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<title>
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Entry
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- *160781 - MYOSIN, LIGHT CHAIN 2, REGULATORY, CARDIAC, SLOW; MYL2
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- OMIM
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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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<li class="dropdown-header">
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Advanced Search
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<a href="/history"> Search History </a>
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</form>
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<div class="row">
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<p />
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<div class="container hidden-print">
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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">*160781</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/160781">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=ENSG00000111245;t=ENST00000228841" 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=4633" 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=160781" 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=ENSG00000111245;t=ENST00000228841" 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_000432,NM_001406745,NM_001406916" 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_000432" 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=160781" 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=01181&isoform_id=01181_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/MYL2" 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/34687,34846,1220301,1519290,2460247,6166556,7689897,16198355,21410233,21411329,31442110,48146041,49456869,94981553,119618349,119618350,119618351,189065228,1034702256,1471816368,1471884969,1471890529,2240897243,2242599991,2299130743,2299130804" 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/P10916" 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=4633" 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=ENSG00000111245;t=ENST00000228841" 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=MYL2" 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=MYL2" 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+4633" 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/MYL2" 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:4633" 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/4633" 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=chr12&hgg_gene=ENST00000228841.15&hgg_start=110910845&hgg_end=110921449&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:7583" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:7583" 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=160781[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=160781[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/MYL2/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/ENSG00000111245" 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=MYL2" 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=MYL2" 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=MYL2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://genepath.med.harvard.edu/~seidman/cg3/genes/MYL2_info.html" title="Sarcomere Protein Gene Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Sarcomere Protein Gene Mut…</a></div><div style="margin-left: 0.5em;"><a href="http://www.angis.org.au/Databases/Heart/heartbreak.html" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">FHC Mutation Database</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MYL2&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/PA31380" 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:7583" 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/FBgn0002773.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:97272" 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/MYL2#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:97272" 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/4633/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=4633" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00003369;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00003369 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00003370;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00003370 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-060331-137" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4633" 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=MYL2&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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160781
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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MYOSIN, LIGHT CHAIN 2, REGULATORY, CARDIAC, SLOW; MYL2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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MLC2<br />
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REGULATORY LIGHT CHAIN OF MYOSIN<br />
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RLC OF MYOSIN<br />
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MYOSIN, LIGHT CHAIN, REGULATORY VENTRICULAR
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MYL2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MYL2</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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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:110910845-110921449&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'})">12:110,910,845-110,921,449</a> </span>
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Cardiomyopathy, hypertrophic, 10
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Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/160781" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/160781" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>The 2 pairs of light chains of muscle myosins are called essential light chains (ELC) and regulatory light chains (RLC). The light chains stabilize the long alpha helical neck of the myosin head. Myosin light chain-2 (MYL2) is an important protein in the regulation of myosin ATPase activity in smooth muscle, skeletal muscle, and cardiac muscle. An increase in ventricular MYL2 is observed in the hypertrophied myocardium of cardiac patients with valvular stenosis (summary by <a href="#10" class="mim-tip-reference" title="Poetter, K., Jiang, H., Hassanzadeh, S., Master, S. R., Chang, A., Dalakas, M. C., Rayment, I., Sellers, J. R., Fananapazir, L., Epstein, N. D. <strong>Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.</strong> Nature Genet. 13: 63-69, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673105</a>] [<a href="https://doi.org/10.1038/ng0596-63" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673105">Poetter et al., 1996</a>; <a href="#8" class="mim-tip-reference" title="Macera, M. J., Szabo, P., Wadgaonkar, R., Siddiqui, M. A. Q., Verma, R. S. <strong>Localization of the gene coding for ventricular myosin regulatory light chain (MYL2) to human chromosome 12q23-q24.3.</strong> Genomics 13: 829-831, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1386340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1386340</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90161-k" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1386340">Macera et al., 1992</a>; <a href="#14" class="mim-tip-reference" title="Weterman, M. A. J., Barth, P. G., van Spaendonck-Zwarts, K. Y., Aronica, E., Poll-The, B.-T., Brouwer, O. F., van Tintelen, J. P., Qahar, Z., Bradley, E. J., de Wissel, M., Salviati, L., Angelini, C., van den Heuvel, L., Thomasse, Y. E. M., Backx, A. P., Nurnberg, G., Nurnberg, P., Baas, F. <strong>Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy.</strong> Brain 136: 282-293, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23365102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23365102</a>] [<a href="https://doi.org/10.1093/brain/aws293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23365102">Weterman et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23365102+1386340+8673105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Libera, L. D., Hoffmann, E., Floroff, M., Jackowski, G. <strong>Isolation and nucleotide sequence of the cDNA encoding human ventricular myosin light chain 2.</strong> Nucleic Acids Res. 17: 2360 only, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2704627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2704627</a>] [<a href="https://doi.org/10.1093/nar/17.6.2360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2704627">Libera et al. (1989)</a> cloned full-length MYL2, which they called HVLC2, from a ventricle cDNA library. The deduced protein contains 165 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2704627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using rat Myl2 to screen ventricle poly(A) RNA, <a href="#13" class="mim-tip-reference" title="Wadgaonkar, R., Shafiq, S., Rajmanickam, C., Siddiqui, M. A. Q. <strong>Interaction of a conserved peptide domain in recombinant human ventricular myosin light chain-2 with myosin heavy chain.</strong> Cell. Molec. Biol. Res. 39: 13-26, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8287067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8287067</a>]" pmid="8287067">Wadgaonkar et al. (1993)</a> cloned human MYL2. The deduced 166-amino acid protein shares 96% homology with rat Myl2. Both proteins contain 2 N-terminal putative phosphorylation sites, an EF-hand domain with a central calcium-binding region, and a putative C-terminal myosin heavy chain (MHC; see <a href="/entry/160710">160710</a>)-binding domain. They are clearly different from mammalian or avian skeletal and smooth muscle myosin light chains, particularly in the C-terminal domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8287067" 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 a cloned cDNA for human MYL2, <a href="#8" class="mim-tip-reference" title="Macera, M. J., Szabo, P., Wadgaonkar, R., Siddiqui, M. A. Q., Verma, R. S. <strong>Localization of the gene coding for ventricular myosin regulatory light chain (MYL2) to human chromosome 12q23-q24.3.</strong> Genomics 13: 829-831, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1386340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1386340</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90161-k" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1386340">Macera et al. (1992)</a> mapped the MYL2 gene to chromosome 12 by Southern blot analysis of DNA from human/rodent somatic cell hybrids. By in situ hybridization, they regionalized the gene to 12q23-q24.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1386340" 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 family with hypertrophic cardiomyopathy due to mutation in the MYL2 gene (CMH10; <a href="/entry/608758">608758</a>), <a href="#3" class="mim-tip-reference" title="Flavigny, J., Richard, P., Isnard, R., Carrier, L., Charron, P., Bonne, G., Forissier, J.-F., Desnos, M., Dubourg, O., Komajda, M., Schwartz, K., Hainque, B. <strong>Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy.</strong> J. Molec. Med. 76: 208-214, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9535554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9535554</a>] [<a href="https://doi.org/10.1007/s001090050210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9535554">Flavigny et al. (1998)</a> performed haplotype analysis using 6 microsatellite markers and refined the interval containing the gene to a 6-cM region between D12S84 and D12S354. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9535554" 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="#13" class="mim-tip-reference" title="Wadgaonkar, R., Shafiq, S., Rajmanickam, C., Siddiqui, M. A. Q. <strong>Interaction of a conserved peptide domain in recombinant human ventricular myosin light chain-2 with myosin heavy chain.</strong> Cell. Molec. Biol. Res. 39: 13-26, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8287067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8287067</a>]" pmid="8287067">Wadgaonkar et al. (1993)</a> demonstrated that recombinant human ventricle MYL2 bound specifically to MHC. Recombinant MYL2 exchanged with native MYL2 in intact isolated myofibrils derived from cardiac and skeletal muscle. Fluorescence-labeled MYL2 stained the A band, with strongest staining of A-band edges. There was no staining of either I or Z bands. Domain analysis indicated that a central conserved domain of 20 amino acids recognized MHC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8287067" 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 human, mouse, and rabbit cardiac tissue, <a href="#2" class="mim-tip-reference" title="Davis, J. S., Hassanzadeh, S., Winitsky, S., Lin, H., Satorius, C., Vemuri, R., Aletras, A. H., Wen, H., Epstein, N. D. <strong>The overall pattern of cardiac contraction depends on a spatial gradient of myosin regulatory light chain phosphorylation.</strong> Cell 107: 631-641, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11733062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11733062</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00586-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11733062">Davis et al. (2001)</a> identified a spatial gradient from high (epicardial) to low (endocardial) levels of phosphorylated myosin RLC that correlated with levels of myosin light chain kinase-2 (MYLK2; <a href="/entry/606566">606566</a>). Mechanical studies of single slow muscle fibers showed that the spatial gradient of RLC phosphorylation increased tension, decreased the stretch activation response of the epicardial fibers, and produced the converse effect in the endocardium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11733062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Hypertrophic Cardiomyopathy 10</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Poetter, K., Jiang, H., Hassanzadeh, S., Master, S. R., Chang, A., Dalakas, M. C., Rayment, I., Sellers, J. R., Fananapazir, L., Epstein, N. D. <strong>Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.</strong> Nature Genet. 13: 63-69, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673105</a>] [<a href="https://doi.org/10.1038/ng0596-63" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673105">Poetter et al. (1996)</a> analyzed the MYL2 gene in 399 unrelated probands with hypertrophic cardiomyopathy (see CMH10, <a href="/entry/608758">608758</a>), and identified heterozygosity for 3 different missense mutations in 4 probands (<a href="#0001">160781.0001</a>-<a href="#0003">160781.0003</a>), 3 of whom had an unusual mid-left ventricular chamber thickening on echocardiography. <a href="#10" class="mim-tip-reference" title="Poetter, K., Jiang, H., Hassanzadeh, S., Master, S. R., Chang, A., Dalakas, M. C., Rayment, I., Sellers, J. R., Fananapazir, L., Epstein, N. D. <strong>Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.</strong> Nature Genet. 13: 63-69, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673105</a>] [<a href="https://doi.org/10.1038/ng0596-63" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673105">Poetter et al. (1996)</a> also identified heterozygous missense mutations in the MYL3 gene (<a href="/entry/160790">160790</a>) in CMH patients (see CMH8, <a href="/entry/608751">608751</a>), some of whom displayed similar mid-left ventricular chamber hypertrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8673105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Flavigny, J., Richard, P., Isnard, R., Carrier, L., Charron, P., Bonne, G., Forissier, J.-F., Desnos, M., Dubourg, O., Komajda, M., Schwartz, K., Hainque, B. <strong>Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy.</strong> J. Molec. Med. 76: 208-214, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9535554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9535554</a>] [<a href="https://doi.org/10.1007/s001090050210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9535554">Flavigny et al. (1998)</a> screened 42 probands from unrelated families with CMH for mutations in the MYL2 gene and identified 2 novel mutations, R58Q (<a href="#0004">160781.0004</a>) and P18L (<a href="#0005">160781.0005</a>), in 3 probands. The mutations were subsequently found in all affected family members, who were classified morphologically as Maron type 1, 2, or 3; none had the variant form of CMH described by <a href="#10" class="mim-tip-reference" title="Poetter, K., Jiang, H., Hassanzadeh, S., Master, S. R., Chang, A., Dalakas, M. C., Rayment, I., Sellers, J. R., Fananapazir, L., Epstein, N. D. <strong>Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.</strong> Nature Genet. 13: 63-69, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673105</a>] [<a href="https://doi.org/10.1038/ng0596-63" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673105">Poetter et al. (1996)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9535554+8673105" 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="#11" class="mim-tip-reference" title="Szczesna, D., Ghosh, D., Li, Q., Gomes, A. V., Guzman, G., Arana, C., Zhi, G., Stull, J. T., Potter, J. D. <strong>Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca(2+) binding, and phosphorylation.</strong> J. Biol. Chem. 276: 7086-7092, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11102452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11102452</a>] [<a href="https://doi.org/10.1074/jbc.M009823200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11102452">Szczesna et al. (2001)</a> studied the effects of 5 mutations in the MYL2 gene on Ca(2+) binding and phosphorylation and found that both processes were significantly affected by all of the mutations. For example, the E22K mutation resulted in a 17-fold decrease in calcium binding compared with wildtype, and the R58Q mutant did not bind Ca(2+) at all. Ca(2+) binding to the R58Q mutant was restored upon phosphorylation, whereas the E22K mutant could not be phosphorylated. In addition, the alpha-helical content of phosphorylated R58Q greatly increased with Ca(2+) binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11102452" 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="#5" class="mim-tip-reference" title="Kabaeva, Z. T., Perrot, A., Wolter, B., Dietz, R., Cardim, N., Correia, J. M., Schulte, H. D., Aldashev, A. A., Mirrakhimov, M. M., Osterziel, K. J. <strong>Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy.</strong> Europ. J. Hum. Genet. 10: 741-748, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12404107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12404107</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200872" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12404107">Kabaeva et al. (2002)</a> analyzed the MYL2 and MYL3 genes in 186 unrelated individuals with CMH and identified 2 missense mutations in MYL2: E22K and R58Q. The former was associated with a more benign phenotype and the latter with a more severe one of asymmetric septal hypertrophic cardiomyopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12404107" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Grey, C., Mery, A., Puceat, M. <strong>Fine-tuning in Ca(2+) homeostasis underlies progression of cardiomyopathy in myocytes derived from genetically modified embryonic stem cells.</strong> Hum. Molec. Genet. 14: 1367-1377, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15829506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15829506</a>] [<a href="https://doi.org/10.1093/hmg/ddi146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15829506">Grey et al. (2005)</a> engineered embryonic stem cell lines to express wildtype or R58Q (<a href="#0004">160781.0004</a>)-mutant MYL2, which differentiated into cardiomyocytes within embryoid bodies. Immunofluorescence studies revealed that mutated MYL2 dramatically prevented myofibrillogenesis, and cardiomyocytes expressing mutant MYL2 showed inhibited spontaneous Ca(2+) spiking and reduced translocation of MEF2C (<a href="/entry/600662">600662</a>) into the nucleus, which is a Ca(2+)-dependent process. Expression in mutated cells of a constitutively active CAMK2A (<a href="/entry/114078">114078</a>) or ionomycin treatment restored translocation of MEF2C into the nucleus, and expression of mRNAs encoding sarcomeric proteins partially rescued contractile activity of embryonic bodies. <a href="#4" class="mim-tip-reference" title="Grey, C., Mery, A., Puceat, M. <strong>Fine-tuning in Ca(2+) homeostasis underlies progression of cardiomyopathy in myocytes derived from genetically modified embryonic stem cells.</strong> Hum. Molec. Genet. 14: 1367-1377, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15829506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15829506</a>] [<a href="https://doi.org/10.1093/hmg/ddi146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15829506">Grey et al. (2005)</a> concluded that alteration of Ca(2+) homeostasis in mutated cardioblasts affects the transcriptional program of cardiac cell differentiation, leading to a defect in myofibrillogenesis and in contractility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15829506" 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>Infantile-Onset Myofibrillar Myopathy 12 with Cardiomyopathy</em></strong></p><p>
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In 11 infants from 5 unrelated Dutch families and 2 sibs from an Italian family with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; <a href="/entry/619424">619424</a>), <a href="#14" class="mim-tip-reference" title="Weterman, M. A. J., Barth, P. G., van Spaendonck-Zwarts, K. Y., Aronica, E., Poll-The, B.-T., Brouwer, O. F., van Tintelen, J. P., Qahar, Z., Bradley, E. J., de Wissel, M., Salviati, L., Angelini, C., van den Heuvel, L., Thomasse, Y. E. M., Backx, A. P., Nurnberg, G., Nurnberg, P., Baas, F. <strong>Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy.</strong> Brain 136: 282-293, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23365102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23365102</a>] [<a href="https://doi.org/10.1093/brain/aws293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23365102">Weterman et al. (2013)</a> identified homozygous or compound heterozygous mutation in the MYL2 gene (<a href="#0006">160781.0006</a>-<a href="#0008">160781.0008</a>) that segregated with the disorder in the families. The mutations, 1 splice site and 2 frameshifts, all occurred in the last exon of the gene and were predicted to result in the production of C-terminally truncated proteins. The mutations, which were found by a combination of homozygosity mapping and candidate gene sequencing or whole-exome sequencing, were confirmed by Sanger sequencing. All patients died of cardiac failure by 6 months of age. The carrier parents were unaffected. Analysis of patient tissue from the Dutch patients showed absence of the full-length MYL2 protein and decreased expression of mutant protein with an altered C-terminal tail. The authors postulated a partial loss-of-function effect. Three of the families had previously been reported by <a href="#1" class="mim-tip-reference" title="Barth, P. G., Wanders, R. J. A., Ruitenbeek, W., Roe, C., Scholte, H. R., van der Harten, H., van Moorsel, J., Duran, M., Dingemans, K. P. <strong>Infantile fibre type disproportion, myofibrillar lysis and cardiomyopathy: a disorder in three unrelated Dutch families.</strong> Neuromusc. Disord. 8: 296-304, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9673982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9673982</a>] [<a href="https://doi.org/10.1016/s0960-8966(98)00028-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9673982">Barth et al. (1998)</a>. Haplotype analysis indicated a founder effect for the Dutch mutation (<a href="#0006">160781.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23365102+9673982" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a male infant, born of consanguineous parents, with MFM12, <a href="#9" class="mim-tip-reference" title="Manivannan, S. N., Darouich, S., Masmoudi, A., Gordon, D., Zender, G., Han, Z., Fitzgerald-Butt, S., White, P., McBride, K. L., Kharrat, M., Garg, V. <strong>Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy.</strong> PLoS Genet. 16: e1008639, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32453731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32453731</a>] [<a href="https://doi.org/10.1371/journal.pgen.1008639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32453731">Manivannan et al. (2020)</a> identified a homozygous frameshift mutation in the last exon of the MYL2 gene (<a href="#0009">160781.0009</a>). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the gnomAD database. The carrier parents were clinically unaffected; 3 additional sibs of the proband died of a similar disorder in infancy. Cardiac muscle tissue from the proband showed decreased protein levels of MYL2 compared to controls, although mRNA levels were similar. In vitro cellular studies showed that the mutant MYL2 variant was degraded by the proteasomal machinery, suggesting instability of the mutant protein. Expression of the mutation failed to rescue developmental lethality and cardiac muscle defects in Myl2-null Drosophila, consistent with a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32453731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By creating transgenic mice overexpressing human MYL2 with the glu22-to-lys mutation (E22K; <a href="#0002">160781.0002</a>), <a href="#12" class="mim-tip-reference" title="Szczesna-Cordary, D., Guzman, G., Zhao, J., Hernandez, O., Wei, J., Diaz-Perez, Z. <strong>The E22K mutation of myosin RLC that causes familial hypertrophic cardiomyopathy increases calcium sensitivity of force and ATPase in transgenic mice.</strong> J. Cell Sci. 118: 3675-3683, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16076902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16076902</a>] [<a href="https://doi.org/10.1242/jcs.02492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16076902">Szczesna-Cordary et al. (2005)</a> recapitulated the familial hypertrophic cardiomyopathy phenotype. Transgenic mice showed enlarged interventricular septa and papillary muscles, but no cardiac hypertrophy was found by echocardiography or by judging heart weight to body weight ratios. The E22K mutation increased calcium sensitivity of myofibrillar ATPase and steady-state force development in mutant cardiac muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16076902" 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 an individual with hypertrophic cardiomyopathy (CMH10; <a href="/entry/608758">608758</a>) who displayed unusual mid-left ventricular chamber thickening on echocardiography, <a href="#10" class="mim-tip-reference" title="Poetter, K., Jiang, H., Hassanzadeh, S., Master, S. R., Chang, A., Dalakas, M. C., Rayment, I., Sellers, J. R., Fananapazir, L., Epstein, N. D. <strong>Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.</strong> Nature Genet. 13: 63-69, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673105</a>] [<a href="https://doi.org/10.1038/ng0596-63" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673105">Poetter et al. (1996)</a> identified heterozygosity for an ala13-to-thr (A13T) substitution at an evolutionarily conserved residue in the MYL2 gene product. The authors noted that preliminary investigation of other family members suggested variable expression and decreased penetrance in the cardiac disease associated with A13T. The mutation was not found in 378 control chromosomes or in 790 chromosomes from CMH patients with diverse ethnic backgrounds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8673105" 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 73-year-old man with mild left ventricular hypertrophy attributed to severe aortic stenosis, who had postoperative resolution of symptoms after valve replacement and single-vessel coronary artery bypass surgery, <a href="#6" class="mim-tip-reference" title="Li, L., Bainbridge, M. N., Tan, Y., Willerson, J. T., Marian, A. J. <strong>A potential oligogenic etiology of hypertrophic cardiomyopathy: a classic single-gene disorder.</strong> Circ. Res. 120: 1084-1090, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28223422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28223422</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.116.310559" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28223422">Li et al. (2017)</a> identified heterozygosity for the A13T variant in the MYL2 gene. The authors noted that an unequivocal diagnosis of CMH could not be established in this patient. His son and daughter, who were heterozygous for the A13T variant in addition to pathogenic variants in the TTN (<a href="/entry/188840">188840</a>) and ALPK3 (<a href="/entry/617608">617608</a>) genes, exhibited a severe CMH phenotype with left ventricular outflow obstruction (see <a href="/entry/618052">618052</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28223422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894368 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894368;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/rs104894368?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=rs104894368" 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=rs104894368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 affected brothers and an unrelated individual from 2 unrelated families segregating hypertrophic cardiomyopathy (CMH10; <a href="/entry/608758">608758</a>), who displayed unusual mid-left ventricular chamber thickening on echocardiography, <a href="#10" class="mim-tip-reference" title="Poetter, K., Jiang, H., Hassanzadeh, S., Master, S. R., Chang, A., Dalakas, M. C., Rayment, I., Sellers, J. R., Fananapazir, L., Epstein, N. D. <strong>Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.</strong> Nature Genet. 13: 63-69, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673105</a>] [<a href="https://doi.org/10.1038/ng0596-63" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673105">Poetter et al. (1996)</a> identified heterozygosity for a glu22-to-lys (E22K) substitution at an evolutionarily conserved residue in the MYL2 gene product. The mutation was not found in 378 control chromosomes or in 790 chromosomes from CMH patients with diverse ethnic backgrounds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8673105" 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="#5" class="mim-tip-reference" title="Kabaeva, Z. T., Perrot, A., Wolter, B., Dietz, R., Cardim, N., Correia, J. M., Schulte, H. D., Aldashev, A. A., Mirrakhimov, M. M., Osterziel, K. J. <strong>Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy.</strong> Europ. J. Hum. Genet. 10: 741-748, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12404107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12404107</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200872" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12404107">Kabaeva et al. (2002)</a> identified the E22K mutation, resulting from a heterozygous 64G-A transition in the MYL2 gene, in 7 members (4 affected and 3 with 'uncertain' phenotypes) of a family with CMH10 who had mild to moderate septal hypertrophy, a late onset of clinical manifestations, and a benign disease course and prognosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12404107" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913658 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913658;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/rs121913658?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=rs121913658" 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=rs121913658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an individual with hypertrophic cardiomyopathy (CMH10; <a href="/entry/608758">608758</a>), <a href="#10" class="mim-tip-reference" title="Poetter, K., Jiang, H., Hassanzadeh, S., Master, S. R., Chang, A., Dalakas, M. C., Rayment, I., Sellers, J. R., Fananapazir, L., Epstein, N. D. <strong>Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.</strong> Nature Genet. 13: 63-69, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673105</a>] [<a href="https://doi.org/10.1038/ng0596-63" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673105">Poetter et al. (1996)</a> identified heterozygosity for a pro94-to-arg (P94R) substitution at an evolutionarily conserved residue in the MYL2 gene product. The mutation was not found in 378 control chromosomes or in 790 chromosomes from CMH patients with diverse ethnic backgrounds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8673105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894369 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894369;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/rs104894369?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=rs104894369" 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=rs104894369" 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=RCV000015111 OR RCV000157369 OR RCV000158923 OR RCV000621867 OR RCV000844711 OR RCV001798005" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015111, RCV000157369, RCV000158923, RCV000621867, RCV000844711, RCV001798005" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015111...</a>
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<p>In affected members of 2 families with familial hypertrophic cardiomyopathy-10 (CMH10; <a href="/entry/608758">608758</a>), <a href="#3" class="mim-tip-reference" title="Flavigny, J., Richard, P., Isnard, R., Carrier, L., Charron, P., Bonne, G., Forissier, J.-F., Desnos, M., Dubourg, O., Komajda, M., Schwartz, K., Hainque, B. <strong>Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy.</strong> J. Molec. Med. 76: 208-214, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9535554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9535554</a>] [<a href="https://doi.org/10.1007/s001090050210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9535554">Flavigny et al. (1998)</a> identified a 173G-A transition in exon 4 of the MYL2 gene, resulting in an arg58-to-gln (R58Q) substitution. Affected individuals were classified morphologically as Maron type 1 or 3, and the mutation segregated with the hypertrophied phenotype in both families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9535554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with asymmetric septal hypertrophic cardiomyopathy, <a href="#5" class="mim-tip-reference" title="Kabaeva, Z. T., Perrot, A., Wolter, B., Dietz, R., Cardim, N., Correia, J. M., Schulte, H. D., Aldashev, A. A., Mirrakhimov, M. M., Osterziel, K. J. <strong>Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy.</strong> Europ. J. Hum. Genet. 10: 741-748, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12404107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12404107</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200872" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12404107">Kabaeva et al. (2002)</a> identified heterozygosity for the R58Q mutation. The patient had first been diagnosed at age 7 years with nonobstructive myocardial hypertrophy and underwent implantation of a cardioverter defibrillator at age 25 years after ventricular tachycardia degenerating into ventricular fibrillation was observed. She had recurrent episodes of supraventricular tachycardia, and echocardiography revealed asymmetric septal hypertrophy. DNA was not available from her sister, who had asymmetric obstructive myocardial hypertrophy and died suddenly at the age of 21 years, or from her father, who died unexpectedly at a young age and was found to have myocardial hypertrophy on autopsy. The mutation was not found in the proband's mother, who had normal cardiac findings. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12404107" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015112 OR RCV000246859 OR RCV002247340 OR RCV002504789 OR RCV004806011" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015112, RCV000246859, RCV002247340, RCV002504789, RCV004806011" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015112...</a>
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<p>In affected members of a family segregating hypertrophic cardiomyopathy-10 (CMH10; <a href="/entry/608758">608758</a>), <a href="#3" class="mim-tip-reference" title="Flavigny, J., Richard, P., Isnard, R., Carrier, L., Charron, P., Bonne, G., Forissier, J.-F., Desnos, M., Dubourg, O., Komajda, M., Schwartz, K., Hainque, B. <strong>Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy.</strong> J. Molec. Med. 76: 208-214, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9535554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9535554</a>] [<a href="https://doi.org/10.1007/s001090050210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9535554">Flavigny et al. (1998)</a> identified a 52T-C transition in exon 2 of the MYL2 gene, resulting in a phe18-to-leu (F18L) substitution. Affected individuals were classified morphologically as Maron type 1, 2, or 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9535554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199474813 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199474813;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/rs199474813?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=rs199474813" 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=rs199474813" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 11 patients from 8 unrelated Dutch families with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; <a href="/entry/619424">619424</a>), <a href="#14" class="mim-tip-reference" title="Weterman, M. A. J., Barth, P. G., van Spaendonck-Zwarts, K. Y., Aronica, E., Poll-The, B.-T., Brouwer, O. F., van Tintelen, J. P., Qahar, Z., Bradley, E. J., de Wissel, M., Salviati, L., Angelini, C., van den Heuvel, L., Thomasse, Y. E. M., Backx, A. P., Nurnberg, G., Nurnberg, P., Baas, F. <strong>Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy.</strong> Brain 136: 282-293, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23365102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23365102</a>] [<a href="https://doi.org/10.1093/brain/aws293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23365102">Weterman et al. (2013)</a> identified a homozygous G-to-C transversion (c.403-1G-C) in the last acceptor splice site of the MYL2 gene. The mutation, which was found by a combination of homozygosity mapping and candidate gene sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The parents were unaffected carriers of the mutations. RT-PCR analysis of patient tissue confirmed that the mutation escaped nonsense-mediated mRNA decay and resulted in a frameshift and premature termination in the C terminus. Immunohistochemical staining and Western blot analysis of patient skeletal muscle tissue showed absence of the full-length MYL2 protein and decreased expression of the mutant protein with an altered C-terminal tail. The authors postulated a partial loss-of-function effect. Three of the families had previously been reported by <a href="#1" class="mim-tip-reference" title="Barth, P. G., Wanders, R. J. A., Ruitenbeek, W., Roe, C., Scholte, H. R., van der Harten, H., van Moorsel, J., Duran, M., Dingemans, K. P. <strong>Infantile fibre type disproportion, myofibrillar lysis and cardiomyopathy: a disorder in three unrelated Dutch families.</strong> Neuromusc. Disord. 8: 296-304, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9673982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9673982</a>] [<a href="https://doi.org/10.1016/s0960-8966(98)00028-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9673982">Barth et al. (1998)</a>. Haplotype analysis was consistent with a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23365102+9673982" 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">rs786205430 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205430;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=rs786205430" 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=rs786205430" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 Italian brothers with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; <a href="/entry/619424">619424</a>), <a href="#14" class="mim-tip-reference" title="Weterman, M. A. J., Barth, P. G., van Spaendonck-Zwarts, K. Y., Aronica, E., Poll-The, B.-T., Brouwer, O. F., van Tintelen, J. P., Qahar, Z., Bradley, E. J., de Wissel, M., Salviati, L., Angelini, C., van den Heuvel, L., Thomasse, Y. E. M., Backx, A. P., Nurnberg, G., Nurnberg, P., Baas, F. <strong>Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy.</strong> Brain 136: 282-293, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23365102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23365102</a>] [<a href="https://doi.org/10.1093/brain/aws293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23365102">Weterman et al. (2013)</a> identified compound heterozygous frameshift mutations affecting adjacent nucleotides in the last exon of the MYL2 gene: c.431delC, causing Pro144LeufsTer2, and c.432delT (<a href="#0008">160781.0008</a>), causing Asp145ThrfsTer2. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed, but they were predicted to result in the production of C-terminally truncated proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23365102" 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">rs2071649414 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2071649414;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=rs2071649414" 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=rs2071649414" 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=RCV001347471 OR RCV001553793" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001347471, RCV001553793" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001347471...</a>
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<p>For discussion of the 1-bp deletion (c.432delT) in the MYL2 gene, resulting in a frameshift and premature termination (Asp145ThrfsTer2), that was found in compound heterozygous state in 2 sibs with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; <a href="/entry/619424">619424</a>) by <a href="#14" class="mim-tip-reference" title="Weterman, M. A. J., Barth, P. G., van Spaendonck-Zwarts, K. Y., Aronica, E., Poll-The, B.-T., Brouwer, O. F., van Tintelen, J. P., Qahar, Z., Bradley, E. J., de Wissel, M., Salviati, L., Angelini, C., van den Heuvel, L., Thomasse, Y. E. M., Backx, A. P., Nurnberg, G., Nurnberg, P., Baas, F. <strong>Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy.</strong> Brain 136: 282-293, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23365102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23365102</a>] [<a href="https://doi.org/10.1093/brain/aws293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23365102">Weterman et al. (2013)</a>, see <a href="#0007">160781.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23365102" 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">rs1566147422 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1566147422;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=rs1566147422" 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=rs1566147422" 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=RCV000770390 OR RCV001089865 OR RCV001507317 OR RCV001553794 OR RCV003166034 OR RCV003999941" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000770390, RCV001089865, RCV001507317, RCV001553794, RCV003166034, RCV003999941" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000770390...</a>
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<p>In a male infant, born of consanguineous parents, with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; <a href="/entry/619424">619424</a>), <a href="#9" class="mim-tip-reference" title="Manivannan, S. N., Darouich, S., Masmoudi, A., Gordon, D., Zender, G., Han, Z., Fitzgerald-Butt, S., White, P., McBride, K. L., Kharrat, M., Garg, V. <strong>Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy.</strong> PLoS Genet. 16: e1008639, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32453731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32453731</a>] [<a href="https://doi.org/10.1371/journal.pgen.1008639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32453731">Manivannan et al. (2020)</a> identified a homozygous 2-bp deletion (c.431_432delCT, NM_000432.3) in exon 6 of the MYL2 gene, predicted to result in a frameshift and termination (Pro144ArgfsTer57) with extension of the reading frame into the 3-prime UTR, leading to the addition of 36 amino acids to the C terminus. The mutation was predicted to disrupt the EF-hand domains in the C terminus. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the gnomAD database. The carrier parents were clinically unaffected. Cardiac muscle tissue from the proband showed decreased protein levels of MYL2 compared to controls, although mRNA levels were similar. In vitro cellular studies showed that the mutant MYL2 variant was degraded by the proteasomal machinery, suggesting instability of the mutant protein. Expression of the mutation failed to rescue developmental lethality and cardiac muscle defects in Myl2-null Drosophila, consistent with a loss-of-function effect. Family history revealed 3 additional sibs of the proband with a similar disorder resulting in death in infancy due to cardiac failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32453731" 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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Barth, P. G., Wanders, R. J. A., Ruitenbeek, W., Roe, C., Scholte, H. R., van der Harten, H., van Moorsel, J., Duran, M., Dingemans, K. P.
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Neuromusc. Disord. 8: 296-304, 1998.
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[<a href="https://doi.org/10.1016/s0960-8966(98)00028-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(01)00586-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s001090050210" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi146" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200872" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/CIRCRESAHA.116.310559" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/nar/17.6.2360" target="_blank">Full Text</a>]
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<strong>Localization of the gene coding for ventricular myosin regulatory light chain (MYL2) to human chromosome 12q23-q24.3.</strong>
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[<a href="https://doi.org/10.1016/0888-7543(92)90161-k" target="_blank">Full Text</a>]
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Manivannan, S. N., Darouich, S., Masmoudi, A., Gordon, D., Zender, G., Han, Z., Fitzgerald-Butt, S., White, P., McBride, K. L., Kharrat, M., Garg, V.
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<strong>Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy.</strong>
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[<a href="https://doi.org/10.1371/journal.pgen.1008639" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0596-63" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M009823200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1242/jcs.02492" target="_blank">Full Text</a>]
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Wadgaonkar, R., Shafiq, S., Rajmanickam, C., Siddiqui, M. A. Q.
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Weterman, M. A. J., Barth, P. G., van Spaendonck-Zwarts, K. Y., Aronica, E., Poll-The, B.-T., Brouwer, O. F., van Tintelen, J. P., Qahar, Z., Bradley, E. J., de Wissel, M., Salviati, L., Angelini, C., van den Heuvel, L., Thomasse, Y. E. M., Backx, A. P., Nurnberg, G., Nurnberg, P., Baas, F.
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<strong>Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy.</strong>
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Brain 136: 282-293, 2013.
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[<a href="https://doi.org/10.1093/brain/aws293" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 07/13/2021
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Marla J. F. O'Neill - updated : 07/12/2018<br>Marla J. F. O'Neill - updated : 6/7/2010<br>Marla J. F. O'Neill - updated : 6/23/2008<br>George E. Tiller - updated : 6/5/2008<br>Patricia A. Hartz - updated : 2/23/2006<br>Patricia A. Hartz - updated : 8/17/2004<br>Patricia A. Hartz - updated : 8/9/2004<br>Marla J. F. O'Neill - updated : 6/22/2004<br>Marla J. F. O'Neill - updated : 3/24/2004<br>Victor A. McKusick - updated : 8/1/1997
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carol : 08/05/2021<br>ckniffin : 07/13/2021<br>carol : 07/13/2018<br>alopez : 07/12/2018<br>alopez : 03/02/2012<br>carol : 6/7/2010<br>alopez : 6/7/2010<br>alopez : 6/7/2010<br>terry : 6/2/2010<br>mgross : 6/23/2008<br>wwang : 6/5/2008<br>mgross : 3/3/2006<br>terry : 2/23/2006<br>mgross : 8/25/2004<br>terry : 8/17/2004<br>mgross : 8/10/2004<br>terry : 8/9/2004<br>carol : 6/22/2004<br>carol : 6/22/2004<br>carol : 5/25/2004<br>carol : 3/30/2004<br>tkritzer : 3/29/2004<br>terry : 3/24/2004<br>alopez : 6/26/2002<br>joanna : 2/7/2002<br>carol : 11/9/2001<br>terry : 11/9/2000<br>alopez : 4/30/1999<br>alopez : 4/30/1999<br>alopez : 4/30/1999<br>mark : 12/8/1997<br>terry : 8/1/1997<br>terry : 5/14/1996<br>terry : 5/7/1996<br>terry : 5/6/1996<br>carol : 6/29/1992
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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 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> 160781
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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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MYOSIN, LIGHT CHAIN 2, REGULATORY, CARDIAC, SLOW; MYL2
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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-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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MLC2<br />
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REGULATORY LIGHT CHAIN OF MYOSIN<br />
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RLC OF MYOSIN<br />
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MYOSIN, LIGHT CHAIN, REGULATORY VENTRICULAR
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MYL2</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>
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Cytogenetic location: 12q24.11
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:110,910,845-110,921,449 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</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>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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12q24.11
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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, hypertrophic, 10
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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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608758
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy
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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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619424
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</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>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The 2 pairs of light chains of muscle myosins are called essential light chains (ELC) and regulatory light chains (RLC). The light chains stabilize the long alpha helical neck of the myosin head. Myosin light chain-2 (MYL2) is an important protein in the regulation of myosin ATPase activity in smooth muscle, skeletal muscle, and cardiac muscle. An increase in ventricular MYL2 is observed in the hypertrophied myocardium of cardiac patients with valvular stenosis (summary by Poetter et al., 1996; Macera et al., 1992; Weterman et al., 2013). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Libera et al. (1989) cloned full-length MYL2, which they called HVLC2, from a ventricle cDNA library. The deduced protein contains 165 amino acids. </p><p>Using rat Myl2 to screen ventricle poly(A) RNA, Wadgaonkar et al. (1993) cloned human MYL2. The deduced 166-amino acid protein shares 96% homology with rat Myl2. Both proteins contain 2 N-terminal putative phosphorylation sites, an EF-hand domain with a central calcium-binding region, and a putative C-terminal myosin heavy chain (MHC; see 160710)-binding domain. They are clearly different from mammalian or avian skeletal and smooth muscle myosin light chains, particularly in the C-terminal domain. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using a cloned cDNA for human MYL2, Macera et al. (1992) mapped the MYL2 gene to chromosome 12 by Southern blot analysis of DNA from human/rodent somatic cell hybrids. By in situ hybridization, they regionalized the gene to 12q23-q24.3. </p><p>In a large family with hypertrophic cardiomyopathy due to mutation in the MYL2 gene (CMH10; 608758), Flavigny et al. (1998) performed haplotype analysis using 6 microsatellite markers and refined the interval containing the gene to a 6-cM region between D12S84 and D12S354. </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>Wadgaonkar et al. (1993) demonstrated that recombinant human ventricle MYL2 bound specifically to MHC. Recombinant MYL2 exchanged with native MYL2 in intact isolated myofibrils derived from cardiac and skeletal muscle. Fluorescence-labeled MYL2 stained the A band, with strongest staining of A-band edges. There was no staining of either I or Z bands. Domain analysis indicated that a central conserved domain of 20 amino acids recognized MHC. </p><p>In human, mouse, and rabbit cardiac tissue, Davis et al. (2001) identified a spatial gradient from high (epicardial) to low (endocardial) levels of phosphorylated myosin RLC that correlated with levels of myosin light chain kinase-2 (MYLK2; 606566). Mechanical studies of single slow muscle fibers showed that the spatial gradient of RLC phosphorylation increased tension, decreased the stretch activation response of the epicardial fibers, and produced the converse effect in the endocardium. </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>Hypertrophic Cardiomyopathy 10</em></strong></p><p>
|
|
Poetter et al. (1996) analyzed the MYL2 gene in 399 unrelated probands with hypertrophic cardiomyopathy (see CMH10, 608758), and identified heterozygosity for 3 different missense mutations in 4 probands (160781.0001-160781.0003), 3 of whom had an unusual mid-left ventricular chamber thickening on echocardiography. Poetter et al. (1996) also identified heterozygous missense mutations in the MYL3 gene (160790) in CMH patients (see CMH8, 608751), some of whom displayed similar mid-left ventricular chamber hypertrophy. </p><p>Flavigny et al. (1998) screened 42 probands from unrelated families with CMH for mutations in the MYL2 gene and identified 2 novel mutations, R58Q (160781.0004) and P18L (160781.0005), in 3 probands. The mutations were subsequently found in all affected family members, who were classified morphologically as Maron type 1, 2, or 3; none had the variant form of CMH described by Poetter et al. (1996). </p><p>Szczesna et al. (2001) studied the effects of 5 mutations in the MYL2 gene on Ca(2+) binding and phosphorylation and found that both processes were significantly affected by all of the mutations. For example, the E22K mutation resulted in a 17-fold decrease in calcium binding compared with wildtype, and the R58Q mutant did not bind Ca(2+) at all. Ca(2+) binding to the R58Q mutant was restored upon phosphorylation, whereas the E22K mutant could not be phosphorylated. In addition, the alpha-helical content of phosphorylated R58Q greatly increased with Ca(2+) binding. </p><p>Kabaeva et al. (2002) analyzed the MYL2 and MYL3 genes in 186 unrelated individuals with CMH and identified 2 missense mutations in MYL2: E22K and R58Q. The former was associated with a more benign phenotype and the latter with a more severe one of asymmetric septal hypertrophic cardiomyopathy. </p><p>Grey et al. (2005) engineered embryonic stem cell lines to express wildtype or R58Q (160781.0004)-mutant MYL2, which differentiated into cardiomyocytes within embryoid bodies. Immunofluorescence studies revealed that mutated MYL2 dramatically prevented myofibrillogenesis, and cardiomyocytes expressing mutant MYL2 showed inhibited spontaneous Ca(2+) spiking and reduced translocation of MEF2C (600662) into the nucleus, which is a Ca(2+)-dependent process. Expression in mutated cells of a constitutively active CAMK2A (114078) or ionomycin treatment restored translocation of MEF2C into the nucleus, and expression of mRNAs encoding sarcomeric proteins partially rescued contractile activity of embryonic bodies. Grey et al. (2005) concluded that alteration of Ca(2+) homeostasis in mutated cardioblasts affects the transcriptional program of cardiac cell differentiation, leading to a defect in myofibrillogenesis and in contractility. </p><p><strong><em>Infantile-Onset Myofibrillar Myopathy 12 with Cardiomyopathy</em></strong></p><p>
|
|
In 11 infants from 5 unrelated Dutch families and 2 sibs from an Italian family with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; 619424), Weterman et al. (2013) identified homozygous or compound heterozygous mutation in the MYL2 gene (160781.0006-160781.0008) that segregated with the disorder in the families. The mutations, 1 splice site and 2 frameshifts, all occurred in the last exon of the gene and were predicted to result in the production of C-terminally truncated proteins. The mutations, which were found by a combination of homozygosity mapping and candidate gene sequencing or whole-exome sequencing, were confirmed by Sanger sequencing. All patients died of cardiac failure by 6 months of age. The carrier parents were unaffected. Analysis of patient tissue from the Dutch patients showed absence of the full-length MYL2 protein and decreased expression of mutant protein with an altered C-terminal tail. The authors postulated a partial loss-of-function effect. Three of the families had previously been reported by Barth et al. (1998). Haplotype analysis indicated a founder effect for the Dutch mutation (160781.0006). </p><p>In a male infant, born of consanguineous parents, with MFM12, Manivannan et al. (2020) identified a homozygous frameshift mutation in the last exon of the MYL2 gene (160781.0009). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the gnomAD database. The carrier parents were clinically unaffected; 3 additional sibs of the proband died of a similar disorder in infancy. Cardiac muscle tissue from the proband showed decreased protein levels of MYL2 compared to controls, although mRNA levels were similar. In vitro cellular studies showed that the mutant MYL2 variant was degraded by the proteasomal machinery, suggesting instability of the mutant protein. Expression of the mutation failed to rescue developmental lethality and cardiac muscle defects in Myl2-null Drosophila, consistent with a loss-of-function effect. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p>By creating transgenic mice overexpressing human MYL2 with the glu22-to-lys mutation (E22K; 160781.0002), Szczesna-Cordary et al. (2005) recapitulated the familial hypertrophic cardiomyopathy phenotype. Transgenic mice showed enlarged interventricular septa and papillary muscles, but no cardiac hypertrophy was found by echocardiography or by judging heart weight to body weight ratios. The E22K mutation increased calcium sensitivity of myofibrillar ATPase and steady-state force development in mutant cardiac 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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<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>9 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, FAMILIAL HYPERTROPHIC, 10</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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MYL2, ALA13THR
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<br />
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SNP: rs104894363,
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gnomAD: rs104894363,
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ClinVar: RCV000015108, RCV000148714, RCV000584799, RCV000620870, RCV000626337, RCV000766474, RCV001184984
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an individual with hypertrophic cardiomyopathy (CMH10; 608758) who displayed unusual mid-left ventricular chamber thickening on echocardiography, Poetter et al. (1996) identified heterozygosity for an ala13-to-thr (A13T) substitution at an evolutionarily conserved residue in the MYL2 gene product. The authors noted that preliminary investigation of other family members suggested variable expression and decreased penetrance in the cardiac disease associated with A13T. The mutation was not found in 378 control chromosomes or in 790 chromosomes from CMH patients with diverse ethnic backgrounds. </p><p>In a 73-year-old man with mild left ventricular hypertrophy attributed to severe aortic stenosis, who had postoperative resolution of symptoms after valve replacement and single-vessel coronary artery bypass surgery, Li et al. (2017) identified heterozygosity for the A13T variant in the MYL2 gene. The authors noted that an unequivocal diagnosis of CMH could not be established in this patient. His son and daughter, who were heterozygous for the A13T variant in addition to pathogenic variants in the TTN (188840) and ALPK3 (617608) genes, exhibited a severe CMH phenotype with left ventricular outflow obstruction (see 618052). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0002 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 10</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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MYL2, GLU22LYS
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<br />
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|
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SNP: rs104894368,
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|
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gnomAD: rs104894368,
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ClinVar: RCV000015109, RCV000158914, RCV000234985, RCV000768488, RCV001170438, RCV002354163, RCV004532354
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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 2 affected brothers and an unrelated individual from 2 unrelated families segregating hypertrophic cardiomyopathy (CMH10; 608758), who displayed unusual mid-left ventricular chamber thickening on echocardiography, Poetter et al. (1996) identified heterozygosity for a glu22-to-lys (E22K) substitution at an evolutionarily conserved residue in the MYL2 gene product. The mutation was not found in 378 control chromosomes or in 790 chromosomes from CMH patients with diverse ethnic backgrounds. </p><p>Kabaeva et al. (2002) identified the E22K mutation, resulting from a heterozygous 64G-A transition in the MYL2 gene, in 7 members (4 affected and 3 with 'uncertain' phenotypes) of a family with CMH10 who had mild to moderate septal hypertrophy, a late onset of clinical manifestations, and a benign disease course and prognosis. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0003 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 10</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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MYL2, PRO94ARG
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<br />
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SNP: rs121913658,
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gnomAD: rs121913658,
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ClinVar: RCV000015110, RCV003996096
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an individual with hypertrophic cardiomyopathy (CMH10; 608758), Poetter et al. (1996) identified heterozygosity for a pro94-to-arg (P94R) substitution at an evolutionarily conserved residue in the MYL2 gene product. The mutation was not found in 378 control chromosomes or in 790 chromosomes from CMH patients with diverse ethnic backgrounds. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 10</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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MYL2, ARG58GLN
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<br />
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SNP: rs104894369,
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gnomAD: rs104894369,
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ClinVar: RCV000015111, RCV000157369, RCV000158923, RCV000621867, RCV000844711, RCV001798005
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 2 families with familial hypertrophic cardiomyopathy-10 (CMH10; 608758), Flavigny et al. (1998) identified a 173G-A transition in exon 4 of the MYL2 gene, resulting in an arg58-to-gln (R58Q) substitution. Affected individuals were classified morphologically as Maron type 1 or 3, and the mutation segregated with the hypertrophied phenotype in both families. </p><p>In a patient with asymmetric septal hypertrophic cardiomyopathy, Kabaeva et al. (2002) identified heterozygosity for the R58Q mutation. The patient had first been diagnosed at age 7 years with nonobstructive myocardial hypertrophy and underwent implantation of a cardioverter defibrillator at age 25 years after ventricular tachycardia degenerating into ventricular fibrillation was observed. She had recurrent episodes of supraventricular tachycardia, and echocardiography revealed asymmetric septal hypertrophy. DNA was not available from her sister, who had asymmetric obstructive myocardial hypertrophy and died suddenly at the age of 21 years, or from her father, who died unexpectedly at a young age and was found to have myocardial hypertrophy on autopsy. The mutation was not found in the proband's mother, who had normal cardiac findings. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 10</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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MYL2, PHE18LEU
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<br />
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SNP: rs104894370,
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ClinVar: RCV000015112, RCV000246859, RCV002247340, RCV002504789, RCV004806011
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family segregating hypertrophic cardiomyopathy-10 (CMH10; 608758), Flavigny et al. (1998) identified a 52T-C transition in exon 2 of the MYL2 gene, resulting in a phe18-to-leu (F18L) substitution. Affected individuals were classified morphologically as Maron type 1, 2, or 3. </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>.0006 MYOPATHY, MYOFIBRILLAR, 12, INFANTILE-ONSET, WITH CARDIOMYOPATHY</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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MYL2, IVS6AS, G-C, -1
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<br />
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SNP: rs199474813,
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gnomAD: rs199474813,
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ClinVar: RCV000024459, RCV000466598, RCV001553791, RCV003162260
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 11 patients from 8 unrelated Dutch families with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; 619424), Weterman et al. (2013) identified a homozygous G-to-C transversion (c.403-1G-C) in the last acceptor splice site of the MYL2 gene. The mutation, which was found by a combination of homozygosity mapping and candidate gene sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The parents were unaffected carriers of the mutations. RT-PCR analysis of patient tissue confirmed that the mutation escaped nonsense-mediated mRNA decay and resulted in a frameshift and premature termination in the C terminus. Immunohistochemical staining and Western blot analysis of patient skeletal muscle tissue showed absence of the full-length MYL2 protein and decreased expression of the mutant protein with an altered C-terminal tail. The authors postulated a partial loss-of-function effect. Three of the families had previously been reported by Barth et al. (1998). Haplotype analysis was consistent with a founder effect. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0007 MYOPATHY, MYOFIBRILLAR, 12, INFANTILE-ONSET, WITH CARDIOMYOPATHY</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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MYL2, 1-BP DEL, 431C
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<br />
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SNP: rs786205430,
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ClinVar: RCV000171842, RCV000618518, RCV001553792, RCV001852081
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 Italian brothers with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; 619424), Weterman et al. (2013) identified compound heterozygous frameshift mutations affecting adjacent nucleotides in the last exon of the MYL2 gene: c.431delC, causing Pro144LeufsTer2, and c.432delT (160781.0008), causing Asp145ThrfsTer2. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed, but they were predicted to result in the production of C-terminally truncated proteins. </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>.0008 MYOPATHY, MYOFIBRILLAR, 12, INFANTILE-ONSET, WITH CARDIOMYOPATHY</strong>
|
|
</span>
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</h4>
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|
</div>
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<div>
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<span class="mim-text-font">
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MYL2, 1-BP DEL, 432T
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<br />
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SNP: rs2071649414,
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ClinVar: RCV001347471, RCV001553793
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion (c.432delT) in the MYL2 gene, resulting in a frameshift and premature termination (Asp145ThrfsTer2), that was found in compound heterozygous state in 2 sibs with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; 619424) by Weterman et al. (2013), see 160781.0007. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 MYOPATHY, MYOFIBRILLAR, 12, INFANTILE-ONSET, WITH CARDIOMYOPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
MYL2, 2-BP DEL, 431CT
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|
<br />
|
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|
|
SNP: rs1566147422,
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|
|
|
|
|
|
|
ClinVar: RCV000770390, RCV001089865, RCV001507317, RCV001553794, RCV003166034, RCV003999941
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male infant, born of consanguineous parents, with infantile-onset myofibrillar myopathy-12 with cardiomyopathy (MFM12; 619424), Manivannan et al. (2020) identified a homozygous 2-bp deletion (c.431_432delCT, NM_000432.3) in exon 6 of the MYL2 gene, predicted to result in a frameshift and termination (Pro144ArgfsTer57) with extension of the reading frame into the 3-prime UTR, leading to the addition of 36 amino acids to the C terminus. The mutation was predicted to disrupt the EF-hand domains in the C terminus. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the gnomAD database. The carrier parents were clinically unaffected. Cardiac muscle tissue from the proband showed decreased protein levels of MYL2 compared to controls, although mRNA levels were similar. In vitro cellular studies showed that the mutant MYL2 variant was degraded by the proteasomal machinery, suggesting instability of the mutant protein. Expression of the mutation failed to rescue developmental lethality and cardiac muscle defects in Myl2-null Drosophila, consistent with a loss-of-function effect. Family history revealed 3 additional sibs of the proband with a similar disorder resulting in death in infancy due to cardiac failure. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
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|
</div>
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|
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
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<div>
|
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<p />
|
|
</div>
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<div>
|
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<ol>
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<li>
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<p class="mim-text-font">
|
|
Barth, P. G., Wanders, R. J. A., Ruitenbeek, W., Roe, C., Scholte, H. R., van der Harten, H., van Moorsel, J., Duran, M., Dingemans, K. P.
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|
<strong>Infantile fibre type disproportion, myofibrillar lysis and cardiomyopathy: a disorder in three unrelated Dutch families.</strong>
|
|
Neuromusc. Disord. 8: 296-304, 1998.
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[PubMed: 9673982]
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[Full Text: https://doi.org/10.1016/s0960-8966(98)00028-5]
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<li>
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<p class="mim-text-font">
|
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Davis, J. S., Hassanzadeh, S., Winitsky, S., Lin, H., Satorius, C., Vemuri, R., Aletras, A. H., Wen, H., Epstein, N. D.
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<strong>The overall pattern of cardiac contraction depends on a spatial gradient of myosin regulatory light chain phosphorylation.</strong>
|
|
Cell 107: 631-641, 2001.
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[PubMed: 11733062]
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<li>
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<p class="mim-text-font">
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Flavigny, J., Richard, P., Isnard, R., Carrier, L., Charron, P., Bonne, G., Forissier, J.-F., Desnos, M., Dubourg, O., Komajda, M., Schwartz, K., Hainque, B.
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<strong>Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy.</strong>
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J. Molec. Med. 76: 208-214, 1998.
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[PubMed: 9535554]
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[Full Text: https://doi.org/10.1007/s001090050210]
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<p class="mim-text-font">
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Grey, C., Mery, A., Puceat, M.
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<strong>Fine-tuning in Ca(2+) homeostasis underlies progression of cardiomyopathy in myocytes derived from genetically modified embryonic stem cells.</strong>
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Hum. Molec. Genet. 14: 1367-1377, 2005.
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[PubMed: 15829506]
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[Full Text: https://doi.org/10.1093/hmg/ddi146]
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<p class="mim-text-font">
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Kabaeva, Z. T., Perrot, A., Wolter, B., Dietz, R., Cardim, N., Correia, J. M., Schulte, H. D., Aldashev, A. A., Mirrakhimov, M. M., Osterziel, K. J.
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<strong>Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy.</strong>
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Europ. J. Hum. Genet. 10: 741-748, 2002.
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[PubMed: 12404107]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5200872]
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Li, L., Bainbridge, M. N., Tan, Y., Willerson, J. T., Marian, A. J.
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<strong>A potential oligogenic etiology of hypertrophic cardiomyopathy: a classic single-gene disorder.</strong>
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Circ. Res. 120: 1084-1090, 2017.
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[PubMed: 28223422]
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[Full Text: https://doi.org/10.1161/CIRCRESAHA.116.310559]
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<p class="mim-text-font">
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Libera, L. D., Hoffmann, E., Floroff, M., Jackowski, G.
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<strong>Isolation and nucleotide sequence of the cDNA encoding human ventricular myosin light chain 2.</strong>
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Nucleic Acids Res. 17: 2360 only, 1989.
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[PubMed: 2704627]
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[Full Text: https://doi.org/10.1093/nar/17.6.2360]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Macera, M. J., Szabo, P., Wadgaonkar, R., Siddiqui, M. A. Q., Verma, R. S.
|
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<strong>Localization of the gene coding for ventricular myosin regulatory light chain (MYL2) to human chromosome 12q23-q24.3.</strong>
|
|
Genomics 13: 829-831, 1992.
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[PubMed: 1386340]
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[Full Text: https://doi.org/10.1016/0888-7543(92)90161-k]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Manivannan, S. N., Darouich, S., Masmoudi, A., Gordon, D., Zender, G., Han, Z., Fitzgerald-Butt, S., White, P., McBride, K. L., Kharrat, M., Garg, V.
|
|
<strong>Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy.</strong>
|
|
PLoS Genet. 16: e1008639, 2020.
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[PubMed: 32453731]
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[Full Text: https://doi.org/10.1371/journal.pgen.1008639]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Poetter, K., Jiang, H., Hassanzadeh, S., Master, S. R., Chang, A., Dalakas, M. C., Rayment, I., Sellers, J. R., Fananapazir, L., Epstein, N. D.
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<strong>Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.</strong>
|
|
Nature Genet. 13: 63-69, 1996.
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[PubMed: 8673105]
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[Full Text: https://doi.org/10.1038/ng0596-63]
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</p>
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<li>
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<p class="mim-text-font">
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Szczesna, D., Ghosh, D., Li, Q., Gomes, A. V., Guzman, G., Arana, C., Zhi, G., Stull, J. T., Potter, J. D.
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<strong>Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca(2+) binding, and phosphorylation.</strong>
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J. Biol. Chem. 276: 7086-7092, 2001.
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[PubMed: 11102452]
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[Full Text: https://doi.org/10.1074/jbc.M009823200]
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<li>
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<p class="mim-text-font">
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Szczesna-Cordary, D., Guzman, G., Zhao, J., Hernandez, O., Wei, J., Diaz-Perez, Z.
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<strong>The E22K mutation of myosin RLC that causes familial hypertrophic cardiomyopathy increases calcium sensitivity of force and ATPase in transgenic mice.</strong>
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J. Cell Sci. 118: 3675-3683, 2005.
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[PubMed: 16076902]
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[Full Text: https://doi.org/10.1242/jcs.02492]
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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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|
Wadgaonkar, R., Shafiq, S., Rajmanickam, C., Siddiqui, M. A. Q.
|
|
<strong>Interaction of a conserved peptide domain in recombinant human ventricular myosin light chain-2 with myosin heavy chain.</strong>
|
|
Cell. Molec. Biol. Res. 39: 13-26, 1993.
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|
|
|
[PubMed: 8287067]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Weterman, M. A. J., Barth, P. G., van Spaendonck-Zwarts, K. Y., Aronica, E., Poll-The, B.-T., Brouwer, O. F., van Tintelen, J. P., Qahar, Z., Bradley, E. J., de Wissel, M., Salviati, L., Angelini, C., van den Heuvel, L., Thomasse, Y. E. M., Backx, A. P., Nurnberg, G., Nurnberg, P., Baas, F.
|
|
<strong>Recessive MYL2 mutations cause infantile type I muscle fibre disease and cardiomyopathy.</strong>
|
|
Brain 136: 282-293, 2013.
|
|
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|
|
|
[PubMed: 23365102]
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[Full Text: https://doi.org/10.1093/brain/aws293]
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Cassandra L. Kniffin - updated : 07/13/2021<br>Marla J. F. O'Neill - updated : 07/12/2018<br>Marla J. F. O'Neill - updated : 6/7/2010<br>Marla J. F. O'Neill - updated : 6/23/2008<br>George E. Tiller - updated : 6/5/2008<br>Patricia A. Hartz - updated : 2/23/2006<br>Patricia A. Hartz - updated : 8/17/2004<br>Patricia A. Hartz - updated : 8/9/2004<br>Marla J. F. O'Neill - updated : 6/22/2004<br>Marla J. F. O'Neill - updated : 3/24/2004<br>Victor A. McKusick - updated : 8/1/1997
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Victor A. McKusick : 6/29/1992
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carol : 08/06/2021<br>carol : 08/05/2021<br>ckniffin : 07/13/2021<br>carol : 07/13/2018<br>alopez : 07/12/2018<br>alopez : 03/02/2012<br>carol : 6/7/2010<br>alopez : 6/7/2010<br>alopez : 6/7/2010<br>terry : 6/2/2010<br>mgross : 6/23/2008<br>wwang : 6/5/2008<br>mgross : 3/3/2006<br>terry : 2/23/2006<br>mgross : 8/25/2004<br>terry : 8/17/2004<br>mgross : 8/10/2004<br>terry : 8/9/2004<br>carol : 6/22/2004<br>carol : 6/22/2004<br>carol : 5/25/2004<br>carol : 3/30/2004<br>tkritzer : 3/29/2004<br>terry : 3/24/2004<br>alopez : 6/26/2002<br>joanna : 2/7/2002<br>carol : 11/9/2001<br>terry : 11/9/2000<br>alopez : 4/30/1999<br>alopez : 4/30/1999<br>alopez : 4/30/1999<br>mark : 12/8/1997<br>terry : 8/1/1997<br>terry : 5/14/1996<br>terry : 5/7/1996<br>terry : 5/6/1996<br>carol : 6/29/1992
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