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<title>
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Entry
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- *601788 - MYOSTATIN; MSTN
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- OMIM
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</ul>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="row">
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<li role="separator" class="divider"></li>
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<a href="/history"> Search History </a>
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</form>
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<p />
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</div>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-2 hidden-sm hidden-xs">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601788</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 role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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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="#geneStructure">Gene Structure</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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/601788">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=ENSG00000138379;t=ENST00000260950" 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=2660" 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=601788" 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=ENSG00000138379;t=ENST00000260950" 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_005259" 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_005259" 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=601788" 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=03474&isoform_id=03474_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/MSTN" 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/2623582,4028596,4885259,6016119,51452098,62988801,113912347,113912349,113912351,113912353,113912355,113912357,113912359,113912361,113912363,113912365,113912367,113912369,113912371,113912373,113912375,113912377,113912379,113912381,113912383,113912385,113912387,113912389,113912391,113912393,113912395,113912397,113912399,113912401,113912403,113912405,113912407,113912409,113912411,113912413,113912415,113912417,113912419,113912421,113912423,113912425,113912427,113912429,113912431,113912433,113912435,113912437,113912439,113912441,113912443,113912445,113912447,113912449,113912451,113912453,113912455,113912457,113912459,113912461,113912463,113912465,113912467,113912469,113912471,113912473,113912475,113912477,113912479,113912481,113912483,113912485,113912487,113912489,113912491,113912493,113912495,113912497,113912499,113912501,113912503,113912505,113912507,113912509,113912511,113912513,113912515,113912517,113912519,113912521,113912523,113912525,113912527,113912529,113912531,113912533,113912535,113912537,113912539,113912541,113912543,113912545,113912547,113912549,113912551,113912553,113912555,113912557,113912559,113912561,113912563,113912565,113912567,113912569,113912571,113912573,113912575,113912577,113912579,113912581,113912583,113912585,113912587,113912589,113912591,113912593,113912595,113912597,113912599,113912601,113912603,113912605,113912607,113912609,113912611,113912613,113912615,113912617,113912619,113912621,113912623,113912625,113912627,113912629,113912631,113912633,113912635,113912637,119631285,158256480,298216570,2240208005" 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/O14793" 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=2660" 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=ENSG00000138379;t=ENST00000260950" 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=MSTN" 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=MSTN" 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+2660" 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/MSTN" 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:2660" 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/2660" 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=chr2&hgg_gene=ENST00000260950.5&hgg_start=190055700&hgg_end=190062729&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 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="#mimMedlinePlusGeneticsFold" id="mimMedlinePlusGeneticsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Consumer-friendly information about the effects of genetic variation on human health."><span id="mimMedlinePlusGeneticsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>MedlinePlus Genetics</div>
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<div id="mimMedlinePlusGeneticsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/condition/myostatin-related-muscle-hypertrophy" title="Myostatin-related muscle hypertrophy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">Myostatin-related muscle h… </a></div><div style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/gene/mstn" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MSTN gene </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601788[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=601788[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://gnomad.broadinstitute.org/gene/ENSG00000138379" 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.gwascentral.org/search?q=MSTN" 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=MSTN" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/MSTN" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MSTN&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/PA162396253" 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:4223" 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/FBgn0026199.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:95691" 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/MSTN#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:95691" 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/2660/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://omia.org/results?search_type=advanced&omia_id=000683,001538,002161" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2660" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00000903;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050208-735" 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:2660" 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=MSTN&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 249829006<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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601788
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</span>
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</span>
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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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MYOSTATIN; MSTN
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</span>
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</h3>
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<div>
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<br />
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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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GROWTH/DIFFERENTIATION FACTOR 8; GDF8
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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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<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=MSTN" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MSTN</a></em></strong>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/2/865?start=-3&limit=10&highlight=865">2q32.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:190055700-190062729&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'})">2:190,055,700-190,062,729</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</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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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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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="1">
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<span class="mim-font">
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<a href="/geneMap/2/865?start=-3&limit=10&highlight=865">
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2q32.2
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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?Muscle hypertrophy
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
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<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
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</span>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614160"> 614160 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/601788" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/601788" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>The transforming growth factor-beta superfamily encompasses a large number of growth and differentiation factors that play important roles in regulating embryonic development and in maintaining tissue homeostasis in adult animals. Myostatin, or GDF8, is a member of this superfamily with a role in the control and maintenance of skeletal muscle mass (<a href="#12" class="mim-tip-reference" title="McPherron, A. C., Lawler, A. M., Lee, S.-J. <strong>Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.</strong> Nature 387: 83-90, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9139826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9139826</a>] [<a href="https://doi.org/10.1038/387083a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9139826">McPherron et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9139826" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>Using degenerate PCR, <a href="#12" class="mim-tip-reference" title="McPherron, A. C., Lawler, A. M., Lee, S.-J. <strong>Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.</strong> Nature 387: 83-90, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9139826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9139826</a>] [<a href="https://doi.org/10.1038/387083a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9139826">McPherron et al. (1997)</a> identified a novel mouse TGF-beta family member, designated growth/differentiation factor-8, which is expressed specifically in developing and adult skeletal muscle. The gene encodes a 376-amino acid polypeptide that contains all the sequence hallmarks of the TGF-beta superfamily (<a href="/entry/190180">190180</a>). During early stages of embryogenesis, Gdf8 expression is restricted to the myotome compartment of developing somites. At later stages and in adult animals, Gdf8 is expressed in many different muscles throughout the body. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9139826" 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="Gonzalez-Cadavid, N. F., Taylor, W. E., Yarasheski, K., Sinha-Hikim, I., Ma, K., Ezzat, S., Shen, R., Lalani, R., Asa, S., Mamita, M., Nair, G., Arver, S., Bhasin, S. <strong>Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting.</strong> Proc. Nat. Acad. Sci. 95: 14938-14943, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9843994[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.25.14938" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843994">Gonzalez-Cadavid et al. (1998)</a> cloned the human myostatin gene and cDNA. MSTN is transcribed as a 3.1-kb mRNA species that encodes a 335-amino acid precursor protein. Myostatin is expressed uniquely in human skeletal muscle as a 26-kD mature glycoprotein (myostatin-immunoreactive protein) and secreted into the plasma. Myostatin immunoreactivity is detectable in human skeletal muscle in both type 1 and type 2 fibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="geneFunction" class="mim-anchor"></a>
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<h4 href="#mimGeneFunctionFold" id="mimGeneFunctionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimGeneFunctionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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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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<div id="mimGeneFunctionFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#5" class="mim-tip-reference" title="Gonzalez-Cadavid, N. F., Taylor, W. E., Yarasheski, K., Sinha-Hikim, I., Ma, K., Ezzat, S., Shen, R., Lalani, R., Asa, S., Mamita, M., Nair, G., Arver, S., Bhasin, S. <strong>Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting.</strong> Proc. Nat. Acad. Sci. 95: 14938-14943, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9843994[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.25.14938" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843994">Gonzalez-Cadavid et al. (1998)</a> examined the hypothesis that myostatin expression correlates inversely with fat-free mass in humans and that increased expression of the myostatin gene is associated with weight loss in men with AIDS wasting syndrome. They examined the expression of myostatin in skeletal muscle and serum of healthy and HIV-infected men. The serum and intramuscular concentrations of myostatin-immunoreactive protein were increased in HIV-infected men with weight loss compared with healthy men and correlated inversely with fat-free mass index. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Zimmers, T. A., Davies, M. V., Koniaris, L. G., Haynes, P., Esquela, A. F., Tomkinson, K. N., McPherron, A. C., Wolfman, N. M., Lee, S.-J. <strong>Induction of cachexia in mice by systemically administered myostatin.</strong> Science 296: 1486-1488, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12029139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12029139</a>] [<a href="https://doi.org/10.1126/science.1069525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12029139">Zimmers et al. (2002)</a> demonstrated that myostatin is synthesized as a preprotein activated by 2 proteolytic cleavages. Removal of the signal sequence is followed by cleavage at a tetrabasic processing site, resulting in a 26-kD amino-terminal propeptide and a 12.5-kD carboxy-terminal peptide, a dimer of which is the biologically active portion of the protein. <a href="#24" class="mim-tip-reference" title="Zimmers, T. A., Davies, M. V., Koniaris, L. G., Haynes, P., Esquela, A. F., Tomkinson, K. N., McPherron, A. C., Wolfman, N. M., Lee, S.-J. <strong>Induction of cachexia in mice by systemically administered myostatin.</strong> Science 296: 1486-1488, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12029139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12029139</a>] [<a href="https://doi.org/10.1126/science.1069525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12029139">Zimmers et al. (2002)</a> demonstrated that myostatin circulates in the blood of adult mice in a latent form that can be activated by acid treatment, similar to TGF-beta. Systemic overexpression of myostatin in adult mice was found to induce profound muscle and fat loss without diminution of nutrient intake. This is similar to that seen in human cachexia syndromes, and suggests that myostatin may be a useful pharmacologic target in clinical settings such as cachexia, where muscle growth is desired. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12029139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="geneStructure" class="mim-anchor"></a>
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<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<div id="mimGeneStructureFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#5" class="mim-tip-reference" title="Gonzalez-Cadavid, N. F., Taylor, W. E., Yarasheski, K., Sinha-Hikim, I., Ma, K., Ezzat, S., Shen, R., Lalani, R., Asa, S., Mamita, M., Nair, G., Arver, S., Bhasin, S. <strong>Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting.</strong> Proc. Nat. Acad. Sci. 95: 14938-14943, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9843994[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.25.14938" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9843994">Gonzalez-Cadavid et al. (1998)</a> determined that the MSTN gene contains 3 exons and has 3 putative transcription initiation sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="mapping" class="mim-anchor"></a>
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<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<div id="mimMappingFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>The Mh locus in cattle is located in the same region as the COL3A1 gene (<a href="/entry/120180">120180</a>), which maps to bovine 2q12-q22. This identified the region flanking COL3A1 on the human map, namely 2q31-q33, as the likely orthologous human chromosome segment containing the MSTN gene (<a href="#20" class="mim-tip-reference" title="Solinas-Toldo, S., Lengauer, C., Fries, R. <strong>Comparative genome map of human and cattle.</strong> Genomics 27: 489-496, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7558031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7558031</a>] [<a href="https://doi.org/10.1006/geno.1995.1081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7558031">Solinas-Toldo et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7558031" 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="#7" class="mim-tip-reference" title="Hartz, P. A. <strong>Personal Communication.</strong> Baltimore, Md. 4/14/2004."None>Hartz (2004)</a> mapped the GDF8 gene to chromosome 2q32.2 based on an alignment of the GDF8 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF019627" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF019627</a>) with the genomic sequence.</p>
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<p><a href="#4" class="mim-tip-reference" title="Ferrell, R. E., Conte, V., Lawrence, E. C., Roth, S. M., Hagberg, J. M., Hurley, B. F. <strong>Frequent sequence variation in the human myostatin (GDF8) gene as a marker for analysis of muscle-related phenotypes.</strong> Genomics 62: 203-207, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10610713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10610713</a>] [<a href="https://doi.org/10.1006/geno.1999.5984" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10610713">Ferrell et al. (1999)</a> determined the nucleotide sequence of human myostatin in 40 individuals. The invariant promoter contains a consensus myogenic differentiation antigen-1 (MYOD; <a href="/entry/159970">159970</a>) binding site, and the coding sequence contains 5 missense substitutions in conserved amino acid residues: A55T, K153R, E164K, P198A, and I225T. A55T in exon 1 and K153R in exon 2 were polymorphic in the general population, with significantly different allele frequencies in Caucasians and African Americans (P less than 0.001). Neither of the common polymorphisms had a significant impact on muscle mass response to strength training in either Caucasians or African Americans, although skewed allele frequencies precluded detection of small effects. <a href="#4" class="mim-tip-reference" title="Ferrell, R. E., Conte, V., Lawrence, E. C., Roth, S. M., Hagberg, J. M., Hurley, B. F. <strong>Frequent sequence variation in the human myostatin (GDF8) gene as a marker for analysis of muscle-related phenotypes.</strong> Genomics 62: 203-207, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10610713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10610713</a>] [<a href="https://doi.org/10.1006/geno.1999.5984" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10610713">Ferrell et al. (1999)</a> concluded that these allelic variants provide markers for examining association between the myostatin gene and interindividual variation in muscle mass and differences in loss of muscle mass with aging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10610713" 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>Myostatin is a negative regulator of muscle growth in mammals, and loss-of-function mutations are associated with increased skeletal muscle mass in mice, cattle, and humans. <a href="#18" class="mim-tip-reference" title="Saunders, M. A., Good, J. M., Lawrence, E. C., Ferrell, R. E., Li, W.-H., Nachman, M. W. <strong>Human adaptive evolution of myostatin (GDF8), a regulator of muscle growth.</strong> Am. J. Hum. Genet. 79: 1089-1097, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17186467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17186467</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17186467[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/509707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17186467">Saunders et al. (2006)</a> showed that positive natural selection has acted on human nucleotide variation at GDF8, since the observed ratio of nonsynonymous:synonymous changes among humans is significantly greater than expected under the neutral model and is strikingly different from patterns observed across mammalian orders. Furthermore, extended haplotypes around GDF8 suggest that 2 amino acid variants have been subject to recent positive selection. Both mutations are rare among non-Africans yet are at frequencies of up to 31% in sub-Saharan Africans. These signatures of selection at the molecular level suggest that human variation at GDF8 is associated with functional differences. The 2 nucleotide polymorphisms of primary interest were G163A and A2246G, corresponding to haplogroups 55 and 153, respectively. The frequency of these among African Americans was found to be 12% and 20%, respectively, but only 1% and 4%, respectively, in the Europeans sampled. The excess of nonsynonymous polymorphism had been previously seen only for a few other genes in humans, e.g., G6PD (<a href="/entry/305900">305900</a>) and the major histocompatibility complex (<a href="/entry/142800">142800</a>) (<a href="#22" class="mim-tip-reference" title="Verrelli, B. C., McDonald, J. H., Argyropoulos, G., Destro-Bisol, G., Froment, A., Drousiotou, A., Lefranc, G., Helal, A. N., Loiselet, J., Tishkoff, S. A. <strong>Evidence for balancing selection from nucleotide sequence analyses of human G6PD.</strong> Am. J. Hum. Genet. 71: 1112-1128, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12378426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12378426</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12378426[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/344345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12378426">Verrelli et al., 2002</a>; <a href="#9" class="mim-tip-reference" title="Hughes, A. L., Nei, M. <strong>Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection.</strong> Proc. Nat. Acad. Sci. 86: 958-962, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2492668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2492668</a>] [<a href="https://doi.org/10.1073/pnas.86.3.958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2492668">Hughes and Nei, 1989</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17186467+12378426+2492668" 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 healthy child with muscle hypertrophy and unusual strength (MSLHP; <a href="/entry/614160">614160</a>), <a href="#19" class="mim-tip-reference" title="Schuelke, M., Wagner, K. R., Stolz, L. E., Huber, C., Riebel, T., Komen, W., Braun, T., Tobin, J. F., Lee, S.-J. <strong>Myostatin mutation associated with gross muscle hypertrophy in a child.</strong> New Eng. J. Med. 350: 2682-2688, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15215484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15215484</a>] [<a href="https://doi.org/10.1056/NEJMoa040933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15215484">Schuelke et al. (2004)</a> identified homozygosity for a splice donor site mutation in the MSTN gene (<a href="#0001">601788.0001</a>). His mother, a former professional athlete, was heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15215484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Prontera, P., Belcastro, V., Calabresi, P., Donti, E. <strong>Myostatin depletion: a therapy for Ehlers-Danlos syndrome?</strong> Ann. Neurol. 67: 147-148, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20186851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20186851</a>] [<a href="https://doi.org/10.1002/ana.21828" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20186851">Prontera et al. (2010)</a> reported a 42-year old Italian man with a complex phenotype of Ehlers-Danlos syndrome (EDS; <a href="/entry/130000">130000</a>) caused by a 13.7-Mb de novo heterozygous deletion of chromosome 2q23.3-q31.2 resulting in deletion of the COL3A1 (<a href="/entry/120180">120180</a>), COL5A2 (<a href="/entry/120190">120190</a>), and myostatin genes. Loss-of-function mutations in COL3A1 and COL5A2 cause EDS types IV (<a href="/entry/130050">130050</a>) and I, respectively. Haploinsufficiency for MSTN results in overgrowth of skeletal muscle. Due to the monosomy for MSTN, the patient had 'an exceptional constitutional muscular mass,' without muscle weakness, myalgia, or easy fatigability. He also had no generalized joint hypomobility or recurrent joint dislocation; symptoms of EDS were limited to recurrent inguinal hernias and mild mitral valve prolapse. <a href="#17" class="mim-tip-reference" title="Prontera, P., Belcastro, V., Calabresi, P., Donti, E. <strong>Myostatin depletion: a therapy for Ehlers-Danlos syndrome?</strong> Ann. Neurol. 67: 147-148, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20186851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20186851</a>] [<a href="https://doi.org/10.1002/ana.21828" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20186851">Prontera et al. (2010)</a> hypothesized that haploinsufficiency for the MSTN allele exerted a protective effect again EDS clinical manifestations in this patient. The findings also indicated that there is direct involvement of muscle damage in EDS and that care of muscle function in these patients may be beneficial. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20186851" 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>To determine the biologic function of Gdf8, <a href="#12" class="mim-tip-reference" title="McPherron, A. C., Lawler, A. M., Lee, S.-J. <strong>Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.</strong> Nature 387: 83-90, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9139826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9139826</a>] [<a href="https://doi.org/10.1038/387083a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9139826">McPherron et al. (1997)</a> disrupted the Gdf8 gene by gene targeting in mice. Gdf8-null animals were significantly larger than wildtype animals and showed a large and widespread increase in skeletal muscle mass. Individual muscles of mutant animals weighed 2 to 3 times more than those of wildtype animals, and the increase in mass appeared to result from a combination of muscle cell hyperplasia and hypertrophy. <a href="#12" class="mim-tip-reference" title="McPherron, A. C., Lawler, A. M., Lee, S.-J. <strong>Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.</strong> Nature 387: 83-90, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9139826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9139826</a>] [<a href="https://doi.org/10.1038/387083a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9139826">McPherron et al. (1997)</a> suggested that Gdf8 functions specifically as a negative regulator of skeletal muscle growth. <a href="#10" class="mim-tip-reference" title="Lin, J., Arnold, H. B., Della-Fera, M. A., Azain, M. J., Hartzell, D. L., Baile, C. A. <strong>Myostatin knockout in mice increases myogenesis and decreases adipogenesis.</strong> Biochem. Biophys. Res. Commun. 291: 701-706, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11855847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11855847</a>] [<a href="https://doi.org/10.1006/bbrc.2002.6500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11855847">Lin et al. (2002)</a> observed increased skeletal muscle mass in their myostatin-null mouse model compared to wildtype animals as early as 4 weeks of age. In addition, the mutant mice showed reduced production and secretion of leptin (<a href="/entry/164160">164160</a>) which was associated with reduced fat deposition. The reduced adipogenesis in the knockout mice suggested that myostatin is involved in regulating adiposity as well as muscularity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11855847+9139826" 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>Several cattle breeds have been observed to show an exceptional muscle development commonly referred to as 'double-muscled.' Double-muscled animals are characterized by an increase in muscle mass of about 20%, due to general skeletal muscle hyperplasia, i.e., an increase in the number of muscle fibers rather than in their individual diameter. <a href="#6" class="mim-tip-reference" title="Grobet, L., Martin, L. J. R., Poncelet, D., Pirottin, D., Brouwers, B., Riquet, J., Schoeberlein, A., Dunner, S., Menissier, F., Massabanda, J., Fries, R., Hanset, R., Georges, M. <strong>A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle.</strong> Nature Genet. 17: 71-74, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288100</a>] [<a href="https://doi.org/10.1038/ng0997-71" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288100">Grobet et al. (1997)</a> stated that autosomal recessive inheritance had been suggested by segregation analysis performed both in experimental crosses and in the outbred population. This was confirmed by <a href="#2" class="mim-tip-reference" title="Charlier, C., Coppieters, W., Farnir, F., Grobet, L., Leroy, P. L., Michaux, C., Mni, M., Schwers, A., Vanmanshoven, P., Hanset, R., Georges, M. <strong>The mh gene causing double-muscling in cattle maps to bovine chromosome 2.</strong> Mammalian Genome 6: 788-792, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8597635/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8597635</a>] [<a href="https://doi.org/10.1007/BF00539005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8597635">Charlier et al. (1995)</a> who showed that the muscular hypertrophy (mh) locus maps to the centromeric end of bovine chromosome 2. <a href="#6" class="mim-tip-reference" title="Grobet, L., Martin, L. J. R., Poncelet, D., Pirottin, D., Brouwers, B., Riquet, J., Schoeberlein, A., Dunner, S., Menissier, F., Massabanda, J., Fries, R., Hanset, R., Georges, M. <strong>A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle.</strong> Nature Genet. 17: 71-74, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9288100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9288100</a>] [<a href="https://doi.org/10.1038/ng0997-71" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9288100">Grobet et al. (1997)</a> used a positional candidate approach to demonstrate that a mutation in the bovine MSTN gene (Mh locus), which encodes myostatin, is responsible for the double-muscled phenotype. They found an 11-bp deletion in the coding sequence for the bioactive C-terminal domain of the protein causing the muscular hypertrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8597635+9288100" 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 the Marchigiana breed of beef cattle in central Italy, <a href="#11" class="mim-tip-reference" title="Marchitelli, C., Savarese, M. C., Crisa, A., Nardone, A., Marsan, P. A., Valentini, A. <strong>Double muscling in Marchigiana beef breed is caused by a stop codon in the third exon of myostatin gene.</strong> Mammalian Genome 14: 392-395, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12879361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12879361</a>] [<a href="https://doi.org/10.1007/s00335-002-2176-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12879361">Marchitelli et al. (2003)</a> demonstrated that double muscling was associated with a G-to-T transversion in the third exon of the myostatin gene, introducing a premature stop codon. This added to the large series of mutations previously found in cattle with double muscling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12879361" 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>An autosomal recessive hypermuscular mouse mutation termed 'compact' (Cmpt) was shown by <a href="#21" class="mim-tip-reference" title="Szabo, G., Dallmann, G., Muller, G., Patthy, L., Soller, M., Varga, L. <strong>A deletion in the myostatin gene causes the compact (Cmpt) hypermuscular mutation in mice.</strong> Mammalian Genome 9: 671-672, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9680391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9680391</a>] [<a href="https://doi.org/10.1007/s003359900843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9680391">Szabo et al. (1998)</a> to be caused by deletion in the myostatin gene. Myostatin became a strong candidate gene for Cmpt when it was mapped to chromosome 1 in a region of homology to human 2q32-q35 and to the centromeric region of bovine chromosome 2 where the mh gene maps. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9680391" 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="#13" class="mim-tip-reference" title="McPherron, A. C., Lee, S.-J. <strong>Suppression of body fat accumulation in myostatin-deficient mice.</strong> J. Clin. Invest. 109: 595-601, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11877467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11877467</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11877467[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI13562" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11877467">McPherron and Lee (2002)</a> showed that myostatin-null mice have a significant reduction in fat accumulation with increasing age as compared to wildtype littermates and that loss of myostatin partially attenuates the obese and diabetic phenotypes of 2 mouse models, the agouti lethal yellow and obese mice. <a href="#13" class="mim-tip-reference" title="McPherron, A. C., Lee, S.-J. <strong>Suppression of body fat accumulation in myostatin-deficient mice.</strong> J. Clin. Invest. 109: 595-601, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11877467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11877467</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11877467[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI13562" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11877467">McPherron and Lee (2002)</a> suggested that pharmacologic agents that block myostatin function may be useful not only for enhancing muscle growth, but also for slowing or preventing the development of obesity and type II diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11877467" 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="#1" class="mim-tip-reference" title="Bogdanovich, S., Krag, T. O. B., Barton, E. R., Morris, L. D., Whittemore, L.-A., Ahima, R. S., Khurana, T. S. <strong>Functional improvement of dystrophic muscle by myostatin blockade.</strong> Nature 420: 418-421, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12459784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12459784</a>] [<a href="https://doi.org/10.1038/nature01154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12459784">Bogdanovich et al. (2002)</a> tested the ability of inhibition of myostatin in vivo to ameliorate the dystrophic phenotype in the mdx mouse model of Duchenne muscular dystrophy (DMD; <a href="/entry/310200">310200</a>). They blocked endogenous myostatin in mdx mice by intraperitoneal injections of blocking antibodies for 3 months and found increase in body weight, muscle mass, muscle size, and absolute muscle strength along with a significant decrease in muscle degeneration and concentrations of serum creatine kinase. <a href="#1" class="mim-tip-reference" title="Bogdanovich, S., Krag, T. O. B., Barton, E. R., Morris, L. D., Whittemore, L.-A., Ahima, R. S., Khurana, T. S. <strong>Functional improvement of dystrophic muscle by myostatin blockade.</strong> Nature 420: 418-421, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12459784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12459784</a>] [<a href="https://doi.org/10.1038/nature01154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12459784">Bogdanovich et al. (2002)</a> concluded that myostatin blockade provides a novel, pharmacologic strategy for treatment of diseases associated with muscle wasting such as DMD, and circumvents the major problems associated with conventional gene therapy in these disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12459784" 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 myostatin-null mice (Mstn -/-) crossed with mdx mice, a model for Duchenne and Becker (<a href="/entry/300376">300376</a>) muscular dystrophy, <a href="#23" class="mim-tip-reference" title="Wagner, K. R., McPherron, A. C., Winik, N., Lee, S.-J. <strong>Loss of myostatin attenuates severity of muscular dystrophy in mdx mice.</strong> Ann. Neurol. 52: 832-836, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447939</a>] [<a href="https://doi.org/10.1002/ana.10385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447939">Wagner et al. (2002)</a> found increased muscle mass, increased body weight, increased muscle fiber size, and increased strength compared to Mstn +/+/mdx mice. There was also a reduction in the extent of muscle fibrosis. They noted that although the loss of myostatin does not correct the primary defect in the mdx mice, it may ameliorate some features of the dystrophic phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12447939" 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>Texel sheep are renowned for their exceptional meatiness. To identify the genes underlying this economically important feature, <a href="#3" class="mim-tip-reference" title="Clop, A., Marcq, F., Takeda, H., Pirottin, D., Tordoir, X., Bibe, B., Bouix, J., Caiment, F., Elsen, J.-M., Eychenne, F., Larzul, C., Laville, E., Meish, F., Milenkovic, D., Tobin, J., Charlier, C., Georges, M. <strong>A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep.</strong> Nature Genet. 38: 813-818, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16751773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16751773</a>] [<a href="https://doi.org/10.1038/ng1810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16751773">Clop et al. (2006)</a> performed a full-genome scan in a Romanov x Texel F2 population. They mapped a quantitative trait locus with a major effect on muscle mass to chromosome 2 and subsequently fine-mapped it to a chromosome interval encompassing the GDF8 gene. They demonstrated that the GDF8 allele of Texel sheep is characterized by a G-to-A transition in the 3-prime untranslated region (UTR) that creates a target site for mir1 (<a href="/entry/609326">609326</a>) and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle. The mutation causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep. Analysis of SNP databases for humans and mice demonstrated that mutations creating or destroying putative miRNA target sites are abundant and might be important effectors of phenotypic variation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16751773" 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 COS-7 cells, <a href="#16" class="mim-tip-reference" title="Ohsawa, Y., Hagiwara, H., Nakatani, M., Yasue, A., Moriyama, K., Murakami, T., Tsuchida, K., Noji, S., Sunada, Y. <strong>Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition.</strong> J. Clin. Invest. 116: 2924-2934, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17039257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17039257</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17039257[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI28520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17039257">Ohsawa et al. (2006)</a> found that myostatin signaling was inhibited by caveolin-3 (CAV3; <a href="/entry/601253">601253</a>), which directly interacted with and inhibited type I myostatin receptors ALK4 (<a href="/entry/601300">601300</a>) and ALK5 (<a href="/entry/190181">190181</a>). Transgenic mice with Cav3 deficiency, a model for limb girdle muscular dystrophy type 1C (see RMD2, <a href="/entry/606072">606072</a>), show muscle atrophy and weakness. <a href="#16" class="mim-tip-reference" title="Ohsawa, Y., Hagiwara, H., Nakatani, M., Yasue, A., Moriyama, K., Murakami, T., Tsuchida, K., Noji, S., Sunada, Y. <strong>Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition.</strong> J. Clin. Invest. 116: 2924-2934, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17039257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17039257</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17039257[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI28520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17039257">Ohsawa et al. (2006)</a> found that doubly transgenic mice with both Cav3 deficiency and myostatin inhibition showed increased numbers and size of myofibers compared to singly Cav3-deficient mice, effectively reversing the muscle atrophy induced by Cav3 deficiency. In addition, intraperitoneal injection of a myostatin inhibitor improved functional muscle weakness in Cav3-deficient mice. <a href="#16" class="mim-tip-reference" title="Ohsawa, Y., Hagiwara, H., Nakatani, M., Yasue, A., Moriyama, K., Murakami, T., Tsuchida, K., Noji, S., Sunada, Y. <strong>Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition.</strong> J. Clin. Invest. 116: 2924-2934, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17039257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17039257</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17039257[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI28520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17039257">Ohsawa et al. (2006)</a> suggested that caveolin-3 normally suppresses myostatin signaling and that hyperactivation of myostatin signaling participates in the pathogenesis of muscular atrophy in this mouse model of LGMD1C. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17039257" 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="#15" class="mim-tip-reference" title="Mosher, D. S., Quignon, P., Bustamante, C. D., Sutter, N. B., Mellersh, C. S., Parker, H. G., Ostrander, E. A. <strong>A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs.</strong> PLoS Genet. 3: e79, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17530926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17530926</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17530926[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.0030079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17530926">Mosher et al. (2007)</a> found that a 2-bp deletion in exon 3 of the canine Mstn gene was associated with increased muscle mass in the whippet racing dog breed. Homozygosity for the mutation was associated with a grossly overmuscled double-muscled phenotype, commonly referred to as the 'bully.' Heterozygous dogs showed an intermediate phenotype and have been reported to be among the fastest dogs in competitive racing events. Analysis of several other dogs breeds, including greyhounds, did not identify the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17530926" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Mendias, C. L., Bakhurin, K. I., Faulkner, J. A. <strong>Tendons of myostatin-deficient mice are small, brittle, and hypocellular.</strong> Proc. Nat. Acad. Sci. 105: 388-393, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18162552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18162552</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18162552[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0707069105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18162552">Mendias et al. (2008)</a> found that tendons of Mstn-null mice were smaller than those of wildtype mice. Mstn-null tendons had decreased fibroblast density, decreased expression of type I collagen (see COL1A1; <a href="/entry/120150">120150</a>), and decreased expression of scleraxis (SCXA; <a href="/entry/609067">609067</a>) and tenomodulin (TNMD; <a href="/entry/300459">300459</a>), 2 genes that promote tendon fibroblast proliferation. Treatment of wildtype tendon fibroblasts with Mstn activated p38 MAP kinase (MAPK14; <a href="/entry/600289">600289</a>) and Smad2 (<a href="/entry/601366">601366</a>)/Smad3 (<a href="/entry/603109">603109</a>) signaling cascades, increased cell proliferation, and increased expression of type I collagen, Scxa, and Tnmd. Compared with tendons from wildtype mice, the mechanical properties of tibialis anterior tendons from Mstn-null mice had a greater peak stress, lower peak strain, and increased stiffness. <a href="#14" class="mim-tip-reference" title="Mendias, C. L., Bakhurin, K. I., Faulkner, J. A. <strong>Tendons of myostatin-deficient mice are small, brittle, and hypocellular.</strong> Proc. Nat. Acad. Sci. 105: 388-393, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18162552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18162552</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18162552[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0707069105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18162552">Mendias et al. (2008)</a> concluded that, in addition to regulating muscle mass and force, MSTN regulates the structure and function of tendon tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18162552" 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="#8" class="mim-tip-reference" title="Hill, E. W., Gu, J., Eivers, S. S., Fonseca, R. G., McGivney, B. A., Govindarajan, P., Orr, N., Katz, L. M., MacHugh, D. E. <strong>A sequence polymorphism in MSTN predicts sprinting ability and racing stamina in thoroughbred horses.</strong> PLoS One 5: e8645, 2010. Note: Electronic Article. Erratum published online.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20098749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20098749</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20098749[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pone.0008645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20098749">Hill et al. (2010)</a> identified a SNP in the equine myostatin gene that was strongly associated with sprinting ability and stamina in thoroughbred racehorses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20098749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a child with muscle hypertrophy and unusual strength (<a href="/entry/614160">614160</a>), <a href="#19" class="mim-tip-reference" title="Schuelke, M., Wagner, K. R., Stolz, L. E., Huber, C., Riebel, T., Komen, W., Braun, T., Tobin, J. F., Lee, S.-J. <strong>Myostatin mutation associated with gross muscle hypertrophy in a child.</strong> New Eng. J. Med. 350: 2682-2688, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15215484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15215484</a>] [<a href="https://doi.org/10.1056/NEJMoa040933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15215484">Schuelke et al. (2004)</a> identified homozygosity for a g.IVS1+5G-A transition at the splice donor site of intron 1, causing a cryptic splice site to occur 108 bp downstream and giving rise to a severely truncated protein. His mother, a former professional athlete, was heterozygous for the mutation, which was not found in 200 control chromosomes. Other family members were said to be exceptionally strong, but they were not available for study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15215484" 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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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17039257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17039257</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17039257[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17039257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI28520" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Prontera2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Prontera, P., Belcastro, V., Calabresi, P., Donti, E.
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|
<strong>Myostatin depletion: a therapy for Ehlers-Danlos syndrome?</strong>
|
|
Ann. Neurol. 67: 147-148, 2010.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20186851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20186851</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20186851" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.21828" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Saunders2006" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Saunders, M. A., Good, J. M., Lawrence, E. C., Ferrell, R. E., Li, W.-H., Nachman, M. W.
|
|
<strong>Human adaptive evolution of myostatin (GDF8), a regulator of muscle growth.</strong>
|
|
Am. J. Hum. Genet. 79: 1089-1097, 2006.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17186467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17186467</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17186467[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17186467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/509707" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Schuelke2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Schuelke, M., Wagner, K. R., Stolz, L. E., Huber, C., Riebel, T., Komen, W., Braun, T., Tobin, J. F., Lee, S.-J.
|
|
<strong>Myostatin mutation associated with gross muscle hypertrophy in a child.</strong>
|
|
New Eng. J. Med. 350: 2682-2688, 2004.
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|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15215484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15215484</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15215484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa040933" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="20" class="mim-anchor"></a>
|
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<a id="Solinas-Toldo1995" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Solinas-Toldo, S., Lengauer, C., Fries, R.
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|
<strong>Comparative genome map of human and cattle.</strong>
|
|
Genomics 27: 489-496, 1995.
|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7558031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7558031</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7558031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1995.1081" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Szabo1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Szabo, G., Dallmann, G., Muller, G., Patthy, L., Soller, M., Varga, L.
|
|
<strong>A deletion in the myostatin gene causes the compact (Cmpt) hypermuscular mutation in mice.</strong>
|
|
Mammalian Genome 9: 671-672, 1998.
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|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9680391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9680391</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9680391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s003359900843" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Verrelli2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Verrelli, B. C., McDonald, J. H., Argyropoulos, G., Destro-Bisol, G., Froment, A., Drousiotou, A., Lefranc, G., Helal, A. N., Loiselet, J., Tishkoff, S. A.
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<strong>Evidence for balancing selection from nucleotide sequence analyses of human G6PD.</strong>
|
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Am. J. Hum. Genet. 71: 1112-1128, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12378426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12378426</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12378426[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12378426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/344345" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Wagner2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wagner, K. R., McPherron, A. C., Winik, N., Lee, S.-J.
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<strong>Loss of myostatin attenuates severity of muscular dystrophy in mdx mice.</strong>
|
|
Ann. Neurol. 52: 832-836, 2002.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447939</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12447939" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.10385" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Zimmers2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zimmers, T. A., Davies, M. V., Koniaris, L. G., Haynes, P., Esquela, A. F., Tomkinson, K. N., McPherron, A. C., Wolfman, N. M., Lee, S.-J.
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<strong>Induction of cachexia in mice by systemically administered myostatin.</strong>
|
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Science 296: 1486-1488, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12029139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12029139</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12029139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1069525" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 12/2/2010
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 5/11/2010<br>Patricia A. Hartz - updated : 4/18/2008<br>Cassandra L. Kniffin - updated : 7/16/2007<br>Cassandra L. Kniffin - updated : 12/7/2006<br>Victor A. McKusick - updated : 11/27/2006<br>Victor A. McKusick - updated : 6/29/2006<br>Marla J. F. O'Neill - updated : 9/14/2004<br>Victor A. McKusick - updated : 7/12/2004<br>Victor A. McKusick - updated : 12/9/2003<br>Cassandra L. Kniffin - updated : 2/21/2003<br>Ada Hamosh - updated : 2/13/2003<br>Deborah L. Stone - updated : 6/12/2002<br>Ada Hamosh - updated : 5/29/2002<br>Patricia A. Hartz - updated : 3/19/2002<br>Victor A. McKusick - updated : 2/3/2000<br>Victor A. McKusick - updated : 12/21/1998<br>Victor A. McKusick - updated : 9/2/1998<br>Victor A. McKusick - updated : 11/21/1997<br>Victor A. McKusick - updated : 8/28/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 5/2/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/27/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/26/2021<br>carol : 09/28/2018<br>carol : 09/27/2018<br>carol : 01/29/2015<br>alopez : 5/5/2014<br>terry : 9/25/2012<br>terry : 9/25/2012<br>carol : 8/12/2011<br>carol : 8/12/2011<br>mgross : 12/2/2010<br>terry : 12/2/2010<br>wwang : 5/13/2010<br>ckniffin : 5/11/2010<br>ckniffin : 5/11/2010<br>mgross : 4/24/2008<br>terry : 4/18/2008<br>terry : 9/14/2007<br>wwang : 7/20/2007<br>ckniffin : 7/16/2007<br>wwang : 12/11/2006<br>ckniffin : 12/7/2006<br>alopez : 11/29/2006<br>terry : 11/27/2006<br>alopez : 7/5/2006<br>terry : 6/29/2006<br>tkritzer : 5/20/2005<br>terry : 4/5/2005<br>tkritzer : 9/20/2004<br>tkritzer : 9/14/2004<br>carol : 7/12/2004<br>carol : 7/12/2004<br>terry : 7/12/2004<br>mgross : 4/14/2004<br>mgross : 4/14/2004<br>terry : 4/1/2004<br>terry : 3/31/2004<br>tkritzer : 12/17/2003<br>terry : 12/9/2003<br>cwells : 2/27/2003<br>ckniffin : 2/21/2003<br>alopez : 2/19/2003<br>terry : 2/13/2003<br>carol : 6/12/2002<br>alopez : 5/30/2002<br>terry : 5/29/2002<br>carol : 3/19/2002<br>mcapotos : 2/17/2000<br>mcapotos : 2/16/2000<br>terry : 2/3/2000<br>terry : 2/3/2000<br>carol : 12/29/1998<br>terry : 12/21/1998<br>alopez : 9/8/1998<br>terry : 9/2/1998<br>dkim : 7/2/1998<br>terry : 11/24/1997<br>terry : 11/21/1997<br>terry : 11/21/1997<br>mark : 10/17/1997<br>dholmes : 9/30/1997<br>dholmes : 9/30/1997<br>jenny : 9/1/1997<br>terry : 8/29/1997<br>terry : 8/28/1997<br>mark : 5/2/1997
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 601788
|
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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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MYOSTATIN; MSTN
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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">
|
|
GROWTH/DIFFERENTIATION FACTOR 8; GDF8
|
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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: MSTN</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>SNOMEDCT:</strong> 249829006;
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</span>
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</p>
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<div>
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<br />
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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: 2q32.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:190,055,700-190,062,729 </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>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
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<th>
|
|
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="1">
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<span class="mim-font">
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2q32.2
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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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?Muscle hypertrophy
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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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614160
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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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<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 transforming growth factor-beta superfamily encompasses a large number of growth and differentiation factors that play important roles in regulating embryonic development and in maintaining tissue homeostasis in adult animals. Myostatin, or GDF8, is a member of this superfamily with a role in the control and maintenance of skeletal muscle mass (McPherron et al., 1997). </p>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using degenerate PCR, McPherron et al. (1997) identified a novel mouse TGF-beta family member, designated growth/differentiation factor-8, which is expressed specifically in developing and adult skeletal muscle. The gene encodes a 376-amino acid polypeptide that contains all the sequence hallmarks of the TGF-beta superfamily (190180). During early stages of embryogenesis, Gdf8 expression is restricted to the myotome compartment of developing somites. At later stages and in adult animals, Gdf8 is expressed in many different muscles throughout the body. </p><p>Gonzalez-Cadavid et al. (1998) cloned the human myostatin gene and cDNA. MSTN is transcribed as a 3.1-kb mRNA species that encodes a 335-amino acid precursor protein. Myostatin is expressed uniquely in human skeletal muscle as a 26-kD mature glycoprotein (myostatin-immunoreactive protein) and secreted into the plasma. Myostatin immunoreactivity is detectable in human skeletal muscle in both type 1 and type 2 fibers. </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>Gonzalez-Cadavid et al. (1998) examined the hypothesis that myostatin expression correlates inversely with fat-free mass in humans and that increased expression of the myostatin gene is associated with weight loss in men with AIDS wasting syndrome. They examined the expression of myostatin in skeletal muscle and serum of healthy and HIV-infected men. The serum and intramuscular concentrations of myostatin-immunoreactive protein were increased in HIV-infected men with weight loss compared with healthy men and correlated inversely with fat-free mass index. </p><p>Zimmers et al. (2002) demonstrated that myostatin is synthesized as a preprotein activated by 2 proteolytic cleavages. Removal of the signal sequence is followed by cleavage at a tetrabasic processing site, resulting in a 26-kD amino-terminal propeptide and a 12.5-kD carboxy-terminal peptide, a dimer of which is the biologically active portion of the protein. Zimmers et al. (2002) demonstrated that myostatin circulates in the blood of adult mice in a latent form that can be activated by acid treatment, similar to TGF-beta. Systemic overexpression of myostatin in adult mice was found to induce profound muscle and fat loss without diminution of nutrient intake. This is similar to that seen in human cachexia syndromes, and suggests that myostatin may be a useful pharmacologic target in clinical settings such as cachexia, where muscle growth is desired. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gonzalez-Cadavid et al. (1998) determined that the MSTN gene contains 3 exons and has 3 putative transcription initiation sites. </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>The Mh locus in cattle is located in the same region as the COL3A1 gene (120180), which maps to bovine 2q12-q22. This identified the region flanking COL3A1 on the human map, namely 2q31-q33, as the likely orthologous human chromosome segment containing the MSTN gene (Solinas-Toldo et al., 1995). </p><p>Hartz (2004) mapped the GDF8 gene to chromosome 2q32.2 based on an alignment of the GDF8 sequence (GenBank AF019627) with the genomic sequence.</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>Ferrell et al. (1999) determined the nucleotide sequence of human myostatin in 40 individuals. The invariant promoter contains a consensus myogenic differentiation antigen-1 (MYOD; 159970) binding site, and the coding sequence contains 5 missense substitutions in conserved amino acid residues: A55T, K153R, E164K, P198A, and I225T. A55T in exon 1 and K153R in exon 2 were polymorphic in the general population, with significantly different allele frequencies in Caucasians and African Americans (P less than 0.001). Neither of the common polymorphisms had a significant impact on muscle mass response to strength training in either Caucasians or African Americans, although skewed allele frequencies precluded detection of small effects. Ferrell et al. (1999) concluded that these allelic variants provide markers for examining association between the myostatin gene and interindividual variation in muscle mass and differences in loss of muscle mass with aging. </p><p>Myostatin is a negative regulator of muscle growth in mammals, and loss-of-function mutations are associated with increased skeletal muscle mass in mice, cattle, and humans. Saunders et al. (2006) showed that positive natural selection has acted on human nucleotide variation at GDF8, since the observed ratio of nonsynonymous:synonymous changes among humans is significantly greater than expected under the neutral model and is strikingly different from patterns observed across mammalian orders. Furthermore, extended haplotypes around GDF8 suggest that 2 amino acid variants have been subject to recent positive selection. Both mutations are rare among non-Africans yet are at frequencies of up to 31% in sub-Saharan Africans. These signatures of selection at the molecular level suggest that human variation at GDF8 is associated with functional differences. The 2 nucleotide polymorphisms of primary interest were G163A and A2246G, corresponding to haplogroups 55 and 153, respectively. The frequency of these among African Americans was found to be 12% and 20%, respectively, but only 1% and 4%, respectively, in the Europeans sampled. The excess of nonsynonymous polymorphism had been previously seen only for a few other genes in humans, e.g., G6PD (305900) and the major histocompatibility complex (142800) (Verrelli et al., 2002; Hughes and Nei, 1989). </p><p>In a healthy child with muscle hypertrophy and unusual strength (MSLHP; 614160), Schuelke et al. (2004) identified homozygosity for a splice donor site mutation in the MSTN gene (601788.0001). His mother, a former professional athlete, was heterozygous for the mutation. </p><p>Prontera et al. (2010) reported a 42-year old Italian man with a complex phenotype of Ehlers-Danlos syndrome (EDS; 130000) caused by a 13.7-Mb de novo heterozygous deletion of chromosome 2q23.3-q31.2 resulting in deletion of the COL3A1 (120180), COL5A2 (120190), and myostatin genes. Loss-of-function mutations in COL3A1 and COL5A2 cause EDS types IV (130050) and I, respectively. Haploinsufficiency for MSTN results in overgrowth of skeletal muscle. Due to the monosomy for MSTN, the patient had 'an exceptional constitutional muscular mass,' without muscle weakness, myalgia, or easy fatigability. He also had no generalized joint hypomobility or recurrent joint dislocation; symptoms of EDS were limited to recurrent inguinal hernias and mild mitral valve prolapse. Prontera et al. (2010) hypothesized that haploinsufficiency for the MSTN allele exerted a protective effect again EDS clinical manifestations in this patient. The findings also indicated that there is direct involvement of muscle damage in EDS and that care of muscle function in these patients may be beneficial. </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">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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|
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|
|
|
|
<span class="mim-text-font">
|
|
<p>To determine the biologic function of Gdf8, McPherron et al. (1997) disrupted the Gdf8 gene by gene targeting in mice. Gdf8-null animals were significantly larger than wildtype animals and showed a large and widespread increase in skeletal muscle mass. Individual muscles of mutant animals weighed 2 to 3 times more than those of wildtype animals, and the increase in mass appeared to result from a combination of muscle cell hyperplasia and hypertrophy. McPherron et al. (1997) suggested that Gdf8 functions specifically as a negative regulator of skeletal muscle growth. Lin et al. (2002) observed increased skeletal muscle mass in their myostatin-null mouse model compared to wildtype animals as early as 4 weeks of age. In addition, the mutant mice showed reduced production and secretion of leptin (164160) which was associated with reduced fat deposition. The reduced adipogenesis in the knockout mice suggested that myostatin is involved in regulating adiposity as well as muscularity. </p><p>Several cattle breeds have been observed to show an exceptional muscle development commonly referred to as 'double-muscled.' Double-muscled animals are characterized by an increase in muscle mass of about 20%, due to general skeletal muscle hyperplasia, i.e., an increase in the number of muscle fibers rather than in their individual diameter. Grobet et al. (1997) stated that autosomal recessive inheritance had been suggested by segregation analysis performed both in experimental crosses and in the outbred population. This was confirmed by Charlier et al. (1995) who showed that the muscular hypertrophy (mh) locus maps to the centromeric end of bovine chromosome 2. Grobet et al. (1997) used a positional candidate approach to demonstrate that a mutation in the bovine MSTN gene (Mh locus), which encodes myostatin, is responsible for the double-muscled phenotype. They found an 11-bp deletion in the coding sequence for the bioactive C-terminal domain of the protein causing the muscular hypertrophy. </p><p>In the Marchigiana breed of beef cattle in central Italy, Marchitelli et al. (2003) demonstrated that double muscling was associated with a G-to-T transversion in the third exon of the myostatin gene, introducing a premature stop codon. This added to the large series of mutations previously found in cattle with double muscling. </p><p>An autosomal recessive hypermuscular mouse mutation termed 'compact' (Cmpt) was shown by Szabo et al. (1998) to be caused by deletion in the myostatin gene. Myostatin became a strong candidate gene for Cmpt when it was mapped to chromosome 1 in a region of homology to human 2q32-q35 and to the centromeric region of bovine chromosome 2 where the mh gene maps. </p><p>McPherron and Lee (2002) showed that myostatin-null mice have a significant reduction in fat accumulation with increasing age as compared to wildtype littermates and that loss of myostatin partially attenuates the obese and diabetic phenotypes of 2 mouse models, the agouti lethal yellow and obese mice. McPherron and Lee (2002) suggested that pharmacologic agents that block myostatin function may be useful not only for enhancing muscle growth, but also for slowing or preventing the development of obesity and type II diabetes. </p><p>Bogdanovich et al. (2002) tested the ability of inhibition of myostatin in vivo to ameliorate the dystrophic phenotype in the mdx mouse model of Duchenne muscular dystrophy (DMD; 310200). They blocked endogenous myostatin in mdx mice by intraperitoneal injections of blocking antibodies for 3 months and found increase in body weight, muscle mass, muscle size, and absolute muscle strength along with a significant decrease in muscle degeneration and concentrations of serum creatine kinase. Bogdanovich et al. (2002) concluded that myostatin blockade provides a novel, pharmacologic strategy for treatment of diseases associated with muscle wasting such as DMD, and circumvents the major problems associated with conventional gene therapy in these disorders. </p><p>In myostatin-null mice (Mstn -/-) crossed with mdx mice, a model for Duchenne and Becker (300376) muscular dystrophy, Wagner et al. (2002) found increased muscle mass, increased body weight, increased muscle fiber size, and increased strength compared to Mstn +/+/mdx mice. There was also a reduction in the extent of muscle fibrosis. They noted that although the loss of myostatin does not correct the primary defect in the mdx mice, it may ameliorate some features of the dystrophic phenotype. </p><p>Texel sheep are renowned for their exceptional meatiness. To identify the genes underlying this economically important feature, Clop et al. (2006) performed a full-genome scan in a Romanov x Texel F2 population. They mapped a quantitative trait locus with a major effect on muscle mass to chromosome 2 and subsequently fine-mapped it to a chromosome interval encompassing the GDF8 gene. They demonstrated that the GDF8 allele of Texel sheep is characterized by a G-to-A transition in the 3-prime untranslated region (UTR) that creates a target site for mir1 (609326) and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle. The mutation causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep. Analysis of SNP databases for humans and mice demonstrated that mutations creating or destroying putative miRNA target sites are abundant and might be important effectors of phenotypic variation. </p><p>In COS-7 cells, Ohsawa et al. (2006) found that myostatin signaling was inhibited by caveolin-3 (CAV3; 601253), which directly interacted with and inhibited type I myostatin receptors ALK4 (601300) and ALK5 (190181). Transgenic mice with Cav3 deficiency, a model for limb girdle muscular dystrophy type 1C (see RMD2, 606072), show muscle atrophy and weakness. Ohsawa et al. (2006) found that doubly transgenic mice with both Cav3 deficiency and myostatin inhibition showed increased numbers and size of myofibers compared to singly Cav3-deficient mice, effectively reversing the muscle atrophy induced by Cav3 deficiency. In addition, intraperitoneal injection of a myostatin inhibitor improved functional muscle weakness in Cav3-deficient mice. Ohsawa et al. (2006) suggested that caveolin-3 normally suppresses myostatin signaling and that hyperactivation of myostatin signaling participates in the pathogenesis of muscular atrophy in this mouse model of LGMD1C. </p><p>Mosher et al. (2007) found that a 2-bp deletion in exon 3 of the canine Mstn gene was associated with increased muscle mass in the whippet racing dog breed. Homozygosity for the mutation was associated with a grossly overmuscled double-muscled phenotype, commonly referred to as the 'bully.' Heterozygous dogs showed an intermediate phenotype and have been reported to be among the fastest dogs in competitive racing events. Analysis of several other dogs breeds, including greyhounds, did not identify the mutation. </p><p>Mendias et al. (2008) found that tendons of Mstn-null mice were smaller than those of wildtype mice. Mstn-null tendons had decreased fibroblast density, decreased expression of type I collagen (see COL1A1; 120150), and decreased expression of scleraxis (SCXA; 609067) and tenomodulin (TNMD; 300459), 2 genes that promote tendon fibroblast proliferation. Treatment of wildtype tendon fibroblasts with Mstn activated p38 MAP kinase (MAPK14; 600289) and Smad2 (601366)/Smad3 (603109) signaling cascades, increased cell proliferation, and increased expression of type I collagen, Scxa, and Tnmd. Compared with tendons from wildtype mice, the mechanical properties of tibialis anterior tendons from Mstn-null mice had a greater peak stress, lower peak strain, and increased stiffness. Mendias et al. (2008) concluded that, in addition to regulating muscle mass and force, MSTN regulates the structure and function of tendon tissues. </p><p>Hill et al. (2010) identified a SNP in the equine myostatin gene that was strongly associated with sprinting ability and stamina in thoroughbred racehorses. </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>1 Selected Example):</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 MUSCLE HYPERTROPHY (1 patient)</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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MSTN, IVS1, G-A, +5
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<br />
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SNP: rs397515373,
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gnomAD: rs397515373,
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ClinVar: RCV000008144
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a child with muscle hypertrophy and unusual strength (614160), Schuelke et al. (2004) identified homozygosity for a g.IVS1+5G-A transition at the splice donor site of intron 1, causing a cryptic splice site to occur 108 bp downstream and giving rise to a severely truncated protein. His mother, a former professional athlete, was heterozygous for the mutation, which was not found in 200 control chromosomes. Other family members were said to be exceptionally strong, but they were not available for study. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
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</span>
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</h4>
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Bogdanovich, S., Krag, T. O. B., Barton, E. R., Morris, L. D., Whittemore, L.-A., Ahima, R. S., Khurana, T. S.
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<strong>Functional improvement of dystrophic muscle by myostatin blockade.</strong>
|
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Nature 420: 418-421, 2002.
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[PubMed: 12459784]
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[Full Text: https://doi.org/10.1038/nature01154]
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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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Charlier, C., Coppieters, W., Farnir, F., Grobet, L., Leroy, P. L., Michaux, C., Mni, M., Schwers, A., Vanmanshoven, P., Hanset, R., Georges, M.
|
|
<strong>The mh gene causing double-muscling in cattle maps to bovine chromosome 2.</strong>
|
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Mammalian Genome 6: 788-792, 1995.
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[PubMed: 8597635]
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[Full Text: https://doi.org/10.1007/BF00539005]
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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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Clop, A., Marcq, F., Takeda, H., Pirottin, D., Tordoir, X., Bibe, B., Bouix, J., Caiment, F., Elsen, J.-M., Eychenne, F., Larzul, C., Laville, E., Meish, F., Milenkovic, D., Tobin, J., Charlier, C., Georges, M.
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<strong>A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep.</strong>
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Nature Genet. 38: 813-818, 2006.
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[PubMed: 16751773]
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[Full Text: https://doi.org/10.1038/ng1810]
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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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Ferrell, R. E., Conte, V., Lawrence, E. C., Roth, S. M., Hagberg, J. M., Hurley, B. F.
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<strong>Frequent sequence variation in the human myostatin (GDF8) gene as a marker for analysis of muscle-related phenotypes.</strong>
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Genomics 62: 203-207, 1999.
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[PubMed: 10610713]
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[Full Text: https://doi.org/10.1006/geno.1999.5984]
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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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Gonzalez-Cadavid, N. F., Taylor, W. E., Yarasheski, K., Sinha-Hikim, I., Ma, K., Ezzat, S., Shen, R., Lalani, R., Asa, S., Mamita, M., Nair, G., Arver, S., Bhasin, S.
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<strong>Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting.</strong>
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Proc. Nat. Acad. Sci. 95: 14938-14943, 1998.
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[PubMed: 9843994]
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[Full Text: https://doi.org/10.1073/pnas.95.25.14938]
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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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Grobet, L., Martin, L. J. R., Poncelet, D., Pirottin, D., Brouwers, B., Riquet, J., Schoeberlein, A., Dunner, S., Menissier, F., Massabanda, J., Fries, R., Hanset, R., Georges, M.
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<strong>A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle.</strong>
|
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Nature Genet. 17: 71-74, 1997.
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[PubMed: 9288100]
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[Full Text: https://doi.org/10.1038/ng0997-71]
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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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Hartz, P. A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 4/14/2004.
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