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<title>
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Entry
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- *102573 - ACTININ, ALPHA-2; ACTN2
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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="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<li role="separator" class="divider"></li>
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<a href="/history"> Search History </a>
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</ul>
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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>
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*102573</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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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>
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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="#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="#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="#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/102573">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=ENSG00000077522;t=ENST00000366578" 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=88" 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=102573" 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=ENSG00000077522;t=ENST00000366578" 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_001103,NM_001278343,NR_184402" 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_001103" 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=102573" 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=00019&isoform_id=00019_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/ACTN2" 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/178054,178056,543742,4501893,6449432,34194598,37589943,62088622,119590470,119590471,189054889,221040428,221041820,221041910,221041914,221042020,507588248,1471157348,1471157350,1471157356,1471157361,1471880161" 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/P35609" 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=88" 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=ENSG00000077522;t=ENST00000366578" 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=ACTN2" 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=ACTN2" 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+88" 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/ACTN2" 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:88" 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/88" 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=ENST00000366578.6&hgg_start=236686499&hgg_end=236764631&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">
|
|
<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:164" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=102573[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=102573[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/ACTN2/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/ENSG00000077522" 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=ACTN2" 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=ACTN2" 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=ACTN2" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ACTN2&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/PA25" 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:164" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0000667.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:109192" 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/ACTN2#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:109192" 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/88/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=88" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00000228;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-051127-39" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<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:88" 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=ACTN2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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102573
|
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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>
|
|
<span class="mim-font">
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ACTININ, ALPHA-2; ACTN2
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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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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ACTN2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ACTN2</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/1/1828?start=-3&limit=10&highlight=1828">1q43</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:236686499-236764631&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'})">1:236,686,499-236,764,631</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=612158,612158,618654,618655" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/1828?start=-3&limit=10&highlight=1828">
|
|
1q43
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, dilated, 1AA, with or without LVNC
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/612158"> 612158 </a>
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<p>The ACTN2 gene encodes alpha-actinin-2, which is highly expressed in the sarcomeric Z-disk or Z-line in both cardiac and skeletal muscle, where it plays important structural and functional roles in the sarcomere and contractile apparatus (summary by <a href="#8" class="mim-tip-reference" title="Lornage, X., Romero, N. B., Grosgogeat, C. A., Malfatti, E., Donkervoort, S., Marchetti, M. M., Neuhaus, S. B., Foley, A. R., Labasse, C., Schneider, R., Carlier, R. Y., Chao, K. R., Medne, L., Deleuze, J.-F., Orlikowski, D., Bonnemann, C. G., Gupta, V. A., Fardeau, M., Bohm, J., Laporte, J. <strong>ACTN2 mutations cause 'multiple structured core disease' (MsCD).</strong> Acta Neuropath. 137: 501-519, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30701273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30701273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30701273[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00401-019-01963-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30701273">Lornage et al., 2019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30701273" 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>Alpha-actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane (see ACTN1; <a href="/entry/102575">102575</a>). In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. <a href="#2" class="mim-tip-reference" title="Beggs, A. H., Byers, T. J., Knoll, J. H. M., Boyce, F. M., Bruns, G. A. P., Kunkel, L. M. <strong>Cloning and characterization of two human skeletal muscle alpha-actinin genes located on chromosomes 1 and 11.</strong> J. Biol. Chem. 267: 9281-9288, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1339456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1339456</a>]" pmid="1339456">Beggs et al. (1992)</a> characterized 2 human muscle-specific alpha-actinin genes, ACTN2 and ACTN3 (<a href="/entry/102574">102574</a>). They identified 3 ACTN2 transcripts that differed only in their use of polyadenylation signals. The deduced 894-amino acid protein has a calculated molecular mass of about 104 kD. ACTN2 has an N-terminal actin-binding domain of about 250 amino acids, followed by 4 central repeats and 2 EF-hand motifs near the C terminus. Northern blot analysis of mouse tissues detected Actn2 expression in skeletal muscle and heart, but not in brain, liver, kidney, or small intestine. Two major ACTN2 bands were detected in human fetal skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1339456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Seto, J. T., Lek, M., Quinlan, K. G. R., Houweling, P. J., Zheng, X. F., Garton, F., MacArthur, D. G., Raftery, J. M., Garvey, S. M., Hauser, M. A., Yang, N., Head, S. I., North, K. N. <strong>Deficiency of alpha-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling.</strong> Hum. Molec. Genet. 20: 2914-2927, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21536590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21536590</a>] [<a href="https://doi.org/10.1093/hmg/ddr196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21536590">Seto et al. (2011)</a> stated that the central repeats of ACTN2 are spectrin (see <a href="/entry/182860">182860</a>)-like repeats that form a rod domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21536590" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using somatic cell hybrids, <a href="#2" class="mim-tip-reference" title="Beggs, A. H., Byers, T. J., Knoll, J. H. M., Boyce, F. M., Bruns, G. A. P., Kunkel, L. M. <strong>Cloning and characterization of two human skeletal muscle alpha-actinin genes located on chromosomes 1 and 11.</strong> J. Biol. Chem. 267: 9281-9288, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1339456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1339456</a>]" pmid="1339456">Beggs et al. (1992)</a> mapped the ACTN2 and ACTN3 genes to chromosomes 1 and 11, respectively. In situ hybridization placed the ACTN2 locus at 1q42-q43. <a href="#3" class="mim-tip-reference" title="Beggs, A. H., Phillips, H. A., Kozman, H., Mulley, J. C., Wilton, S. D., Kunkel, L. M., Laing, N. G. <strong>A (CA)n repeat polymorphism for the human skeletal muscle alpha-actinin gene ACTN2 and its localization on the linkage map of chromosome 1.</strong> Genomics 13: 1314-1315, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1505962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1505962</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90054-v" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1505962">Beggs et al. (1992)</a> identified a polymorphic (CA)n repeat within the ACTN2 gene and used it to position the ACTN2 gene on the CEPH linkage map of chromosome 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1339456+1505962" 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="#9" class="mim-tip-reference" title="Mills, M. A., Yang, N., Weinberger, R. P., Vander Woude, D. L., Beggs, A. H., Easteal, S., North, K. N. <strong>Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy.</strong> Hum. Molec. Genet. 10: 1335-1346, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11440986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11440986</a>] [<a href="https://doi.org/10.1093/hmg/10.13.1335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11440986">Mills et al. (2001)</a> mapped the 4 murine actinin orthologs, which were all located at evolutionarily conserved syntenic regions for the 4 human genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11440986" 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="#9" class="mim-tip-reference" title="Mills, M. A., Yang, N., Weinberger, R. P., Vander Woude, D. L., Beggs, A. H., Easteal, S., North, K. N. <strong>Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy.</strong> Hum. Molec. Genet. 10: 1335-1346, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11440986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11440986</a>] [<a href="https://doi.org/10.1093/hmg/10.13.1335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11440986">Mills et al. (2001)</a> observed that murine Actn2 and Actn3 were differentially expressed, spatially and temporally, during embryonic development and, in contrast to humans, alpha-actinin-2 expression did not completely overlap with alpha-actinin-3 in postnatal skeletal muscle, suggesting independent function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11440986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Seto, J. T., Lek, M., Quinlan, K. G. R., Houweling, P. J., Zheng, X. F., Garton, F., MacArthur, D. G., Raftery, J. M., Garvey, S. M., Hauser, M. A., Yang, N., Head, S. I., North, K. N. <strong>Deficiency of alpha-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling.</strong> Hum. Molec. Genet. 20: 2914-2927, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21536590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21536590</a>] [<a href="https://doi.org/10.1093/hmg/ddr196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21536590">Seto et al. (2011)</a> found that expression of Actn2 was upregulated in Actn3 -/- mouse extensor digitorum longus muscle such that the total sarcomeric content of alpha-actinin was unchanged. Actn3 -/- muscle was susceptible to contraction-induced damage compared with wildtype. The Z-disc proteins Zasp (LDB3; <a href="/entry/605906">605906</a>), titin (TTN; <a href="/entry/188840">188840</a>), and vinculin (VCL; <a href="/entry/193065">193065</a>) bound more avidly to Actn2 than to Actn3, suggesting a biochemical basis for altered mechanics and fragility in Actn3 -/- muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21536590" 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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In a 7-year-old girl who died of dilated cardiomyopathy (CMD1AA; <a href="/entry/612158">612158</a>) and was negative for mutation in 8 known cardiomyopathy genes, <a href="#10" class="mim-tip-reference" title="Mohapatra, B., Jimenez, S., Lin, J. H., Bowles, K. R., Coveler, K. J., Marx, J. G., Chrisco, M. A., Murphy, R. T., Lurie, P. R., Schwartz, R. J., Elliott, P. M., Vatta, M., McKenna, W., Towbin, J. A., Bowles, N. E. <strong>Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis.</strong> Molec. Genet. Metab. 80: 207-215, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14567970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14567970</a>] [<a href="https://doi.org/10.1016/s1096-7192(03)00142-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14567970">Mohapatra et al. (2003)</a> identified heterozygosity for a missense mutation in the ACTN2 gene (Q9R; <a href="#0001">102573.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14567970" 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 sporadic patients with hypertrophic cardiomyopathy (CMH23; see <a href="/entry/612158">612158</a>), <a href="#13" class="mim-tip-reference" title="Theis, J. L., Bos, J. M., Bartleson, V. B., Will, M. L., Binder, J., Vatta, M., Towbin, J. A., Gersh, B. J., Ommen, S. R., Ackerman, M. J. <strong>Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.</strong> Biochem. Biophys. Res. Commun. 351: 896-902, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17097056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17097056</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.10.119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17097056">Theis et al. (2006)</a> identified heterozygous missense mutations in the ACTN2 gene (<a href="#0002">102573.0002</a>-<a href="#0004">102573.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17097056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a large 3-generation Australian family with clinically heterogeneous CMH mapping to chromosome 1, <a href="#4" class="mim-tip-reference" title="Chiu, C., Bagnall, R. D., Ingles, J., BBIOMEDSC, Yeates, L., Kennerson, M., Donald, J. A., Jormakka, M., Lind, J. M., Semsarian, C. <strong>Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis.</strong> J. Am. Coll. Cardiol. 55: 1127-1135, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20022194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20022194</a>] [<a href="https://doi.org/10.1016/j.jacc.2009.11.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20022194">Chiu et al. (2010)</a> identified heterozygosity for a missense mutation in the ACTN2 gene (A119T; <a href="#0005">102573.0005</a>). Screening of an additional 297 CMH probands identified 3 heterozygous missense mutations that segregated with disease in the respective families (see, e.g., <a href="#0003">102573.0003</a> and <a href="#0006">102573.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20022194" 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 affected members over 2 generations of an Australian family with marked cardiac phenotype heterogeneity, including CMD, left ventricular noncompaction (LVNC), ventricular fibrillation, and sudden death, <a href="#1" class="mim-tip-reference" title="Bagnall, R. D., Molloy, L. K., Kalman, J. M., Semsarian, C. <strong>Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.</strong> BMC Med. Genet. 15: 99, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25224718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25224718</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25224718[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s12881-014-0099-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25224718">Bagnall et al. (2014)</a> identified heterozygosity for the same A119T substitution in the ACTN2 gene that had previously been detected in an apparently unrelated Australian family with clinically heterogeneous CMH by <a href="#4" class="mim-tip-reference" title="Chiu, C., Bagnall, R. D., Ingles, J., BBIOMEDSC, Yeates, L., Kennerson, M., Donald, J. A., Jormakka, M., Lind, J. M., Semsarian, C. <strong>Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis.</strong> J. Am. Coll. Cardiol. 55: 1127-1135, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20022194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20022194</a>] [<a href="https://doi.org/10.1016/j.jacc.2009.11.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20022194">Chiu et al. (2010)</a>. Haplotype analysis was consistent with a common ancestor for the 2 Australian families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25224718+20022194" 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 large 4-generation Italian family with clinically heterogeneous cardiomyopathic disease comprising variable combinations of asymmetric left ventricular hypertrophy (LVH) consistent with CMH, early-onset supraventricular arrhythmias and atrioventricular (AV) block, and regional LVNC, <a href="#5" class="mim-tip-reference" title="Girolami, F., Iascone, M., Tomberli, B., Bardi, S., Benelli, M., Marseglia, G., Pescucci, C., Pezzoli, L., Sana, M. E., Basso, C., Marziliano, N., Merlini, P. A., Fornaro, A., Cecchi, F., Torricelli, F., Olivotto, I. <strong>Novel alpha-actinin 2 variant associated with familial hypertrophic cardiomyopathy and juvenile atrial arrhythmias: a massively parallel sequencing study.</strong> Circ. Cardiovasc. Genet. 7: 741-750, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25173926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25173926</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.113.000486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25173926">Girolami et al. (2014)</a> performed next-generation sequencing and identified heterozygosity for a missense mutation in ACTN2 (M228T; <a href="#0007">102573.0007</a>). The mutation, which segregated fully with disease in the family, was not found in 570 control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25173926" 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 8</em></strong></p><p>
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In 2 unrelated patients with congenital myopathy-8 (CMYO8; <a href="/entry/618654">618654</a>), <a href="#8" class="mim-tip-reference" title="Lornage, X., Romero, N. B., Grosgogeat, C. A., Malfatti, E., Donkervoort, S., Marchetti, M. M., Neuhaus, S. B., Foley, A. R., Labasse, C., Schneider, R., Carlier, R. Y., Chao, K. R., Medne, L., Deleuze, J.-F., Orlikowski, D., Bonnemann, C. G., Gupta, V. A., Fardeau, M., Bohm, J., Laporte, J. <strong>ACTN2 mutations cause 'multiple structured core disease' (MsCD).</strong> Acta Neuropath. 137: 501-519, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30701273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30701273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30701273[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00401-019-01963-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30701273">Lornage et al. (2019)</a> identified de novo heterozygous mutations in exon 18 of the ACTN2 gene (L727R, <a href="#0008">102573.0008</a> and an in-frame deletion, <a href="#0009">102573.0009</a>); both were located in the fourth spectrin repeat. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. In addition, patient 1 was heterozygous and patient 2 was homozygous for the common R577X polymorphism in the ACTN3 gene (<a href="/entry/102574#0001">102574.0001</a>). Western blot analysis of skeletal muscle from the patient with the L727R mutation and analysis of cells transfected with that mutation showed normal protein expression, dimerization, and localization. However, <a href="#8" class="mim-tip-reference" title="Lornage, X., Romero, N. B., Grosgogeat, C. A., Malfatti, E., Donkervoort, S., Marchetti, M. M., Neuhaus, S. B., Foley, A. R., Labasse, C., Schneider, R., Carlier, R. Y., Chao, K. R., Medne, L., Deleuze, J.-F., Orlikowski, D., Bonnemann, C. G., Gupta, V. A., Fardeau, M., Bohm, J., Laporte, J. <strong>ACTN2 mutations cause 'multiple structured core disease' (MsCD).</strong> Acta Neuropath. 137: 501-519, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30701273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30701273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30701273[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00401-019-01963-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30701273">Lornage et al. (2019)</a> found that expression of human mutant ACTN2 L727R in zebrafish embryos resulted in hatching defects, smaller myotome, dorsal curvature, and impaired motor function, although levels of protein expression were not affected. Skeletal muscle from mutant fish showed significant myofibrillar disarray, sarcomeric disorganization, abnormal Z-lines, and abnormal actin-myosin interaction compared to wildtype. AAV-mediated expression of the mutation in skeletal muscle of 3-week-old mice resulted in reduced maximal force as well as abnormal Z-line organization and core formation. The findings in both animal models recapitulated the specific phenotype in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30701273" 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>Adult-Onset Distal Myopathy 6, Autosomal Dominant</em></strong></p><p>
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In affected members of 3 unrelated families from northern Spain with autosomal dominant adult-onset distal myopathy-6 (MPD6; <a href="/entry/618655">618655</a>), <a href="#11" class="mim-tip-reference" title="Savarese, M., Palmio, J., Poza, J. J., Weinberg, J., Olive, M., Cobo, A. M., Vihola, A., Jonson, P. H., Sarparanta, J., Garcia-Bragado, F., Urtizberea, J. A., Hackman, P., Udd, B. <strong>Actininopathy: a new muscular dystrophy caused by ACTN2 dominant mutations.</strong> Ann. Neurol. 85: 899-906, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30900782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30900782</a>] [<a href="https://doi.org/10.1002/ana.25470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30900782">Savarese et al. (2019)</a> identified a heterozygous missense mutation in the ACTN2 gene (C487R; <a href="#0010">102573.0010</a>). In a Swedish father and daughter with a similar disorder, they identified a different heterozygous mutation in the ACTN2 gene (L131P; <a href="#0011">102573.0011</a>). The variants, which were found by targeted panel sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families and were not found in the gnomAD database. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30900782" 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 dystrophin gene (DMD; <a href="/entry/300377">300377</a>) result in Duchenne muscular dystrophy. Dystrophin is a multidomain protein that functions to stabilize the sarcolemmal membrane during muscle contraction. Dystrophin shares considerable homology with alpha-actinin. To explore the hypothesis that the dystrophin rod domain acts as a spacer region, <a href="#7" class="mim-tip-reference" title="Harper, S. Q., Crawford, R. W., DellRusso, C., Chamberlain, J. S. <strong>Spectrin-like repeats from dystrophin and alpha-actinin-2 are not functionally interchangeable.</strong> Hum. Molec. Genet. 11: 1807-1815, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12140183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12140183</a>] [<a href="https://doi.org/10.1093/hmg/11.16.1807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12140183">Harper et al. (2002)</a> expressed a chimeric micro-dystrophin transgene containing the 4-repeat rod domain of alpha-actinin-2 in mdx mice. The transgene was incapable of correcting the morphologic pathology of the mdx mouse, but still functioned to assemble the dystrophin-glycoprotein complex at the membrane and provided some protection from contraction-induced injury. The authors concluded that different spectrin-like repeats are not equivalent, and proposed that the dystrophin rod domain is not merely a spacer but likely contributes an important mechanical role to overall dystrophin function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12140183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Gupta, V., Discenza, M., Guyon, J. R., Kunkel, L. M., Beggs, A. H. <strong>Alpha-actinin-2 deficiency results in sarcomeric defects in zebrafish that cannot be rescued by alpha-actinin-3 revealing functional differences between sarcomeric isoforms.</strong> FASEB J. 26: 1892-1908, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22253474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22253474</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22253474[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/10.1096/fj.11-194548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22253474">Gupta et al. (2012)</a> performed targeted knockdown of actn2 in zebrafish and observed developmental defects in eye, heart, and skeletal muscle. Morphant fish were largely immotile with a blunted touch-evoked response, suggesting a significant degree of overall muscle weakness. Morphants consistently exhibited smaller eyes, enlarged hearts with reduced heartbeat, and abnormal organization of skeletal muscles. Skeletal muscles showed a significant decrease in birefringence, and histologic analysis of longitudinal sections revealed disorganized muscle fibers, with occasional fibers completely lacking in myofibrillar organization; on electron microscopy, many fibers showed reduced sarcomeric organization and rounded multiple nuclei. The cardiac phenotype presented as a reduction in heart rate between 1 and 2 days postfertilization (dpf), and by 3 dpf, morphants exhibited clearly enlarged hearts; histologic examination showed enlarged hearts with both atrial and ventricular dilation and remarkably thin walls, and there was a marked decrease in the size and number of sarcomeric assemblies in both atrial and ventricular morphant cardiomyocytes by electron microscopy. The morphants also exhibited smaller eyes than control fish, with absent or undifferentiated photoreceptors and disorganized inner layers at 3 dpf; the lens lacked the normal crystalline organization, and many of the fiber cells retained their nuclei. The phenotype could be rescued by overexpression of actn2 but not actn3 mRNAs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22253474" 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 a 7-year-old girl who died of dilated cardiomyopathy (CMD1AA; <a href="/entry/612158">612158</a>), <a href="#10" class="mim-tip-reference" title="Mohapatra, B., Jimenez, S., Lin, J. H., Bowles, K. R., Coveler, K. J., Marx, J. G., Chrisco, M. A., Murphy, R. T., Lurie, P. R., Schwartz, R. J., Elliott, P. M., Vatta, M., McKenna, W., Towbin, J. A., Bowles, N. E. <strong>Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis.</strong> Molec. Genet. Metab. 80: 207-215, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14567970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14567970</a>] [<a href="https://doi.org/10.1016/s1096-7192(03)00142-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14567970">Mohapatra et al. (2003)</a> identified heterozygosity for a 26A-G transition in exon 1 of the ACTN2 gene, resulting in a substitution of arg for the conserved residue gln9 (Q9R). The mutation was not found in the unaffected mother or in 200 controls; DNA was not available from the father, who had died from idiopathic CMD at 42 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14567970" 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">rs786204949 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786204949;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=rs786204949" 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=rs786204949" 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=RCV001850411 OR RCV004819192" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001850411, RCV004819192" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001850411...</a>
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<p>In a man who was diagnosed with hypertrophic cardiomyopathy (CMH23; see <a href="/entry/612158">612158</a>) at 31 years of age, <a href="#13" class="mim-tip-reference" title="Theis, J. L., Bos, J. M., Bartleson, V. B., Will, M. L., Binder, J., Vatta, M., Towbin, J. A., Gersh, B. J., Ommen, S. R., Ackerman, M. J. <strong>Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.</strong> Biochem. Biophys. Res. Commun. 351: 896-902, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17097056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17097056</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.10.119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17097056">Theis et al. (2006)</a> identified heterozygosity for a gly111-to-val (G111V) substitution in the ACTN2 gene. The patient had a maximum left ventricular wall thickness of 20 mm, with a sigmoid septal shape. He was treated with myectomy, and histopathologic analysis showed marked myocyte hypertrophy, focal myocyte disarray, and endocardial fibrosis. There was no family history of CMH or sudden cardiac death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17097056" 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 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 23</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs200248944 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200248944;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/rs200248944?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=rs200248944" 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=rs200248944" 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=RCV000036880 OR RCV000171827 OR RCV000470355 OR RCV000769759 OR RCV001703876 OR RCV004018816 OR RCV004819189" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000036880, RCV000171827, RCV000470355, RCV000769759, RCV001703876, RCV004018816, RCV004819189" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000036880...</a>
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<p>In a man who was diagnosed with hypertrophic cardiomyopathy (CMH23; see <a href="/entry/612158">612158</a>) at 32 years of age, <a href="#13" class="mim-tip-reference" title="Theis, J. L., Bos, J. M., Bartleson, V. B., Will, M. L., Binder, J., Vatta, M., Towbin, J. A., Gersh, B. J., Ommen, S. R., Ackerman, M. J. <strong>Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.</strong> Biochem. Biophys. Res. Commun. 351: 896-902, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17097056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17097056</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.10.119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17097056">Theis et al. (2006)</a> identified heterozygosity for a thr495-to-met (T495M) substitution in the ACTN2 gene. The patient had a maximum left ventricular wall thickness of 16 mm, with a sigmoid septal shape. He was treated with myectomy, and histopathologic analysis showed marked endocardial fibrosis, myocyte hypertrophy, and interstitial fibrosis. There was no family history of CMH or sudden cardiac death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17097056" 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 European and a South American proband with CMH, <a href="#4" class="mim-tip-reference" title="Chiu, C., Bagnall, R. D., Ingles, J., BBIOMEDSC, Yeates, L., Kennerson, M., Donald, J. A., Jormakka, M., Lind, J. M., Semsarian, C. <strong>Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis.</strong> J. Am. Coll. Cardiol. 55: 1127-1135, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20022194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20022194</a>] [<a href="https://doi.org/10.1016/j.jacc.2009.11.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20022194">Chiu et al. (2010)</a> identified heterozygosity for the T495M substitution in ACTN2, which the authors noted was located at a highly conserved residue within the second spectrin repeat of the rod domain. SNP analysis indicated that the mutation arose from different founders in the 2 families. One of the probands, who had an affected sister, also had a daughter who carried the T495M mutation. The 15-year-old girl had localized thickening of the interventricular septal wall, indicating early CMH. The other proband was a 20-year-old man with severe hypertrophy. His parents and sister were clinically unaffected but declined genetic testing. <a href="#4" class="mim-tip-reference" title="Chiu, C., Bagnall, R. D., Ingles, J., BBIOMEDSC, Yeates, L., Kennerson, M., Donald, J. A., Jormakka, M., Lind, J. M., Semsarian, C. <strong>Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis.</strong> J. Am. Coll. Cardiol. 55: 1127-1135, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20022194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20022194</a>] [<a href="https://doi.org/10.1016/j.jacc.2009.11.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20022194">Chiu et al. (2010)</a> noted that in contrast to the patient reported by <a href="#13" class="mim-tip-reference" title="Theis, J. L., Bos, J. M., Bartleson, V. B., Will, M. L., Binder, J., Vatta, M., Towbin, J. A., Gersh, B. J., Ommen, S. R., Ackerman, M. J. <strong>Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.</strong> Biochem. Biophys. Res. Commun. 351: 896-902, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17097056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17097056</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.10.119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17097056">Theis et al. (2006)</a>, none of these patients displayed sigmoidal morphology. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20022194+17097056" 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">rs786204950 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786204950;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=rs786204950" 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=rs786204950" 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=RCV004819193" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004819193" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004819193</a>
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<p>In a man who was diagnosed with hypertrophic cardiomyopathy (CMH23; see <a href="/entry/612158">612158</a>) at 18 years of age, <a href="#13" class="mim-tip-reference" title="Theis, J. L., Bos, J. M., Bartleson, V. B., Will, M. L., Binder, J., Vatta, M., Towbin, J. A., Gersh, B. J., Ommen, S. R., Ackerman, M. J. <strong>Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.</strong> Biochem. Biophys. Res. Commun. 351: 896-902, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17097056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17097056</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.10.119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17097056">Theis et al. (2006)</a> identified heterozygosity for an arg759-to-thr (R759T) substitution in the ACTN2 gene. The patient had a maximum left ventricular wall thickness of 16 mm, with a sigmoid septal shape. He was treated with myectomy, but the histopathologic report was unavailable. There was no family history of CMH or sudden cardiac death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17097056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 CARDIOMYOPATHY, DILATED, 1AA, WITH OR WITHOUT LEFT VENTRICULAR NONCOMPACTION</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">rs727502886 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs727502886;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=rs727502886" 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=rs727502886" 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=RCV000150148 OR RCV000169904 OR RCV001206449 OR RCV001265546 OR RCV004601116 OR RCV004819191" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000150148, RCV000169904, RCV001206449, RCV001265546, RCV004601116, RCV004819191" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000150148...</a>
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In 4 affected members over 2 generations of an Australian family with marked cardiac phenotype heterogeneity, including dilated cardiomyopathy (CMD1AA; <a href="/entry/612158">612158</a>), left ventricular noncompaction, ventricular fibrillation, and sudden death, <a href="#1" class="mim-tip-reference" title="Bagnall, R. D., Molloy, L. K., Kalman, J. M., Semsarian, C. <strong>Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.</strong> BMC Med. Genet. 15: 99, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25224718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25224718</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25224718[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s12881-014-0099-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25224718">Bagnall et al. (2014)</a> identified heterozygosity for a G-A transition in the ACTN2 gene (chr1.236,882,307G-A, GRCh37), resulting in an ala119-to-thr (A119T) substitution. The mutation was also present in an asymptomatic 35-year-old female cousin of the proband, in whom cardiac evaluation at age 29 was normal, including electrocardiography, echocardiography, electrophysiologic study, and 7-day Holter monitor. Haplotype analysis was consistent with a common ancestor shared by this family and the Australian family reported by <a href="#4" class="mim-tip-reference" title="Chiu, C., Bagnall, R. D., Ingles, J., BBIOMEDSC, Yeates, L., Kennerson, M., Donald, J. A., Jormakka, M., Lind, J. M., Semsarian, C. <strong>Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis.</strong> J. Am. Coll. Cardiol. 55: 1127-1135, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20022194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20022194</a>] [<a href="https://doi.org/10.1016/j.jacc.2009.11.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20022194">Chiu et al. (2010)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25224718+20022194" 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>Familial Hypertrophic Cardiomyopathy 23</em></strong></p><p>
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In affected members of a large 3-generation Australian family with clinically heterogeneous CMH mapping to chromosome 1 (CMH23; see <a href="/entry/612158">612158</a>), <a href="#4" class="mim-tip-reference" title="Chiu, C., Bagnall, R. D., Ingles, J., BBIOMEDSC, Yeates, L., Kennerson, M., Donald, J. A., Jormakka, M., Lind, J. M., Semsarian, C. <strong>Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis.</strong> J. Am. Coll. Cardiol. 55: 1127-1135, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20022194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20022194</a>] [<a href="https://doi.org/10.1016/j.jacc.2009.11.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20022194">Chiu et al. (2010)</a> identified heterozygosity for a G-A transition in exon 3 of the ACTN2 gene, resulting in an A119T substitution at a highly conserved residue within the CH1 domain of the actin-binding domain. Overexpression of the A119T variant in stably transfected myoblast cells resulted in a significant increase in RNA markers of hypertrophy. <a href="#4" class="mim-tip-reference" title="Chiu, C., Bagnall, R. D., Ingles, J., BBIOMEDSC, Yeates, L., Kennerson, M., Donald, J. A., Jormakka, M., Lind, J. M., Semsarian, C. <strong>Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis.</strong> J. Am. Coll. Cardiol. 55: 1127-1135, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20022194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20022194</a>] [<a href="https://doi.org/10.1016/j.jacc.2009.11.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20022194">Chiu et al. (2010)</a> stated that in contrast to previously reported patients with ACTN2 mutations <a href="#13" class="mim-tip-reference" title="Theis, J. L., Bos, J. M., Bartleson, V. B., Will, M. L., Binder, J., Vatta, M., Towbin, J. A., Gersh, B. J., Ommen, S. R., Ackerman, M. J. <strong>Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.</strong> Biochem. Biophys. Res. Commun. 351: 896-902, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17097056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17097056</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.10.119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17097056">Theis et al. (2006)</a>, none of these patients displayed sigmoidal morphology; rather, they exhibited generally mild hypertrophy with a diverse distribution, involving the septum in some individuals, whereas others showed apical, concentric, or right ventricular hypertrophy, with progression to a dilated phenotype and severe heart failure in some cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20022194+17097056" 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">rs786204951 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786204951;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=rs786204951" 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=rs786204951" 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=RCV004819194" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004819194" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004819194</a>
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<p>In a 44-year-old woman with moderate hypertrophic cardiomyopathy (CMH23; see <a href="/entry/612158">612158</a>), <a href="#4" class="mim-tip-reference" title="Chiu, C., Bagnall, R. D., Ingles, J., BBIOMEDSC, Yeates, L., Kennerson, M., Donald, J. A., Jormakka, M., Lind, J. M., Semsarian, C. <strong>Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis.</strong> J. Am. Coll. Cardiol. 55: 1127-1135, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20022194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20022194</a>] [<a href="https://doi.org/10.1016/j.jacc.2009.11.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20022194">Chiu et al. (2010)</a> identified heterozygosity for a glu628-to-gly (E628G) substitution at a highly conserved residue within the third spectrin repeat of the rod domain. The proband had 2 sons who also carried the mutation; 1 showed mild asymmetric septal hypertrophy with borderline voltage criteria for left ventricular hypertrophy on electrocardiogram, whereas the other son, who was only 15 years of age, was clinically normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20022194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 23, WITH OR WITHOUT LEFT VENTRICULAR NONCOMPACTION</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">rs786205144 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205144;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=rs786205144" 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=rs786205144" 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=RCV000169907 OR RCV000621721" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000169907, RCV000621721" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000169907...</a>
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<p>In 11 affected members of a large 4-generation Italian family with clinically heterogeneous cardiomyopathic disease comprising variable combinations of asymmetric left ventricular hypertrophy consistent with hypertrophic cardiomyopathy (CMH23; see <a href="/entry/612158">612158</a>) as well as early-onset supraventricular arrhythmias and AV block, and regional left ventricular noncompaction, <a href="#5" class="mim-tip-reference" title="Girolami, F., Iascone, M., Tomberli, B., Bardi, S., Benelli, M., Marseglia, G., Pescucci, C., Pezzoli, L., Sana, M. E., Basso, C., Marziliano, N., Merlini, P. A., Fornaro, A., Cecchi, F., Torricelli, F., Olivotto, I. <strong>Novel alpha-actinin 2 variant associated with familial hypertrophic cardiomyopathy and juvenile atrial arrhythmias: a massively parallel sequencing study.</strong> Circ. Cardiovasc. Genet. 7: 741-750, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25173926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25173926</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.113.000486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25173926">Girolami et al. (2014)</a> identified heterozygosity for a c.683T-C transition (c.683T-C, NM_001103.2) in the ACTN2 gene, resulting in a met228-to-thr (M228T) substitution at a conserved residue within the actin-binding domain. The mutation, which segregated fully with disease in the family, was not found in 570 control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25173926" 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">rs1572148902 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1572148902;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=rs1572148902" 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=rs1572148902" 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=RCV000855691" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000855691" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000855691</a>
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<p>In a 45-year-old man (patient 1) with congenital myopathy with structured cores and Z-line abnormalities (CMYO8; <a href="/entry/618654">618654</a>), <a href="#8" class="mim-tip-reference" title="Lornage, X., Romero, N. B., Grosgogeat, C. A., Malfatti, E., Donkervoort, S., Marchetti, M. M., Neuhaus, S. B., Foley, A. R., Labasse, C., Schneider, R., Carlier, R. Y., Chao, K. R., Medne, L., Deleuze, J.-F., Orlikowski, D., Bonnemann, C. G., Gupta, V. A., Fardeau, M., Bohm, J., Laporte, J. <strong>ACTN2 mutations cause 'multiple structured core disease' (MsCD).</strong> Acta Neuropath. 137: 501-519, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30701273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30701273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30701273[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00401-019-01963-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30701273">Lornage et al. (2019)</a> identified a de novo heterozygous c.2180T-G transversion (c.2180T-G, NM_001103.3) in exon 18 of the ACTN2 gene, resulting in a leu727-to-arg (L727R) substitution at a conserved residue in the fourth spectrin repeat. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Western blot analysis of skeletal muscle and analysis of cells transfected with the L727R mutation showed normal protein expression, dimerization, and localization. <a href="#8" class="mim-tip-reference" title="Lornage, X., Romero, N. B., Grosgogeat, C. A., Malfatti, E., Donkervoort, S., Marchetti, M. M., Neuhaus, S. B., Foley, A. R., Labasse, C., Schneider, R., Carlier, R. Y., Chao, K. R., Medne, L., Deleuze, J.-F., Orlikowski, D., Bonnemann, C. G., Gupta, V. A., Fardeau, M., Bohm, J., Laporte, J. <strong>ACTN2 mutations cause 'multiple structured core disease' (MsCD).</strong> Acta Neuropath. 137: 501-519, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30701273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30701273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30701273[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00401-019-01963-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30701273">Lornage et al. (2019)</a> found that expression of human mutant ACTN2 L727R in zebrafish embryos resulted in hatching defects, smaller myotome, dorsal curvature, and impaired motor function, although levels of protein expression were not affected. Skeletal muscle from mutant fish showed significant myofibrillar disarray, abnormal Z-lines, and abnormal actin-myosin interaction compared to wildtype. AAV-mediated expression of the mutation in skeletal muscle of 3-week-old mice resulted in reduced maximal force as well as abnormal Z-line organization and core formation. The findings in both animal models recapitulated the specific phenotype in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30701273" 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">rs1572148914 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1572148914;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=rs1572148914" 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=rs1572148914" 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=RCV000855692" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000855692" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000855692</a>
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<p>In a 40-year-old woman (patient 2) with congenital myopathy-8 (CMYO8; <a href="/entry/618654">618654</a>), <a href="#8" class="mim-tip-reference" title="Lornage, X., Romero, N. B., Grosgogeat, C. A., Malfatti, E., Donkervoort, S., Marchetti, M. M., Neuhaus, S. B., Foley, A. R., Labasse, C., Schneider, R., Carlier, R. Y., Chao, K. R., Medne, L., Deleuze, J.-F., Orlikowski, D., Bonnemann, C. G., Gupta, V. A., Fardeau, M., Bohm, J., Laporte, J. <strong>ACTN2 mutations cause 'multiple structured core disease' (MsCD).</strong> Acta Neuropath. 137: 501-519, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30701273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30701273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30701273[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00401-019-01963-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30701273">Lornage et al. (2019)</a> identified a de novo heterozygous 33-bp in-frame deletion (c.2194_2226del, NM_001103.3) in exon 18 of the ACTN2 gene, resulting in an Ala732_Ile742del in the fourth spectrin repeat. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30701273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 MYOPATHY, DISTAL, 6, ADULT-ONSET, 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">rs1572140109 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1572140109;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=rs1572140109" 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=rs1572140109" 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=RCV000855694" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000855694" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000855694</a>
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<p>In affected members of 3 unrelated families from northern Spain with autosomal dominant adult-onset distal myopathy-6 (MPD6; <a href="/entry/618655">618655</a>), <a href="#11" class="mim-tip-reference" title="Savarese, M., Palmio, J., Poza, J. J., Weinberg, J., Olive, M., Cobo, A. M., Vihola, A., Jonson, P. H., Sarparanta, J., Garcia-Bragado, F., Urtizberea, J. A., Hackman, P., Udd, B. <strong>Actininopathy: a new muscular dystrophy caused by ACTN2 dominant mutations.</strong> Ann. Neurol. 85: 899-906, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30900782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30900782</a>] [<a href="https://doi.org/10.1002/ana.25470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30900782">Savarese et al. (2019)</a> identified a heterozygous c.1459T-C transition (c.1459T-C, NM_001103) in the ACTN2 gene, resulting in a cys487-to-arg (C487R) substitution at a conserved residue in the second spectrin repeat, which is important for dimerization. The variant, which was found by targeted panel sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The variant was not found in the gnomAD database. The families all came from the same small village, suggesting a possible founder effect. Functional studies of the variant were not performed, but cDNA analysis showed that the variant did not affect splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30900782" 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>.0011 MYOPATHY, DISTAL, 6, ADULT-ONSET, AUTOSOMAL DOMINANT</strong>
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ACTN2, LEU131PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1572114611 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1572114611;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=rs1572114611" 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=rs1572114611" 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=RCV000855693" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000855693" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000855693</a>
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<p>In a Swedish father and daughter with autosomal dominant adult-onset distal myopathy-6 (MPD6; <a href="/entry/618655">618655</a>), <a href="#11" class="mim-tip-reference" title="Savarese, M., Palmio, J., Poza, J. J., Weinberg, J., Olive, M., Cobo, A. M., Vihola, A., Jonson, P. H., Sarparanta, J., Garcia-Bragado, F., Urtizberea, J. A., Hackman, P., Udd, B. <strong>Actininopathy: a new muscular dystrophy caused by ACTN2 dominant mutations.</strong> Ann. Neurol. 85: 899-906, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30900782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30900782</a>] [<a href="https://doi.org/10.1002/ana.25470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30900782">Savarese et al. (2019)</a> identified a heterozygous c.392T-C transition (c.392T-C, NM_001103) in the ACTN2 gene, resulting in a leu131-to-pro (L131P) substitution in the actin-binding domain. The variant, which was found by targeted panel sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30900782" 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="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Bagnall2014" class="mim-anchor"></a>
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Bagnall, R. D., Molloy, L. K., Kalman, J. M., Semsarian, C.
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<strong>Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.</strong>
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BMC Med. Genet. 15: 99, 2014. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25224718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25224718</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25224718[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=25224718" 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/10.1186/s12881-014-0099-0" target="_blank">Full Text</a>]
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<a id="Beggs1992" class="mim-anchor"></a>
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Beggs, A. H., Byers, T. J., Knoll, J. H. M., Boyce, F. M., Bruns, G. A. P., Kunkel, L. M.
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<strong>Cloning and characterization of two human skeletal muscle alpha-actinin genes located on chromosomes 1 and 11.</strong>
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J. Biol. Chem. 267: 9281-9288, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1339456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1339456</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1339456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Beggs1992" class="mim-anchor"></a>
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Beggs, A. H., Phillips, H. A., Kozman, H., Mulley, J. C., Wilton, S. D., Kunkel, L. M., Laing, N. G.
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<strong>A (CA)n repeat polymorphism for the human skeletal muscle alpha-actinin gene ACTN2 and its localization on the linkage map of chromosome 1.</strong>
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Genomics 13: 1314-1315, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1505962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1505962</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1505962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(92)90054-v" target="_blank">Full Text</a>]
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<a id="Chiu2010" class="mim-anchor"></a>
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Chiu, C., Bagnall, R. D., Ingles, J., BBIOMEDSC, Yeates, L., Kennerson, M., Donald, J. A., Jormakka, M., Lind, J. M., Semsarian, C.
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<strong>Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis.</strong>
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J. Am. Coll. Cardiol. 55: 1127-1135, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20022194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20022194</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20022194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jacc.2009.11.016" target="_blank">Full Text</a>]
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<a id="Girolami2014" class="mim-anchor"></a>
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Girolami, F., Iascone, M., Tomberli, B., Bardi, S., Benelli, M., Marseglia, G., Pescucci, C., Pezzoli, L., Sana, M. E., Basso, C., Marziliano, N., Merlini, P. A., Fornaro, A., Cecchi, F., Torricelli, F., Olivotto, I.
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<strong>Novel alpha-actinin 2 variant associated with familial hypertrophic cardiomyopathy and juvenile atrial arrhythmias: a massively parallel sequencing study.</strong>
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Circ. Cardiovasc. Genet. 7: 741-750, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25173926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25173926</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25173926" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/CIRCGENETICS.113.000486" target="_blank">Full Text</a>]
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<a id="Gupta2012" class="mim-anchor"></a>
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Gupta, V., Discenza, M., Guyon, J. R., Kunkel, L. M., Beggs, A. H.
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<strong>Alpha-actinin-2 deficiency results in sarcomeric defects in zebrafish that cannot be rescued by alpha-actinin-3 revealing functional differences between sarcomeric isoforms.</strong>
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FASEB J. 26: 1892-1908, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22253474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22253474</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22253474[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=22253474" 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/10.1096/fj.11-194548" target="_blank">Full Text</a>]
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<a id="Harper2002" class="mim-anchor"></a>
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Harper, S. Q., Crawford, R. W., DellRusso, C., Chamberlain, J. S.
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<strong>Spectrin-like repeats from dystrophin and alpha-actinin-2 are not functionally interchangeable.</strong>
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Hum. Molec. Genet. 11: 1807-1815, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12140183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12140183</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12140183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/11.16.1807" target="_blank">Full Text</a>]
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<a id="Lornage2019" class="mim-anchor"></a>
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Lornage, X., Romero, N. B., Grosgogeat, C. A., Malfatti, E., Donkervoort, S., Marchetti, M. M., Neuhaus, S. B., Foley, A. R., Labasse, C., Schneider, R., Carlier, R. Y., Chao, K. R., Medne, L., Deleuze, J.-F., Orlikowski, D., Bonnemann, C. G., Gupta, V. A., Fardeau, M., Bohm, J., Laporte, J.
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<strong>ACTN2 mutations cause 'multiple structured core disease' (MsCD).</strong>
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Acta Neuropath. 137: 501-519, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30701273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30701273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30701273[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=30701273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00401-019-01963-8" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Mills2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Mills, M. A., Yang, N., Weinberger, R. P., Vander Woude, D. L., Beggs, A. H., Easteal, S., North, K. N.
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|
<strong>Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy.</strong>
|
|
Hum. Molec. Genet. 10: 1335-1346, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11440986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11440986</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11440986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/10.13.1335" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Mohapatra2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Mohapatra, B., Jimenez, S., Lin, J. H., Bowles, K. R., Coveler, K. J., Marx, J. G., Chrisco, M. A., Murphy, R. T., Lurie, P. R., Schwartz, R. J., Elliott, P. M., Vatta, M., McKenna, W., Towbin, J. A., Bowles, N. E.
|
|
<strong>Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis.</strong>
|
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Molec. Genet. Metab. 80: 207-215, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14567970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14567970</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14567970" 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/s1096-7192(03)00142-2" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Savarese2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Savarese, M., Palmio, J., Poza, J. J., Weinberg, J., Olive, M., Cobo, A. M., Vihola, A., Jonson, P. H., Sarparanta, J., Garcia-Bragado, F., Urtizberea, J. A., Hackman, P., Udd, B.
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|
<strong>Actininopathy: a new muscular dystrophy caused by ACTN2 dominant mutations.</strong>
|
|
Ann. Neurol. 85: 899-906, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30900782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30900782</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30900782" 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.25470" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Seto2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Seto, J. T., Lek, M., Quinlan, K. G. R., Houweling, P. J., Zheng, X. F., Garton, F., MacArthur, D. G., Raftery, J. M., Garvey, S. M., Hauser, M. A., Yang, N., Head, S. I., North, K. N.
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<strong>Deficiency of alpha-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling.</strong>
|
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Hum. Molec. Genet. 20: 2914-2927, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21536590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21536590</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21536590" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddr196" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Theis2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Theis, J. L., Bos, J. M., Bartleson, V. B., Will, M. L., Binder, J., Vatta, M., Towbin, J. A., Gersh, B. J., Ommen, S. R., Ackerman, M. J.
|
|
<strong>Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.</strong>
|
|
Biochem. Biophys. Res. Commun. 351: 896-902, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17097056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17097056</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17097056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2006.10.119" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 11/07/2019
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 4/17/2015<br>Patricia A. Hartz - updated : 4/10/2013<br>Marla J. F. O'Neill - updated : 6/30/2008<br>George E. Tiller - updated : 7/3/2003<br>George E. Tiller - updated : 11/12/2001
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 8/14/1992
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 07/16/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 03/09/2023<br>ckniffin : 03/08/2023<br>carol : 01/11/2023<br>carol : 01/10/2023<br>carol : 11/11/2019<br>carol : 11/08/2019<br>ckniffin : 11/07/2019<br>carol : 04/25/2017<br>carol : 08/05/2016<br>mcolton : 05/26/2015<br>carol : 4/20/2015<br>carol : 4/18/2015<br>carol : 4/17/2015<br>carol : 11/4/2013<br>carol : 8/5/2013<br>mgross : 4/10/2013<br>terry : 7/3/2008<br>alopez : 7/1/2008<br>alopez : 6/30/2008<br>terry : 6/30/2008<br>cwells : 7/3/2003<br>alopez : 11/21/2001<br>cwells : 11/20/2001<br>cwells : 11/20/2001<br>cwells : 11/20/2001<br>cwells : 11/12/2001<br>carol : 10/13/1992<br>carol : 9/9/1992<br>carol : 8/14/1992
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</span>
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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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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 102573
|
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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ACTININ, ALPHA-2; ACTN2
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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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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ACTN2</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
|
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<em>
|
|
Cytogenetic location: 1q43
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 1:236,686,499-236,764,631 </span>
|
|
</em>
|
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</strong>
|
|
<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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</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-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<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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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
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</th>
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</tr>
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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">
|
|
1q43
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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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Cardiomyopathy, dilated, 1AA, with or without LVNC
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
612158
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
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">
|
|
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">
|
|
Cardiomyopathy, hypertrophic, 23, with or without LVNC
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
612158
|
|
</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
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">
|
|
Congenital myopathy 8
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
618654
|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
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">
|
|
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>
|
|
<span class="mim-font">
|
|
Myopathy, distal, 6, adult onset
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
618655
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</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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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
<span class="mim-text-font">
|
|
<p>The ACTN2 gene encodes alpha-actinin-2, which is highly expressed in the sarcomeric Z-disk or Z-line in both cardiac and skeletal muscle, where it plays important structural and functional roles in the sarcomere and contractile apparatus (summary by Lornage et al., 2019). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<span class="mim-text-font">
|
|
<p>Alpha-actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane (see ACTN1; 102575). In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. Beggs et al. (1992) characterized 2 human muscle-specific alpha-actinin genes, ACTN2 and ACTN3 (102574). They identified 3 ACTN2 transcripts that differed only in their use of polyadenylation signals. The deduced 894-amino acid protein has a calculated molecular mass of about 104 kD. ACTN2 has an N-terminal actin-binding domain of about 250 amino acids, followed by 4 central repeats and 2 EF-hand motifs near the C terminus. Northern blot analysis of mouse tissues detected Actn2 expression in skeletal muscle and heart, but not in brain, liver, kidney, or small intestine. Two major ACTN2 bands were detected in human fetal skeletal muscle. </p><p>Seto et al. (2011) stated that the central repeats of ACTN2 are spectrin (see 182860)-like repeats that form a rod domain. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</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>Using somatic cell hybrids, Beggs et al. (1992) mapped the ACTN2 and ACTN3 genes to chromosomes 1 and 11, respectively. In situ hybridization placed the ACTN2 locus at 1q42-q43. Beggs et al. (1992) identified a polymorphic (CA)n repeat within the ACTN2 gene and used it to position the ACTN2 gene on the CEPH linkage map of chromosome 1. </p><p>Mills et al. (2001) mapped the 4 murine actinin orthologs, which were all located at evolutionarily conserved syntenic regions for the 4 human genes. </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>Mills et al. (2001) observed that murine Actn2 and Actn3 were differentially expressed, spatially and temporally, during embryonic development and, in contrast to humans, alpha-actinin-2 expression did not completely overlap with alpha-actinin-3 in postnatal skeletal muscle, suggesting independent function. </p><p>Seto et al. (2011) found that expression of Actn2 was upregulated in Actn3 -/- mouse extensor digitorum longus muscle such that the total sarcomeric content of alpha-actinin was unchanged. Actn3 -/- muscle was susceptible to contraction-induced damage compared with wildtype. The Z-disc proteins Zasp (LDB3; 605906), titin (TTN; 188840), and vinculin (VCL; 193065) bound more avidly to Actn2 than to Actn3, suggesting a biochemical basis for altered mechanics and fragility in Actn3 -/- muscle. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Cardiac Phenotypes</em></strong></p><p>
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|
In a 7-year-old girl who died of dilated cardiomyopathy (CMD1AA; 612158) and was negative for mutation in 8 known cardiomyopathy genes, Mohapatra et al. (2003) identified heterozygosity for a missense mutation in the ACTN2 gene (Q9R; 102573.0001). </p><p>In 3 sporadic patients with hypertrophic cardiomyopathy (CMH23; see 612158), Theis et al. (2006) identified heterozygous missense mutations in the ACTN2 gene (102573.0002-102573.0004). </p><p>In affected members of a large 3-generation Australian family with clinically heterogeneous CMH mapping to chromosome 1, Chiu et al. (2010) identified heterozygosity for a missense mutation in the ACTN2 gene (A119T; 102573.0005). Screening of an additional 297 CMH probands identified 3 heterozygous missense mutations that segregated with disease in the respective families (see, e.g., 102573.0003 and 102573.0006). </p><p>In 4 affected members over 2 generations of an Australian family with marked cardiac phenotype heterogeneity, including CMD, left ventricular noncompaction (LVNC), ventricular fibrillation, and sudden death, Bagnall et al. (2014) identified heterozygosity for the same A119T substitution in the ACTN2 gene that had previously been detected in an apparently unrelated Australian family with clinically heterogeneous CMH by Chiu et al. (2010). Haplotype analysis was consistent with a common ancestor for the 2 Australian families. </p><p>In a large 4-generation Italian family with clinically heterogeneous cardiomyopathic disease comprising variable combinations of asymmetric left ventricular hypertrophy (LVH) consistent with CMH, early-onset supraventricular arrhythmias and atrioventricular (AV) block, and regional LVNC, Girolami et al. (2014) performed next-generation sequencing and identified heterozygosity for a missense mutation in ACTN2 (M228T; 102573.0007). The mutation, which segregated fully with disease in the family, was not found in 570 control alleles. </p><p><strong><em>Congenital Myopathy 8</em></strong></p><p>
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|
In 2 unrelated patients with congenital myopathy-8 (CMYO8; 618654), Lornage et al. (2019) identified de novo heterozygous mutations in exon 18 of the ACTN2 gene (L727R, 102573.0008 and an in-frame deletion, 102573.0009); both were located in the fourth spectrin repeat. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. In addition, patient 1 was heterozygous and patient 2 was homozygous for the common R577X polymorphism in the ACTN3 gene (102574.0001). Western blot analysis of skeletal muscle from the patient with the L727R mutation and analysis of cells transfected with that mutation showed normal protein expression, dimerization, and localization. However, Lornage et al. (2019) found that expression of human mutant ACTN2 L727R in zebrafish embryos resulted in hatching defects, smaller myotome, dorsal curvature, and impaired motor function, although levels of protein expression were not affected. Skeletal muscle from mutant fish showed significant myofibrillar disarray, sarcomeric disorganization, abnormal Z-lines, and abnormal actin-myosin interaction compared to wildtype. AAV-mediated expression of the mutation in skeletal muscle of 3-week-old mice resulted in reduced maximal force as well as abnormal Z-line organization and core formation. The findings in both animal models recapitulated the specific phenotype in humans. </p><p><strong><em>Adult-Onset Distal Myopathy 6, Autosomal Dominant</em></strong></p><p>
|
|
In affected members of 3 unrelated families from northern Spain with autosomal dominant adult-onset distal myopathy-6 (MPD6; 618655), Savarese et al. (2019) identified a heterozygous missense mutation in the ACTN2 gene (C487R; 102573.0010). In a Swedish father and daughter with a similar disorder, they identified a different heterozygous mutation in the ACTN2 gene (L131P; 102573.0011). The variants, which were found by targeted panel sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families and were not found in the gnomAD database. Functional studies of the variants were not performed. </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>Mutations in the dystrophin gene (DMD; 300377) result in Duchenne muscular dystrophy. Dystrophin is a multidomain protein that functions to stabilize the sarcolemmal membrane during muscle contraction. Dystrophin shares considerable homology with alpha-actinin. To explore the hypothesis that the dystrophin rod domain acts as a spacer region, Harper et al. (2002) expressed a chimeric micro-dystrophin transgene containing the 4-repeat rod domain of alpha-actinin-2 in mdx mice. The transgene was incapable of correcting the morphologic pathology of the mdx mouse, but still functioned to assemble the dystrophin-glycoprotein complex at the membrane and provided some protection from contraction-induced injury. The authors concluded that different spectrin-like repeats are not equivalent, and proposed that the dystrophin rod domain is not merely a spacer but likely contributes an important mechanical role to overall dystrophin function. </p><p>Gupta et al. (2012) performed targeted knockdown of actn2 in zebrafish and observed developmental defects in eye, heart, and skeletal muscle. Morphant fish were largely immotile with a blunted touch-evoked response, suggesting a significant degree of overall muscle weakness. Morphants consistently exhibited smaller eyes, enlarged hearts with reduced heartbeat, and abnormal organization of skeletal muscles. Skeletal muscles showed a significant decrease in birefringence, and histologic analysis of longitudinal sections revealed disorganized muscle fibers, with occasional fibers completely lacking in myofibrillar organization; on electron microscopy, many fibers showed reduced sarcomeric organization and rounded multiple nuclei. The cardiac phenotype presented as a reduction in heart rate between 1 and 2 days postfertilization (dpf), and by 3 dpf, morphants exhibited clearly enlarged hearts; histologic examination showed enlarged hearts with both atrial and ventricular dilation and remarkably thin walls, and there was a marked decrease in the size and number of sarcomeric assemblies in both atrial and ventricular morphant cardiomyocytes by electron microscopy. The morphants also exhibited smaller eyes than control fish, with absent or undifferentiated photoreceptors and disorganized inner layers at 3 dpf; the lens lacked the normal crystalline organization, and many of the fiber cells retained their nuclei. The phenotype could be rescued by overexpression of actn2 but not actn3 mRNAs. </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>11 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CARDIOMYOPATHY, DILATED, 1AA</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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ACTN2, GLN9ARG
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<br />
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SNP: rs121434525,
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gnomAD: rs121434525,
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ClinVar: RCV000019977, RCV000036908, RCV000172514, RCV000245795, RCV000461895, RCV000769743, RCV003224104, RCV003327363, RCV003993748, RCV004549383
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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-year-old girl who died of dilated cardiomyopathy (CMD1AA; 612158), Mohapatra et al. (2003) identified heterozygosity for a 26A-G transition in exon 1 of the ACTN2 gene, resulting in a substitution of arg for the conserved residue gln9 (Q9R). The mutation was not found in the unaffected mother or in 200 controls; DNA was not available from the father, who had died from idiopathic CMD at 42 years of age. </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>.0002 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 23</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ACTN2, GLY111VAL
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<br />
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SNP: rs786204949,
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ClinVar: RCV001850411, RCV004819192
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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 man who was diagnosed with hypertrophic cardiomyopathy (CMH23; see 612158) at 31 years of age, Theis et al. (2006) identified heterozygosity for a gly111-to-val (G111V) substitution in the ACTN2 gene. The patient had a maximum left ventricular wall thickness of 20 mm, with a sigmoid septal shape. He was treated with myectomy, and histopathologic analysis showed marked myocyte hypertrophy, focal myocyte disarray, and endocardial fibrosis. There was no family history of CMH or sudden cardiac death. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 23</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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ACTN2, THR495MET
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<br />
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|
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SNP: rs200248944,
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|
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gnomAD: rs200248944,
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|
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ClinVar: RCV000036880, RCV000171827, RCV000470355, RCV000769759, RCV001703876, RCV004018816, RCV004819189
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a man who was diagnosed with hypertrophic cardiomyopathy (CMH23; see 612158) at 32 years of age, Theis et al. (2006) identified heterozygosity for a thr495-to-met (T495M) substitution in the ACTN2 gene. The patient had a maximum left ventricular wall thickness of 16 mm, with a sigmoid septal shape. He was treated with myectomy, and histopathologic analysis showed marked endocardial fibrosis, myocyte hypertrophy, and interstitial fibrosis. There was no family history of CMH or sudden cardiac death. </p><p>In a European and a South American proband with CMH, Chiu et al. (2010) identified heterozygosity for the T495M substitution in ACTN2, which the authors noted was located at a highly conserved residue within the second spectrin repeat of the rod domain. SNP analysis indicated that the mutation arose from different founders in the 2 families. One of the probands, who had an affected sister, also had a daughter who carried the T495M mutation. The 15-year-old girl had localized thickening of the interventricular septal wall, indicating early CMH. The other proband was a 20-year-old man with severe hypertrophy. His parents and sister were clinically unaffected but declined genetic testing. Chiu et al. (2010) noted that in contrast to the patient reported by Theis et al. (2006), none of these patients displayed sigmoidal morphology. </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>.0004 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 23</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
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ACTN2, ARG759THR
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<br />
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|
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SNP: rs786204950,
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|
|
ClinVar: RCV004819193
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|
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|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a man who was diagnosed with hypertrophic cardiomyopathy (CMH23; see 612158) at 18 years of age, Theis et al. (2006) identified heterozygosity for an arg759-to-thr (R759T) substitution in the ACTN2 gene. The patient had a maximum left ventricular wall thickness of 16 mm, with a sigmoid septal shape. He was treated with myectomy, but the histopathologic report was unavailable. There was no family history of CMH or sudden cardiac death. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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|
</div>
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</div>
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|
<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CARDIOMYOPATHY, DILATED, 1AA, WITH OR WITHOUT LEFT VENTRICULAR NONCOMPACTION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 23, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ACTN2, ALA119THR
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|
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|
|
|
<br />
|
|
|
|
SNP: rs727502886,
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|
|
|
|
|
|
|
ClinVar: RCV000150148, RCV000169904, RCV001206449, RCV001265546, RCV004601116, RCV004819191
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Dilated Cardiomyopathy 1AA</em></strong></p><p>
|
|
In 4 affected members over 2 generations of an Australian family with marked cardiac phenotype heterogeneity, including dilated cardiomyopathy (CMD1AA; 612158), left ventricular noncompaction, ventricular fibrillation, and sudden death, Bagnall et al. (2014) identified heterozygosity for a G-A transition in the ACTN2 gene (chr1.236,882,307G-A, GRCh37), resulting in an ala119-to-thr (A119T) substitution. The mutation was also present in an asymptomatic 35-year-old female cousin of the proband, in whom cardiac evaluation at age 29 was normal, including electrocardiography, echocardiography, electrophysiologic study, and 7-day Holter monitor. Haplotype analysis was consistent with a common ancestor shared by this family and the Australian family reported by Chiu et al. (2010). </p><p><strong><em>Familial Hypertrophic Cardiomyopathy 23</em></strong></p><p>
|
|
In affected members of a large 3-generation Australian family with clinically heterogeneous CMH mapping to chromosome 1 (CMH23; see 612158), Chiu et al. (2010) identified heterozygosity for a G-A transition in exon 3 of the ACTN2 gene, resulting in an A119T substitution at a highly conserved residue within the CH1 domain of the actin-binding domain. Overexpression of the A119T variant in stably transfected myoblast cells resulted in a significant increase in RNA markers of hypertrophy. Chiu et al. (2010) stated that in contrast to previously reported patients with ACTN2 mutations Theis et al. (2006), none of these patients displayed sigmoidal morphology; rather, they exhibited generally mild hypertrophy with a diverse distribution, involving the septum in some individuals, whereas others showed apical, concentric, or right ventricular hypertrophy, with progression to a dilated phenotype and severe heart failure in some cases. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 23</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
ACTN2, GLU628GLY
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<br />
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|
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SNP: rs786204951,
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|
|
ClinVar: RCV004819194
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 44-year-old woman with moderate hypertrophic cardiomyopathy (CMH23; see 612158), Chiu et al. (2010) identified heterozygosity for a glu628-to-gly (E628G) substitution at a highly conserved residue within the third spectrin repeat of the rod domain. The proband had 2 sons who also carried the mutation; 1 showed mild asymmetric septal hypertrophy with borderline voltage criteria for left ventricular hypertrophy on electrocardiogram, whereas the other son, who was only 15 years of age, was clinically normal. </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>.0007 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 23, WITH OR WITHOUT LEFT VENTRICULAR NONCOMPACTION</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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ACTN2, MET228THR
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<br />
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SNP: rs786205144,
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|
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ClinVar: RCV000169907, RCV000621721
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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 11 affected members of a large 4-generation Italian family with clinically heterogeneous cardiomyopathic disease comprising variable combinations of asymmetric left ventricular hypertrophy consistent with hypertrophic cardiomyopathy (CMH23; see 612158) as well as early-onset supraventricular arrhythmias and AV block, and regional left ventricular noncompaction, Girolami et al. (2014) identified heterozygosity for a c.683T-C transition (c.683T-C, NM_001103.2) in the ACTN2 gene, resulting in a met228-to-thr (M228T) substitution at a conserved residue within the actin-binding domain. The mutation, which segregated fully with disease in the family, was not found in 570 control alleles. </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>
|
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<span class="mim-font">
|
|
<strong>.0008 CONGENITAL MYOPATHY 8</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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ACTN2, LEU727ARG
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<br />
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SNP: rs1572148902,
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ClinVar: RCV000855691
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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 (patient 1) with congenital myopathy with structured cores and Z-line abnormalities (CMYO8; 618654), Lornage et al. (2019) identified a de novo heterozygous c.2180T-G transversion (c.2180T-G, NM_001103.3) in exon 18 of the ACTN2 gene, resulting in a leu727-to-arg (L727R) substitution at a conserved residue in the fourth spectrin repeat. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Western blot analysis of skeletal muscle and analysis of cells transfected with the L727R mutation showed normal protein expression, dimerization, and localization. Lornage et al. (2019) found that expression of human mutant ACTN2 L727R in zebrafish embryos resulted in hatching defects, smaller myotome, dorsal curvature, and impaired motor function, although levels of protein expression were not affected. Skeletal muscle from mutant fish showed significant myofibrillar disarray, abnormal Z-lines, and abnormal actin-myosin interaction compared to wildtype. AAV-mediated expression of the mutation in skeletal muscle of 3-week-old mice resulted in reduced maximal force as well as abnormal Z-line organization and core formation. The findings in both animal models recapitulated the specific phenotype in humans. </p>
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<span class="mim-font">
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<strong>.0009 CONGENITAL MYOPATHY 8</strong>
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<span class="mim-text-font">
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ACTN2, 33-BP DEL, NT2194
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SNP: rs1572148914,
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ClinVar: RCV000855692
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<p>In a 40-year-old woman (patient 2) with congenital myopathy-8 (CMYO8; 618654), Lornage et al. (2019) identified a de novo heterozygous 33-bp in-frame deletion (c.2194_2226del, NM_001103.3) in exon 18 of the ACTN2 gene, resulting in an Ala732_Ile742del in the fourth spectrin repeat. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>.0010 MYOPATHY, DISTAL, 6, ADULT-ONSET, AUTOSOMAL DOMINANT</strong>
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</span>
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<span class="mim-text-font">
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ACTN2, CYS487ARG
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<br />
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SNP: rs1572140109,
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ClinVar: RCV000855694
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<p>In affected members of 3 unrelated families from northern Spain with autosomal dominant adult-onset distal myopathy-6 (MPD6; 618655), Savarese et al. (2019) identified a heterozygous c.1459T-C transition (c.1459T-C, NM_001103) in the ACTN2 gene, resulting in a cys487-to-arg (C487R) substitution at a conserved residue in the second spectrin repeat, which is important for dimerization. The variant, which was found by targeted panel sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The variant was not found in the gnomAD database. The families all came from the same small village, suggesting a possible founder effect. Functional studies of the variant were not performed, but cDNA analysis showed that the variant did not affect splicing. </p>
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<h4>
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<span class="mim-font">
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<strong>.0011 MYOPATHY, DISTAL, 6, ADULT-ONSET, AUTOSOMAL DOMINANT</strong>
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</span>
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<span class="mim-text-font">
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ACTN2, LEU131PRO
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<br />
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SNP: rs1572114611,
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ClinVar: RCV000855693
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<div>
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<span class="mim-text-font">
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<p>In a Swedish father and daughter with autosomal dominant adult-onset distal myopathy-6 (MPD6; 618655), Savarese et al. (2019) identified a heterozygous c.392T-C transition (c.392T-C, NM_001103) in the ACTN2 gene, resulting in a leu131-to-pro (L131P) substitution in the actin-binding domain. The variant, which was found by targeted panel sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<p />
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</div>
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<ol>
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<p class="mim-text-font">
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Bagnall, R. D., Molloy, L. K., Kalman, J. M., Semsarian, C.
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<strong>Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.</strong>
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BMC Med. Genet. 15: 99, 2014. Note: Electronic Article.
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[PubMed: 25224718]
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[Full Text: https://doi.org/10.1186/s12881-014-0099-0]
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</p>
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</li>
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<li>
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Beggs, A. H., Byers, T. J., Knoll, J. H. M., Boyce, F. M., Bruns, G. A. P., Kunkel, L. M.
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<strong>Cloning and characterization of two human skeletal muscle alpha-actinin genes located on chromosomes 1 and 11.</strong>
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J. Biol. Chem. 267: 9281-9288, 1992.
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[PubMed: 1339456]
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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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Beggs, A. H., Phillips, H. A., Kozman, H., Mulley, J. C., Wilton, S. D., Kunkel, L. M., Laing, N. G.
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<strong>A (CA)n repeat polymorphism for the human skeletal muscle alpha-actinin gene ACTN2 and its localization on the linkage map of chromosome 1.</strong>
|
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Genomics 13: 1314-1315, 1992.
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[PubMed: 1505962]
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[Full Text: https://doi.org/10.1016/0888-7543(92)90054-v]
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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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Chiu, C., Bagnall, R. D., Ingles, J., BBIOMEDSC, Yeates, L., Kennerson, M., Donald, J. A., Jormakka, M., Lind, J. M., Semsarian, C.
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<strong>Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis.</strong>
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J. Am. Coll. Cardiol. 55: 1127-1135, 2010.
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[PubMed: 20022194]
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[Full Text: https://doi.org/10.1016/j.jacc.2009.11.016]
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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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Girolami, F., Iascone, M., Tomberli, B., Bardi, S., Benelli, M., Marseglia, G., Pescucci, C., Pezzoli, L., Sana, M. E., Basso, C., Marziliano, N., Merlini, P. A., Fornaro, A., Cecchi, F., Torricelli, F., Olivotto, I.
|
|
<strong>Novel alpha-actinin 2 variant associated with familial hypertrophic cardiomyopathy and juvenile atrial arrhythmias: a massively parallel sequencing study.</strong>
|
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Circ. Cardiovasc. Genet. 7: 741-750, 2014.
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[PubMed: 25173926]
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[Full Text: https://doi.org/10.1161/CIRCGENETICS.113.000486]
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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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Gupta, V., Discenza, M., Guyon, J. R., Kunkel, L. M., Beggs, A. H.
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<strong>Alpha-actinin-2 deficiency results in sarcomeric defects in zebrafish that cannot be rescued by alpha-actinin-3 revealing functional differences between sarcomeric isoforms.</strong>
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FASEB J. 26: 1892-1908, 2012.
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[PubMed: 22253474]
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[Full Text: https://doi.org/10.1096/fj.11-194548]
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</li>
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<p class="mim-text-font">
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Harper, S. Q., Crawford, R. W., DellRusso, C., Chamberlain, J. S.
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<strong>Spectrin-like repeats from dystrophin and alpha-actinin-2 are not functionally interchangeable.</strong>
|
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Hum. Molec. Genet. 11: 1807-1815, 2002.
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[PubMed: 12140183]
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[Full Text: https://doi.org/10.1093/hmg/11.16.1807]
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</p>
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<li>
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<p class="mim-text-font">
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Lornage, X., Romero, N. B., Grosgogeat, C. A., Malfatti, E., Donkervoort, S., Marchetti, M. M., Neuhaus, S. B., Foley, A. R., Labasse, C., Schneider, R., Carlier, R. Y., Chao, K. R., Medne, L., Deleuze, J.-F., Orlikowski, D., Bonnemann, C. G., Gupta, V. A., Fardeau, M., Bohm, J., Laporte, J.
|
|
<strong>ACTN2 mutations cause 'multiple structured core disease' (MsCD).</strong>
|
|
Acta Neuropath. 137: 501-519, 2019.
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[PubMed: 30701273]
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[Full Text: https://doi.org/10.1007/s00401-019-01963-8]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Mills, M. A., Yang, N., Weinberger, R. P., Vander Woude, D. L., Beggs, A. H., Easteal, S., North, K. N.
|
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<strong>Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy.</strong>
|
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Hum. Molec. Genet. 10: 1335-1346, 2001.
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[PubMed: 11440986]
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[Full Text: https://doi.org/10.1093/hmg/10.13.1335]
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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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Mohapatra, B., Jimenez, S., Lin, J. H., Bowles, K. R., Coveler, K. J., Marx, J. G., Chrisco, M. A., Murphy, R. T., Lurie, P. R., Schwartz, R. J., Elliott, P. M., Vatta, M., McKenna, W., Towbin, J. A., Bowles, N. E.
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<strong>Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis.</strong>
|
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Molec. Genet. Metab. 80: 207-215, 2003.
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[PubMed: 14567970]
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[Full Text: https://doi.org/10.1016/s1096-7192(03)00142-2]
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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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Savarese, M., Palmio, J., Poza, J. J., Weinberg, J., Olive, M., Cobo, A. M., Vihola, A., Jonson, P. H., Sarparanta, J., Garcia-Bragado, F., Urtizberea, J. A., Hackman, P., Udd, B.
|
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<strong>Actininopathy: a new muscular dystrophy caused by ACTN2 dominant mutations.</strong>
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Ann. Neurol. 85: 899-906, 2019.
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[PubMed: 30900782]
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[Full Text: https://doi.org/10.1002/ana.25470]
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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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Seto, J. T., Lek, M., Quinlan, K. G. R., Houweling, P. J., Zheng, X. F., Garton, F., MacArthur, D. G., Raftery, J. M., Garvey, S. M., Hauser, M. A., Yang, N., Head, S. I., North, K. N.
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<strong>Deficiency of alpha-actinin-3 is associated with increased susceptibility to contraction-induced damage and skeletal muscle remodeling.</strong>
|
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Hum. Molec. Genet. 20: 2914-2927, 2011.
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[PubMed: 21536590]
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[Full Text: https://doi.org/10.1093/hmg/ddr196]
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</li>
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<li>
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<p class="mim-text-font">
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Theis, J. L., Bos, J. M., Bartleson, V. B., Will, M. L., Binder, J., Vatta, M., Towbin, J. A., Gersh, B. J., Ommen, S. R., Ackerman, M. J.
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<strong>Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.</strong>
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Biochem. Biophys. Res. Commun. 351: 896-902, 2006.
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[PubMed: 17097056]
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[Full Text: https://doi.org/10.1016/j.bbrc.2006.10.119]
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 11/07/2019<br>Marla J. F. O'Neill - updated : 4/17/2015<br>Patricia A. Hartz - updated : 4/10/2013<br>Marla J. F. O'Neill - updated : 6/30/2008<br>George E. Tiller - updated : 7/3/2003<br>George E. Tiller - updated : 11/12/2001
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 8/14/1992
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<span class="text-nowrap mim-text-font">
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Edit History:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 07/16/2024<br>alopez : 03/09/2023<br>ckniffin : 03/08/2023<br>carol : 01/11/2023<br>carol : 01/10/2023<br>carol : 11/11/2019<br>carol : 11/08/2019<br>ckniffin : 11/07/2019<br>carol : 04/25/2017<br>carol : 08/05/2016<br>mcolton : 05/26/2015<br>carol : 4/20/2015<br>carol : 4/18/2015<br>carol : 4/17/2015<br>carol : 11/4/2013<br>carol : 8/5/2013<br>mgross : 4/10/2013<br>terry : 7/3/2008<br>alopez : 7/1/2008<br>alopez : 6/30/2008<br>terry : 6/30/2008<br>cwells : 7/3/2003<br>alopez : 11/21/2001<br>cwells : 11/20/2001<br>cwells : 11/20/2001<br>cwells : 11/20/2001<br>cwells : 11/12/2001<br>carol : 10/13/1992<br>carol : 9/9/1992<br>carol : 8/14/1992
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