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<title>
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Entry
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- *602775 - SHOC2 LEUCINE-RICH REPEAT SCAFFOLD PROTEIN; SHOC2
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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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<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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<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="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<a href="/history"> Search History </a>
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</form>
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<div class="row">
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<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">*602775</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 role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602775">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 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=ENSG00000108061;t=ENST00000369452" 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=8036" 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=602775" 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=ENSG00000108061;t=ENST00000369452" 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_001269039,NM_001324336,NM_001324337,NM_007373,NR_136749,XM_047425796" 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_007373" 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=602775" 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=04144&isoform_id=04144_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/SHOC2" 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/3252979,3293320,14423936,29792199,41281398,119569933,119569934,119569935,158259127,193786912,194373409,392841224,929654155,1024249284,1024249321,2217278782,2462521186,2462521188,2462521190" 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/Q9UQ13" 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=8036" 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=ENSG00000108061;t=ENST00000369452" 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=SHOC2" 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=SHOC2" 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+8036" 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/SHOC2" 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:8036" 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/8036" 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=chr10&hgg_gene=ENST00000369452.9&hgg_start=110919370&hgg_end=111013665&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:15454" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:15454" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=602775[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=602775[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/SHOC2/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000108061" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=SHOC2" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=SHOC2" 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=SHOC2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SHOC2&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/PA37960" 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:15454" 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/FBgn0038504.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:1927197" 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/SHOC2#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:1927197" 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/8036/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=8036" 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=WBGene00004929;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-050208-523" 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:8036" 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=SHOC2&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> 723444009<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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602775
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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SHOC2 LEUCINE-RICH REPEAT SCAFFOLD PROTEIN; SHOC2
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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SUPPRESSOR OF CLEAR, C. ELEGANS, HOMOLOG OF<br />
|
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RAS-BINDING PROTEIN SUR8, C. ELEGANS, HOMOLOG OF; SUR8
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SHOC2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SHOC2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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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/10/563?start=-3&limit=10&highlight=563">10q25.2</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr10:110919370-111013665&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'})">10:110,919,370-111,013,665</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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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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10q25.2
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Noonan syndrome-like with loose anagen hair 1
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<a href="/entry/607721"> 607721 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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PheneGene Graphics <span class="caret"></span>
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</button>
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<li><a href="/graph/linear/602775" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/602775" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>SHOC2 is a scaffold protein that plays a key role in activation of the ERK1 (MAPK3; <a href="/entry/601795">601795</a>)/ERK2 (MAPK1; <a href="/entry/176948">176948</a>) signaling pathway (summary by <a href="#5" class="mim-tip-reference" title="Jang, H., Oakley, E., Forbes-Osborne, M., Kesler, M. V., Norcross, R., Morris, A. C., Galperin, E. <strong>Hematopoietic and neural crest defects in zebrafish shoc2 mutants: a novel vertebrate model for Noonan-like syndrome.</strong> Hum. Molec. Genet. 28: 501-514, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30329053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30329053</a>] [<a href="https://doi.org/10.1093/hmg/ddy366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30329053">Jang et al., 2019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30329053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Cloning and Expression</strong>
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<p>Activation of fibroblast growth factor (FGF) receptors elicits diverse cellular responses, including growth, mitogenesis, migration, and differentiation. <a href="#8" class="mim-tip-reference" title="Selfors, L. M., Schutzman, J. L., Borland, C. Z., Stern, M. J. <strong>Soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling.</strong> Proc. Nat. Acad. Sci. 95: 6903-6908, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9618511[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.95.12.6903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618511">Selfors et al. (1998)</a> shed light on the intracellular signaling pathways that mediate these processes by studies in Caenorhabditis elegans. In this organism, they screened for genes that suppress the activity of an activated form of the EGL-15 FGF receptor consistent with the functioning of these genes downstream of EGL-15. Two of these genes were soc1 and soc2, symbolized thus for 'suppressor of clear (Clr)' phenotype; the third was sem5. <a href="#8" class="mim-tip-reference" title="Selfors, L. M., Schutzman, J. L., Borland, C. Z., Stern, M. J. <strong>Soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling.</strong> Proc. Nat. Acad. Sci. 95: 6903-6908, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9618511[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.95.12.6903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618511">Selfors et al. (1998)</a> showed that soc2 encodes a protein composed almost entirely of leucine-rich repeats, a domain implicated in protein-protein interactions. They identified a putative human homolog, SHOC2, which is 54% identical to soc2. They showed that SHOC2 mRNA was expressed in all tissues assayed and that the SHOC2 protein is localized to the cytoplasm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9618511" 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="Selfors, L. M., Schutzman, J. L., Borland, C. Z., Stern, M. J. <strong>Soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling.</strong> Proc. Nat. Acad. Sci. 95: 6903-6908, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9618511[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.95.12.6903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618511">Selfors et al. (1998)</a> showed that within the leucine-rich repeats of both soc2 and SHOC2 are 2 YXNX motifs that are potential tyrosine-phosphorylated docking sites for the SEM5/GRB2 Src homology 2 domain. However, phosphorylation of these residues was not required for soc2 function in vivo, and SHOC2 was not observed to be tyrosine phosphorylated in response to FGF stimulation. <a href="#8" class="mim-tip-reference" title="Selfors, L. M., Schutzman, J. L., Borland, C. Z., Stern, M. J. <strong>Soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling.</strong> Proc. Nat. Acad. Sci. 95: 6903-6908, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9618511[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.95.12.6903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618511">Selfors et al. (1998)</a> concluded that this genetic system identified a conserved gene implicated in mediating FGF receptor signaling in C. elegans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9618511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Komatsuzaki, S., Aoki, Y., Niihori, T., Okamoto, N., Hennekam, R. C. M., Hopman, S., Ohashi, H., Mizuno, S., Watanabe, Y., Kamasaki, H., Kondo, I., Moriyama, N., Kurosawa, K., Kawame, H., Okuyama, R., Imaizumi, M., Rikiishi, T., Tsuchiya, S., Kure, S., Matsubara, Y. <strong>Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies.</strong> J. Hum. Genet. 55: 801-809, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20882035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20882035</a>] [<a href="https://doi.org/10.1038/jhg.2010.116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20882035">Komatsuzaki et al. (2010)</a> examined the relative expression of SHOC2 in various tissues, including blood leukocytes and lymphocytes. In the adult human cDNA panel, the highest expression was observed in testis, with relatively high expression in several immune tissues, including spleen, bone marrow, tonsil, and lymph nodes. The authors noted that expression of SHOC2 was 6 times higher in polymorphonuclear (PMN) leukocytes than in mononuclear cells, and suggested that SHOC2 might be important to proliferation or survival of PMNs. Among fetal tissues, brain showed the highest expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20882035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Mapping</strong>
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<p>By FISH analysis, <a href="#8" class="mim-tip-reference" title="Selfors, L. M., Schutzman, J. L., Borland, C. Z., Stern, M. J. <strong>Soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling.</strong> Proc. Nat. Acad. Sci. 95: 6903-6908, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9618511[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.95.12.6903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618511">Selfors et al. (1998)</a> mapped the SHOC2 gene to chromosome 10q25. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9618511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Sieburth, D. S., Sun, Q., Han, M. <strong>SUR-8, a conserved Ras-binding protein with leucine-rich repeats, positively regulates Ras-mediated signaling in C. elegans.</strong> Cell 94: 119-130, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674433</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81227-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9674433">Sieburth et al. (1998)</a> identified and characterized the sur8 gene in C. elegans, which positively regulates Ras-mediated signal transduction during vulval development. The authors found that reduction of sur8 function suppresses an activated Ras mutation and dramatically enhances phenotypes of mpk1/sur1 MAP kinase (see <a href="/entry/176948">176948</a>) and ksr1 (<a href="/entry/601132">601132</a>) mutations, whereas increase of sur8 dosage enhances an activated Ras mutation. Sur8 appears to act downstream of or in parallel to Ras but upstream of Raf. Sur8 encodes a conserved protein that is composed predominantly of leucine-rich repeats. The sur8 protein interacts directly with Ras but not with the Ras(P34G) mutant protein, suggesting that sur8 may mediate its effects through Ras binding. By use of EST primers and 5-prime RACE, <a href="#9" class="mim-tip-reference" title="Sieburth, D. S., Sun, Q., Han, M. <strong>SUR-8, a conserved Ras-binding protein with leucine-rich repeats, positively regulates Ras-mediated signaling in C. elegans.</strong> Cell 94: 119-130, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674433</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81227-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9674433">Sieburth et al. (1998)</a> cloned a structural and functional SUR8 homolog in humans that specifically binds K-Ras (<a href="/entry/190070">190070</a>) and N-Ras (<a href="/entry/164790">164790</a>) but not H-Ras (<a href="/entry/190020">190020</a>) in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9674433" 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>MRAS (<a href="/entry/608435">608435</a>), SHOC2, and protein phosphatase-1 (PP1; see <a href="/entry/176875">176875</a>) interact to form a heterotrimeric holoenzyme that dephosphorylates the S259 inhibitory site on RAF kinases, activating downstream signaling. <a href="#11" class="mim-tip-reference" title="Young, L. C., Hartig, N., del Rio, L. B., Sari, S., Ringham-Terry, B., Wainwright, J. R., Jones, G. G., McCormick, F., Rodriguez-Viciana, P. <strong>SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.</strong> Proc. Nat. Acad. Sci. 115: E10576-E10585, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30348783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30348783</a>] [<a href="https://doi.org/10.1073/pnas.1720352115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30348783">Young et al. (2018)</a> showed that MRAS and SHOC2 function as PP1 regulatory subunits, providing the complex with striking specificity against RAF. MRAS also functions as a targeting subunit, as membrane localization is required for efficient RAF dephosphorylation and ERK (see <a href="/entry/601795">601795</a>) pathway regulation in cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30348783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunoprecipitation of endogenous LZTR1 (<a href="/entry/600574">600574</a>) followed by Western blotting, <a href="#10" class="mim-tip-reference" title="Umeki, I., Niihori, T., Abe, T., Kanno, S., Okamoto, N., Mizuno, S., Kurosawa, K., Nagasaki, K., Yoshida, M., Ohashi, H., Inoue, S., Matsubara, Y., Fujiwara, I., Kure, S., Aoki, Y. <strong>Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.</strong> Hum. Genet. 138: 21-35, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30368668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30368668</a>] [<a href="https://doi.org/10.1007/s00439-018-1951-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30368668">Umeki et al. (2019)</a> showed that LZTR1 bound to the RAF1 (<a href="/entry/164760">164760</a>)-SHOC2-PPP1CB (<a href="/entry/600590">600590</a>) complex. Mutations in all these genes cause Noonan syndrome or Noonan-like phenotypes. Cells transfected with siRNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at ser259. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30368668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using a systems biology approach based on in silico protein network analysis that identified SHOC2 as a candidate gene, <a href="#1" class="mim-tip-reference" title="Cordeddu, V., Di Schiavi, E., Pennacchio, L. A., Ma'ayan, A., Sarkozy, A., Fodale, V., Cecchetti, S., Cardinale, A., Martin, J., Schackwitz, W., Lipzen, A., Zampino, G., and 19 others. <strong>Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair.</strong> Nature Genet. 41: 1022-1026, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19684605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19684605</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19684605[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19684605">Cordeddu et al. (2009)</a> sequenced SHOC2 coding exons in a Noonan syndrome (see <a href="/entry/163950">163950</a>) cohort that included 96 individuals who were negative for mutations in known disease genes. The authors identified a heterozygous mutation (S2G; <a href="#0001">602775.0001</a>) in the SHOC2 gene in 4 unrelated individuals. They then analyzed the SHOC2 gene in a cohort of 410 mutation-negative patients with Noonan syndrome or a related phenotype and identified 21 individuals with the same S2G mutation. All of the patients with the S2G mutation had a relatively consistent Noonan syndrome-like disorder with loose anagen hair (NSLH; <a href="/entry/607721">607721</a>). Functional studies of S2G-mutant SHOC2 demonstrated introduction of an N-myristoylation site, resulting in aberrant localization and signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19684605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a male infant with typical dysmorphic facial features and other signs of Noonan syndrome, who died of congestive heart failure at 4 months of age, <a href="#4" class="mim-tip-reference" title="Hoban, R., Roberts, A. E., Demmer, L., Jethva, R., Shephard, B. <strong>Noonan syndrome due to a SHOC2 mutation presenting with fetal distress and fatal hypertrophic cardiomyopathy in a premature infant.</strong> Am. J. Med. Genet. 158A: 1411-1413, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22528146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22528146</a>] [<a href="https://doi.org/10.1002/ajmg.a.35318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22528146">Hoban et al. (2012)</a> identified heterozygosity for the S2G mutation in SHOC2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22528146" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The MRAS (<a href="/entry/608435">608435</a>) GTPase, a close relative of RAS oncoproteins, interacts with SHOC2 and protein phosphatase-1 (PP1; see <a href="/entry/176875">176875</a>) to form a heterotrimeric holoenzyme that dephosphorylates an inhibitory site on RAF kinases, activating downstream signaling. <a href="#11" class="mim-tip-reference" title="Young, L. C., Hartig, N., del Rio, L. B., Sari, S., Ringham-Terry, B., Wainwright, J. R., Jones, G. G., McCormick, F., Rodriguez-Viciana, P. <strong>SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.</strong> Proc. Nat. Acad. Sci. 115: E10576-E10585, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30348783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30348783</a>] [<a href="https://doi.org/10.1073/pnas.1720352115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30348783">Young et al. (2018)</a> showed that mutations in MRAS, SHOC2, and PPP1CB (<a href="/entry/600590">600590</a>) that result in Noonan syndrome invariably promote complex formation with each other, but not necessarily with other interactors. Thus, Noonan syndrome in individuals with SHOC2, MRAS, or PPPC1B mutations is likely driven at the biochemical level by enhanced ternary complex formation and highlights the crucial role of this phosphatase holoenzyme in RAF S259 dephosphorylation, ERK pathway dynamics, and normal human development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30348783" 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 cohort of 92 patients with Noonan syndrome and related disorders, who were negative for mutation in 8 genes known to be associated with these disorders, <a href="#6" class="mim-tip-reference" title="Komatsuzaki, S., Aoki, Y., Niihori, T., Okamoto, N., Hennekam, R. C. M., Hopman, S., Ohashi, H., Mizuno, S., Watanabe, Y., Kamasaki, H., Kondo, I., Moriyama, N., Kurosawa, K., Kawame, H., Okuyama, R., Imaizumi, M., Rikiishi, T., Tsuchiya, S., Kure, S., Matsubara, Y. <strong>Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies.</strong> J. Hum. Genet. 55: 801-809, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20882035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20882035</a>] [<a href="https://doi.org/10.1038/jhg.2010.116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20882035">Komatsuzaki et al. (2010)</a> sequenced all coding regions of the SHOC2 gene and identified the S2G mutation in 8 patients. The mutation was shown to have arisen de novo in the 3 families for which parental DNA was available. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20882035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a father and daughter with features overlapping those of NSLH1, <a href="#3" class="mim-tip-reference" title="Hannig, V., Jeoung, M., Jang, E. R., Phillips, J. A., III, Galperin, E. <strong>A novel SHOC2 variant in rasopathy.</strong> Hum. Mutat. 35: 1290-1294, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25137548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25137548</a>] [<a href="https://doi.org/10.1002/humu.22634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25137548">Hannig et al. (2014)</a> analyzed a RASopathy gene panel and identified heterozygosity for a missense mutation in the SHOC2 gene (M173I; <a href="#0002">602775.0002</a>). Functional analysis appeared to show loss of function in the ERK1/2 pathway, in contrast to the recurrent S2G variant. However, <a href="#11" class="mim-tip-reference" title="Young, L. C., Hartig, N., del Rio, L. B., Sari, S., Ringham-Terry, B., Wainwright, J. R., Jones, G. G., McCormick, F., Rodriguez-Viciana, P. <strong>SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.</strong> Proc. Nat. Acad. Sci. 115: E10576-E10585, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30348783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30348783</a>] [<a href="https://doi.org/10.1073/pnas.1720352115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30348783">Young et al. (2018)</a> demonstrated gain-of-function effects with the M173I mutant, which showed enhanced interaction with MRAS and PP1 and rescued ERK activation in SHOC2-deficient cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30348783+25137548" 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 an infant boy with NSLH1, <a href="#7" class="mim-tip-reference" title="Motta, M., Giancotti, A., Mastromoro, G., Chandramouli, B., Pinna, V., Pantaleoni, F., Di Giosaffatte, N., Petrini, S., Mazza, T., D'Ambrosio, V., Versacci, P., Ventriglia, F., Chillemi, G., Pizzuti, A., Tartaglia, M., De Luca, A. <strong>Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy.</strong> Hum. Mutat. 40: 1046-1056, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31059601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31059601</a>] [<a href="https://doi.org/10.1002/humu.23767" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31059601">Motta et al. (2019)</a> identified heterozygosity for a de novo deletion/insertion in the SHOC2 gene (<a href="#0003">602775.0003</a>). The mutation was not found in an in-house RASopathy database of more than 1,000 families or in public variant databases. Functional analysis demonstrated that the mutant protein, like the 2 previously reported NSLH1-associated mutants, upregulates RAS signaling through the MAPK cascade, selectively promoting SHOC2 complex formation with MRAS and the catalytic subunit of PP1 (PP1C; see <a href="/entry/176875">176875</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31059601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Jang, H., Oakley, E., Forbes-Osborne, M., Kesler, M. V., Norcross, R., Morris, A. C., Galperin, E. <strong>Hematopoietic and neural crest defects in zebrafish shoc2 mutants: a novel vertebrate model for Noonan-like syndrome.</strong> Hum. Molec. Genet. 28: 501-514, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30329053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30329053</a>] [<a href="https://doi.org/10.1093/hmg/ddy366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30329053">Jang et al. (2019)</a> found that knockdown of shoc2 at early stages of zebrafish embryonic development affected the number of erythropoietic and myelopoietic cells and resulted in hematopoietic defects. The authors generated shoc2-knockout zebrafish and found that loss of shoc2 resulted in multiple deficiencies during embryogenesis, including gross defects in blood cell differentiation and abnormal craniofacial development. Shoc2 -/- zebrafish displayed systemic defects in neural crest specification and hematopoiesis, indicating a central role for shoc2 in embryogenesis. In addition, shoc2 -/- zebrafish displayed an array of developmental defects, emphasizing the essential role of shoc2 in coordinating activities of linear components of the erk1/erk2 pathway. Overall, shoc2 -/- zebrafish exhibited many of the clinical hallmarks associated with human NSLH1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30329053" 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 25 patients with a Noonan syndrome-like disorder with loose anagen hair (NSLH1; <a href="/entry/607721">607721</a>), <a href="#1" class="mim-tip-reference" title="Cordeddu, V., Di Schiavi, E., Pennacchio, L. A., Ma'ayan, A., Sarkozy, A., Fodale, V., Cecchetti, S., Cardinale, A., Martin, J., Schackwitz, W., Lipzen, A., Zampino, G., and 19 others. <strong>Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair.</strong> Nature Genet. 41: 1022-1026, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19684605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19684605</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19684605[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.425" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19684605">Cordeddu et al. (2009)</a> identified heterozygosity for a 4A-G transition in exon 2 of the SHOC2 gene, resulting in a ser2-to-gly (S2G) substitution. The mutation was shown to be de novo in the 15 patients for whom parental DNA was available. Functional studies demonstrated that the S2G mutation introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. In vitro expression of mutant SHOC2 enhanced MAPK (see <a href="/entry/176948">176948</a>) activation in a cell type-specific fashion. Induction of mutant SHOC2 in C. elegans engendered protruding vulva, a neomorphic phenotype previously associated with aberrant signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19684605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a male infant with typical dysmorphic facial features and other signs of Noonan syndrome, who died of congestive heart failure at 4 months of age, <a href="#4" class="mim-tip-reference" title="Hoban, R., Roberts, A. E., Demmer, L., Jethva, R., Shephard, B. <strong>Noonan syndrome due to a SHOC2 mutation presenting with fetal distress and fatal hypertrophic cardiomyopathy in a premature infant.</strong> Am. J. Med. Genet. 158A: 1411-1413, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22528146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22528146</a>] [<a href="https://doi.org/10.1002/ajmg.a.35318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22528146">Hoban et al. (2012)</a> identified heterozygosity for a de novo S2G mutation in SHOC2. The authors noted that the 'loose anagen hair' phenotype and skin features previously reported in patients with the S2G mutation were not present in this young infant, and stated that the cardiac anomaly expanded the clinical phenotype associated with the SHOC2 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22528146" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 5 unrelated children with Noonan syndrome-like disorder and loose anagen hair, <a href="#2" class="mim-tip-reference" title="Gripp, K. W., Zand, D. J., Demmer, L., Anderson, C. E., Dobyns, W. B., Zackai, E. H., Denenberg, E., Jenny, K., Stabley, D. L., Sol-Church, K. <strong>Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.</strong> Am. J. Med. Genet. 161A: 2420-2430, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23918763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23918763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23918763[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.36098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23918763">Gripp et al. (2013)</a> identified heterozygosity for the S2G mutation in the SHOC2 gene. The mutation was shown to have occurred de novo in 2 of the patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23918763" 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 8 unrelated patients with Noonan syndrome-like disorder and loose anagen hair, <a href="#6" class="mim-tip-reference" title="Komatsuzaki, S., Aoki, Y., Niihori, T., Okamoto, N., Hennekam, R. C. M., Hopman, S., Ohashi, H., Mizuno, S., Watanabe, Y., Kamasaki, H., Kondo, I., Moriyama, N., Kurosawa, K., Kawame, H., Okuyama, R., Imaizumi, M., Rikiishi, T., Tsuchiya, S., Kure, S., Matsubara, Y. <strong>Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies.</strong> J. Hum. Genet. 55: 801-809, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20882035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20882035</a>] [<a href="https://doi.org/10.1038/jhg.2010.116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20882035">Komatsuzaki et al. (2010)</a> identified heterozygosity for the S2G mutation, which was shown to have arisen de novo in the 3 patients for whom parental DNA was available. The authors noted that short stature, relative macrocephaly, hypertelorism, low-set ears, sparse/easily pluckable hair, and a variety of skin abnormalities, including dark skin and atopic dermatitis, were commonly seen in patients positive for the S2G mutation. <a href="#11" class="mim-tip-reference" title="Young, L. C., Hartig, N., del Rio, L. B., Sari, S., Ringham-Terry, B., Wainwright, J. R., Jones, G. G., McCormick, F., Rodriguez-Viciana, P. <strong>SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.</strong> Proc. Nat. Acad. Sci. 115: E10576-E10585, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30348783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30348783</a>] [<a href="https://doi.org/10.1073/pnas.1720352115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30348783">Young et al. (2018)</a> studied the SHOC2 S2G mutation in HEK293T cells and observed increased ability of the mutant protein to interact with MRAS (<a href="/entry/608435">608435</a>) and PP1 (<a href="/entry/601790">601790</a>) compared to wildtype SHOC2. In cotransfection assays, the S2G mutant also efficiently dephosphorylated positions S365 in BRAF (<a href="/entry/164757">164757</a>) and S259 in CRAF (<a href="/entry/164760">164760</a>). In addition, when reexpressed in SHOC2-knockout DLD1 cells, the S2G mutant decreased the higher basal levels of S365-BRAF and S259-CRAF phosphorylation as well as the impaired epidermal growth factor (EGF; <a href="/entry/131530">131530</a>)-induced ERK (see <a href="/entry/601795">601795</a>) pathway activation caused by SHOC2 ablation. Serum-starved DLD1 cells reexpressing SHOC2 S2G had modestly lower phosphorylated S365-BRAF and S259-CRAF levels and modestly higher phosphorylated MEK (see <a href="/entry/176872">176872</a>) and RSK (see <a href="/entry/601684">601684</a>) levels compared to cells expressing wildtype SHOC2, which the authors noted was consistent with RASopathy gain-of-function mutations being only weakly activating and ERK pathway activation by such mutants being difficult to detect in many experimental systems. <a href="#11" class="mim-tip-reference" title="Young, L. C., Hartig, N., del Rio, L. B., Sari, S., Ringham-Terry, B., Wainwright, J. R., Jones, G. G., McCormick, F., Rodriguez-Viciana, P. <strong>SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.</strong> Proc. Nat. Acad. Sci. 115: E10576-E10585, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30348783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30348783</a>] [<a href="https://doi.org/10.1073/pnas.1720352115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30348783">Young et al. (2018)</a> concluded that the recurrent S2G variant is a gain-of-function mutant that upregulates the ERK pathway during development by selectively promoting phosphatase complex formation with MRAS and PP1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20882035+30348783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs730881020 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs730881020;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs730881020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs730881020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000169685 OR RCV000523270 OR RCV000586119 OR RCV001030821 OR RCV001376015 OR RCV002336369 OR RCV003156077" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000169685, RCV000523270, RCV000586119, RCV001030821, RCV001376015, RCV002336369, RCV003156077" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000169685...</a>
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<p>In a father and daughter with features overlapping those of Noonan syndrome, with sparse and slow-growing hair (NSLH1; <a href="/entry/607721">607721</a>), <a href="#3" class="mim-tip-reference" title="Hannig, V., Jeoung, M., Jang, E. R., Phillips, J. A., III, Galperin, E. <strong>A novel SHOC2 variant in rasopathy.</strong> Hum. Mutat. 35: 1290-1294, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25137548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25137548</a>] [<a href="https://doi.org/10.1002/humu.22634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25137548">Hannig et al. (2014)</a> identified heterozygosity for a c.519G-A transition (c.519G-A, NM_007373.3) in the SHOC2 gene, resulting in a met173-to-ile (M173I) substitution at a highly conserved residue within the fourth leucine-rich repeat in the LRR domain. The mutation was not found in 6,500 asymptomatic individuals. Functional analysis in COS1 cells with constitutive knockdown of SHOC2 showed that, although wildtype SHOC2 rescued epidermal growth factor (EGF; <a href="/entry/131530">131530</a>)-induced ERK1 (<a href="/entry/601795">601795</a>)/2 (<a href="/entry/176948">176948</a>) phosphorylation to the extent of endogenous SHOC2, the M173I mutant was able to restore only approximately 10% above the basal level of activity. In addition, overexpression of the M173I mutant did not lead to changes in ERK1/2 activity or in AKT (see <a href="/entry/164730">164730</a>) phosphorylation. Immunoprecipitation studies in transfected 293FT cells showed that the M173I mutant failed to precipitate endogenous PP1c (see <a href="/entry/176875">176875</a>) effectively, and stimulation with EGF resulted in only a mild increase in RAF1 (<a href="/entry/164760">164760</a>) S338 phosphorylation, compared to a dramatic increase with wildtype SHOC2. The authors concluded that the M1713 SHOC2 substitution causes loss of function in the ERK1/2 pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25137548" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Young, L. C., Hartig, N., del Rio, L. B., Sari, S., Ringham-Terry, B., Wainwright, J. R., Jones, G. G., McCormick, F., Rodriguez-Viciana, P. <strong>SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.</strong> Proc. Nat. Acad. Sci. 115: E10576-E10585, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30348783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30348783</a>] [<a href="https://doi.org/10.1073/pnas.1720352115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30348783">Young et al. (2018)</a> studied the SHOC2 M173I mutation in HEK293T cells and observed increased ability to interact with MRAS (<a href="/entry/608435">608435</a>) and PP1 (<a href="/entry/601790">601790</a>) compared to wildtype SHOC2. In cotransfection assays, the M173I mutant also efficiently dephosphorylated BRAF (<a href="/entry/164757">164757</a>) S365 and CRAF (<a href="/entry/164760">164760</a>) S259. In addition, when reexpressed in SHOC2-knockout DLD1 cells, the M173I mutant decreased the higher basal levels of S365-BRAF and S259-CRAF phosphorylation as well as the impaired EGF-induced ERK pathway activation caused by SHOC2 ablation. Serum-starved DLD1 cells reexpressing SHOC2 M173I had modestly lower phosphorylated S365-BRAF and S259-CRAF levels and modestly higher phosphorylated MEK (see <a href="/entry/176872">176872</a>) and RSK (see <a href="/entry/601684">601684</a>) levels compared to cells expressing wildtype SHOC2, which the authors noted was consistent with RASopathy gain-of-function mutations being only weakly activating and ERK pathway activation by such mutants being difficult to detect in many experimental systems. <a href="#11" class="mim-tip-reference" title="Young, L. C., Hartig, N., del Rio, L. B., Sari, S., Ringham-Terry, B., Wainwright, J. R., Jones, G. G., McCormick, F., Rodriguez-Viciana, P. <strong>SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.</strong> Proc. Nat. Acad. Sci. 115: E10576-E10585, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30348783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30348783</a>] [<a href="https://doi.org/10.1073/pnas.1720352115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30348783">Young et al. (2018)</a> concluded that, like the recurrent S2G mutation (<a href="#0001">602775.0001</a>), the M173I variant is a gain-of-function mutant that upregulates the ERK pathway during development by selectively promoting phosphatase complex formation with MRAS and PP1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30348783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1848064627 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1848064627;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1848064627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1848064627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001250488" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001250488" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001250488</a>
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<p>In an infant boy with Noonan syndrome-like disorder with loose anagen hair (NSLH1; <a href="/entry/607721">607721</a>), <a href="#7" class="mim-tip-reference" title="Motta, M., Giancotti, A., Mastromoro, G., Chandramouli, B., Pinna, V., Pantaleoni, F., Di Giosaffatte, N., Petrini, S., Mazza, T., D'Ambrosio, V., Versacci, P., Ventriglia, F., Chillemi, G., Pizzuti, A., Tartaglia, M., De Luca, A. <strong>Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy.</strong> Hum. Mutat. 40: 1046-1056, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31059601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31059601</a>] [<a href="https://doi.org/10.1002/humu.23767" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31059601">Motta et al. (2019)</a> identified heterozygosity for a de novo deletion/insertion (c.807_808delinsTT, NM_007373.3) in the SHOC2 gene, resulting in a Gln269_His270delinsHisTyr substitution at 2 highly conserved residues within the eighth leucine-rich repeat in the LRR domain. The mutation was not found in an in-house RASopathy database of more than 1,000 families, or in the 1000 Genomes Project, NSEuroNet, ExAC, or gnomAD databases. In transiently transfected Neuro2 cells, the mutant protein showed significantly enhanced ERK (see <a href="/entry/601795">601795</a>) activation. Coimmunoprecipitation assays from cell lysates showed increased MRAS (<a href="/entry/608435">608435</a>) binding as well as augmented binding to the catalytic subunit of PP1 (PP1C; see <a href="/entry/176875">176875</a>) with the mutant compared to wildtype SHOC2. The authors concluded that the Gln269_His270delinsHisTyr mutant is activating and enhances signaling through the MAPK (see <a href="/entry/176948">176948</a>) cascade. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31059601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair.</strong>
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Nature Genet. 41: 1022-1026, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19684605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19684605</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19684605[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=19684605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Gripp, K. W., Zand, D. J., Demmer, L., Anderson, C. E., Dobyns, W. B., Zackai, E. H., Denenberg, E., Jenny, K., Stabley, D. L., Sol-Church, K.
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<strong>Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.</strong>
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Am. J. Med. Genet. 161A: 2420-2430, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23918763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23918763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23918763[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=23918763" 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/ajmg.a.36098" target="_blank">Full Text</a>]
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</p>
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<a id="3" class="mim-anchor"></a>
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<a id="Hannig2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Hannig, V., Jeoung, M., Jang, E. R., Phillips, J. A., III, Galperin, E.
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<strong>A novel SHOC2 variant in rasopathy.</strong>
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Hum. Mutat. 35: 1290-1294, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25137548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25137548</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25137548" 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/humu.22634" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Hoban2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Hoban, R., Roberts, A. E., Demmer, L., Jethva, R., Shephard, B.
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<strong>Noonan syndrome due to a SHOC2 mutation presenting with fetal distress and fatal hypertrophic cardiomyopathy in a premature infant.</strong>
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Am. J. Med. Genet. 158A: 1411-1413, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22528146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22528146</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22528146" 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/ajmg.a.35318" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="5" class="mim-anchor"></a>
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<a id="Jang2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Jang, H., Oakley, E., Forbes-Osborne, M., Kesler, M. V., Norcross, R., Morris, A. C., Galperin, E.
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<strong>Hematopoietic and neural crest defects in zebrafish shoc2 mutants: a novel vertebrate model for Noonan-like syndrome.</strong>
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Hum. Molec. Genet. 28: 501-514, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30329053/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30329053</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30329053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddy366" target="_blank">Full Text</a>]
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</p>
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<a id="6" class="mim-anchor"></a>
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<a id="Komatsuzaki2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Komatsuzaki, S., Aoki, Y., Niihori, T., Okamoto, N., Hennekam, R. C. M., Hopman, S., Ohashi, H., Mizuno, S., Watanabe, Y., Kamasaki, H., Kondo, I., Moriyama, N., Kurosawa, K., Kawame, H., Okuyama, R., Imaizumi, M., Rikiishi, T., Tsuchiya, S., Kure, S., Matsubara, Y.
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<strong>Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies.</strong>
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J. Hum. Genet. 55: 801-809, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20882035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20882035</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20882035" 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/10.1038/jhg.2010.116" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Motta2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Motta, M., Giancotti, A., Mastromoro, G., Chandramouli, B., Pinna, V., Pantaleoni, F., Di Giosaffatte, N., Petrini, S., Mazza, T., D'Ambrosio, V., Versacci, P., Ventriglia, F., Chillemi, G., Pizzuti, A., Tartaglia, M., De Luca, A.
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<strong>Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy.</strong>
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Hum. Mutat. 40: 1046-1056, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31059601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31059601</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31059601" 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/humu.23767" target="_blank">Full Text</a>]
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Selfors1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Selfors, L. M., Schutzman, J. L., Borland, C. Z., Stern, M. J.
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<strong>Soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling.</strong>
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Proc. Nat. Acad. Sci. 95: 6903-6908, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9618511[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=9618511" 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/10.1073/pnas.95.12.6903" target="_blank">Full Text</a>]
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Sieburth1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sieburth, D. S., Sun, Q., Han, M.
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<strong>SUR-8, a conserved Ras-binding protein with leucine-rich repeats, positively regulates Ras-mediated signaling in C. elegans.</strong>
|
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Cell 94: 119-130, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9674433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9674433</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9674433" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)81227-1" target="_blank">Full Text</a>]
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Umeki2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Umeki, I., Niihori, T., Abe, T., Kanno, S., Okamoto, N., Mizuno, S., Kurosawa, K., Nagasaki, K., Yoshida, M., Ohashi, H., Inoue, S., Matsubara, Y., Fujiwara, I., Kure, S., Aoki, Y.
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<strong>Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.</strong>
|
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Hum. Genet. 138: 21-35, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30368668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30368668</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30368668" 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/s00439-018-1951-7" target="_blank">Full Text</a>]
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Young2018" class="mim-anchor"></a>
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<div class="">
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Young, L. C., Hartig, N., del Rio, L. B., Sari, S., Ringham-Terry, B., Wainwright, J. R., Jones, G. G., McCormick, F., Rodriguez-Viciana, P.
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<strong>SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.</strong>
|
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Proc. Nat. Acad. Sci. 115: E10576-E10585, 2018. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30348783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30348783</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30348783" 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/10.1073/pnas.1720352115" target="_blank">Full Text</a>]
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</ol>
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<br />
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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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<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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Bao Lige - updated : 07/08/2021
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</span>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 07/27/2020<br>Ada Hamosh - updated : 07/11/2019<br>Ada Hamosh - updated : 01/10/2019<br>Marla J. F. O'Neill - updated : 01/20/2016<br>Marla J. F. O'Neill - updated : 7/26/2012<br>Marla J. F. O'Neill - updated : 10/9/2009<br>Stylianos E. Antonarakis - updated : 8/6/1998
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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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 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 : 7/6/1998
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 07/08/2021
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 07/30/2020<br>alopez : 07/30/2020<br>alopez : 07/27/2020<br>carol : 01/02/2020<br>alopez : 07/11/2019<br>alopez : 05/28/2019<br>alopez : 01/10/2019<br>carol : 01/20/2016<br>carol : 7/27/2012<br>terry : 7/26/2012<br>wwang : 6/2/2011<br>wwang : 10/19/2010<br>wwang : 10/6/2010<br>wwang : 10/12/2009<br>terry : 10/9/2009<br>joanna : 9/10/2009<br>carol : 3/29/2001<br>carol : 8/6/1998<br>alopez : 7/7/1998<br>alopez : 7/6/1998
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 602775
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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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SHOC2 LEUCINE-RICH REPEAT SCAFFOLD PROTEIN; SHOC2
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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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<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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SUPPRESSOR OF CLEAR, C. ELEGANS, HOMOLOG OF<br />
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RAS-BINDING PROTEIN SUR8, C. ELEGANS, HOMOLOG OF; SUR8
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</span>
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</h4>
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</div>
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<div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SHOC2</em></strong>
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</span>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 723444009;
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</span>
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<br />
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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: 10q25.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 10:110,919,370-111,013,665 </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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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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10q25.2
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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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Noonan syndrome-like with loose anagen hair 1
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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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607721
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>SHOC2 is a scaffold protein that plays a key role in activation of the ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) signaling pathway (summary by Jang et al., 2019). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Activation of fibroblast growth factor (FGF) receptors elicits diverse cellular responses, including growth, mitogenesis, migration, and differentiation. Selfors et al. (1998) shed light on the intracellular signaling pathways that mediate these processes by studies in Caenorhabditis elegans. In this organism, they screened for genes that suppress the activity of an activated form of the EGL-15 FGF receptor consistent with the functioning of these genes downstream of EGL-15. Two of these genes were soc1 and soc2, symbolized thus for 'suppressor of clear (Clr)' phenotype; the third was sem5. Selfors et al. (1998) showed that soc2 encodes a protein composed almost entirely of leucine-rich repeats, a domain implicated in protein-protein interactions. They identified a putative human homolog, SHOC2, which is 54% identical to soc2. They showed that SHOC2 mRNA was expressed in all tissues assayed and that the SHOC2 protein is localized to the cytoplasm. </p><p>Selfors et al. (1998) showed that within the leucine-rich repeats of both soc2 and SHOC2 are 2 YXNX motifs that are potential tyrosine-phosphorylated docking sites for the SEM5/GRB2 Src homology 2 domain. However, phosphorylation of these residues was not required for soc2 function in vivo, and SHOC2 was not observed to be tyrosine phosphorylated in response to FGF stimulation. Selfors et al. (1998) concluded that this genetic system identified a conserved gene implicated in mediating FGF receptor signaling in C. elegans. </p><p>Komatsuzaki et al. (2010) examined the relative expression of SHOC2 in various tissues, including blood leukocytes and lymphocytes. In the adult human cDNA panel, the highest expression was observed in testis, with relatively high expression in several immune tissues, including spleen, bone marrow, tonsil, and lymph nodes. The authors noted that expression of SHOC2 was 6 times higher in polymorphonuclear (PMN) leukocytes than in mononuclear cells, and suggested that SHOC2 might be important to proliferation or survival of PMNs. Among fetal tissues, brain showed the highest expression. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By FISH analysis, Selfors et al. (1998) mapped the SHOC2 gene to chromosome 10q25. </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>Sieburth et al. (1998) identified and characterized the sur8 gene in C. elegans, which positively regulates Ras-mediated signal transduction during vulval development. The authors found that reduction of sur8 function suppresses an activated Ras mutation and dramatically enhances phenotypes of mpk1/sur1 MAP kinase (see 176948) and ksr1 (601132) mutations, whereas increase of sur8 dosage enhances an activated Ras mutation. Sur8 appears to act downstream of or in parallel to Ras but upstream of Raf. Sur8 encodes a conserved protein that is composed predominantly of leucine-rich repeats. The sur8 protein interacts directly with Ras but not with the Ras(P34G) mutant protein, suggesting that sur8 may mediate its effects through Ras binding. By use of EST primers and 5-prime RACE, Sieburth et al. (1998) cloned a structural and functional SUR8 homolog in humans that specifically binds K-Ras (190070) and N-Ras (164790) but not H-Ras (190020) in vitro. </p><p>MRAS (608435), SHOC2, and protein phosphatase-1 (PP1; see 176875) interact to form a heterotrimeric holoenzyme that dephosphorylates the S259 inhibitory site on RAF kinases, activating downstream signaling. Young et al. (2018) showed that MRAS and SHOC2 function as PP1 regulatory subunits, providing the complex with striking specificity against RAF. MRAS also functions as a targeting subunit, as membrane localization is required for efficient RAF dephosphorylation and ERK (see 601795) pathway regulation in cells. </p><p>Using immunoprecipitation of endogenous LZTR1 (600574) followed by Western blotting, Umeki et al. (2019) showed that LZTR1 bound to the RAF1 (164760)-SHOC2-PPP1CB (600590) complex. Mutations in all these genes cause Noonan syndrome or Noonan-like phenotypes. Cells transfected with siRNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at ser259. </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>Using a systems biology approach based on in silico protein network analysis that identified SHOC2 as a candidate gene, Cordeddu et al. (2009) sequenced SHOC2 coding exons in a Noonan syndrome (see 163950) cohort that included 96 individuals who were negative for mutations in known disease genes. The authors identified a heterozygous mutation (S2G; 602775.0001) in the SHOC2 gene in 4 unrelated individuals. They then analyzed the SHOC2 gene in a cohort of 410 mutation-negative patients with Noonan syndrome or a related phenotype and identified 21 individuals with the same S2G mutation. All of the patients with the S2G mutation had a relatively consistent Noonan syndrome-like disorder with loose anagen hair (NSLH; 607721). Functional studies of S2G-mutant SHOC2 demonstrated introduction of an N-myristoylation site, resulting in aberrant localization and signaling. </p><p>In a male infant with typical dysmorphic facial features and other signs of Noonan syndrome, who died of congestive heart failure at 4 months of age, Hoban et al. (2012) identified heterozygosity for the S2G mutation in SHOC2. </p><p>The MRAS (608435) GTPase, a close relative of RAS oncoproteins, interacts with SHOC2 and protein phosphatase-1 (PP1; see 176875) to form a heterotrimeric holoenzyme that dephosphorylates an inhibitory site on RAF kinases, activating downstream signaling. Young et al. (2018) showed that mutations in MRAS, SHOC2, and PPP1CB (600590) that result in Noonan syndrome invariably promote complex formation with each other, but not necessarily with other interactors. Thus, Noonan syndrome in individuals with SHOC2, MRAS, or PPPC1B mutations is likely driven at the biochemical level by enhanced ternary complex formation and highlights the crucial role of this phosphatase holoenzyme in RAF S259 dephosphorylation, ERK pathway dynamics, and normal human development. </p><p>In a cohort of 92 patients with Noonan syndrome and related disorders, who were negative for mutation in 8 genes known to be associated with these disorders, Komatsuzaki et al. (2010) sequenced all coding regions of the SHOC2 gene and identified the S2G mutation in 8 patients. The mutation was shown to have arisen de novo in the 3 families for which parental DNA was available. </p><p>In a father and daughter with features overlapping those of NSLH1, Hannig et al. (2014) analyzed a RASopathy gene panel and identified heterozygosity for a missense mutation in the SHOC2 gene (M173I; 602775.0002). Functional analysis appeared to show loss of function in the ERK1/2 pathway, in contrast to the recurrent S2G variant. However, Young et al. (2018) demonstrated gain-of-function effects with the M173I mutant, which showed enhanced interaction with MRAS and PP1 and rescued ERK activation in SHOC2-deficient cells. </p><p>In an infant boy with NSLH1, Motta et al. (2019) identified heterozygosity for a de novo deletion/insertion in the SHOC2 gene (602775.0003). The mutation was not found in an in-house RASopathy database of more than 1,000 families or in public variant databases. Functional analysis demonstrated that the mutant protein, like the 2 previously reported NSLH1-associated mutants, upregulates RAS signaling through the MAPK cascade, selectively promoting SHOC2 complex formation with MRAS and the catalytic subunit of PP1 (PP1C; see 176875). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Jang et al. (2019) found that knockdown of shoc2 at early stages of zebrafish embryonic development affected the number of erythropoietic and myelopoietic cells and resulted in hematopoietic defects. The authors generated shoc2-knockout zebrafish and found that loss of shoc2 resulted in multiple deficiencies during embryogenesis, including gross defects in blood cell differentiation and abnormal craniofacial development. Shoc2 -/- zebrafish displayed systemic defects in neural crest specification and hematopoiesis, indicating a central role for shoc2 in embryogenesis. In addition, shoc2 -/- zebrafish displayed an array of developmental defects, emphasizing the essential role of shoc2 in coordinating activities of linear components of the erk1/erk2 pathway. Overall, shoc2 -/- zebrafish exhibited many of the clinical hallmarks associated with human NSLH1. </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>3 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0001 NOONAN SYNDROME-LIKE DISORDER WITH LOOSE ANAGEN HAIR 1</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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SHOC2, SER2GLY
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<br />
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SNP: rs267607048,
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gnomAD: rs267607048,
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ClinVar: RCV000007223, RCV000149834, RCV000208379, RCV000213000, RCV000624656, RCV000853278, RCV001813181, RCV002221469, RCV003330311, RCV004752691
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 25 patients with a Noonan syndrome-like disorder with loose anagen hair (NSLH1; 607721), Cordeddu et al. (2009) identified heterozygosity for a 4A-G transition in exon 2 of the SHOC2 gene, resulting in a ser2-to-gly (S2G) substitution. The mutation was shown to be de novo in the 15 patients for whom parental DNA was available. Functional studies demonstrated that the S2G mutation introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. In vitro expression of mutant SHOC2 enhanced MAPK (see 176948) activation in a cell type-specific fashion. Induction of mutant SHOC2 in C. elegans engendered protruding vulva, a neomorphic phenotype previously associated with aberrant signaling. </p><p>In a male infant with typical dysmorphic facial features and other signs of Noonan syndrome, who died of congestive heart failure at 4 months of age, Hoban et al. (2012) identified heterozygosity for a de novo S2G mutation in SHOC2. The authors noted that the 'loose anagen hair' phenotype and skin features previously reported in patients with the S2G mutation were not present in this young infant, and stated that the cardiac anomaly expanded the clinical phenotype associated with the SHOC2 mutation. </p><p>In 5 unrelated children with Noonan syndrome-like disorder and loose anagen hair, Gripp et al. (2013) identified heterozygosity for the S2G mutation in the SHOC2 gene. The mutation was shown to have occurred de novo in 2 of the patients. </p><p>In 8 unrelated patients with Noonan syndrome-like disorder and loose anagen hair, Komatsuzaki et al. (2010) identified heterozygosity for the S2G mutation, which was shown to have arisen de novo in the 3 patients for whom parental DNA was available. The authors noted that short stature, relative macrocephaly, hypertelorism, low-set ears, sparse/easily pluckable hair, and a variety of skin abnormalities, including dark skin and atopic dermatitis, were commonly seen in patients positive for the S2G mutation. Young et al. (2018) studied the SHOC2 S2G mutation in HEK293T cells and observed increased ability of the mutant protein to interact with MRAS (608435) and PP1 (601790) compared to wildtype SHOC2. In cotransfection assays, the S2G mutant also efficiently dephosphorylated positions S365 in BRAF (164757) and S259 in CRAF (164760). In addition, when reexpressed in SHOC2-knockout DLD1 cells, the S2G mutant decreased the higher basal levels of S365-BRAF and S259-CRAF phosphorylation as well as the impaired epidermal growth factor (EGF; 131530)-induced ERK (see 601795) pathway activation caused by SHOC2 ablation. Serum-starved DLD1 cells reexpressing SHOC2 S2G had modestly lower phosphorylated S365-BRAF and S259-CRAF levels and modestly higher phosphorylated MEK (see 176872) and RSK (see 601684) levels compared to cells expressing wildtype SHOC2, which the authors noted was consistent with RASopathy gain-of-function mutations being only weakly activating and ERK pathway activation by such mutants being difficult to detect in many experimental systems. Young et al. (2018) concluded that the recurrent S2G variant is a gain-of-function mutant that upregulates the ERK pathway during development by selectively promoting phosphatase complex formation with MRAS and PP1. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0002 NOONAN SYNDROME-LIKE DISORDER WITH LOOSE ANAGEN HAIR 1</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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SHOC2, MET173ILE
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<br />
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SNP: rs730881020,
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ClinVar: RCV000169685, RCV000523270, RCV000586119, RCV001030821, RCV001376015, RCV002336369, RCV003156077
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a father and daughter with features overlapping those of Noonan syndrome, with sparse and slow-growing hair (NSLH1; 607721), Hannig et al. (2014) identified heterozygosity for a c.519G-A transition (c.519G-A, NM_007373.3) in the SHOC2 gene, resulting in a met173-to-ile (M173I) substitution at a highly conserved residue within the fourth leucine-rich repeat in the LRR domain. The mutation was not found in 6,500 asymptomatic individuals. Functional analysis in COS1 cells with constitutive knockdown of SHOC2 showed that, although wildtype SHOC2 rescued epidermal growth factor (EGF; 131530)-induced ERK1 (601795)/2 (176948) phosphorylation to the extent of endogenous SHOC2, the M173I mutant was able to restore only approximately 10% above the basal level of activity. In addition, overexpression of the M173I mutant did not lead to changes in ERK1/2 activity or in AKT (see 164730) phosphorylation. Immunoprecipitation studies in transfected 293FT cells showed that the M173I mutant failed to precipitate endogenous PP1c (see 176875) effectively, and stimulation with EGF resulted in only a mild increase in RAF1 (164760) S338 phosphorylation, compared to a dramatic increase with wildtype SHOC2. The authors concluded that the M1713 SHOC2 substitution causes loss of function in the ERK1/2 pathway. </p><p>Young et al. (2018) studied the SHOC2 M173I mutation in HEK293T cells and observed increased ability to interact with MRAS (608435) and PP1 (601790) compared to wildtype SHOC2. In cotransfection assays, the M173I mutant also efficiently dephosphorylated BRAF (164757) S365 and CRAF (164760) S259. In addition, when reexpressed in SHOC2-knockout DLD1 cells, the M173I mutant decreased the higher basal levels of S365-BRAF and S259-CRAF phosphorylation as well as the impaired EGF-induced ERK pathway activation caused by SHOC2 ablation. Serum-starved DLD1 cells reexpressing SHOC2 M173I had modestly lower phosphorylated S365-BRAF and S259-CRAF levels and modestly higher phosphorylated MEK (see 176872) and RSK (see 601684) levels compared to cells expressing wildtype SHOC2, which the authors noted was consistent with RASopathy gain-of-function mutations being only weakly activating and ERK pathway activation by such mutants being difficult to detect in many experimental systems. Young et al. (2018) concluded that, like the recurrent S2G mutation (602775.0001), the M173I variant is a gain-of-function mutant that upregulates the ERK pathway during development by selectively promoting phosphatase complex formation with MRAS and PP1. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
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<strong>.0003 NOONAN SYNDROME-LIKE DISORDER WITH LOOSE ANAGEN HAIR 1</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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SHOC2, DEL/INS, NT807
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<br />
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SNP: rs1848064627,
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ClinVar: RCV001250488
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an infant boy with Noonan syndrome-like disorder with loose anagen hair (NSLH1; 607721), Motta et al. (2019) identified heterozygosity for a de novo deletion/insertion (c.807_808delinsTT, NM_007373.3) in the SHOC2 gene, resulting in a Gln269_His270delinsHisTyr substitution at 2 highly conserved residues within the eighth leucine-rich repeat in the LRR domain. The mutation was not found in an in-house RASopathy database of more than 1,000 families, or in the 1000 Genomes Project, NSEuroNet, ExAC, or gnomAD databases. In transiently transfected Neuro2 cells, the mutant protein showed significantly enhanced ERK (see 601795) activation. Coimmunoprecipitation assays from cell lysates showed increased MRAS (608435) binding as well as augmented binding to the catalytic subunit of PP1 (PP1C; see 176875) with the mutant compared to wildtype SHOC2. The authors concluded that the Gln269_His270delinsHisTyr mutant is activating and enhances signaling through the MAPK (see 176948) cascade. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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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Cordeddu, V., Di Schiavi, E., Pennacchio, L. A., Ma'ayan, A., Sarkozy, A., Fodale, V., Cecchetti, S., Cardinale, A., Martin, J., Schackwitz, W., Lipzen, A., Zampino, G., and 19 others.
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<strong>Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair.</strong>
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Nature Genet. 41: 1022-1026, 2009.
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[PubMed: 19684605]
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[Full Text: https://doi.org/10.1038/ng.425]
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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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Gripp, K. W., Zand, D. J., Demmer, L., Anderson, C. E., Dobyns, W. B., Zackai, E. H., Denenberg, E., Jenny, K., Stabley, D. L., Sol-Church, K.
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<strong>Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.</strong>
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Am. J. Med. Genet. 161A: 2420-2430, 2013.
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[PubMed: 23918763]
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[Full Text: https://doi.org/10.1002/ajmg.a.36098]
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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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Hannig, V., Jeoung, M., Jang, E. R., Phillips, J. A., III, Galperin, E.
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<strong>A novel SHOC2 variant in rasopathy.</strong>
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Hum. Mutat. 35: 1290-1294, 2014.
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