. N.
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<strong>Intranuclear rod myopathy: molecular pathogenesis and mechanisms of weakness.</strong>
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Ann. Neurol. 62: 597-608, 2007.
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[PubMed: 17705262]
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[Full Text: https://doi.org/10.1002/ana.21200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Feng, J.-J., Marston, S.
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<strong>Genotype-phenotype correlations in ACTA1 mutations that cause congenital myopathies.</strong>
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Neuromusc. Disord. 19: 6-16, 2009.
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[PubMed: 18976909]
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[Full Text: https://doi.org/10.1016/j.nmd.2008.09.005]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Garcia-Angarita, N., Kirschner, J., Heiliger, M., Thirion, C., Walter, M. C., Schnittfeld-Acarlioglu, S., Albrecht, M., Muller, K., Wieczorek, D., Lochmuller, H., Krause, S.
|
|
<strong>Severe nemaline myopathy associated with consecutive mutations E74D and H75Y on a single ACTA1 allele.</strong>
|
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Neuromusc. Disord. 19: 481-484, 2009.
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[PubMed: 19553116]
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[Full Text: https://doi.org/10.1016/j.nmd.2009.05.001]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gatayama, R., Ueno, K., Nakamura, H., Yanagi, S., Ueda, H., Yamagishi, H., Yasui, S.
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<strong>Nemaline myopathy with dilated cardiomyopathy in childhood.</strong>
|
|
Pediatrics 131: e1986-1990, 2013. Note: Electronic Article.
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[PubMed: 23650303]
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[Full Text: https://doi.org/10.1542/peds.2012-1139]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Goebel, H. H., Anderson, J. R., Hubner, C., Oexle, K., Warlo, I.
|
|
<strong>Congenital myopathy with excess of thin myofilaments.</strong>
|
|
Neuromusc. Disord. 7: 160-168, 1997.
|
|
|
|
|
|
[PubMed: 9185179]
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[Full Text: https://doi.org/10.1016/s0960-8966(97)00441-0]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gunning, P., Ponte, P., Kedes, L., Eddy, R., Shows, T.
|
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<strong>Chromosomal location of the co-expressed human skeletal and cardiac actin genes.</strong>
|
|
Proc. Nat. Acad. Sci. 81: 1813-1817, 1984.
|
|
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|
|
[PubMed: 6584914]
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|
[Full Text: https://doi.org/10.1073/pnas.81.6.1813]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Gunning, P., Ponte, P., Okayama, H., Engel, J., Blau, H., Kedes, L.
|
|
<strong>Isolation and characterization of full-length cDNA clones for human alpha-, beta-, and gamma-actin mRNAs: skeletal but not cytoplasmic actins have an amino-terminal cysteine that is subsequently removed.</strong>
|
|
Molec. Cell. Biol. 3: 787-795, 1983.
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|
|
[PubMed: 6865942]
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[Full Text: https://doi.org/10.1128/mcb.3.5.787-795.1983]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Hanauer, A., Heilig, R., Levin, M., Moisan, J. P., Grzeschik, K. H., Mandel, J. L.
|
|
<strong>The actin gene family in man: assignment of the gene for skeletal muscle alpha-actin to chromosome 1, and presence of actin sequences on autosomes 2 and 3, and on the X and Y chromosomes. (Abstract)</strong>
|
|
Cytogenet. Cell Genet. 37: 487-488, 1984.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Hanauer, A., Levin, M., Heilig, R., Daegelen, D., Kahn, A., Mandel, J. L.
|
|
<strong>Isolation and characterization of cDNA clones for human skeletal muscle alpha actin.</strong>
|
|
Nucleic Acids Res. 11: 3503-3516, 1983.
|
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|
|
[PubMed: 6190133]
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[Full Text: https://doi.org/10.1093/nar/11.11.3503]
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</p>
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Cassandra L. Kniffin - updated : 03/01/2023<br>Cassandra L. Kniffin - updated : 3/11/2016<br>Cassandra L. Kniffin - updated : 4/30/2014<br>Cassandra L. Kniffin - updated : 5/6/2013<br>Cassandra L. Kniffin - updated : 11/23/2009<br>Cassandra L. Kniffin - updated : 10/12/2009<br>Ada Hamosh - updated : 3/4/2009<br>Cassandra L. Kniffin - updated : 3/21/2008<br>Cassandra L. Kniffin - updated : 12/28/2007<br>George E. Tiller - updated : 1/16/2007<br>Cassandra L. Kniffin - updated : 7/1/2005<br>Cassandra L. Kniffin - reorganized : 4/7/2005<br>Cassandra L. Kniffin - updated : 4/4/2005<br>Victor A. McKusick - updated : 1/18/2005<br>Cassandra L. Kniffin - updated : 12/10/2004<br>Patricia A. Hartz - updated : 11/5/2002<br>Victor A. McKusick - updated : 6/20/2001<br>Victor A. McKusick - updated : 9/28/1999
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Victor A. McKusick : 6/4/1986
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alopez : 07/16/2024<br>carol : 03/10/2023<br>ckniffin : 03/08/2023<br>carol : 03/08/2023<br>carol : 03/06/2023<br>ckniffin : 03/01/2023<br>alopez : 02/20/2023<br>carol : 04/02/2021<br>carol : 03/11/2016<br>ckniffin : 3/11/2016<br>ckniffin : 3/11/2016<br>carol : 8/20/2015<br>mcolton : 8/19/2015<br>carol : 1/14/2015<br>carol : 6/18/2014<br>carol : 5/1/2014<br>ckniffin : 4/30/2014<br>alopez : 5/10/2013<br>ckniffin : 5/6/2013<br>mgross : 11/20/2012<br>terry : 10/26/2012<br>alopez : 12/11/2009<br>wwang : 12/10/2009<br>ckniffin : 11/23/2009<br>wwang : 11/23/2009<br>ckniffin : 10/12/2009<br>ckniffin : 9/28/2009<br>carol : 9/17/2009<br>alopez : 3/4/2009<br>terry : 3/4/2009<br>terry : 7/30/2008<br>terry : 7/30/2008<br>wwang : 3/31/2008<br>ckniffin : 3/21/2008<br>wwang : 1/14/2008<br>ckniffin : 12/28/2007<br>terry : 12/17/2007<br>carol : 9/5/2007<br>wwang : 1/26/2007<br>wwang : 1/23/2007<br>terry : 1/16/2007<br>ckniffin : 3/14/2006<br>carol : 7/13/2005<br>carol : 7/13/2005<br>ckniffin : 7/1/2005<br>carol : 4/8/2005<br>carol : 4/7/2005<br>ckniffin : 4/4/2005<br>tkritzer : 1/18/2005<br>tkritzer : 12/21/2004<br>ckniffin : 12/10/2004<br>ckniffin : 7/21/2004<br>joanna : 3/17/2004<br>carol : 7/9/2003<br>mgross : 11/5/2002<br>cwells : 7/2/2001<br>cwells : 6/25/2001<br>terry : 6/20/2001<br>carol : 8/9/2000<br>alopez : 11/15/1999<br>alopez : 11/5/1999<br>alopez : 10/11/1999<br>alopez : 10/11/1999<br>alopez : 9/30/1999<br>terry : 9/28/1999<br>dkim : 12/18/1998<br>mark : 3/20/1997<br>terry : 6/16/1995<br>carol : 5/27/1994<br>carol : 2/3/1993<br>carol : 5/28/1992<br>supermim : 3/16/1992<br>carol : 7/3/1991
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