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Entry
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- *184429 - SRY-BOX 2; SOX2
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- OMIM
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<div id="mimAlertBanner">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*184429</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFamily">Gene Family</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li 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="#biochemicalFeatures">Biochemical Features</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="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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>
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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/184429">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000181449;t=ENST00000325404" 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=6657" 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=184429" 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=ENSG00000181449;t=ENST00000325404" 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_003106" 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_003106" 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=184429" 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=08921&isoform_id=08921_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/SOX2" 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/184240,854182,1351091,15530270,28195386,119598760,189069149,751333735,751333737,751333739,751333741,751333743,751333783,751333785,751333787,751333789,751333791,751333793,751333795,751333797,751333799,751333801,751333803,751333805,751333807,751333809,827795412,969822263,969822265,1001946549,1001946551,2430294554" 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/P48431" 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=6657" 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=ENSG00000181449;t=ENST00000325404" 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=SOX2" 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=SOX2" 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+6657" 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/SOX2" 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:6657" 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/6657" 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=chr3&hgg_gene=ENST00000325404.3&hgg_start=181711925&hgg_end=181714436&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:11195" 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://medlineplus.gov/genetics/gene/sox2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=184429[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=184429[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/SOX2/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/ENSG00000181449" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.gwascentral.org/search?q=SOX2" 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=SOX2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://lsdb.hgu.mrc.ac.uk/home.php?select_db=SOX2" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SOX2&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/PA36032" 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:11195" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:98364" 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/SOX2#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:98364" 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/6657/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=6657" 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=WBGene00004949;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-030909-1" 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">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<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:6657" 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=SOX2&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> 698851003<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>
|
|
184429
|
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</span>
|
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</span>
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</div>
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</div>
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
|
<span class="mim-font">
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|
SRY-BOX 2; SOX2
|
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
|
<br />
|
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</div>
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<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SRY-RELATED HMG-BOX GENE 2
|
|
</span>
|
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</h4>
|
|
</div>
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SOX2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SOX2</a></em></strong>
|
|
</span>
|
|
</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/3/890?start=-3&limit=10&highlight=890">3q26.33</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:181711925-181714436&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'})">3:181,711,925-181,714,436</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/3/890?start=-3&limit=10&highlight=890">
|
|
3q26.33
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Microphthalmia, syndromic 3
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/206900"> 206900 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Optic nerve hypoplasia and abnormalities of the central nervous system
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/206900"> 206900 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<p><a href="#43" class="mim-tip-reference" title="Stevanovic, M., Zuffardi, O., Collignon, J., Lovell-Badge, R., Goodfellow, P. <strong>The cDNA sequence and chromosomal location of the human SOX2 gene.</strong> Mammalian Genome 5: 640-642, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849401</a>] [<a href="https://doi.org/10.1007/BF00411460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849401">Stevanovic et al. (1994)</a> found that the SOX2 gene encodes a 317-amino acid protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849401" 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>Genetic analysis by <a href="#14" class="mim-tip-reference" title="Fantes, J., Ragge, N. K., Lynch, S.-A., McGill, N. I., Collin, J. R. O., Howard-Peebles, P. N., Hayward, C., Vivian, A. J., Williamson, K., van Heyningen, V., FitzPatrick, D. R. <strong>Mutations in SOX2 cause anophthalmia.</strong> Nature Genet. 33: 461-462, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612584</a>] [<a href="https://doi.org/10.1038/ng1120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612584">Fantes et al. (2003)</a> indicated that the single-exon SOX2 gene lies in an intron of the SOX2OT gene (<a href="/entry/616338">616338</a>), which is transcribed in the same orientation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612584" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By fluorescence in situ hybridization, <a href="#43" class="mim-tip-reference" title="Stevanovic, M., Zuffardi, O., Collignon, J., Lovell-Badge, R., Goodfellow, P. <strong>The cDNA sequence and chromosomal location of the human SOX2 gene.</strong> Mammalian Genome 5: 640-642, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849401</a>] [<a href="https://doi.org/10.1007/BF00411460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849401">Stevanovic et al. (1994)</a> assigned the SOX2 gene to chromosome 3q26.3-q27. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7849401" 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 developing chick spinal cord, <a href="#4" class="mim-tip-reference" title="Bylund, M., Andersson, E., Novitch, B. G., Muhr, J. <strong>Vertebrate neurogenesis is counteracted by Sox1-3 activity.</strong> Nature Neurosci. 6: 1162-1168, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14517545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14517545</a>] [<a href="https://doi.org/10.1038/nn1131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14517545">Bylund et al. (2003)</a> found that Sox1 (<a href="/entry/602148">602148</a>), Sox2, and Sox3 (<a href="/entry/313430">313430</a>) were coexpressed in self-renewing progenitor cells and acted to inhibit neuronal differentiation. Active repression of the Sox genes promoted neural progenitor cells to initiate differentiation prematurely. Further studies showed that the ability of the proneural transcription factor neurogenin-2 (NEUROG2; <a href="/entry/606624">606624</a>) to promote neuronal differentiation was based on its ability to suppress Sox gene expression, thus showing that neurogenesis is regulated by an interplay between proneural proteins and inhibitory proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14517545" 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="#18" class="mim-tip-reference" title="Hever, A. M., Williamson, K. A., van Heyningen, V. <strong>Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2.</strong> Clin. Genet. 69: 459-470, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16712695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16712695</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00619.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16712695">Hever et al. (2006)</a> reviewed the expression patterns and complex interactions of 3 genes associated with the development of the eye, SOX2, OTX2 (<a href="/entry/600037">600037</a>), and PAX6 (<a href="/entry/607108">607108</a>), noting that these interactions may explain the significant phenotypic overlap between mutations at these 3 loci. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16712695" 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="#30" class="mim-tip-reference" title="Okubo, T., Pevny, L. H., Hogan, B. L. M. <strong>Sox2 is required for development of taste bud sensory cells.</strong> Genes Dev. 20: 2654-2659, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17015430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17015430</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17015430[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/10.1101/gad.1457106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17015430">Okubo et al. (2006)</a> reported that Sox2 is required for development of taste bud sensory cells in mouse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17015430" 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>Induced pluripotent stem (iPS) cells can be generated from mouse fibroblasts by retrovirus-mediated introduction of 4 transcription factors, Oct3/4 (<a href="/entry/164177">164177</a>), Sox2, c-Myc (<a href="/entry/190080">190080</a>), and Klf4 (<a href="/entry/602253">602253</a>), and subsequent selection for Fbx15 (<a href="/entry/609093">609093</a>) expression (<a href="#44" class="mim-tip-reference" title="Takahashi, K., Yamanaka, S. <strong>Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.</strong> Cell 126: 663-676, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16904174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16904174</a>] [<a href="https://doi.org/10.1016/j.cell.2006.07.024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16904174">Takahashi and Yamanaka, 2006</a>). These iPS cells, hereafter called Fbx15 iPS cells, are similar to embryonic stem (ES) cells in morphology, proliferation, and teratoma formation; however, they are different with regard to gene expression and DNA methylation patterns, and fail to produce adult chimeras. <a href="#28" class="mim-tip-reference" title="Okita, K., Ichisaka, T., Yamanaka, S. <strong>Generation of germline-competent induced pluripotent stem cells.</strong> Nature 448: 313-317, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17554338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17554338</a>] [<a href="https://doi.org/10.1038/nature05934" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17554338">Okita et al. (2007)</a> showed that selection for Nanog (<a href="/entry/607937">607937</a>) expression results in germline-competent iPS cells with increased ES cell-like gene expression and DNA methylation patterns compared with Fbx15 iPS cells. The 4 transgenes were strongly silenced in Nanog iPS cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17554338+16904174" 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="#48" class="mim-tip-reference" title="Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger, K., Bernstein, B. E., Jaenisch, R. <strong>In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state.</strong> Nature 448: 318-324, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17554336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17554336</a>] [<a href="https://doi.org/10.1038/nature05944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17554336">Wernig et al. (2007)</a> independently demonstrated that the transcription factors Oct4, Sox2, c-Myc, and Klf4 can induce epigenetic reprogramming of a somatic genome to an embryonic pluripotent state. In contrast to selection for Fbx15 activation (<a href="#44" class="mim-tip-reference" title="Takahashi, K., Yamanaka, S. <strong>Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.</strong> Cell 126: 663-676, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16904174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16904174</a>] [<a href="https://doi.org/10.1016/j.cell.2006.07.024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16904174">Takahashi and Yamanaka, 2006</a>), fibroblasts that had reactivated the endogenous Oct4 (Oct4-neo) or Nanog (Nanog-neo) loci grew independently of feeder cells, expressed normal Oct4, Nanog, and Sox2 RNA and protein levels, were epigenetically identical to ES cells by a number of criteria, and were able to generate viable chimeras, contribute to the germline, and generate viable late-gestation embryos after injection into tetraploid blastocysts. Transduction of the 4 factors generated significantly more drug-resistant cells from Nanog-neo than from Oct4-neo fibroblasts, but a higher fraction of Oct4-selected cells had all the characteristics of pluripotent ES cells, suggesting that Nanog activation is a less stringent criterion for pluripotency than Oct4 activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17554336+16904174" 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="#51" class="mim-tip-reference" title="Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., Slukvin, I. I., Thomson, J. A. <strong>Induced pluripotent stem cell lines derived from human somatic cells.</strong> Science 318: 1917-1920, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18029452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18029452</a>] [<a href="https://doi.org/10.1126/science.1151526" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18029452">Yu et al. (2007)</a> showed that 4 factors, OCT4, SOX2, NANOG, and LIN28 (<a href="/entry/611043">611043</a>), are sufficient to reprogram human somatic cells to pluripotent stem cells that exhibit the essential characteristics of embryonic stem cells. These induced pluripotent human stem cells have normal karyotypes, express telomerase (see <a href="/entry/602322">602322</a>) activity, express cell surface markers and genes that characterize human ES cells, and maintain the developmental potential to differentiate into advanced derivatives of all 3 primary germ layers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18029452" 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 Oct4, Sox2, Klf4, and Myc, <a href="#31" class="mim-tip-reference" title="Park, I.-H., Zhao, R., West, J. A., Yabuuchi, A., Huo, H., Ince, T. A., Lerou, P. H., Lensch, M. W., Daley, G. Q. <strong>Reprogramming of human somatic cells to pluripotency with defined factors.</strong> Nature 451: 141-146, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18157115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18157115</a>] [<a href="https://doi.org/10.1038/nature06534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18157115">Park et al. (2008)</a> derived iPS cells from fetal, neonatal, and adult human primary cells, including dermal fibroblasts isolated from a skin biopsy of a healthy research subject. Human iPS cells resemble embryonic stem cells in morphology and gene expression and in the capacity to form teratomas in immune-deficient mice. <a href="#31" class="mim-tip-reference" title="Park, I.-H., Zhao, R., West, J. A., Yabuuchi, A., Huo, H., Ince, T. A., Lerou, P. H., Lensch, M. W., Daley, G. Q. <strong>Reprogramming of human somatic cells to pluripotency with defined factors.</strong> Nature 451: 141-146, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18157115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18157115</a>] [<a href="https://doi.org/10.1038/nature06534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18157115">Park et al. (2008)</a> concluded that defined factors can reprogram human cells to pluripotency, and they established a method whereby patient-specific cells might be established in culture. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18157115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Masui, S., Nakatake, Y., Toyooka, Y., Shimosato, D., Yagi, R., Takahashi, K., Okochi, H., Okuda, A., Matoba, R., Sharov, A. A., Ko, M. S. H., Niwa, H. <strong>Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells.</strong> Nature Cell Biol. 9: 625-635, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17515932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17515932</a>] [<a href="https://doi.org/10.1038/ncb1589" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17515932">Masui et al. (2007)</a> found that Sox2 was indispensable for maintaining embryonic stem (ES) cell pluripotency, since Sox2-null mouse ES cells differentiated primarily into trophectoderm-like cells. However, Sox2 was not required for activation of Oct-Sox enhancers. Microarray analysis showed that Sox2 regulates multiple transcription factors that affect Oct3/4 expression. Forced expression of Oct3/4 rescued the pluripotency of Sox2-null ES cells. <a href="#24" class="mim-tip-reference" title="Masui, S., Nakatake, Y., Toyooka, Y., Shimosato, D., Yagi, R., Takahashi, K., Okochi, H., Okuda, A., Matoba, R., Sharov, A. A., Ko, M. S. H., Niwa, H. <strong>Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells.</strong> Nature Cell Biol. 9: 625-635, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17515932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17515932</a>] [<a href="https://doi.org/10.1038/ncb1589" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17515932">Masui et al. (2007)</a> concluded that SOX2 regulates OCT3/4 expression and maintains ES pluripotency through upstream transcription factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17515932" 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 studies in Xenopus oocytes, <a href="#8" class="mim-tip-reference" title="Danno, H., Michiue, T., Hitachi, K., Yukita, A., Ishiura, S., Asashima, M. <strong>Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression.</strong> Proc. Nat. Acad. Sci. 105: 5408-5413, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18385377[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.0710954105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18385377">Danno et al. (2008)</a> demonstrated specific binding of endogenous OTX2 and SOX2 proteins to a conserved noncoding sequence (CNS1) located approximately 2 kb upstream of the RAX (<a href="/entry/601881">601881</a>) promoter; reporter assays in Xenopus and HEK93T cells revealed that OTX2 and SOX2 synergistically activated RAX transcription via CNS1. GST pull-down and coimmunoprecipitation assays showed that OTX2 and SOX2 physically interacted, and this interaction was affected by missense mutations located in helices 2 and 3 of the SOX2 HMG domain (R74P, <a href="#0008">184429.0008</a>; L97P, <a href="#0004">184429.0004</a>, respectively), resulting in reduced induction of transcription via RAX CNS1. <a href="#8" class="mim-tip-reference" title="Danno, H., Michiue, T., Hitachi, K., Yukita, A., Ishiura, S., Asashima, M. <strong>Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression.</strong> Proc. Nat. Acad. Sci. 105: 5408-5413, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18385377[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.0710954105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18385377">Danno et al. (2008)</a> concluded that direct interaction between OTX2 and SOX2 proteins <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18385377" 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="#41" class="mim-tip-reference" title="Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G., Hochedlinger, K. <strong>Induced pluripotent stem cells generated without viral integration.</strong> Science 322: 945-949, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18818365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18818365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18818365[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/10.1126/science.1162494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18818365">Stadtfeld et al. (2008)</a> generated mouse iPS cells from fibroblasts and liver cells by using nonintegrating adenoviruses transiently expressing Oct4, Sox2, Klf4, and c-Myc. These adenoviral iPS cells showed DNA demethylation characteristic of reprogrammed cells, expressed endogenous pluripotency genes, formed teratomas, and contributed to multiple tissues, including the germ cell line, in chimeric mice. <a href="#41" class="mim-tip-reference" title="Stadtfeld, M., Nagaya, M., Utikal, J., Weir, G., Hochedlinger, K. <strong>Induced pluripotent stem cells generated without viral integration.</strong> Science 322: 945-949, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18818365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18818365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18818365[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/10.1126/science.1162494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18818365">Stadtfeld et al. (2008)</a> concluded that their results provided strong evidence that insertional mutagenesis is not required for in vitro reprogramming. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18818365" 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="#29" class="mim-tip-reference" title="Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T., Yamanaka, S. <strong>Generation of mouse induced pluripotent stem cells without viral vectors.</strong> Science 322: 949-953, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18845712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18845712</a>] [<a href="https://doi.org/10.1126/science.1164270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18845712">Okita et al. (2008)</a> independently reported the generation of mouse iPS cells without viral vectors. Repeated transfection of 2 expression plasmids, one containing the cDNAs of Oct3/4, Sox2, and Klf4 and the other containing the c-Myc cDNA, into mouse embryonic fibroblasts resulted in iPS cells without evidence of plasmid integration, which produced teratomas when transplanted into mice and contributed to adult chimeras. <a href="#29" class="mim-tip-reference" title="Okita, K., Nakagawa, M., Hyenjong, H., Ichisaka, T., Yamanaka, S. <strong>Generation of mouse induced pluripotent stem cells without viral vectors.</strong> Science 322: 949-953, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18845712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18845712</a>] [<a href="https://doi.org/10.1126/science.1164270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18845712">Okita et al. (2008)</a> concluded that the production of virus-free iPS cells, albeit from embryonic fibroblasts, addresses a critical safety concern for potential use of iPS cells in regenerative medicine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18845712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Hanna, J., Saha, K., Pando, B., van Zon, J., Lengner, C. J., Creyghton, M. P., van Oudenaarden, A., Jaenisch, R. <strong>Direct cell reprogramming is a stochastic process amenable to acceleration.</strong> Nature 462: 595-601, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19898493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19898493</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19898493[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/nature08592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19898493">Hanna et al. (2009)</a> demonstrated that the reprogramming by Oct4, Sox2, Klf4, and Myc transcription factors is a continuous stochastic process where almost all mouse donor cells eventually give rise to induced pluripotent stem (iPS) cells on continued growth and transcription factor expression. Additional inhibition of the p53 (<a href="/entry/191170">191170</a>)/p21 (<a href="/entry/116899">116899</a>) pathway or overexpression of Lin28 (<a href="/entry/611043">611043</a>) increased the cell division rate and resulted in an accelerated kinetics of iPS cell formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog (<a href="/entry/607937">607937</a>) overexpression accelerated reprogramming in a predominantly cell division rate-independent manner. Quantitative analyses defined distinct cell division rate-dependent and -independent modes for accelerating the stochastic course of reprogramming, and suggested that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19898493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bass, A. J., Watanabe, H., Mermel, C. H., Yu, S., Perner, S., Verhaak, R. G., Kim, S. Y., Wardwell, L., Tamayo, P., Gat-Viks, I., Ramos, A. H., Woo, M. S., and 36 others. <strong>SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas.</strong> Nature Genet. 41: 1238-1242, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19801978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19801978</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19801978[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.465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19801978">Bass et al. (2009)</a> showed that a peak of genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas of the lung and esophagus contains the transcription factor gene SOX2, which is necessary for normal esophageal squamous development (<a href="#35" class="mim-tip-reference" title="Que, J., Okubo, T., Goldenring, J. R., Nam, K.-T., Kurotani, R., Morrisey, E. E., Taranova, O., Pevny, L. H., Hogan, B. L. M. <strong>Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm.</strong> Development 134: 2521-2531, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17522155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17522155</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17522155[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/10.1242/dev.003855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17522155">Que et al., 2007</a>) and differentiation and proliferation of basal tracheal cells (<a href="#34" class="mim-tip-reference" title="Que, J., Luo, X., Schwartz, R. J., Hogan, B. L. M. <strong>Multiple roles for Sox2 in the developing and adult mouse trachea.</strong> Development 136: 1899-1907, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19403656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19403656</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19403656[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/10.1242/dev.034629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19403656">Que et al., 2009</a>), and cooperates in induction of pluripotent stem cells, as summarized by <a href="#2" class="mim-tip-reference" title="Bass, A. J., Watanabe, H., Mermel, C. H., Yu, S., Perner, S., Verhaak, R. G., Kim, S. Y., Wardwell, L., Tamayo, P., Gat-Viks, I., Ramos, A. H., Woo, M. S., and 36 others. <strong>SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas.</strong> Nature Genet. 41: 1238-1242, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19801978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19801978</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19801978[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.465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19801978">Bass et al. (2009)</a>. <a href="#2" class="mim-tip-reference" title="Bass, A. J., Watanabe, H., Mermel, C. H., Yu, S., Perner, S., Verhaak, R. G., Kim, S. Y., Wardwell, L., Tamayo, P., Gat-Viks, I., Ramos, A. H., Woo, M. S., and 36 others. <strong>SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas.</strong> Nature Genet. 41: 1238-1242, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19801978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19801978</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19801978[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.465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19801978">Bass et al. (2009)</a> found that SOX2 expression was required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 in this study cooperated with FOXE1 (<a href="/entry/602617">602617</a>) or FGFR2 (<a href="/entry/176943">176943</a>) to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors showed expression of markers of both squamous differentiation and pluripotency. <a href="#2" class="mim-tip-reference" title="Bass, A. J., Watanabe, H., Mermel, C. H., Yu, S., Perner, S., Verhaak, R. G., Kim, S. Y., Wardwell, L., Tamayo, P., Gat-Viks, I., Ramos, A. H., Woo, M. S., and 36 others. <strong>SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas.</strong> Nature Genet. 41: 1238-1242, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19801978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19801978</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19801978[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.465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19801978">Bass et al. (2009)</a> concluded that these characteristics identified SOX2 as a lineage-survival oncogene in lung and esophageal squamous cell carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19801978+19403656+17522155" 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 chromatin immunoprecipitation analysis, <a href="#50" class="mim-tip-reference" title="Yu, H., Kunarso, G., Hong, F. H., Stanton, L. W. <strong>Zfp206, Oct4, and Sox2 are integrated components of a transcriptional regulatory network in embryonic stem cells.</strong> J. Biol. Chem. 284: 31327-31335, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19740739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19740739</a>] [<a href="https://doi.org/10.1074/jbc.M109.016162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19740739">Yu et al. (2009)</a> showed that mouse Zfp206 (ZSCAN10; <a href="/entry/618365">618365</a>) and Oct4 reciprocally regulated expression of one another in ES cells through promoter binding. Genomewide mapping of Zfp206 targets in mouse ES cells identified Zfp206, Oct4, and Sox2 as key components of a large transcriptional regulatory network. Zfp206 selectively activated or repressed transcription of its target genes by binding to their promoters in ES cells. Many of these same genes were also regulated by Oct4 and Sox2, which colocalized and physically interacted with Zfp206 in a macromolecular complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19740739" 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="#45" class="mim-tip-reference" title="Takemoto, T., Uchikawa, M., Yoshida, M., Bell, D. M., Lovell-Badge, R., Papaioannou, V. E., Kondoh, H. <strong>Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells.</strong> Nature 470: 394-398, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21331042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21331042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21331042[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/nature09729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21331042">Takemoto et al. (2011)</a> demonstrated that TBX6 (<a href="/entry/602427">602427</a>)-dependent regulation of SOX2 determines the fate of axial stem cells. In wildtype mouse embryos, enhancer N1 of the neural primordial gene Sox2 is activated in the caudal lateral epiblast, and the cells staying in the superficial layer sustain N1 activity and activate Sox2 expression in the neural plate. In contrast, the cells destined to become mesoderm activate Tbx6 and turn off enhancer N1 before migrating into the paraxial mesoderm compartment. In Tbx6 mutant embryos, however, enhancer N1 activity persists in the paraxial mesoderm compartment, eliciting ectopic Sox2 activation and transforming the paraxial mesoderm into neural tubes. An enhancer-N1-specific deletion mutation introduced into Tbx6 mutant embryos prevented this Sox2 activation into the mesodermal compartment and subsequent development of ectopic neural tubes, indicating that Tbx6 regulates Sox2 via enhancer N1. Tbx6-dependent repression of Wnt3a (<a href="/entry/606359">606359</a>) in the paraxial mesodermal compartment is implicated in this regulatory process. Paraxial mesoderm-specific misexpression of a Sox2 transgene in wildtype embryos resulted in ectopic neural tube development. Thus, <a href="#45" class="mim-tip-reference" title="Takemoto, T., Uchikawa, M., Yoshida, M., Bell, D. M., Lovell-Badge, R., Papaioannou, V. E., Kondoh, H. <strong>Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells.</strong> Nature 470: 394-398, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21331042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21331042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21331042[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/nature09729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21331042">Takemoto et al. (2011)</a> concluded that Tbx6 represses Sox2 by inactivating enhancer N1 to inhibit neural development, and this is an essential step for the specification of paraxial mesoderm from the axial stem cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21331042" 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 and mass spectrometry, <a href="#12" class="mim-tip-reference" title="Engelen, E., Akinci, U., Bryne, J. C., Hou, J., Gontan, C., Moen, M., Szumska, D., Kockx, C., van IJcken, W., Dekkers, D. H. W., Demmers, J., Rijkers, E.-J., Bhattacharya, S., Philipsen, S., Pevny, L. H., Grosveld, F. G., Rottier, R. J., Lenhard, B., Poot, R. A. <strong>Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes.</strong> Nature Genet. 43: 607-611, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21532573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21532573</a>] [<a href="https://doi.org/10.1038/ng.825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21532573">Engelen et al. (2011)</a> identified Chd7 (<a href="/entry/608892">608892</a>) among 50 proteins that interacted with epitope-tagged Sox2 in mouse neural stem cells. Reverse immunoprecipitation and protein pull-down experiments confirmed direct interaction between Sox2 and Chd7. Knockdown of Sox2 or Chd7 via short hairpin RNA revealed an overlapping set of target genes. Sequencing of DNA bound by Sox2 and Chd7 in chromatin immunoprecipitation experiments and analysis of genes disrupted by knockdown of Sox2 or Chd7 revealed that the 2 proteins cooperated in gene activation. <a href="#12" class="mim-tip-reference" title="Engelen, E., Akinci, U., Bryne, J. C., Hou, J., Gontan, C., Moen, M., Szumska, D., Kockx, C., van IJcken, W., Dekkers, D. H. W., Demmers, J., Rijkers, E.-J., Bhattacharya, S., Philipsen, S., Pevny, L. H., Grosveld, F. G., Rottier, R. J., Lenhard, B., Poot, R. A. <strong>Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes.</strong> Nature Genet. 43: 607-611, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21532573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21532573</a>] [<a href="https://doi.org/10.1038/ng.825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21532573">Engelen et al. (2011)</a> concluded that Chd7 is an important Sox2 cofactor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21532573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Rais, Y., Zviran, A., Geula, S., Gafni, O., Chomsky, E., Viukov, S., Mansour, A. A., Caspi, I., Krupalnik, V., Zerbib, M., Maza, I., Mor, N., and 14 others. <strong>Deterministic direct reprogramming of somatic cells to pluripotency.</strong> Nature 502: 65-70, 2013. Note: Erratum: Nature 520: 710 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24048479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24048479</a>] [<a href="https://doi.org/10.1038/nature12587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24048479">Rais et al. (2013)</a> showed that depleting MBD3 (<a href="/entry/603573">603573</a>), a core member of the MBD3/NURD (nucleosome remodeling and deacetylation) repressor complex, together with OSKM (OCT4, <a href="/entry/164177">164177</a>; SOX2; KLF4, <a href="/entry/602253">602253</a>; and MYC, <a href="/entry/190080">190080</a>) transduction and reprogramming in naive pluripotency-promoting conditions, result in deterministic and synchronized iPS cell reprogramming (nearly 100% efficiency within 7 days from mouse and human cells). <a href="#37" class="mim-tip-reference" title="Rais, Y., Zviran, A., Geula, S., Gafni, O., Chomsky, E., Viukov, S., Mansour, A. A., Caspi, I., Krupalnik, V., Zerbib, M., Maza, I., Mor, N., and 14 others. <strong>Deterministic direct reprogramming of somatic cells to pluripotency.</strong> Nature 502: 65-70, 2013. Note: Erratum: Nature 520: 710 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24048479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24048479</a>] [<a href="https://doi.org/10.1038/nature12587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24048479">Rais et al. (2013)</a> stated that their findings uncovered a dichotomous molecular function for the reprogramming factors, serving to reactivate endogenous pluripotency networks while simultaneously directly recruiting the MBD3/NURD repressor complex that potently restrains the reactivation of OSKM downstream target genes. Subsequently, the latter interactions, which are largely depleted during early preimplantation development in vivo, lead to a stochastic and protracted reprogramming trajectory toward pluripotency in vitro. <a href="#37" class="mim-tip-reference" title="Rais, Y., Zviran, A., Geula, S., Gafni, O., Chomsky, E., Viukov, S., Mansour, A. A., Caspi, I., Krupalnik, V., Zerbib, M., Maza, I., Mor, N., and 14 others. <strong>Deterministic direct reprogramming of somatic cells to pluripotency.</strong> Nature 502: 65-70, 2013. Note: Erratum: Nature 520: 710 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24048479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24048479</a>] [<a href="https://doi.org/10.1038/nature12587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24048479">Rais et al. (2013)</a> concluded that their deterministic reprogramming approach offered a novel platform for the dissection of molecular dynamics leading to establishing pluripotency at unprecedented flexibility and resolution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24048479" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Boumahdi, S., Driessens, G., Lapouge, G., Rorive, S., Nassar, D., Le Mercier, M., Delatte, B., Caauwe, A., Lenglez, S., Nkusi, E., Brohee, S., Salmon, I., Dubois, C., del Marmol, V., Fuks, F., Beck, B., Blanpain, C. <strong>SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma.</strong> Nature 511: 246-250, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24909994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24909994</a>] [<a href="https://doi.org/10.1038/nature13305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24909994">Boumahdi et al. (2014)</a> found that Sox2 was the most upregulated transcription factor in the cancer stem cells (CSCs) of squamous skin tumors in mice. SOX2 is absent in normal epidermis but begins to be expressed in the vast majority of mouse and human preneoplastic skin tumors, and continues to be expressed in a heterogeneous manner in invasive mouse and human squamous cell carcinomas (SCCs). In contrast to other SCCs, in which SOX2 is frequently genetically amplified, the expression of SOX2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis markedly decreases skin tumor formation after chemical-induced carcinogenesis. Using green fluorescent protein (GFP) as a reporter of Sox2 transcriptional expression (Sox2-GFP knockin mice), <a href="#3" class="mim-tip-reference" title="Boumahdi, S., Driessens, G., Lapouge, G., Rorive, S., Nassar, D., Le Mercier, M., Delatte, B., Caauwe, A., Lenglez, S., Nkusi, E., Brohee, S., Salmon, I., Dubois, C., del Marmol, V., Fuks, F., Beck, B., Blanpain, C. <strong>SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma.</strong> Nature 511: 246-250, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24909994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24909994</a>] [<a href="https://doi.org/10.1038/nature13305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24909994">Boumahdi et al. (2014)</a> showed that SOX2-expressing cells in invasive SCC are greatly enriched in tumor-propagating cells, which further increase upon serial transplantations. Lineage ablation of SOX2-expressing cells within primary benign and malignant SCCs leads to tumor regression, consistent with the critical role of SOX2-expressing cells in tumor maintenance. Conditional Sox2 deletion in preexisting skin papilloma and SCC leads to tumor regression and decreases the ability of cancer cells to be propagated upon transplantation into immunodeficient mice, supporting the essential role of SOX2 in regulating CSC function. Transcriptional profiling of SOX2-GFP-expressing CSCs and of tumor epithelial cells upon Sox2 deletion uncovered a gene network regulated by SOX2 in primary tumor cells in vivo. Chromatin immunoprecipitation identified several direct SOX2 target genes controlling tumor stemness, survival, proliferation, adhesion, invasion, and paraneoplastic syndrome. <a href="#3" class="mim-tip-reference" title="Boumahdi, S., Driessens, G., Lapouge, G., Rorive, S., Nassar, D., Le Mercier, M., Delatte, B., Caauwe, A., Lenglez, S., Nkusi, E., Brohee, S., Salmon, I., Dubois, C., del Marmol, V., Fuks, F., Beck, B., Blanpain, C. <strong>SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma.</strong> Nature 511: 246-250, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24909994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24909994</a>] [<a href="https://doi.org/10.1038/nature13305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24909994">Boumahdi et al. (2014)</a> demonstrated that SOX2, by marking and regulating the functions of skin tumor-initiating cells and CSCs, establishes a continuum between tumor initiation and progression in primary skin tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24909994" 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 chromatin immunoprecipitation analysis, <a href="#5" class="mim-tip-reference" title="Chassaing, N., Davis, E. E., McKnight, K. L., Niederriter, A. R., Causse, A., David, V., Desmaison, A., Lamarre, S., Vincent-Delorme, C., Pasquier, L., Coubes, C., Lacombe, D., Rossi, M., Dufier, J.-L., Dollfus, H., Kaplan, J., Katsanis, N., Etchevers, H. C., Faguer, S., Calvas, P. <strong>Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network.</strong> Genome Res. 26: 474-485, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26893459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26893459</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26893459[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/10.1101/gr.196048.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26893459">Chassaing et al. (2016)</a> found that Sox2 bound to a sequence within intron 15 of the mouse Ptch1 (<a href="/entry/601309">601309</a>) gene. Suppression of sox2 expression in zebrafish upregulated ptch1 expression and resulted in reduced eye and retina size. Knockdown of ptch1 in zebrafish also caused ocular defects, including reduced eye size. Reduced ptch1 protein in zebrafish led to overactive SHH signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26893459" 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="#54" class="mim-tip-reference" title="Zhang, C., Leng, F., Saxena, L., Hoang, N., Yu, J., Alejo, S., Lee, L., Qi, D., Lu, F., Sun, H., Zhang, H. <strong>Proteolysis of methylated SOX2 protein is regulated by L3MBTL3 and CRL4-DCAF5 ubiquitin ligase.</strong> J. Biol. Chem. 294: 476-489, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30442713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30442713</a>] [<a href="https://doi.org/10.1074/jbc.RA118.005336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30442713">Zhang et al. (2019)</a> found that human L3MBTL3 (<a href="/entry/618844">618844</a>) preferentially bound monomethylated lys42 in SOX2 and regulated stability of the SOX2 protein, which was sensitive to loss of both LSD1 (KDM1A; <a href="/entry/609132">609132</a>) and PHF20L1, in human PA-1 teratocarcinoma cells. L3MBTL3 also interacted with DCAF5 (<a href="/entry/603812">603812</a>), a subunit of a CRL4 ubiquitin E3 ligase complex (see CUL4A, <a href="/entry/603137">603137</a>), and cooperatively targeted methylated SOX2 for polyubiquitination-dependent proteolysis. Similarly, L3mbtl3 interacted with Sox2 and destabilized the Sox2 protein in mouse embryonic stem (ES) cells. Loss of L3mbtl3 stabilized Sox2 and restored self-renewal and pluripotency in Lsd1- or Phf20l1-knockdown mouse ES cells. Methylated Sox2 was a critical target of Lsd1 in mouse ES cells, and it appeared that methylation at both lys42 and lys117 was important for Lsd1 to maintain self-renewal and pluripotency of mouse ES cells. Induction of mouse ES cell differentiation enhanced proteolytic degradation of Sox2, which also depended on methylation of both lys42 and lys117 in Sox2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30442713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#9" class="mim-tip-reference" title="Dodonova, S. O., Zhu, F., Dienemann, C., Taipale, J., Cramer, P. <strong>Nucleosome-bound SOX2 and SOX11 structures elucidate pioneer factor function.</strong> Nature 580: 669-672, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32350470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32350470</a>] [<a href="https://doi.org/10.1038/s41586-020-2195-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32350470">Dodonova et al. (2020)</a> reported cryoelectron microscopy structures of the DNA-binding domains of SOX2 and its close homolog SOX11 (<a href="/entry/600898">600898</a>) bound to nucleosomes. The structures showed that SOX factors can bind and locally distort DNA at superhelical location 2. The factors also facilitated detachment of terminal nucleosomal DNA from the histone octamer, which increases DNA accessibility. SOX-factor binding to the nucleosome can also lead to a repositioning of the N-terminal tail of histone H4 (see <a href="/entry/602822">602822</a>) that includes residue lys16. <a href="#9" class="mim-tip-reference" title="Dodonova, S. O., Zhu, F., Dienemann, C., Taipale, J., Cramer, P. <strong>Nucleosome-bound SOX2 and SOX11 structures elucidate pioneer factor function.</strong> Nature 580: 669-672, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32350470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32350470</a>] [<a href="https://doi.org/10.1038/s41586-020-2195-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32350470">Dodonova et al. (2020)</a> speculated that this repositioning is incompatible with higher-order nucleosome stacking, which involves contacts of the H4 tail with a neighboring nucleosome. <a href="#9" class="mim-tip-reference" title="Dodonova, S. O., Zhu, F., Dienemann, C., Taipale, J., Cramer, P. <strong>Nucleosome-bound SOX2 and SOX11 structures elucidate pioneer factor function.</strong> Nature 580: 669-672, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32350470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32350470</a>] [<a href="https://doi.org/10.1038/s41586-020-2195-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32350470">Dodonova et al. (2020)</a> concluded that pioneer transcription factors that maintain pluripotency can use binding energy to initiate chromatin opening, and thereby facilitate nucleosome remodeling and subsequent transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32350470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Chitayat, D., Babul, R., Silver, M. M., Jay, V., Teshima, I. E., Babyn, P., Becker, L. E. <strong>Terminal deletion of the long arm of chromosome 3 [46,XX,del(3)(q27-qter)].</strong> Am. J. Med. Genet. 61: 45-48, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8741917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8741917</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19960102)61:1<45::AID-AJMG9>3.0.CO;2-W" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8741917">Chitayat et al. (1996)</a> and <a href="#23" class="mim-tip-reference" title="Male, A., Davies, A., Bergbaum, A., Keeling, J., FitzPatrick, D., Ogilvie, C. M., Berg, J. <strong>Delineation of an estimated 6.7 MB candidate interval for an anophthalmia gene at 3q26.33-q28 and description of the syndrome associated with visible chromosome deletions of this region.</strong> Europ. J. Hum. Genet. 10: 807-812, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12461687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12461687</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200890" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12461687">Male et al. (2002)</a> identified constitutional deletions involving 3q27 in 3 unrelated individuals with clinical anophthalmia and microphthalmia. <a href="#11" class="mim-tip-reference" title="Driggers, R. W., Macri, C. J., Greenwald, J., Carpenter, D., Avallone, J., Howard-Peebles, P. N., Levin, S. W. <strong>Isolated bilateral anophthalmia in a girl with an apparently balanced de novo translocation: 46,XX,t(3;11)(q27;p11.2).</strong> Am. J. Med. Genet. 87: 201-202, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10564870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10564870</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19991126)87:3<201::aid-ajmg1>3.0.co;2-h" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10564870">Driggers et al. (1999)</a> and <a href="#22" class="mim-tip-reference" title="Kurbasic, M., Jones, V. F., Cook, L. N. <strong>Bilateral microphthalmos with colobomatous orbital cyst and de-novo balanced translocation t(3;5).</strong> Ophthal. Genet. 21: 239-242, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11135495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11135495</a>]" pmid="11135495">Kurbasic et al. (2000)</a> reported de novo apparently balanced reciprocal translocations involving 3q27 in 2 patients with severe bilateral microphthalmia and microphthalmia/clinical anophthalmia. In the female infant reported by <a href="#11" class="mim-tip-reference" title="Driggers, R. W., Macri, C. J., Greenwald, J., Carpenter, D., Avallone, J., Howard-Peebles, P. N., Levin, S. W. <strong>Isolated bilateral anophthalmia in a girl with an apparently balanced de novo translocation: 46,XX,t(3;11)(q27;p11.2).</strong> Am. J. Med. Genet. 87: 201-202, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10564870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10564870</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19991126)87:3<201::aid-ajmg1>3.0.co;2-h" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10564870">Driggers et al. (1999)</a> with isolated bilateral clinical anophthalmia and a de novo t(3;11)(q27;p11.2), <a href="#14" class="mim-tip-reference" title="Fantes, J., Ragge, N. K., Lynch, S.-A., McGill, N. I., Collin, J. R. O., Howard-Peebles, P. N., Hayward, C., Vivian, A. J., Williamson, K., van Heyningen, V., FitzPatrick, D. R. <strong>Mutations in SOX2 cause anophthalmia.</strong> Nature Genet. 33: 461-462, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612584</a>] [<a href="https://doi.org/10.1038/ng1120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612584">Fantes et al. (2003)</a> identified a submicroscopic deletion at the 3q breakpoint. This deletion contained SOX2. Subsequent SOX2 mutation analysis identified de novo truncating mutations of SOX2 (<a href="#0001">184429.0001</a>-<a href="#0003">184429.0003</a>) in 4 (11%) of 35 individuals with clinical anophthalmia and other features (MCOPS3; <a href="/entry/206900">206900</a>). Both eyes were affected in all cases with an identified mutation. In each case the mutation was present in heterozygous state; the parents of each individual with a mutation in SOX2 had normal SOX2 sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12461687+10564870+8741917+11135495+12612584" 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="#36" class="mim-tip-reference" title="Ragge, N. K., Lorenz, B., Schneider, A., Bushby, K., de Sanctis, L., de Sanctis, U., Salt, A., Collin, J. R. O., Vivian, A. J., Free, S. L., Thompson, P., Williamson, K. A., Sisodiya, S. M., van Heyningen, V., FitzPatrick, D. R. <strong>SOX2 anophthalmia syndrome.</strong> Am. J. Med. Genet. 135A: 1-7, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15812812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15812812</a>] [<a href="https://doi.org/10.1002/ajmg.a.30642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15812812">Ragge et al. (2005)</a> reported 4 patients with bilateral anophthalmia/microphthalmia and de novo heterozygous mutations in SOX2, including a missense mutation (<a href="#0004">184429.0004</a>) and 3 frameshift mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15812812" 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 12-year-old girl with bilateral clinical anophthalmia, <a href="#16" class="mim-tip-reference" title="Hagstrom, S. A., Pauer, G. J. T., Reid, J., Simpson, E., Crowe, S., Maumenee, I. H., Traboulsi, E. I. <strong>SOX2 mutation causes anophthalmia, hearing loss, and brain anomalies.</strong> Am. J. Med. Genet. 138A: 95-98, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16145681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16145681</a>] [<a href="https://doi.org/10.1002/ajmg.a.30803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16145681">Hagstrom et al. (2005)</a> identified heterozygosity for a nonsense mutation in the SOX2 gene (<a href="#0005">184429.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16145681" 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 11-month-old Mexican girl with bilateral clinical anophthalmia, mild facial dysmorphism, and developmental delay, <a href="#52" class="mim-tip-reference" title="Zenteno, J. C., Gascon-Guzman, G., Tovilla-Canales, J. L. <strong>Bilateral anophthalmia and brain malformations caused by a 20-bp deletion in the SOX2 gene. (Letter)</strong> Clin. Genet. 68: 564-566, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16283891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16283891</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00518.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16283891">Zenteno et al. (2005)</a> identified heterozygosity for a 20-bp deletion in the SOX2 gene (70del20; <a href="#0010">184429.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16283891" 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="#49" class="mim-tip-reference" title="Williamson, K. A., Hever, A. M., Rainger, J., Rogers, R. C., Magee, A., Fiedler, Z., Keng, W. T., Sharkey, F. H., McGill, N., Hill, C. J., Schneider, A., Messina, M., Turnpenny, P. D., Fantes, J. A., van Heyningen, V., FitzPatrick, D. R. <strong>Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome.</strong> Hum. Molec. Genet. 15: 1413-1422, 2006. Note: Erratum: Hum. Molec. Genet. 15: 2030 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16543359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16543359</a>] [<a href="https://doi.org/10.1093/hmg/ddl064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16543359">Williamson et al. (2006)</a> identified heterozygous loss-of-function mutations in the SOX2 gene in 3 unrelated patients with microphthalmia and esophageal atresia: the original patient reported by <a href="#38" class="mim-tip-reference" title="Rogers, R. C. <strong>Unknown cases: S.C.B. (GGC-10079) 11 month old white male.</strong> Proc. Greenwood Genet. Center 7: 57 only, 1988."None>Rogers (1988)</a> was found to have a 2.7-Mb deletion encompassing the SOX2 gene (<a href="#0006">184429.0006</a>); the male infant described by <a href="#33" class="mim-tip-reference" title="Petrackova, I., Pozler, O., Kokstein, Z., Zizka, J., Dedkova, J., Rejtar, P., Fiedler, Z., Kuliacek, P. <strong>Association of oesophageal atresia, anophthalmia and renal duplex.</strong> Europ. J. Pediat. 163: 333-334, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15346919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15346919</a>] [<a href="https://doi.org/10.1007/s00431-004-1424-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15346919">Petrackova et al. (2004)</a> was found to have a nonsense mutation (<a href="#0007">184429.0007</a>); and a newly reported female infant was found to have a missense mutation (<a href="#0008">184429.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15346919+16543359" 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 female infant with bilateral clinical anophthalmos, very narrow palpebral fissures with synechiae, microcephaly, and psychomotor retardation (<a href="/entry/206900">206900</a>), <a href="#13" class="mim-tip-reference" title="Faivre, L., Williamson, K. A., Faber, V., Laurent, N., Grimaldi, M., Thauvin-Robinet, C., Durand, C., Mugneret, F., Gouyon, J.-B., Bron, A., Huet, F., Hayward, C., van Heyningen, V., FitzPatrick, D. R. <strong>Recurrence of SOX2 anophthalmia syndrome with gonosomal mosaicism in a phenotypically normal mother. (Letter)</strong> Am. J. Med. Genet. 140A: 636-639, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16470798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16470798</a>] [<a href="https://doi.org/10.1002/ajmg.a.31114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16470798">Faivre et al. (2006)</a> identified heterozygosity for a missense mutation in the SOX2 gene (<a href="#0009">184429.0009</a>). The unaffected mother was also found to be heterozygous for the mutation; restriction enzyme digestion products were always lower in the mother than the proband, consistent with a lower level of mutant allele in the mother due to somatic mosaicism. An earlier pregnancy had been terminated due to severe hydrocephaly; examination of the fetus had revealed left cryptophthalmos, bilateral clinical anophthalmos, and multiple brain abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16470798" 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="#53" class="mim-tip-reference" title="Zenteno, J. C., Perez-Cano, H. J., Aguinaga, M. <strong>Anophthalmia-esophageal atresia syndrome caused by an SOX2 gene deletion in monozygotic twin brothers with markedly discordant phenotypes.</strong> Am. J. Med. Genet. 140A: 1899-1903, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16892407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16892407</a>] [<a href="https://doi.org/10.1002/ajmg.a.31384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16892407">Zenteno et al. (2006)</a> reported male monozygotic twins with esophageal atresia and a discordant ocular phenotype in whom they identified heterozygosity for the 70del20 mutation in the SOX2 gene. One of the infants had unilateral clinical anophthalmia, whereas the other had normal ocular globes; the authors stated that this was the first reported case of SOX2 mutation causing a unilateral eye defect, and the first example of monozygotic twins discordant for anophthalmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16892407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Kelberman, D., Rizzoti, K., Avilion, A., Bitner-Glindicz, M., Cianfarani, S., Collins, J., Chong, W. K., Kirk, J. M. W., Achermann, J. C., Ross, R., Carmignac, D., Lovell-Badge, R., Robinson, I. C. A. F., Dattani, M. T. <strong>Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.</strong> J. Clin. Invest. 116: 2442-2455, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16932809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16932809</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16932809[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI28658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16932809">Kelberman et al. (2006)</a> screened 235 probands with congenital hypothalamo-pituitary disorders for mutations in the SOX2 gene and identified 6 patients with clinical anophthalmia or microphthalmia who had heterozygous de novo mutations (see, e.g., <a href="#0001">184429.0001</a>, <a href="#0010">184429.0010</a>, and <a href="#0011">184429.0011</a>), and 2 patients with bilateral optic nerve hypoplasia who had inherited heterozygous mutations (see <a href="#0012">184429.0012</a> and <a href="#0013">184429.0013</a>). In addition to bilateral eye defects, all patients with SOX2 mutations had various associated anomalies, including anterior pituitary hypoplasia and hypogonadotropic hypogonadism, variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, learning difficulties, sensorineural hearing loss, and esophageal atresia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16932809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 female sibs, 1 of whom was previously reported by <a href="#25" class="mim-tip-reference" title="Menetrey, C., Belin, V., Odent, S., de Lumley, L., Gilbert, B. <strong>Bilateral anophthalmia and oesophageal atresia in a newborn female: a new case of the anophthalmia-oesophageal-genital (AEG) syndrome.</strong> Clin. Dysmorph. 11: 139-140, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12002146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12002146</a>] [<a href="https://doi.org/10.1097/00019605-200204000-00013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12002146">Menetrey et al. (2002)</a>, <a href="#6" class="mim-tip-reference" title="Chassaing, N., Gilbert-Dussardier, B., Nicot, F., Fermeaux, V., Encha-Razavi, F., Fiorenza, M., Toutain, A., Calvas, P. <strong>Germinal mosaicism and familial recurrence of a SOX2 mutation with highly variable phenotypic expression extending from AEG syndrome to absence of ocular involvement.</strong> Am. J. Med. Genet. 143A: 289-291, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17219395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17219395</a>] [<a href="https://doi.org/10.1002/ajmg.a.31524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17219395">Chassaing et al. (2007)</a> identified heterozygosity for a 17-bp deletion in the SOX2 gene (<a href="#0014">184429.0014</a>). The sibs were discordant for anophthalmia. <a href="#6" class="mim-tip-reference" title="Chassaing, N., Gilbert-Dussardier, B., Nicot, F., Fermeaux, V., Encha-Razavi, F., Fiorenza, M., Toutain, A., Calvas, P. <strong>Germinal mosaicism and familial recurrence of a SOX2 mutation with highly variable phenotypic expression extending from AEG syndrome to absence of ocular involvement.</strong> Am. J. Med. Genet. 143A: 289-291, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17219395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17219395</a>] [<a href="https://doi.org/10.1002/ajmg.a.31524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17219395">Chassaing et al. (2007)</a> concluded that SOX2 haploinsufficiency can cause a variable ocular phenotype ranging from normal eyes to anophthalmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17219395+12002146" 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="#19" class="mim-tip-reference" title="Kelberman, D., de Castro, S. C. P., Huang, S., Crolla, J. A., Palmer, R., Gregory, J. W., Taylor, D., Cavallo, L., Faienza, M. F., Fischetto, R., Achermann, J. C., Martinez-Barbera, J. P., Rizzoti, K., Lovell-Badge, R., Robinson, I. C. A. F., Gerrelli, D., Dattani, M. T. <strong>SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development.</strong> J. Clin. Endocr. Metab. 93: 1865-1873, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285410</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18285410[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/10.1210/jc.2007-2337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285410">Kelberman et al. (2008)</a> ascertained 3 patients with severe eye defects and pituitary abnormalities who were screened for mutations in SOX2; one patient had been described by <a href="#23" class="mim-tip-reference" title="Male, A., Davies, A., Bergbaum, A., Keeling, J., FitzPatrick, D., Ogilvie, C. M., Berg, J. <strong>Delineation of an estimated 6.7 MB candidate interval for an anophthalmia gene at 3q26.33-q28 and description of the syndrome associated with visible chromosome deletions of this region.</strong> Europ. J. Hum. Genet. 10: 807-812, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12461687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12461687</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200890" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12461687">Male et al. (2002)</a>. All 3 harbored heterozygous SOX2 mutations: a deletion encompassing the entire gene, an intragenic deletion (70_89del; <a href="#0010">184429.0010</a>), and a novel nonsense mutation within the DNA binding domain that resulted in impaired transactivation. <a href="#19" class="mim-tip-reference" title="Kelberman, D., de Castro, S. C. P., Huang, S., Crolla, J. A., Palmer, R., Gregory, J. W., Taylor, D., Cavallo, L., Faienza, M. F., Fischetto, R., Achermann, J. C., Martinez-Barbera, J. P., Rizzoti, K., Lovell-Badge, R., Robinson, I. C. A. F., Gerrelli, D., Dattani, M. T. <strong>SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development.</strong> J. Clin. Endocr. Metab. 93: 1865-1873, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285410</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18285410[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/10.1210/jc.2007-2337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285410">Kelberman et al. (2008)</a> showed that human SOX2 can inhibit beta-catenin (<a href="/entry/116806">116806</a>)-driven reporter gene expression in vitro, whereas mutant SOX2 proteins are unable to repress this activity efficiently. They also showed that SOX2 is expressed throughout the human brain, including the developing hypothalamus, as well as the Rathke pouch, the developing anterior pituitary, and the eye. <a href="#19" class="mim-tip-reference" title="Kelberman, D., de Castro, S. C. P., Huang, S., Crolla, J. A., Palmer, R., Gregory, J. W., Taylor, D., Cavallo, L., Faienza, M. F., Fischetto, R., Achermann, J. C., Martinez-Barbera, J. P., Rizzoti, K., Lovell-Badge, R., Robinson, I. C. A. F., Gerrelli, D., Dattani, M. T. <strong>SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development.</strong> J. Clin. Endocr. Metab. 93: 1865-1873, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285410</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18285410[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/10.1210/jc.2007-2337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285410">Kelberman et al. (2008)</a> concluded that a failure to repress the Wnt (see <a href="/entry/164820">164820</a>)-beta-catenin pathway could be one of the underlying pathogenic mechanisms associated with the effects of loss-of-function mutations in SOX2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12461687+18285410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sisters with bilateral clinical anophthalmia/microphthalmia and brain anomalies, <a href="#39" class="mim-tip-reference" title="Schneider, A., Bardakjian, T. M., Zhou, J., Hughes, N., Keep, R., Dorsainville, D., Kherani, F., Katowitz, J., Schimmenti, L. A., Hummel, M., FitzPatrick, D. R., Young, T. L. <strong>Familial recurrence of SOX2 anophthalmia syndrome: phenotypically normal mother with two affected daughters.</strong> Am. J. Med. Genet. 146A: 2794-2798, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18831064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18831064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18831064[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.32384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18831064">Schneider et al. (2008)</a> identified heterozygosity for a 1-bp deletion in the SOX2 gene (<a href="#0015">184429.0015</a>). The unaffected mother had a reduced signal for the deletion in peripheral blood and buccal cell DNA, confirming somatic mosaicism; the mutation was not found in the maternal grandparents. <a href="#39" class="mim-tip-reference" title="Schneider, A., Bardakjian, T. M., Zhou, J., Hughes, N., Keep, R., Dorsainville, D., Kherani, F., Katowitz, J., Schimmenti, L. A., Hummel, M., FitzPatrick, D. R., Young, T. L. <strong>Familial recurrence of SOX2 anophthalmia syndrome: phenotypically normal mother with two affected daughters.</strong> Am. J. Med. Genet. 146A: 2794-2798, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18831064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18831064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18831064[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.32384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18831064">Schneider et al. (2008)</a> noted that this was the third report of a family in which an unaffected mosaic mother transmitted bilateral clinical anophthalmia to 2 female offspring (see <a href="#13" class="mim-tip-reference" title="Faivre, L., Williamson, K. A., Faber, V., Laurent, N., Grimaldi, M., Thauvin-Robinet, C., Durand, C., Mugneret, F., Gouyon, J.-B., Bron, A., Huet, F., Hayward, C., van Heyningen, V., FitzPatrick, D. R. <strong>Recurrence of SOX2 anophthalmia syndrome with gonosomal mosaicism in a phenotypically normal mother. (Letter)</strong> Am. J. Med. Genet. 140A: 636-639, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16470798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16470798</a>] [<a href="https://doi.org/10.1002/ajmg.a.31114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16470798">Faivre et al., 2006</a> and <a href="#6" class="mim-tip-reference" title="Chassaing, N., Gilbert-Dussardier, B., Nicot, F., Fermeaux, V., Encha-Razavi, F., Fiorenza, M., Toutain, A., Calvas, P. <strong>Germinal mosaicism and familial recurrence of a SOX2 mutation with highly variable phenotypic expression extending from AEG syndrome to absence of ocular involvement.</strong> Am. J. Med. Genet. 143A: 289-291, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17219395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17219395</a>] [<a href="https://doi.org/10.1002/ajmg.a.31524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17219395">Chassaing et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16470798+17219395+18831064" 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 6-month-old Italian boy with clinical anophthalmia and severe microphthalmia of the right and left eyes, respectively, associated with micropenis, <a href="#32" class="mim-tip-reference" title="Pedace, L., Castori, M., Binni, F., Pingi, A., Grammatico, B., Scommegna, S., Majore, S., Grammatico, P. <strong>A novel heterozygous SOX2 mutation causing anophthalmia/microphthalmia with genital anomalies. (Letter)</strong> Europ. J. Med. Genet. 52: 273-276, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19254784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19254784</a>] [<a href="https://doi.org/10.1016/j.ejmg.2009.02.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19254784">Pedace et al. (2009)</a> analyzed the SOX2 gene and identified heterozygosity for a 2-bp insertion (<a href="#0016">184429.0016</a>). No morphologic or functional anomaly of the hypothalamic-pituitary axis was detected in this patient, suggesting that SOX2 might have a direct influence on male genital development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19254784" 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 21-year-old Japanese man with bilateral clinical anophthalmia, hypogonadotropic hypogonadism, seizures, spastic diplegia, and intellectual disability, who was negative for mutation in the HESX1 gene (<a href="/entry/601802">601802</a>), <a href="#27" class="mim-tip-reference" title="Numakura, C., Kitanaka, S., Kato, M., Ishikawa, S., Hamamoto, Y., Katsushima, Y., Kimura, T., Hayasaka, K. <strong>Supernumerary impacted teeth in a patient with SOX2 anophthalmia syndrome.</strong> Am. J. Med. Genet. 152A: 2355-2359, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20803647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20803647</a>] [<a href="https://doi.org/10.1002/ajmg.a.33556" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20803647">Numakura et al. (2010)</a> identified heterozygosity for a nonsense mutation in SOX2 (L82X; <a href="#0017">184429.0017</a>). The patient also had a dental anomaly consisting of multiple supernumerary impacted teeth and persistence of deciduous teeth. Although the role of SOX2 in dental development was unknown, the authors considered the supernumerary teeth to be an extraocular symptom of the SOX2 anophthalmia syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20803647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Alatzoglou, K. S., Andoniadou, C. L., Kelberman, D., Buchanan, C. R., Crolla, J., Arriazu, M. C., Roubicek, M., Moncet, D., Martinez-Barbera, J. P., Dattani, M. T. <strong>SOX2 haploinsufficiency is associated with slow progressing hypothalamo-pituitary tumours.</strong> Hum. Mutat. 32: 1376-1380, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21919124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21919124</a>] [<a href="https://doi.org/10.1002/humu.21606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21919124">Alatzoglou et al. (2011)</a> reported 2 unrelated patients with bilateral clinical anophthalmia and nonprogressive pituitary tumors of early onset associated with SOX2 haploinsufficiency, due to heterozygosity for a 731-kb deletion on chromosome 3q26 encompassing SOX2 in 1 patient and a SOX2 nonsense mutation (F48X; <a href="#0018">184429.0018</a>) in the other. <a href="#1" class="mim-tip-reference" title="Alatzoglou, K. S., Andoniadou, C. L., Kelberman, D., Buchanan, C. R., Crolla, J., Arriazu, M. C., Roubicek, M., Moncet, D., Martinez-Barbera, J. P., Dattani, M. T. <strong>SOX2 haploinsufficiency is associated with slow progressing hypothalamo-pituitary tumours.</strong> Hum. Mutat. 32: 1376-1380, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21919124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21919124</a>] [<a href="https://doi.org/10.1002/humu.21606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21919124">Alatzoglou et al. (2011)</a> stated that this was the first time that SOX2 haploinsufficiency had been implicated in the generation of pituitary tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21919124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sibs with microphthalmia, 1 of whom also had endocrinologic abnormalities, and their mother, who was diagnosed with idiopathic hypogonadotropic hypogonadism (see <a href="/entry/147950">147950</a>) but had no other dysmorphic features and normal ophthalmologic examination, <a href="#42" class="mim-tip-reference" title="Stark, Z., Storen, R., Bennetts, B., Savarirayan, R., Jamieson, R. V. <strong>Isolated hypogonadotropic hypogonadism with SOX2 mutation and anophthalmia/microphthalmia in offspring.</strong> Europ. J. Hum. Genet. 19: 753-756, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21326281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21326281</a>] [<a href="https://doi.org/10.1038/ejhg.2011.11" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21326281">Stark et al. (2011)</a> identified heterozygosity for a 1-bp deletion in SOX2 (<a href="#0019">184429.0019</a>). Sequencing results in the mother suggested possible mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21326281" 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="#40" class="mim-tip-reference" title="Schneider, A., Bardakjian, T., Reis, L. M., Tyler, R. C., Semina, E. V. <strong>Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia.</strong> Am. J. Med. Genet. 149A: 2706-2715, 2009. Note: Erratum: Am. J. Med. Genet. 158A: 267 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19921648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19921648</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19921648[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.33098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19921648">Schneider et al. (2009)</a> screened the SOX2 gene in 51 unrelated patients with clinical anophthalmia and/or microphthalmia and identified heterozygous SOX2 mutations in 10 of them, including 3 patients with the recurrent 20-bp deletion (70del20; <a href="#0010">184429.0010</a>). Analysis of all reported patients with SOX2 mutations suggested a potential genotype/phenotype correlation, with missense changes generally resulting in less severe ocular defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19921648" 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="#10" class="mim-tip-reference" title="Dong, S., Leung, K. K. H., Pelling, A. L., Lee, P. Y. T., Tang, A. S. P., Heng, H. H. Q., Tsui, L. C., Tease, C., Fisher, G., Steel, K. P., Cheah, K. S. E. <strong>Circling, deafness, and yellow coat displayed by yellow submarine (Ysb) and light coat and circling (Lcc) mice with mutations on chromosome 3.</strong> Genomics 79: 777-784, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12036291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12036291</a>] [<a href="https://doi.org/10.1006/geno.2002.6783" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12036291">Dong et al. (2002)</a> identified 2 allelic mouse mutants, 'light coat and circling' (Lcc) and 'yellow submarine' (Ysb), that show hearing and balance impairment. Lcc/Lcc mice are completely deaf, whereas Ysb/Ysb mice are severely hearing impaired. <a href="#21" class="mim-tip-reference" title="Kiernan, A. E., Pelling, A. L., Leung, K. K. H., Tang, A. S. P., Bell, D. M., Tease, C., Lovell-Badge, R., Steel, K. P., Cheah, K. S. E. <strong>Sox2 is required for sensory organ development in the mammalian inner ear.</strong> Nature 434: 1031-1035, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15846349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15846349</a>] [<a href="https://doi.org/10.1038/nature03487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15846349">Kiernan et al. (2005)</a> reported that inner ears of Lcc/Lcc mice failed to establish a prosensory domain and neither hair cells nor supporting cells differentiated, resulting in a severe inner ear malformation, whereas the sensory epithelium of Ysb/Ysb mice showed abnormal development with disorganized and fewer hair cells. These phenotypes are due to the absence (in Lcc mutants) or reduced expression (in Ysb mutants) of the transcription factor Sox2, specifically within the developing inner ear. <a href="#21" class="mim-tip-reference" title="Kiernan, A. E., Pelling, A. L., Leung, K. K. H., Tang, A. S. P., Bell, D. M., Tease, C., Lovell-Badge, R., Steel, K. P., Cheah, K. S. E. <strong>Sox2 is required for sensory organ development in the mammalian inner ear.</strong> Nature 434: 1031-1035, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15846349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15846349</a>] [<a href="https://doi.org/10.1038/nature03487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15846349">Kiernan et al. (2005)</a> showed that Sox2 continues to be expressed in the inner ears of mice lacking Math1 (<a href="/entry/601461">601461</a>), a gene essential for hair cell differentiation, whereas Math1 expression is absent in Lcc mutants, suggesting that Sox2 acts upstream of Math1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12036291+15846349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Ferri, A. L. M., Cavallaro, M., Braida, D., Di Cristofano, A., Canta, A., Vezzani, A., Ottolenghi, S., Pandolfi, P. P., Sala, M., DeBiasi, S., Nicolis, S. K. <strong>Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain.</strong> Development 131: 3805-3819, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15240551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15240551</a>] [<a href="https://doi.org/10.1242/dev.01204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15240551">Ferri et al. (2004)</a> developed mice that lacked one Sox2 allele and had a deletion in the other Sox2 allele that removed a neural cell-specific enhancer. These compound heterozygotes were born with cerebral malformations and neural cell pathology, and they showed proliferative defects in adult neural stem/progenitor cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15240551" 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="#46" class="mim-tip-reference" title="Taranova, O. V., Magness, S. T., Fagan, B. M., Wu, Y., Surzenko, N., Hutton, S. R., Pevny, L. H. <strong>SOX2 is a dose-dependent regulator of retinal neural progenitor competence.</strong> Genes Dev. 20: 1187-1202, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16651659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16651659</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16651659[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/10.1101/gad.1407906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16651659">Taranova et al. (2006)</a> generated a gene-dosage allelic series of Sox2 mutations in mice. The mutant mice had a range of eye phenotypes, the severity of which directly related to the level of Sox2 expression in neural retinal progenitor cells. Retinal progenitor cells with conditionally ablated Sox2 lost competence both to proliferate and to differentiate terminally. Mice with less than 40% of normal Sox2 expression in the neural retina showed variable microphthalmia as a result of aberrant neural progenitor differentiation. In addition, <a href="#46" class="mim-tip-reference" title="Taranova, O. V., Magness, S. T., Fagan, B. M., Wu, Y., Surzenko, N., Hutton, S. R., Pevny, L. H. <strong>SOX2 is a dose-dependent regulator of retinal neural progenitor competence.</strong> Genes Dev. 20: 1187-1202, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16651659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16651659</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16651659[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/10.1101/gad.1407906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16651659">Taranova et al. (2006)</a> found that Sox2 regulated Notch1 (<a href="/entry/190198">190198</a>) signaling in a concentration-dependent manner in retinal progenitor cells. They concluded that precise regulation of SOX2 dosage is critical for temporal and spatial regulation of retinal progenitor cell differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16651659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Kelberman, D., Rizzoti, K., Avilion, A., Bitner-Glindicz, M., Cianfarani, S., Collins, J., Chong, W. K., Kirk, J. M. W., Achermann, J. C., Ross, R., Carmignac, D., Lovell-Badge, R., Robinson, I. C. A. F., Dattani, M. T. <strong>Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.</strong> J. Clin. Invest. 116: 2442-2455, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16932809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16932809</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16932809[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI28658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16932809">Kelberman et al. (2006)</a> generated mice heterozygous for a targeted disruption of Sox2. The mutant mice did not manifest eye defects but showed abnormal anterior pituitary development with reduced levels of growth hormone, luteinizing hormone, and thyroid-stimulating hormone, and mutant males had impaired fertility. <a href="#20" class="mim-tip-reference" title="Kelberman, D., Rizzoti, K., Avilion, A., Bitner-Glindicz, M., Cianfarani, S., Collins, J., Chong, W. K., Kirk, J. M. W., Achermann, J. C., Ross, R., Carmignac, D., Lovell-Badge, R., Robinson, I. C. A. F., Dattani, M. T. <strong>Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.</strong> J. Clin. Invest. 116: 2442-2455, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16932809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16932809</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16932809[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI28658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16932809">Kelberman et al. (2006)</a> concluded that Sox2 is necessary for the normal development of the hypothalamo-pituitary and reproductive axes in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16932809" 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="#47" class="mim-tip-reference" title="Tay, Y., Zhang, J., Thomson, A. M., Lim, B., Rigoutsos, I. <strong>MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation.</strong> Nature 455: 1124-1128, 2008. Note: Erratum: Nature 458: 538 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18806776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18806776</a>] [<a href="https://doi.org/10.1038/nature07299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18806776">Tay et al. (2008)</a> demonstrated the existence of many naturally occurring miRNA targets in the amino acid coding sequences of the mouse Nanog (<a href="/entry/607937">607937</a>), Oct4 (<a href="/entry/164177">164177</a>), and Sox2 genes. Some of the mouse targets analyzed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. MiRNA134 (<a href="/entry/610164">610164</a>), miRNA296 (<a href="/entry/610945">610945</a>), and miRNA470, upregulated on retinoic acid-induced differentiation of mouse embryonic stem cells, target the coding sequence of each transcription factor in various combinations, leading to transcriptional and morphologic changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolished miRNA activity, prevented the downregulation of the corresponding genes, and delayed the induced phenotype. <a href="#47" class="mim-tip-reference" title="Tay, Y., Zhang, J., Thomson, A. M., Lim, B., Rigoutsos, I. <strong>MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation.</strong> Nature 455: 1124-1128, 2008. Note: Erratum: Nature 458: 538 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18806776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18806776</a>] [<a href="https://doi.org/10.1038/nature07299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18806776">Tay et al. (2008)</a> concluded that their findings demonstrated the abundance of coding sequence-located miRNA targets, some of which can be species-specific, and supported an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3-prime untranslated region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18806776" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893799 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893799;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=rs104893799" 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=rs104893799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 male patients with bilateral clinical anophthalmia and associated features (MCOPS3; <a href="/entry/206900">206900</a>), <a href="#14" class="mim-tip-reference" title="Fantes, J., Ragge, N. K., Lynch, S.-A., McGill, N. I., Collin, J. R. O., Howard-Peebles, P. N., Hayward, C., Vivian, A. J., Williamson, K., van Heyningen, V., FitzPatrick, D. R. <strong>Mutations in SOX2 cause anophthalmia.</strong> Nature Genet. 33: 461-462, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612584</a>] [<a href="https://doi.org/10.1038/ng1120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612584">Fantes et al. (2003)</a> identified heterozygosity for a de novo 529C-T transition in the SOX2 gene resulting in a terminating change, gln177 to stop (Q177X). One of the affected males had a small remnant at the orbital apex bilaterally; he also had microcephaly, cryptorchidism, micropenis, sensorineural deafness, and learning difficulties (possibly due to bacterial meningitis). The other patient had hypospadias, hypotonia, delayed motor development, and febrile convulsions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612584" 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 18-year-old male with bilateral clinical anophthalmia, <a href="#20" class="mim-tip-reference" title="Kelberman, D., Rizzoti, K., Avilion, A., Bitner-Glindicz, M., Cianfarani, S., Collins, J., Chong, W. K., Kirk, J. M. W., Achermann, J. C., Ross, R., Carmignac, D., Lovell-Badge, R., Robinson, I. C. A. F., Dattani, M. T. <strong>Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.</strong> J. Clin. Invest. 116: 2442-2455, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16932809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16932809</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16932809[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI28658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16932809">Kelberman et al. (2006)</a> identified heterozygosity for a de novo Q177X mutation in the SOX2 gene. In infancy the patient was noted to have mild facial dysmorphism with a prominent forehead and abnormal nares and philtrum, micropenis with bilateral cryptorchidism, neurodevelopmental delay, and hypotonia with abnormal movements. Short stature led to endocrinologic evaluation at age 9 that ultimately resulted in a diagnosis of gonadotropin deficiency with complete hypogonadotropic hypogonadism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16932809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013663" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013663" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013663</a>
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<p>In a female patient with clinical anophthalmia of the right eye, microphthalmia and sclerocornea of the left eye (MCOPS3; <a href="/entry/206900">206900</a>), and proximal myopathy, <a href="#14" class="mim-tip-reference" title="Fantes, J., Ragge, N. K., Lynch, S.-A., McGill, N. I., Collin, J. R. O., Howard-Peebles, P. N., Hayward, C., Vivian, A. J., Williamson, K., van Heyningen, V., FitzPatrick, D. R. <strong>Mutations in SOX2 cause anophthalmia.</strong> Nature Genet. 33: 461-462, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612584</a>] [<a href="https://doi.org/10.1038/ng1120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612584">Fantes et al. (2003)</a> found a de novo heterozygous glu93-to-stop (E93X) mutation of the SOX2 gene. Intelligence was normal in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612584" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 MICROPHTHALMIA, SYNDROMIC 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893801 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893801;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=rs104893801" 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=rs104893801" 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=RCV000013664" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013664" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013664</a>
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<p>In a female patient with clinical anophthalmia of the right eye, microphthalmia with persistent pupillary membrane of the left eye, spastic diplegia, learning difficulties, and seizures (MCOPS3; <a href="/entry/206900">206900</a>), <a href="#14" class="mim-tip-reference" title="Fantes, J., Ragge, N. K., Lynch, S.-A., McGill, N. I., Collin, J. R. O., Howard-Peebles, P. N., Hayward, C., Vivian, A. J., Williamson, K., van Heyningen, V., FitzPatrick, D. R. <strong>Mutations in SOX2 cause anophthalmia.</strong> Nature Genet. 33: 461-462, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612584</a>] [<a href="https://doi.org/10.1038/ng1120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612584">Fantes et al. (2003)</a> identified a de novo heterozygous ser83-to-stop (S83X) mutation in the SOX2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612584" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 MICROPHTHALMIA, SYNDROMIC 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893802 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893802;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=rs104893802" 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=rs104893802" 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=RCV000013665" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013665" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013665</a>
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<p>In a 6-year-old girl with microphthalmia, sclerocornea, and coloboma of the right eye, sclerocornea and aphakia of the left eye, a mild learning disability, and seizures (MCOPS3; <a href="/entry/206900">206900</a>), <a href="#36" class="mim-tip-reference" title="Ragge, N. K., Lorenz, B., Schneider, A., Bushby, K., de Sanctis, L., de Sanctis, U., Salt, A., Collin, J. R. O., Vivian, A. J., Free, S. L., Thompson, P., Williamson, K. A., Sisodiya, S. M., van Heyningen, V., FitzPatrick, D. R. <strong>SOX2 anophthalmia syndrome.</strong> Am. J. Med. Genet. 135A: 1-7, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15812812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15812812</a>] [<a href="https://doi.org/10.1002/ajmg.a.30642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15812812">Ragge et al. (2005)</a> identified heterozygosity for a de novo 290T-C transition in the SOX2 gene, resulting in a leu97-to-pro (L97P) substitution in the highly conserved HMG box of the protein. The mutation is predicted to cause loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15812812" 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 studies in Xenopus cells, <a href="#8" class="mim-tip-reference" title="Danno, H., Michiue, T., Hitachi, K., Yukita, A., Ishiura, S., Asashima, M. <strong>Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression.</strong> Proc. Nat. Acad. Sci. 105: 5408-5413, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18385377[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.0710954105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18385377">Danno et al. (2008)</a> demonstrated that the L97P mutation affected physical interaction between the SOX2 and OTX2 (<a href="/entry/600037">600037</a>) proteins and reduced induction of transcription of RAX (<a href="/entry/601881">601881</a>), another gene involved in eye development. Wildtype SOX2 potently bound to a conserved noncoding sequence 2 kb upstream of the RAX promoter, but L97P-mutant SOX2 did not. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18385377" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 MICROPHTHALMIA, SYNDROMIC 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104893803 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893803;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs104893803?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104893803" 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=rs104893803" 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=RCV000013666" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013666" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013666</a>
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<p>In a 12-year-old girl with bilateral clinical anophthalmia, mild bilateral sensorineural hearing loss, and global developmental delay (MCOPS3; <a href="/entry/206900">206900</a>), <a href="#16" class="mim-tip-reference" title="Hagstrom, S. A., Pauer, G. J. T., Reid, J., Simpson, E., Crowe, S., Maumenee, I. H., Traboulsi, E. I. <strong>SOX2 mutation causes anophthalmia, hearing loss, and brain anomalies.</strong> Am. J. Med. Genet. 138A: 95-98, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16145681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16145681</a>] [<a href="https://doi.org/10.1002/ajmg.a.30803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16145681">Hagstrom et al. (2005)</a> identified heterozygosity for a de novo 463C-T transition in the SOX2 gene, predicting a gln155-to-ter (Q155X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16145681" 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>.0006 MICROPHTHALMIA, SYNDROMIC 3</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013667" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013667" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013667</a>
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<p>In a patient with bilateral clinical anophthalmia, esophageal atresia, and glanular hypospadias (MCOPS3; <a href="/entry/206900">206900</a>), originally reported by <a href="#38" class="mim-tip-reference" title="Rogers, R. C. <strong>Unknown cases: S.C.B. (GGC-10079) 11 month old white male.</strong> Proc. Greenwood Genet. Center 7: 57 only, 1988."None>Rogers (1988)</a>, <a href="#49" class="mim-tip-reference" title="Williamson, K. A., Hever, A. M., Rainger, J., Rogers, R. C., Magee, A., Fiedler, Z., Keng, W. T., Sharkey, F. H., McGill, N., Hill, C. J., Schneider, A., Messina, M., Turnpenny, P. D., Fantes, J. A., van Heyningen, V., FitzPatrick, D. R. <strong>Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome.</strong> Hum. Molec. Genet. 15: 1413-1422, 2006. Note: Erratum: Hum. Molec. Genet. 15: 2030 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16543359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16543359</a>] [<a href="https://doi.org/10.1093/hmg/ddl064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16543359">Williamson et al. (2006)</a> identified heterozygosity for a 2.7-Mb deletion encompassing the SOX2 gene, extending from RP11-145M9 to RP11-296J4 and associated with a cryptic translocation t(3,7)(q28;p21.3). The deletion and translocation breakpoints on chromosome 3q are more than 8.6 Mb apart, and both chromosomal rearrangements occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16543359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 MICROPHTHALMIA, SYNDROMIC 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893804 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893804;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=rs104893804" 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=rs104893804" 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=RCV000013668" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013668" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013668</a>
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<p>In a male infant with bilateral clinical anophthalmia, esophageal atresia, duplication of the left kidney, and significant psychomotor delay (MCOPS3; <a href="/entry/206900">206900</a>), originally reported by <a href="#33" class="mim-tip-reference" title="Petrackova, I., Pozler, O., Kokstein, Z., Zizka, J., Dedkova, J., Rejtar, P., Fiedler, Z., Kuliacek, P. <strong>Association of oesophageal atresia, anophthalmia and renal duplex.</strong> Europ. J. Pediat. 163: 333-334, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15346919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15346919</a>] [<a href="https://doi.org/10.1007/s00431-004-1424-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15346919">Petrackova et al. (2004)</a>, <a href="#49" class="mim-tip-reference" title="Williamson, K. A., Hever, A. M., Rainger, J., Rogers, R. C., Magee, A., Fiedler, Z., Keng, W. T., Sharkey, F. H., McGill, N., Hill, C. J., Schneider, A., Messina, M., Turnpenny, P. D., Fantes, J. A., van Heyningen, V., FitzPatrick, D. R. <strong>Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome.</strong> Hum. Molec. Genet. 15: 1413-1422, 2006. Note: Erratum: Hum. Molec. Genet. 15: 2030 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16543359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16543359</a>] [<a href="https://doi.org/10.1093/hmg/ddl064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16543359">Williamson et al. (2006)</a> identified heterozygosity for a 163C-T transition in the SOX2 gene, resulting in a gln55-to-ter (Q55X) substitution with production of a protein truncated within the HMG domain and therefore with no DNA-binding or transactivation activity. The mutation was not found in either parent. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15346919+16543359" 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>.0008 MICROPHTHALMIA, SYNDROMIC 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893805 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893805;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=rs104893805" 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=rs104893805" 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=RCV000013669" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013669" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013669</a>
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<p>In a female infant with extreme bilateral microphthalmia and esophageal atresia (MCOPS3; <a href="/entry/206900">206900</a>), <a href="#49" class="mim-tip-reference" title="Williamson, K. A., Hever, A. M., Rainger, J., Rogers, R. C., Magee, A., Fiedler, Z., Keng, W. T., Sharkey, F. H., McGill, N., Hill, C. J., Schneider, A., Messina, M., Turnpenny, P. D., Fantes, J. A., van Heyningen, V., FitzPatrick, D. R. <strong>Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome.</strong> Hum. Molec. Genet. 15: 1413-1422, 2006. Note: Erratum: Hum. Molec. Genet. 15: 2030 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16543359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16543359</a>] [<a href="https://doi.org/10.1093/hmg/ddl064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16543359">Williamson et al. (2006)</a> identified heterozygosity for a 221G-C transversion, resulting in an arg74-to-pro (R74P) substitution. The authors noted that R74 is located within the HMG domain and is invariant in all known SOX2 genes and is conserved in all human SOX group B genes. The mutation was not found in either parent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16543359" 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 studies in Xenopus cells, <a href="#8" class="mim-tip-reference" title="Danno, H., Michiue, T., Hitachi, K., Yukita, A., Ishiura, S., Asashima, M. <strong>Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression.</strong> Proc. Nat. Acad. Sci. 105: 5408-5413, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18385377[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.0710954105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18385377">Danno et al. (2008)</a> demonstrated that the R74P mutation affected physical interaction between the SOX2 and OTX2 (<a href="/entry/600037">600037</a>) proteins and reduced induction of transcription of RAX (<a href="/entry/601881">601881</a>), another gene involved in eye development. Wildtype SOX2 potently bound to a conserved noncoding sequence 2 kb upstream of the RAX promoter, but R74P-mutant SOX2 did not. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18385377" 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">rs104893806 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893806;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=rs104893806" 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=rs104893806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a female infant with bilateral clinical anophthalmos, very narrow palpebral fissures with synechiae, microcephaly, and psychomotor retardation (MCOPS3; <a href="/entry/206900">206900</a>), <a href="#13" class="mim-tip-reference" title="Faivre, L., Williamson, K. A., Faber, V., Laurent, N., Grimaldi, M., Thauvin-Robinet, C., Durand, C., Mugneret, F., Gouyon, J.-B., Bron, A., Huet, F., Hayward, C., van Heyningen, V., FitzPatrick, D. R. <strong>Recurrence of SOX2 anophthalmia syndrome with gonosomal mosaicism in a phenotypically normal mother. (Letter)</strong> Am. J. Med. Genet. 140A: 636-639, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16470798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16470798</a>] [<a href="https://doi.org/10.1002/ajmg.a.31114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16470798">Faivre et al. (2006)</a> identified heterozygosity for a 138T-G transversion in the SOX2 gene, resulting in an asn46-to-lys (N46K) substitution predicted to alter a critical residue in the HMG box domain. The unaffected mother was also found to be heterozygous for the mutation; restriction enzyme digestion products were always lower in the mother than the proband, consistent with a lower level of mutant allele in the mother due to somatic mosaicism. An earlier pregnancy had been terminated due to severe hydrocephaly; examination of the fetus had revealed left cryptophthalmos, bilateral clinical anophthalmos, and multiple brain abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16470798" 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">rs398123693 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398123693;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=rs398123693" 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=rs398123693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 11-month-old Mexican girl with bilateral clinical anophthalmia, mild facial dysmorphism, and developmental delay (MCOPS3; <a href="/entry/206900">206900</a>), <a href="#52" class="mim-tip-reference" title="Zenteno, J. C., Gascon-Guzman, G., Tovilla-Canales, J. L. <strong>Bilateral anophthalmia and brain malformations caused by a 20-bp deletion in the SOX2 gene. (Letter)</strong> Clin. Genet. 68: 564-566, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16283891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16283891</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00518.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16283891">Zenteno et al. (2005)</a> identified heterozygosity for a 20-bp deletion at nucleotide 70 (70del20) of the SOX2 gene, resulting in a frameshift upstream of the HMG box and a premature termination signal 65 codons downstream. The authors noted that the deleted segment was flanked by the short GGCGGC repeat sequence, suggesting slipped-strand misrepairing as the origin of the deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16283891" 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 male monozygotic twins with ocular defects, esophageal atresia, and genital abnormalities, <a href="#53" class="mim-tip-reference" title="Zenteno, J. C., Perez-Cano, H. J., Aguinaga, M. <strong>Anophthalmia-esophageal atresia syndrome caused by an SOX2 gene deletion in monozygotic twin brothers with markedly discordant phenotypes.</strong> Am. J. Med. Genet. 140A: 1899-1903, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16892407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16892407</a>] [<a href="https://doi.org/10.1002/ajmg.a.31384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16892407">Zenteno et al. (2006)</a> identified heterozygosity for the 70del20 mutation in the SOX2 gene. Both infants had tracheoesophageal fistula, but otherwise exhibited a discordant phenotype: 1 twin had left clinical anophthalmia and bilateral cryptorchidism, whereas the other had normal globes, narrowing of the right palpebral fissure, and no genital abnormalities. The authors stated that this was the first reported case of SOX2 mutation causing a unilateral eye defect and the first example of monozygotic twins discordant for anophthalmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16892407" 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 22-year-old female with left clinical anophthalmia and right microphthalmia, learning difficulties, and primary amenorrhea, <a href="#20" class="mim-tip-reference" title="Kelberman, D., Rizzoti, K., Avilion, A., Bitner-Glindicz, M., Cianfarani, S., Collins, J., Chong, W. K., Kirk, J. M. W., Achermann, J. C., Ross, R., Carmignac, D., Lovell-Badge, R., Robinson, I. C. A. F., Dattani, M. T. <strong>Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.</strong> J. Clin. Invest. 116: 2442-2455, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16932809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16932809</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16932809[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI28658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16932809">Kelberman et al. (2006)</a> identified heterozygosity for a de novo 70del20 mutation in the SOX2 gene. Brain MRI revealed an abnormal hypoplastic pituitary gland in a small sella turcica with an absent left eye and optic nerve. Functional analysis of the mutant protein revealed impaired nuclear localization, DNA binding, and transcriptional activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16932809" 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="#19" class="mim-tip-reference" title="Kelberman, D., de Castro, S. C. P., Huang, S., Crolla, J. A., Palmer, R., Gregory, J. W., Taylor, D., Cavallo, L., Faienza, M. F., Fischetto, R., Achermann, J. C., Martinez-Barbera, J. P., Rizzoti, K., Lovell-Badge, R., Robinson, I. C. A. F., Gerrelli, D., Dattani, M. T. <strong>SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development.</strong> J. Clin. Endocr. Metab. 93: 1865-1873, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285410</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18285410[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/10.1210/jc.2007-2337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285410">Kelberman et al. (2008)</a> identified this deletion (70_89del) in a 14.5-year-old girl who presented with bilateral anophthalmia at birth. Brain MRI showed an arachnoid cyst in the suprasellar area, with right deflection of the pituitary pedunculus. She later developed gonadotropin deficiency with low basal gonadotropin concentrations and poor response to gonadotropin-releasing hormone (GNRH; <a href="/entry/152760">152760</a>) stimulation. There was no evidence of learning difficulties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18285410" 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 girl and 2 boys with bilateral clinical anophthalmia or severe microphthalmia, <a href="#40" class="mim-tip-reference" title="Schneider, A., Bardakjian, T., Reis, L. M., Tyler, R. C., Semina, E. V. <strong>Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia.</strong> Am. J. Med. Genet. 149A: 2706-2715, 2009. Note: Erratum: Am. J. Med. Genet. 158A: 267 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19921648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19921648</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19921648[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.33098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19921648">Schneider et al. (2009)</a> identified the 70del20 mutation in the SOX2 gene. All 3 patients had developmental delay. Neuroimaging showed a hamartoma of the tuber cinereum in the 2-year-old girl, but was normal in the other 2 patients; none had pituitary anomalies. The 2 boys displayed genital anomalies, including micropenis, cryptorchidism, and foreskin adhesion. Other features seen in the 2 boys included a heart murmur in 1 patient and 2-3 toe syndactyly, febrile seizures, and mild pectus excavatum in the other. The girl had a half-sister with unilateral clinical anophthalmia and mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19921648" 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">rs398122803 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122803;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=rs398122803" 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=rs398122803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 13-year-old girl with bilateral clinical anophthalmia, learning difficulties, spastic diplegia, and a history of esophageal atresia (MCOPS3; <a href="/entry/206900">206900</a>), previously reported by <a href="#26" class="mim-tip-reference" title="Morini, F., Pacilli, M., Spitz, L. <strong>Bilateral anophthalmia and esophageal atresia: report of a new patient and review of the literature. (Letter)</strong> Am. J. Med. Genet. 132A: 60-62, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15389708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15389708</a>] [<a href="https://doi.org/10.1002/ajmg.a.30283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15389708">Morini et al. (2005)</a>, <a href="#20" class="mim-tip-reference" title="Kelberman, D., Rizzoti, K., Avilion, A., Bitner-Glindicz, M., Cianfarani, S., Collins, J., Chong, W. K., Kirk, J. M. W., Achermann, J. C., Ross, R., Carmignac, D., Lovell-Badge, R., Robinson, I. C. A. F., Dattani, M. T. <strong>Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.</strong> J. Clin. Invest. 116: 2442-2455, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16932809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16932809</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16932809[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI28658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16932809">Kelberman et al. (2006)</a> identified heterozygosity for a 1-bp insertion (60insG) in the SOX2 gene, predicted to result in a truncation at codon 95 that completely removes the HMG box. Pelvic ultrasound revealed small ovaries and an infantile uterus, suggesting a diagnosis of hypogonadotropic hypogonadism. Brain MRI revealed hippocampal abnormalities with anterior pituitary hypoplasia, hypothalamic hamartoma, small corpus callosum, generalized reduction of white matter, and absent optic nerves. Functional analysis of the mutant protein revealed impaired nuclear localization, DNA binding, and transcriptional activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16932809+15389708" 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>.0012 OPTIC NERVE HYPOPLASIA AND ABNORMALITIES OF THE CENTRAL NERVOUS SYSTEM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918652 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918652;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121918652?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918652" 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=rs121918652" 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=RCV000013673 OR RCV003227462" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013673, RCV003227462" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013673...</a>
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<p>In an 11-year-old girl with roving eye movements, severe visual impairment, bilateral optic nerve hypoplasia, developmental delay, short stature, and spastic diplegia (see <a href="/entry/206900">206900</a>), <a href="#20" class="mim-tip-reference" title="Kelberman, D., Rizzoti, K., Avilion, A., Bitner-Glindicz, M., Cianfarani, S., Collins, J., Chong, W. K., Kirk, J. M. W., Achermann, J. C., Ross, R., Carmignac, D., Lovell-Badge, R., Robinson, I. C. A. F., Dattani, M. T. <strong>Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.</strong> J. Clin. Invest. 116: 2442-2455, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16932809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16932809</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16932809[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI28658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16932809">Kelberman et al. (2006)</a> identified heterozygosity for a 389G-C transversion in the SOX2 gene, resulting in a gly130-to-ala (G130A) substitution. Brain MRI revealed an absent septum pellucidum, bilateral optic nerve hypoplasia, bilateral schizencephaly, right porencephalic cyst, and normal anterior and posterior pituitary. A brother died at age 11 years with hydranencephaly. The mutation was inherited from her phenotypically normal father; the mutation was not found in 100 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16932809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 OPTIC NERVE HYPOPLASIA AND ABNORMALITIES OF THE CENTRAL NERVOUS SYSTEM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104893808 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893808;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs104893808?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104893808" 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=rs104893808" 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=RCV000013674 OR RCV000624040 OR RCV002513019" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013674, RCV000624040, RCV002513019" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013674...</a>
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<p>In a 2-year-old girl who was hypoglycemic at birth and noted to have roving eye movements and bilateral optic nerve hypoplasia (see <a href="/entry/206900">206900</a>), <a href="#20" class="mim-tip-reference" title="Kelberman, D., Rizzoti, K., Avilion, A., Bitner-Glindicz, M., Cianfarani, S., Collins, J., Chong, W. K., Kirk, J. M. W., Achermann, J. C., Ross, R., Carmignac, D., Lovell-Badge, R., Robinson, I. C. A. F., Dattani, M. T. <strong>Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.</strong> J. Clin. Invest. 116: 2442-2455, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16932809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16932809</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16932809[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI28658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16932809">Kelberman et al. (2006)</a> identified heterozygosity for a 571G-A transition in the SOX2 gene, resulting in an ala191-to-thr (A191T) substitution. Brain MRI revealed an absent septum pellucidum, small optic chiasm, absent infundibulum, severe hypoplasia of the anterior pituitary, and an ectopic or undescended posterior pituitary. Endocrine evaluation revealed deficiencies in growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone. The mutation was inherited from her phenotypically normal father; the mutation was not found in 100 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16932809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 MICROPHTHALMIA, SYNDROMIC 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1553862927 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553862927;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=rs1553862927" 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=rs1553862927" 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=RCV000622595 OR RCV002307563 OR RCV004719905" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000622595, RCV002307563, RCV004719905" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000622595...</a>
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<p>In 2 female sibs with syndromid microphthalmia (MCOPS3; <a href="/entry/206900">206900</a>), 1 of whom was previously reported by <a href="#25" class="mim-tip-reference" title="Menetrey, C., Belin, V., Odent, S., de Lumley, L., Gilbert, B. <strong>Bilateral anophthalmia and oesophageal atresia in a newborn female: a new case of the anophthalmia-oesophageal-genital (AEG) syndrome.</strong> Clin. Dysmorph. 11: 139-140, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12002146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12002146</a>] [<a href="https://doi.org/10.1097/00019605-200204000-00013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12002146">Menetrey et al. (2002)</a>, <a href="#6" class="mim-tip-reference" title="Chassaing, N., Gilbert-Dussardier, B., Nicot, F., Fermeaux, V., Encha-Razavi, F., Fiorenza, M., Toutain, A., Calvas, P. <strong>Germinal mosaicism and familial recurrence of a SOX2 mutation with highly variable phenotypic expression extending from AEG syndrome to absence of ocular involvement.</strong> Am. J. Med. Genet. 143A: 289-291, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17219395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17219395</a>] [<a href="https://doi.org/10.1002/ajmg.a.31524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17219395">Chassaing et al. (2007)</a> identified heterozygosity for a 17-bp deletion (70del17) in the SOX2 gene, predicted to cause a frameshift resulting in a premature termination signal at codon 66. The first sib had bilateral anophthalmia and esophageal atresia. During the mother's subsequent pregnancy, the fetus showed severe and progressive triventricular hydrocephalus on ultrasound, and the pregnancy was interrupted. Autopsy showed stenosis of the Sylvian aqueduct, and hypoplasia of the corpus callosum, but age-appropriate ocular length and normal external and microscopic ocular examination. The mother was found to have germinal mosaicism for the mutation, estimated at approximately 3%. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17219395+12002146" 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">rs587776776 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776776;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=rs587776776" 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=rs587776776" 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=RCV000013676" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013676" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013676</a>
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<p>In 2 sisters with bilateral clinical anophthalmia/microphthalmia and brain anomalies (MCOPS3; <a href="/entry/206900">206900</a>), <a href="#39" class="mim-tip-reference" title="Schneider, A., Bardakjian, T. M., Zhou, J., Hughes, N., Keep, R., Dorsainville, D., Kherani, F., Katowitz, J., Schimmenti, L. A., Hummel, M., FitzPatrick, D. R., Young, T. L. <strong>Familial recurrence of SOX2 anophthalmia syndrome: phenotypically normal mother with two affected daughters.</strong> Am. J. Med. Genet. 146A: 2794-2798, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18831064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18831064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18831064[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.32384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18831064">Schneider et al. (2008)</a> identified heterozygosity for a 1-bp deletion (551delC) in the SOX2 gene, predicted to cause a frameshift and premature termination resulting in a nonfunctional protein. The unaffected mother, who had 2 healthy older children, was found to have a reduced signal for the deletion in peripheral blood and buccal cell DNA, confirming somatic mosaicism; the mutation was not found in the maternal grandparents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18831064" 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>.0016 MICROPHTHALMIA, SYNDROMIC 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122803 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122803;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=rs398122803" 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=rs398122803" 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=RCV000022771" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022771" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022771</a>
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<p>In a 6-month-old Italian boy with clinical anophthalmia and severe microphthalmia of the right and left eyes, respectively, associated with micropenis (MCOPS3; <a href="/entry/206900">206900</a>), <a href="#32" class="mim-tip-reference" title="Pedace, L., Castori, M., Binni, F., Pingi, A., Grammatico, B., Scommegna, S., Majore, S., Grammatico, P. <strong>A novel heterozygous SOX2 mutation causing anophthalmia/microphthalmia with genital anomalies. (Letter)</strong> Europ. J. Med. Genet. 52: 273-276, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19254784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19254784</a>] [<a href="https://doi.org/10.1016/j.ejmg.2009.02.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19254784">Pedace et al. (2009)</a> identified heterozygosity for a de novo 2-bp insertion (60insGG) in the SOX2 gene, causing a frameshift resulting in a premature termination codon that was predicted to cause loss of 94% of the encoded protein. The mutation was not detected in the patient's unaffected second-cousin parents or in his unaffected dizygotic twin, and was not found in 200 control chromosomes. Repeated endocrinologic evaluation and brain MRI in this patient did not reveal any morphologic or functional anomaly of the hypothalamic-pituitary axis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19254784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0017 MICROPHTHALMIA, SYNDROMIC 3</strong>
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SOX2, LEU82TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906688 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906688;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=rs387906688" 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=rs387906688" 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=RCV000022772" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022772" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022772</a>
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<p>In a 21-year-old Japanese man with bilateral clinical anophthalmia, hypogonadotropic hypogonadism, seizures, spastic diplegia, intellectual disability, and dental anomalies including multiple supernumerary impacted teeth, <a href="#27" class="mim-tip-reference" title="Numakura, C., Kitanaka, S., Kato, M., Ishikawa, S., Hamamoto, Y., Katsushima, Y., Kimura, T., Hayasaka, K. <strong>Supernumerary impacted teeth in a patient with SOX2 anophthalmia syndrome.</strong> Am. J. Med. Genet. 152A: 2355-2359, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20803647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20803647</a>] [<a href="https://doi.org/10.1002/ajmg.a.33556" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20803647">Numakura et al. (2010)</a> identified heterozygosity for a 245T-A transversion in the SOX2 gene, resulting in a leu82-to-ter (L82X) substitution, predicted to produce a protein truncated within the HMG domain that would lack DNA-binding and transactivation activity. The patient's mother did not carry the mutation; DNA from the father was not available. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20803647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0018 MICROPHTHALMIA, SYNDROMIC 3</strong>
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SOX2, PHE48TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122915 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122915;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=rs398122915" 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=rs398122915" 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=RCV000033025" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033025" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033025</a>
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<p>In a male infant born with bilateral clinical anophthalmia who was referred for evaluation of micropenis (MCOPS3; <a href="/entry/206900">206900</a>), <a href="#1" class="mim-tip-reference" title="Alatzoglou, K. S., Andoniadou, C. L., Kelberman, D., Buchanan, C. R., Crolla, J., Arriazu, M. C., Roubicek, M., Moncet, D., Martinez-Barbera, J. P., Dattani, M. T. <strong>SOX2 haploinsufficiency is associated with slow progressing hypothalamo-pituitary tumours.</strong> Hum. Mutat. 32: 1376-1380, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21919124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21919124</a>] [<a href="https://doi.org/10.1002/humu.21606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21919124">Alatzoglou et al. (2011)</a> identified heterozygosity for a 143TC-AA change in the SOX2 gene, resulting in a phe48-to-ter (F48X) substitution that was predicted to generate a truncated protein lacking most of the HMG domain and the C-terminal domain. DNA from the parents was unavailable. Immunostaining of transfected HEK293T cells showed mainly cytoplasmic localization of the mutant compared to the nuclear localization of wildtype protein, and luciferase expression studies showed only a 1.59-fold activation of the basal reporter activity with the F48X mutant compared to a 3.31-fold increase with wildtype. In addition, the mutant failed to suppress beta-catenin (<a href="/entry/116806">116806</a>) transcriptional activity in vitro, whereas it was significantly reduced by wildtype SOX2. Examination at 17 months of age revealed a stretched penile length of 2.5 cm and a hypoplastic scrotum with testes of 0.5 to 1.0 ml palpable high in the scrotal sacs. Endocrine evaluation showed low IGF1 (<a href="/entry/147440">147440</a>), and the testosterone response to a 3-week hCG test was consistent with hypogonadotropic hypogonadism. MRI at 17 months of age revealed a pituitary mass with a cystic component extending to the suprasellar area, and review of an MRI from the neonatal period, which was thought to have been normal apart from absent prechiasmatic optic nerves, showed that the mass had been present at that stage. A follow-up MRI at 32 months of age demonstrated only a modest increase in size of the mass. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21919124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0019 MICROPHTHALMIA, SYNDROMIC 3</strong>
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SOX2, 1-BP DEL, 837C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs398122916 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122916;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs398122916?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs398122916" 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=rs398122916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000033026" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033026" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033026</a>
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<p>In an 8-year-old boy with bilateral clinical anophthalmia and endocrinologic abnormalities (MCOPS3; <a href="/entry/206900">206900</a>) and his sister who had only unilateral microphthalmia, <a href="#42" class="mim-tip-reference" title="Stark, Z., Storen, R., Bennetts, B., Savarirayan, R., Jamieson, R. V. <strong>Isolated hypogonadotropic hypogonadism with SOX2 mutation and anophthalmia/microphthalmia in offspring.</strong> Europ. J. Hum. Genet. 19: 753-756, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21326281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21326281</a>] [<a href="https://doi.org/10.1038/ejhg.2011.11" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21326281">Stark et al. (2011)</a> identified heterozygosity for a 1-bp deletion (837delC) in the SOX2 gene, predicted to cause a frameshift and addition of 90 abnormal C-terminal residues (Gly208AlafsTer91). The boy had transient growth and growth hormone disturbances in infancy, but was not dysmorphic and had descended testes with a normal phallus; subsequently his growth normalized and pituitary function was normal on yearly monitoring. MRI of the brain at 1 year of age showed no eye remnants and absent optic nerves, an intact corpus callosum and a normal pituitary, but a dysplastic right hippocampus. His 8-month-old sister had left microphthalmia and a large left retinal coloboma, but no associated anomalies or dysmorphic features. Their mother, who had been evaluated at 18 years of age for primary amenorrhea and limited development of secondary sexual characteristics and was diagnosed with isolated hypogonadotropic hypogonadism, had a normal sense of smell, no dysmorphism, and a normal ophthalmologic examination. Sequencing results from the mother's lymphocyte DNA showed the presence of the mutation but at lower levels compared to her children, suggesting possible mosaicism. The unaffected father's sequencing results were normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21326281" 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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Alatzoglou, K. S., Andoniadou, C. L., Kelberman, D., Buchanan, C. R., Crolla, J., Arriazu, M. C., Roubicek, M., Moncet, D., Martinez-Barbera, J. P., Dattani, M. T.
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<strong>SOX2 haploinsufficiency is associated with slow progressing hypothalamo-pituitary tumours.</strong>
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Hum. Mutat. 32: 1376-1380, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21919124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21919124</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21919124" 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.21606" target="_blank">Full Text</a>]
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Bass, A. J., Watanabe, H., Mermel, C. H., Yu, S., Perner, S., Verhaak, R. G., Kim, S. Y., Wardwell, L., Tamayo, P., Gat-Viks, I., Ramos, A. H., Woo, M. S., and 36 others.
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<strong>SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas.</strong>
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Nature Genet. 41: 1238-1242, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19801978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19801978</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19801978[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=19801978" 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/ng.465" target="_blank">Full Text</a>]
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Boumahdi, S., Driessens, G., Lapouge, G., Rorive, S., Nassar, D., Le Mercier, M., Delatte, B., Caauwe, A., Lenglez, S., Nkusi, E., Brohee, S., Salmon, I., Dubois, C., del Marmol, V., Fuks, F., Beck, B., Blanpain, C.
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<strong>SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma.</strong>
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Nature 511: 246-250, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24909994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24909994</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24909994" 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/nature13305" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2007-2337" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI28658" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature03487" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ncb1589" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1151526" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="52" class="mim-anchor"></a>
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<a id="Zenteno2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
|
Zenteno, J. C., Gascon-Guzman, G., Tovilla-Canales, J. L.
|
|
<strong>Bilateral anophthalmia and brain malformations caused by a 20-bp deletion in the SOX2 gene. (Letter)</strong>
|
|
Clin. Genet. 68: 564-566, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16283891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16283891</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16283891" 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/10.1111/j.1399-0004.2005.00518.x" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="53" class="mim-anchor"></a>
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<a id="Zenteno2006" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Zenteno, J. C., Perez-Cano, H. J., Aguinaga, M.
|
|
<strong>Anophthalmia-esophageal atresia syndrome caused by an SOX2 gene deletion in monozygotic twin brothers with markedly discordant phenotypes.</strong>
|
|
Am. J. Med. Genet. 140A: 1899-1903, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16892407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16892407</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16892407" 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.31384" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="54" class="mim-anchor"></a>
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<a id="Zhang2019" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Zhang, C., Leng, F., Saxena, L., Hoang, N., Yu, J., Alejo, S., Lee, L., Qi, D., Lu, F., Sun, H., Zhang, H.
|
|
<strong>Proteolysis of methylated SOX2 protein is regulated by L3MBTL3 and CRL4-DCAF5 ubiquitin ligase.</strong>
|
|
J. Biol. Chem. 294: 476-489, 2019.
|
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30442713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30442713</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30442713" 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/10.1074/jbc.RA118.005336" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 06/08/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 04/08/2020<br>Bao Lige - updated : 03/22/2019<br>Patricia A. Hartz - updated : 04/01/2016<br>Ada Hamosh - updated : 8/28/2014<br>Ada Hamosh - updated : 12/5/2013<br>Marla J. F. O'Neill - updated : 11/21/2012<br>Marla J. F. O'Neill - updated : 11/20/2012<br>Marla J. F. O'Neill - updated : 6/12/2012<br>Marla J. F. O'Neill - updated : 9/22/2011<br>Patricia A. Hartz - updated : 8/31/2011<br>Ada Hamosh - updated : 6/29/2011<br>Marla J. F. O'Neill - updated : 4/15/2011<br>Ada Hamosh - updated : 1/7/2011<br>Ada Hamosh - updated : 2/16/2010<br>Ada Hamosh - updated : 1/12/2010<br>Marla J. F. O'Neill - updated : 8/31/2009<br>Ada Hamosh - updated : 4/28/2009<br>John A. Phillips, III - updated : 1/14/2009<br>Ada Hamosh - updated : 12/30/2008<br>Ada Hamosh - updated : 11/26/2008<br>Marla J. F. O'Neill - updated : 6/6/2008<br>Patricia A. Hartz - updated : 3/3/2008<br>Patricia A. Hartz - updated : 2/7/2008<br>Ada Hamosh - updated : 1/23/2008<br>Ada Hamosh - updated : 8/29/2007<br>Marla J. F. O'Neill - updated : 7/2/2007<br>Marla J. F. O'Neill - updated : 1/19/2007<br>Patricia A. Hartz - updated : 11/1/2006<br>Marla J. F. O'Neill - updated : 10/25/2006<br>Victor A. McKusick - updated : 9/13/2006<br>Marla J. F. O'Neill - updated : 7/27/2006<br>Patricia A. Hartz - updated : 6/23/2006<br>Marla J. F. O'Neill - updated : 6/20/2006<br>Marla J. F. O'Neill - updated : 4/26/2006<br>Marla J. F. O'Neill - updated : 4/20/2006<br>Marla J. F. O'Neill - updated : 11/7/2005<br>Marla J. F. O'Neill - updated : 5/23/2005<br>Ada Hamosh - updated : 5/3/2005<br>Cassandra L. Kniffin - updated : 10/3/2003<br>Victor A. McKusick - updated : 3/19/2003<br>Victor A. McKusick - updated : 8/18/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
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Creation Date:
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Victor A. McKusick : 4/14/1994
|
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
|
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 06/08/2020
|
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</span>
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</div>
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</div>
|
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<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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mgross : 04/08/2020<br>carol : 12/26/2019<br>carol : 06/28/2019<br>mgross : 03/22/2019<br>carol : 01/19/2018<br>carol : 08/11/2016<br>joanna : 08/04/2016<br>mgross : 04/01/2016<br>mgross : 4/30/2015<br>alopez : 8/28/2014<br>alopez : 8/28/2014<br>alopez : 12/5/2013<br>carol : 9/17/2013<br>carol : 11/21/2012<br>terry : 11/21/2012<br>alopez : 11/20/2012<br>terry : 11/20/2012<br>alopez : 6/13/2012<br>terry : 6/12/2012<br>terry : 6/12/2012<br>carol : 9/23/2011<br>terry : 9/22/2011<br>mgross : 8/31/2011<br>terry : 8/31/2011<br>alopez : 7/5/2011<br>terry : 6/29/2011<br>wwang : 4/19/2011<br>terry : 4/15/2011<br>alopez : 1/7/2011<br>terry : 4/2/2010<br>alopez : 3/2/2010<br>terry : 2/16/2010<br>alopez : 1/12/2010<br>carol : 9/2/2009<br>terry : 8/31/2009<br>terry : 4/28/2009<br>alopez : 1/14/2009<br>alopez : 12/31/2008<br>terry : 12/30/2008<br>alopez : 12/29/2008<br>alopez : 12/9/2008<br>alopez : 12/9/2008<br>terry : 11/26/2008<br>alopez : 10/21/2008<br>wwang : 6/9/2008<br>terry : 6/6/2008<br>terry : 6/6/2008<br>terry : 6/6/2008<br>mgross : 3/3/2008<br>mgross : 3/3/2008<br>mgross : 2/20/2008<br>terry : 2/7/2008<br>alopez : 2/4/2008<br>terry : 1/23/2008<br>alopez : 9/7/2007<br>alopez : 9/7/2007<br>terry : 8/29/2007<br>wwang : 7/9/2007<br>terry : 7/2/2007<br>carol : 1/22/2007<br>terry : 1/19/2007<br>mgross : 11/2/2006<br>terry : 11/1/2006<br>wwang : 10/26/2006<br>terry : 10/25/2006<br>alopez : 9/14/2006<br>terry : 9/13/2006<br>wwang : 8/1/2006<br>terry : 7/27/2006<br>mgross : 6/26/2006<br>mgross : 6/26/2006<br>terry : 6/23/2006<br>wwang : 6/22/2006<br>terry : 6/20/2006<br>carol : 4/26/2006<br>carol : 4/26/2006<br>carol : 4/20/2006<br>terry : 4/20/2006<br>wwang : 11/7/2005<br>wwang : 10/31/2005<br>wwang : 5/31/2005<br>terry : 5/23/2005<br>alopez : 5/10/2005<br>alopez : 5/10/2005<br>terry : 5/3/2005<br>terry : 7/27/2004<br>alopez : 10/31/2003<br>carol : 10/3/2003<br>ckniffin : 10/3/2003<br>alopez : 4/2/2003<br>alopez : 3/21/2003<br>terry : 3/19/2003<br>carol : 9/8/1999<br>terry : 8/23/1999<br>terry : 8/18/1999<br>dkim : 12/4/1998<br>alopez : 7/10/1997<br>mark : 6/25/1996<br>carol : 11/28/1994<br>warfield : 4/14/1994
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
|
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<strong>*</strong> 184429
|
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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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|
|
SRY-BOX 2; SOX2
|
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</span>
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</h3>
|
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
|
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<p>
|
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
SRY-RELATED HMG-BOX GENE 2
|
|
</span>
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: SOX2</em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
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<p>
|
|
<span class="mim-text-font">
|
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|
|
<strong>SNOMEDCT:</strong> 698851003;
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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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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: 3q26.33
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 3:181,711,925-181,714,436 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
|
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
3q26.33
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Microphthalmia, syndromic 3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
206900
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
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|
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|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Optic nerve hypoplasia and abnormalities of the central nervous system
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
206900
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
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|
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|
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|
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</tbody>
|
|
</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>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Stevanovic et al. (1994) found that the SOX2 gene encodes a 317-amino acid protein. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Family</strong>
|
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</span>
|
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</h4>
|
|
</div>
|
|
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|
|
<span class="mim-text-font">
|
|
<p>See SOX1 (602148) for a discussion of the SOX gene family.</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Genetic analysis by Fantes et al. (2003) indicated that the single-exon SOX2 gene lies in an intron of the SOX2OT gene (616338), which is transcribed in the same orientation. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>By fluorescence in situ hybridization, Stevanovic et al. (1994) assigned the SOX2 gene to chromosome 3q26.3-q27. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
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|
<div>
|
|
<h4>
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<strong>Gene Function</strong>
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</h4>
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<p>In developing chick spinal cord, Bylund et al. (2003) found that Sox1 (602148), Sox2, and Sox3 (313430) were coexpressed in self-renewing progenitor cells and acted to inhibit neuronal differentiation. Active repression of the Sox genes promoted neural progenitor cells to initiate differentiation prematurely. Further studies showed that the ability of the proneural transcription factor neurogenin-2 (NEUROG2; 606624) to promote neuronal differentiation was based on its ability to suppress Sox gene expression, thus showing that neurogenesis is regulated by an interplay between proneural proteins and inhibitory proteins. </p><p>Hever et al. (2006) reviewed the expression patterns and complex interactions of 3 genes associated with the development of the eye, SOX2, OTX2 (600037), and PAX6 (607108), noting that these interactions may explain the significant phenotypic overlap between mutations at these 3 loci. </p><p>Okubo et al. (2006) reported that Sox2 is required for development of taste bud sensory cells in mouse. </p><p>Induced pluripotent stem (iPS) cells can be generated from mouse fibroblasts by retrovirus-mediated introduction of 4 transcription factors, Oct3/4 (164177), Sox2, c-Myc (190080), and Klf4 (602253), and subsequent selection for Fbx15 (609093) expression (Takahashi and Yamanaka, 2006). These iPS cells, hereafter called Fbx15 iPS cells, are similar to embryonic stem (ES) cells in morphology, proliferation, and teratoma formation; however, they are different with regard to gene expression and DNA methylation patterns, and fail to produce adult chimeras. Okita et al. (2007) showed that selection for Nanog (607937) expression results in germline-competent iPS cells with increased ES cell-like gene expression and DNA methylation patterns compared with Fbx15 iPS cells. The 4 transgenes were strongly silenced in Nanog iPS cells. </p><p>Wernig et al. (2007) independently demonstrated that the transcription factors Oct4, Sox2, c-Myc, and Klf4 can induce epigenetic reprogramming of a somatic genome to an embryonic pluripotent state. In contrast to selection for Fbx15 activation (Takahashi and Yamanaka, 2006), fibroblasts that had reactivated the endogenous Oct4 (Oct4-neo) or Nanog (Nanog-neo) loci grew independently of feeder cells, expressed normal Oct4, Nanog, and Sox2 RNA and protein levels, were epigenetically identical to ES cells by a number of criteria, and were able to generate viable chimeras, contribute to the germline, and generate viable late-gestation embryos after injection into tetraploid blastocysts. Transduction of the 4 factors generated significantly more drug-resistant cells from Nanog-neo than from Oct4-neo fibroblasts, but a higher fraction of Oct4-selected cells had all the characteristics of pluripotent ES cells, suggesting that Nanog activation is a less stringent criterion for pluripotency than Oct4 activation. </p><p>Yu et al. (2007) showed that 4 factors, OCT4, SOX2, NANOG, and LIN28 (611043), are sufficient to reprogram human somatic cells to pluripotent stem cells that exhibit the essential characteristics of embryonic stem cells. These induced pluripotent human stem cells have normal karyotypes, express telomerase (see 602322) activity, express cell surface markers and genes that characterize human ES cells, and maintain the developmental potential to differentiate into advanced derivatives of all 3 primary germ layers. </p><p>Using Oct4, Sox2, Klf4, and Myc, Park et al. (2008) derived iPS cells from fetal, neonatal, and adult human primary cells, including dermal fibroblasts isolated from a skin biopsy of a healthy research subject. Human iPS cells resemble embryonic stem cells in morphology and gene expression and in the capacity to form teratomas in immune-deficient mice. Park et al. (2008) concluded that defined factors can reprogram human cells to pluripotency, and they established a method whereby patient-specific cells might be established in culture. </p><p>Masui et al. (2007) found that Sox2 was indispensable for maintaining embryonic stem (ES) cell pluripotency, since Sox2-null mouse ES cells differentiated primarily into trophectoderm-like cells. However, Sox2 was not required for activation of Oct-Sox enhancers. Microarray analysis showed that Sox2 regulates multiple transcription factors that affect Oct3/4 expression. Forced expression of Oct3/4 rescued the pluripotency of Sox2-null ES cells. Masui et al. (2007) concluded that SOX2 regulates OCT3/4 expression and maintains ES pluripotency through upstream transcription factors. </p><p>In studies in Xenopus oocytes, Danno et al. (2008) demonstrated specific binding of endogenous OTX2 and SOX2 proteins to a conserved noncoding sequence (CNS1) located approximately 2 kb upstream of the RAX (601881) promoter; reporter assays in Xenopus and HEK93T cells revealed that OTX2 and SOX2 synergistically activated RAX transcription via CNS1. GST pull-down and coimmunoprecipitation assays showed that OTX2 and SOX2 physically interacted, and this interaction was affected by missense mutations located in helices 2 and 3 of the SOX2 HMG domain (R74P, 184429.0008; L97P, 184429.0004, respectively), resulting in reduced induction of transcription via RAX CNS1. Danno et al. (2008) concluded that direct interaction between OTX2 and SOX2 proteins </p><p>Stadtfeld et al. (2008) generated mouse iPS cells from fibroblasts and liver cells by using nonintegrating adenoviruses transiently expressing Oct4, Sox2, Klf4, and c-Myc. These adenoviral iPS cells showed DNA demethylation characteristic of reprogrammed cells, expressed endogenous pluripotency genes, formed teratomas, and contributed to multiple tissues, including the germ cell line, in chimeric mice. Stadtfeld et al. (2008) concluded that their results provided strong evidence that insertional mutagenesis is not required for in vitro reprogramming. </p><p>Okita et al. (2008) independently reported the generation of mouse iPS cells without viral vectors. Repeated transfection of 2 expression plasmids, one containing the cDNAs of Oct3/4, Sox2, and Klf4 and the other containing the c-Myc cDNA, into mouse embryonic fibroblasts resulted in iPS cells without evidence of plasmid integration, which produced teratomas when transplanted into mice and contributed to adult chimeras. Okita et al. (2008) concluded that the production of virus-free iPS cells, albeit from embryonic fibroblasts, addresses a critical safety concern for potential use of iPS cells in regenerative medicine. </p><p>Hanna et al. (2009) demonstrated that the reprogramming by Oct4, Sox2, Klf4, and Myc transcription factors is a continuous stochastic process where almost all mouse donor cells eventually give rise to induced pluripotent stem (iPS) cells on continued growth and transcription factor expression. Additional inhibition of the p53 (191170)/p21 (116899) pathway or overexpression of Lin28 (611043) increased the cell division rate and resulted in an accelerated kinetics of iPS cell formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog (607937) overexpression accelerated reprogramming in a predominantly cell division rate-independent manner. Quantitative analyses defined distinct cell division rate-dependent and -independent modes for accelerating the stochastic course of reprogramming, and suggested that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency. </p><p>Bass et al. (2009) showed that a peak of genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas of the lung and esophagus contains the transcription factor gene SOX2, which is necessary for normal esophageal squamous development (Que et al., 2007) and differentiation and proliferation of basal tracheal cells (Que et al., 2009), and cooperates in induction of pluripotent stem cells, as summarized by Bass et al. (2009). Bass et al. (2009) found that SOX2 expression was required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 in this study cooperated with FOXE1 (602617) or FGFR2 (176943) to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors showed expression of markers of both squamous differentiation and pluripotency. Bass et al. (2009) concluded that these characteristics identified SOX2 as a lineage-survival oncogene in lung and esophageal squamous cell carcinoma. </p><p>Using chromatin immunoprecipitation analysis, Yu et al. (2009) showed that mouse Zfp206 (ZSCAN10; 618365) and Oct4 reciprocally regulated expression of one another in ES cells through promoter binding. Genomewide mapping of Zfp206 targets in mouse ES cells identified Zfp206, Oct4, and Sox2 as key components of a large transcriptional regulatory network. Zfp206 selectively activated or repressed transcription of its target genes by binding to their promoters in ES cells. Many of these same genes were also regulated by Oct4 and Sox2, which colocalized and physically interacted with Zfp206 in a macromolecular complex. </p><p>Takemoto et al. (2011) demonstrated that TBX6 (602427)-dependent regulation of SOX2 determines the fate of axial stem cells. In wildtype mouse embryos, enhancer N1 of the neural primordial gene Sox2 is activated in the caudal lateral epiblast, and the cells staying in the superficial layer sustain N1 activity and activate Sox2 expression in the neural plate. In contrast, the cells destined to become mesoderm activate Tbx6 and turn off enhancer N1 before migrating into the paraxial mesoderm compartment. In Tbx6 mutant embryos, however, enhancer N1 activity persists in the paraxial mesoderm compartment, eliciting ectopic Sox2 activation and transforming the paraxial mesoderm into neural tubes. An enhancer-N1-specific deletion mutation introduced into Tbx6 mutant embryos prevented this Sox2 activation into the mesodermal compartment and subsequent development of ectopic neural tubes, indicating that Tbx6 regulates Sox2 via enhancer N1. Tbx6-dependent repression of Wnt3a (606359) in the paraxial mesodermal compartment is implicated in this regulatory process. Paraxial mesoderm-specific misexpression of a Sox2 transgene in wildtype embryos resulted in ectopic neural tube development. Thus, Takemoto et al. (2011) concluded that Tbx6 represses Sox2 by inactivating enhancer N1 to inhibit neural development, and this is an essential step for the specification of paraxial mesoderm from the axial stem cells. </p><p>Using immunoprecipitation and mass spectrometry, Engelen et al. (2011) identified Chd7 (608892) among 50 proteins that interacted with epitope-tagged Sox2 in mouse neural stem cells. Reverse immunoprecipitation and protein pull-down experiments confirmed direct interaction between Sox2 and Chd7. Knockdown of Sox2 or Chd7 via short hairpin RNA revealed an overlapping set of target genes. Sequencing of DNA bound by Sox2 and Chd7 in chromatin immunoprecipitation experiments and analysis of genes disrupted by knockdown of Sox2 or Chd7 revealed that the 2 proteins cooperated in gene activation. Engelen et al. (2011) concluded that Chd7 is an important Sox2 cofactor. </p><p>Rais et al. (2013) showed that depleting MBD3 (603573), a core member of the MBD3/NURD (nucleosome remodeling and deacetylation) repressor complex, together with OSKM (OCT4, 164177; SOX2; KLF4, 602253; and MYC, 190080) transduction and reprogramming in naive pluripotency-promoting conditions, result in deterministic and synchronized iPS cell reprogramming (nearly 100% efficiency within 7 days from mouse and human cells). Rais et al. (2013) stated that their findings uncovered a dichotomous molecular function for the reprogramming factors, serving to reactivate endogenous pluripotency networks while simultaneously directly recruiting the MBD3/NURD repressor complex that potently restrains the reactivation of OSKM downstream target genes. Subsequently, the latter interactions, which are largely depleted during early preimplantation development in vivo, lead to a stochastic and protracted reprogramming trajectory toward pluripotency in vitro. Rais et al. (2013) concluded that their deterministic reprogramming approach offered a novel platform for the dissection of molecular dynamics leading to establishing pluripotency at unprecedented flexibility and resolution. </p><p>Boumahdi et al. (2014) found that Sox2 was the most upregulated transcription factor in the cancer stem cells (CSCs) of squamous skin tumors in mice. SOX2 is absent in normal epidermis but begins to be expressed in the vast majority of mouse and human preneoplastic skin tumors, and continues to be expressed in a heterogeneous manner in invasive mouse and human squamous cell carcinomas (SCCs). In contrast to other SCCs, in which SOX2 is frequently genetically amplified, the expression of SOX2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis markedly decreases skin tumor formation after chemical-induced carcinogenesis. Using green fluorescent protein (GFP) as a reporter of Sox2 transcriptional expression (Sox2-GFP knockin mice), Boumahdi et al. (2014) showed that SOX2-expressing cells in invasive SCC are greatly enriched in tumor-propagating cells, which further increase upon serial transplantations. Lineage ablation of SOX2-expressing cells within primary benign and malignant SCCs leads to tumor regression, consistent with the critical role of SOX2-expressing cells in tumor maintenance. Conditional Sox2 deletion in preexisting skin papilloma and SCC leads to tumor regression and decreases the ability of cancer cells to be propagated upon transplantation into immunodeficient mice, supporting the essential role of SOX2 in regulating CSC function. Transcriptional profiling of SOX2-GFP-expressing CSCs and of tumor epithelial cells upon Sox2 deletion uncovered a gene network regulated by SOX2 in primary tumor cells in vivo. Chromatin immunoprecipitation identified several direct SOX2 target genes controlling tumor stemness, survival, proliferation, adhesion, invasion, and paraneoplastic syndrome. Boumahdi et al. (2014) demonstrated that SOX2, by marking and regulating the functions of skin tumor-initiating cells and CSCs, establishes a continuum between tumor initiation and progression in primary skin tumors. </p><p>Using chromatin immunoprecipitation analysis, Chassaing et al. (2016) found that Sox2 bound to a sequence within intron 15 of the mouse Ptch1 (601309) gene. Suppression of sox2 expression in zebrafish upregulated ptch1 expression and resulted in reduced eye and retina size. Knockdown of ptch1 in zebrafish also caused ocular defects, including reduced eye size. Reduced ptch1 protein in zebrafish led to overactive SHH signaling. </p><p>Zhang et al. (2019) found that human L3MBTL3 (618844) preferentially bound monomethylated lys42 in SOX2 and regulated stability of the SOX2 protein, which was sensitive to loss of both LSD1 (KDM1A; 609132) and PHF20L1, in human PA-1 teratocarcinoma cells. L3MBTL3 also interacted with DCAF5 (603812), a subunit of a CRL4 ubiquitin E3 ligase complex (see CUL4A, 603137), and cooperatively targeted methylated SOX2 for polyubiquitination-dependent proteolysis. Similarly, L3mbtl3 interacted with Sox2 and destabilized the Sox2 protein in mouse embryonic stem (ES) cells. Loss of L3mbtl3 stabilized Sox2 and restored self-renewal and pluripotency in Lsd1- or Phf20l1-knockdown mouse ES cells. Methylated Sox2 was a critical target of Lsd1 in mouse ES cells, and it appeared that methylation at both lys42 and lys117 was important for Lsd1 to maintain self-renewal and pluripotency of mouse ES cells. Induction of mouse ES cell differentiation enhanced proteolytic degradation of Sox2, which also depended on methylation of both lys42 and lys117 in Sox2. </p>
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<strong>Biochemical Features</strong>
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<span class="mim-text-font">
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<p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Dodonova et al. (2020) reported cryoelectron microscopy structures of the DNA-binding domains of SOX2 and its close homolog SOX11 (600898) bound to nucleosomes. The structures showed that SOX factors can bind and locally distort DNA at superhelical location 2. The factors also facilitated detachment of terminal nucleosomal DNA from the histone octamer, which increases DNA accessibility. SOX-factor binding to the nucleosome can also lead to a repositioning of the N-terminal tail of histone H4 (see 602822) that includes residue lys16. Dodonova et al. (2020) speculated that this repositioning is incompatible with higher-order nucleosome stacking, which involves contacts of the H4 tail with a neighboring nucleosome. Dodonova et al. (2020) concluded that pioneer transcription factors that maintain pluripotency can use binding energy to initiate chromatin opening, and thereby facilitate nucleosome remodeling and subsequent transcription. </p>
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<strong>Molecular Genetics</strong>
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<p>Chitayat et al. (1996) and Male et al. (2002) identified constitutional deletions involving 3q27 in 3 unrelated individuals with clinical anophthalmia and microphthalmia. Driggers et al. (1999) and Kurbasic et al. (2000) reported de novo apparently balanced reciprocal translocations involving 3q27 in 2 patients with severe bilateral microphthalmia and microphthalmia/clinical anophthalmia. In the female infant reported by Driggers et al. (1999) with isolated bilateral clinical anophthalmia and a de novo t(3;11)(q27;p11.2), Fantes et al. (2003) identified a submicroscopic deletion at the 3q breakpoint. This deletion contained SOX2. Subsequent SOX2 mutation analysis identified de novo truncating mutations of SOX2 (184429.0001-184429.0003) in 4 (11%) of 35 individuals with clinical anophthalmia and other features (MCOPS3; 206900). Both eyes were affected in all cases with an identified mutation. In each case the mutation was present in heterozygous state; the parents of each individual with a mutation in SOX2 had normal SOX2 sequence. </p><p>Ragge et al. (2005) reported 4 patients with bilateral anophthalmia/microphthalmia and de novo heterozygous mutations in SOX2, including a missense mutation (184429.0004) and 3 frameshift mutations. </p><p>In a 12-year-old girl with bilateral clinical anophthalmia, Hagstrom et al. (2005) identified heterozygosity for a nonsense mutation in the SOX2 gene (184429.0005). </p><p>In an 11-month-old Mexican girl with bilateral clinical anophthalmia, mild facial dysmorphism, and developmental delay, Zenteno et al. (2005) identified heterozygosity for a 20-bp deletion in the SOX2 gene (70del20; 184429.0010). </p><p>Williamson et al. (2006) identified heterozygous loss-of-function mutations in the SOX2 gene in 3 unrelated patients with microphthalmia and esophageal atresia: the original patient reported by Rogers (1988) was found to have a 2.7-Mb deletion encompassing the SOX2 gene (184429.0006); the male infant described by Petrackova et al. (2004) was found to have a nonsense mutation (184429.0007); and a newly reported female infant was found to have a missense mutation (184429.0008). </p><p>In a female infant with bilateral clinical anophthalmos, very narrow palpebral fissures with synechiae, microcephaly, and psychomotor retardation (206900), Faivre et al. (2006) identified heterozygosity for a missense mutation in the SOX2 gene (184429.0009). The unaffected mother was also found to be heterozygous for the mutation; restriction enzyme digestion products were always lower in the mother than the proband, consistent with a lower level of mutant allele in the mother due to somatic mosaicism. An earlier pregnancy had been terminated due to severe hydrocephaly; examination of the fetus had revealed left cryptophthalmos, bilateral clinical anophthalmos, and multiple brain abnormalities. </p><p>Zenteno et al. (2006) reported male monozygotic twins with esophageal atresia and a discordant ocular phenotype in whom they identified heterozygosity for the 70del20 mutation in the SOX2 gene. One of the infants had unilateral clinical anophthalmia, whereas the other had normal ocular globes; the authors stated that this was the first reported case of SOX2 mutation causing a unilateral eye defect, and the first example of monozygotic twins discordant for anophthalmia. </p><p>Kelberman et al. (2006) screened 235 probands with congenital hypothalamo-pituitary disorders for mutations in the SOX2 gene and identified 6 patients with clinical anophthalmia or microphthalmia who had heterozygous de novo mutations (see, e.g., 184429.0001, 184429.0010, and 184429.0011), and 2 patients with bilateral optic nerve hypoplasia who had inherited heterozygous mutations (see 184429.0012 and 184429.0013). In addition to bilateral eye defects, all patients with SOX2 mutations had various associated anomalies, including anterior pituitary hypoplasia and hypogonadotropic hypogonadism, variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, learning difficulties, sensorineural hearing loss, and esophageal atresia. </p><p>In 2 female sibs, 1 of whom was previously reported by Menetrey et al. (2002), Chassaing et al. (2007) identified heterozygosity for a 17-bp deletion in the SOX2 gene (184429.0014). The sibs were discordant for anophthalmia. Chassaing et al. (2007) concluded that SOX2 haploinsufficiency can cause a variable ocular phenotype ranging from normal eyes to anophthalmia. </p><p>Kelberman et al. (2008) ascertained 3 patients with severe eye defects and pituitary abnormalities who were screened for mutations in SOX2; one patient had been described by Male et al. (2002). All 3 harbored heterozygous SOX2 mutations: a deletion encompassing the entire gene, an intragenic deletion (70_89del; 184429.0010), and a novel nonsense mutation within the DNA binding domain that resulted in impaired transactivation. Kelberman et al. (2008) showed that human SOX2 can inhibit beta-catenin (116806)-driven reporter gene expression in vitro, whereas mutant SOX2 proteins are unable to repress this activity efficiently. They also showed that SOX2 is expressed throughout the human brain, including the developing hypothalamus, as well as the Rathke pouch, the developing anterior pituitary, and the eye. Kelberman et al. (2008) concluded that a failure to repress the Wnt (see 164820)-beta-catenin pathway could be one of the underlying pathogenic mechanisms associated with the effects of loss-of-function mutations in SOX2. </p><p>In 2 sisters with bilateral clinical anophthalmia/microphthalmia and brain anomalies, Schneider et al. (2008) identified heterozygosity for a 1-bp deletion in the SOX2 gene (184429.0015). The unaffected mother had a reduced signal for the deletion in peripheral blood and buccal cell DNA, confirming somatic mosaicism; the mutation was not found in the maternal grandparents. Schneider et al. (2008) noted that this was the third report of a family in which an unaffected mosaic mother transmitted bilateral clinical anophthalmia to 2 female offspring (see Faivre et al., 2006 and Chassaing et al., 2007). </p><p>In a 6-month-old Italian boy with clinical anophthalmia and severe microphthalmia of the right and left eyes, respectively, associated with micropenis, Pedace et al. (2009) analyzed the SOX2 gene and identified heterozygosity for a 2-bp insertion (184429.0016). No morphologic or functional anomaly of the hypothalamic-pituitary axis was detected in this patient, suggesting that SOX2 might have a direct influence on male genital development. </p><p>In a 21-year-old Japanese man with bilateral clinical anophthalmia, hypogonadotropic hypogonadism, seizures, spastic diplegia, and intellectual disability, who was negative for mutation in the HESX1 gene (601802), Numakura et al. (2010) identified heterozygosity for a nonsense mutation in SOX2 (L82X; 184429.0017). The patient also had a dental anomaly consisting of multiple supernumerary impacted teeth and persistence of deciduous teeth. Although the role of SOX2 in dental development was unknown, the authors considered the supernumerary teeth to be an extraocular symptom of the SOX2 anophthalmia syndrome. </p><p>Alatzoglou et al. (2011) reported 2 unrelated patients with bilateral clinical anophthalmia and nonprogressive pituitary tumors of early onset associated with SOX2 haploinsufficiency, due to heterozygosity for a 731-kb deletion on chromosome 3q26 encompassing SOX2 in 1 patient and a SOX2 nonsense mutation (F48X; 184429.0018) in the other. Alatzoglou et al. (2011) stated that this was the first time that SOX2 haploinsufficiency had been implicated in the generation of pituitary tumors. </p><p>In 2 sibs with microphthalmia, 1 of whom also had endocrinologic abnormalities, and their mother, who was diagnosed with idiopathic hypogonadotropic hypogonadism (see 147950) but had no other dysmorphic features and normal ophthalmologic examination, Stark et al. (2011) identified heterozygosity for a 1-bp deletion in SOX2 (184429.0019). Sequencing results in the mother suggested possible mosaicism. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Schneider et al. (2009) screened the SOX2 gene in 51 unrelated patients with clinical anophthalmia and/or microphthalmia and identified heterozygous SOX2 mutations in 10 of them, including 3 patients with the recurrent 20-bp deletion (70del20; 184429.0010). Analysis of all reported patients with SOX2 mutations suggested a potential genotype/phenotype correlation, with missense changes generally resulting in less severe ocular defects. </p>
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<strong>Animal Model</strong>
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<p>Dong et al. (2002) identified 2 allelic mouse mutants, 'light coat and circling' (Lcc) and 'yellow submarine' (Ysb), that show hearing and balance impairment. Lcc/Lcc mice are completely deaf, whereas Ysb/Ysb mice are severely hearing impaired. Kiernan et al. (2005) reported that inner ears of Lcc/Lcc mice failed to establish a prosensory domain and neither hair cells nor supporting cells differentiated, resulting in a severe inner ear malformation, whereas the sensory epithelium of Ysb/Ysb mice showed abnormal development with disorganized and fewer hair cells. These phenotypes are due to the absence (in Lcc mutants) or reduced expression (in Ysb mutants) of the transcription factor Sox2, specifically within the developing inner ear. Kiernan et al. (2005) showed that Sox2 continues to be expressed in the inner ears of mice lacking Math1 (601461), a gene essential for hair cell differentiation, whereas Math1 expression is absent in Lcc mutants, suggesting that Sox2 acts upstream of Math1. </p><p>Ferri et al. (2004) developed mice that lacked one Sox2 allele and had a deletion in the other Sox2 allele that removed a neural cell-specific enhancer. These compound heterozygotes were born with cerebral malformations and neural cell pathology, and they showed proliferative defects in adult neural stem/progenitor cells. </p><p>Taranova et al. (2006) generated a gene-dosage allelic series of Sox2 mutations in mice. The mutant mice had a range of eye phenotypes, the severity of which directly related to the level of Sox2 expression in neural retinal progenitor cells. Retinal progenitor cells with conditionally ablated Sox2 lost competence both to proliferate and to differentiate terminally. Mice with less than 40% of normal Sox2 expression in the neural retina showed variable microphthalmia as a result of aberrant neural progenitor differentiation. In addition, Taranova et al. (2006) found that Sox2 regulated Notch1 (190198) signaling in a concentration-dependent manner in retinal progenitor cells. They concluded that precise regulation of SOX2 dosage is critical for temporal and spatial regulation of retinal progenitor cell differentiation. </p><p>Kelberman et al. (2006) generated mice heterozygous for a targeted disruption of Sox2. The mutant mice did not manifest eye defects but showed abnormal anterior pituitary development with reduced levels of growth hormone, luteinizing hormone, and thyroid-stimulating hormone, and mutant males had impaired fertility. Kelberman et al. (2006) concluded that Sox2 is necessary for the normal development of the hypothalamo-pituitary and reproductive axes in mice. </p><p>Tay et al. (2008) demonstrated the existence of many naturally occurring miRNA targets in the amino acid coding sequences of the mouse Nanog (607937), Oct4 (164177), and Sox2 genes. Some of the mouse targets analyzed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. MiRNA134 (610164), miRNA296 (610945), and miRNA470, upregulated on retinoic acid-induced differentiation of mouse embryonic stem cells, target the coding sequence of each transcription factor in various combinations, leading to transcriptional and morphologic changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolished miRNA activity, prevented the downregulation of the corresponding genes, and delayed the induced phenotype. Tay et al. (2008) concluded that their findings demonstrated the abundance of coding sequence-located miRNA targets, some of which can be species-specific, and supported an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3-prime untranslated region. </p>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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<strong>19 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 MICROPHTHALMIA, SYNDROMIC 3</strong>
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SOX2, GLN177TER
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SNP: rs104893799,
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ClinVar: RCV000013662, RCV004719643
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</span>
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|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 male patients with bilateral clinical anophthalmia and associated features (MCOPS3; 206900), Fantes et al. (2003) identified heterozygosity for a de novo 529C-T transition in the SOX2 gene resulting in a terminating change, gln177 to stop (Q177X). One of the affected males had a small remnant at the orbital apex bilaterally; he also had microcephaly, cryptorchidism, micropenis, sensorineural deafness, and learning difficulties (possibly due to bacterial meningitis). The other patient had hypospadias, hypotonia, delayed motor development, and febrile convulsions. </p><p>In an 18-year-old male with bilateral clinical anophthalmia, Kelberman et al. (2006) identified heterozygosity for a de novo Q177X mutation in the SOX2 gene. In infancy the patient was noted to have mild facial dysmorphism with a prominent forehead and abnormal nares and philtrum, micropenis with bilateral cryptorchidism, neurodevelopmental delay, and hypotonia with abnormal movements. Short stature led to endocrinologic evaluation at age 9 that ultimately resulted in a diagnosis of gonadotropin deficiency with complete hypogonadotropic hypogonadism. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 MICROPHTHALMIA, SYNDROMIC 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX2, GLU93TER
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|
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|
<br />
|
|
|
|
SNP: rs104893800,
|
|
|
|
|
|
|
|
ClinVar: RCV000013663
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
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|
<div>
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<span class="mim-text-font">
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|
<p>In a female patient with clinical anophthalmia of the right eye, microphthalmia and sclerocornea of the left eye (MCOPS3; 206900), and proximal myopathy, Fantes et al. (2003) found a de novo heterozygous glu93-to-stop (E93X) mutation of the SOX2 gene. Intelligence was normal in this patient. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 MICROPHTHALMIA, SYNDROMIC 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
<div>
|
|
<span class="mim-text-font">
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|
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|
SOX2, SER83TER
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|
<br />
|
|
|
|
SNP: rs104893801,
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|
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|
|
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|
|
ClinVar: RCV000013664
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female patient with clinical anophthalmia of the right eye, microphthalmia with persistent pupillary membrane of the left eye, spastic diplegia, learning difficulties, and seizures (MCOPS3; 206900), Fantes et al. (2003) identified a de novo heterozygous ser83-to-stop (S83X) mutation in the SOX2 gene. </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
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|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 MICROPHTHALMIA, SYNDROMIC 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
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|
SOX2, LEU97PRO
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|
|
<br />
|
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|
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SNP: rs104893802,
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|
|
|
|
ClinVar: RCV000013665
|
|
|
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|
|
</span>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a 6-year-old girl with microphthalmia, sclerocornea, and coloboma of the right eye, sclerocornea and aphakia of the left eye, a mild learning disability, and seizures (MCOPS3; 206900), Ragge et al. (2005) identified heterozygosity for a de novo 290T-C transition in the SOX2 gene, resulting in a leu97-to-pro (L97P) substitution in the highly conserved HMG box of the protein. The mutation is predicted to cause loss of function. </p><p>In studies in Xenopus cells, Danno et al. (2008) demonstrated that the L97P mutation affected physical interaction between the SOX2 and OTX2 (600037) proteins and reduced induction of transcription of RAX (601881), another gene involved in eye development. Wildtype SOX2 potently bound to a conserved noncoding sequence 2 kb upstream of the RAX promoter, but L97P-mutant SOX2 did not. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MICROPHTHALMIA, SYNDROMIC 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX2, GLN155TER
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|
<br />
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|
|
SNP: rs104893803,
|
|
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|
|
gnomAD: rs104893803,
|
|
|
|
|
|
ClinVar: RCV000013666
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 12-year-old girl with bilateral clinical anophthalmia, mild bilateral sensorineural hearing loss, and global developmental delay (MCOPS3; 206900), Hagstrom et al. (2005) identified heterozygosity for a de novo 463C-T transition in the SOX2 gene, predicting a gln155-to-ter (Q155X) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MICROPHTHALMIA, SYNDROMIC 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX2, DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000013667
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with bilateral clinical anophthalmia, esophageal atresia, and glanular hypospadias (MCOPS3; 206900), originally reported by Rogers (1988), Williamson et al. (2006) identified heterozygosity for a 2.7-Mb deletion encompassing the SOX2 gene, extending from RP11-145M9 to RP11-296J4 and associated with a cryptic translocation t(3,7)(q28;p21.3). The deletion and translocation breakpoints on chromosome 3q are more than 8.6 Mb apart, and both chromosomal rearrangements occurred de novo. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MICROPHTHALMIA, SYNDROMIC 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX2, GLN55TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104893804,
|
|
|
|
|
|
|
|
ClinVar: RCV000013668
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male infant with bilateral clinical anophthalmia, esophageal atresia, duplication of the left kidney, and significant psychomotor delay (MCOPS3; 206900), originally reported by Petrackova et al. (2004), Williamson et al. (2006) identified heterozygosity for a 163C-T transition in the SOX2 gene, resulting in a gln55-to-ter (Q55X) substitution with production of a protein truncated within the HMG domain and therefore with no DNA-binding or transactivation activity. The mutation was not found in either parent. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 MICROPHTHALMIA, SYNDROMIC 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX2, ARG74PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104893805,
|
|
|
|
|
|
|
|
ClinVar: RCV000013669
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female infant with extreme bilateral microphthalmia and esophageal atresia (MCOPS3; 206900), Williamson et al. (2006) identified heterozygosity for a 221G-C transversion, resulting in an arg74-to-pro (R74P) substitution. The authors noted that R74 is located within the HMG domain and is invariant in all known SOX2 genes and is conserved in all human SOX group B genes. The mutation was not found in either parent. </p><p>In studies in Xenopus cells, Danno et al. (2008) demonstrated that the R74P mutation affected physical interaction between the SOX2 and OTX2 (600037) proteins and reduced induction of transcription of RAX (601881), another gene involved in eye development. Wildtype SOX2 potently bound to a conserved noncoding sequence 2 kb upstream of the RAX promoter, but R74P-mutant SOX2 did not. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 MICROPHTHALMIA, SYNDROMIC 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX2, ASN46LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104893806,
|
|
|
|
|
|
|
|
ClinVar: RCV000013670
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female infant with bilateral clinical anophthalmos, very narrow palpebral fissures with synechiae, microcephaly, and psychomotor retardation (MCOPS3; 206900), Faivre et al. (2006) identified heterozygosity for a 138T-G transversion in the SOX2 gene, resulting in an asn46-to-lys (N46K) substitution predicted to alter a critical residue in the HMG box domain. The unaffected mother was also found to be heterozygous for the mutation; restriction enzyme digestion products were always lower in the mother than the proband, consistent with a lower level of mutant allele in the mother due to somatic mosaicism. An earlier pregnancy had been terminated due to severe hydrocephaly; examination of the fetus had revealed left cryptophthalmos, bilateral clinical anophthalmos, and multiple brain abnormalities. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 MICROPHTHALMIA, SYNDROMIC 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX2, 20-BP DEL, NT70
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398123693,
|
|
|
|
|
|
|
|
ClinVar: RCV000080064, RCV001067610, RCV002293417, RCV004549501
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 11-month-old Mexican girl with bilateral clinical anophthalmia, mild facial dysmorphism, and developmental delay (MCOPS3; 206900), Zenteno et al. (2005) identified heterozygosity for a 20-bp deletion at nucleotide 70 (70del20) of the SOX2 gene, resulting in a frameshift upstream of the HMG box and a premature termination signal 65 codons downstream. The authors noted that the deleted segment was flanked by the short GGCGGC repeat sequence, suggesting slipped-strand misrepairing as the origin of the deletion. </p><p>In male monozygotic twins with ocular defects, esophageal atresia, and genital abnormalities, Zenteno et al. (2006) identified heterozygosity for the 70del20 mutation in the SOX2 gene. Both infants had tracheoesophageal fistula, but otherwise exhibited a discordant phenotype: 1 twin had left clinical anophthalmia and bilateral cryptorchidism, whereas the other had normal globes, narrowing of the right palpebral fissure, and no genital abnormalities. The authors stated that this was the first reported case of SOX2 mutation causing a unilateral eye defect and the first example of monozygotic twins discordant for anophthalmia. </p><p>In a 22-year-old female with left clinical anophthalmia and right microphthalmia, learning difficulties, and primary amenorrhea, Kelberman et al. (2006) identified heterozygosity for a de novo 70del20 mutation in the SOX2 gene. Brain MRI revealed an abnormal hypoplastic pituitary gland in a small sella turcica with an absent left eye and optic nerve. Functional analysis of the mutant protein revealed impaired nuclear localization, DNA binding, and transcriptional activation. </p><p>Kelberman et al. (2008) identified this deletion (70_89del) in a 14.5-year-old girl who presented with bilateral anophthalmia at birth. Brain MRI showed an arachnoid cyst in the suprasellar area, with right deflection of the pituitary pedunculus. She later developed gonadotropin deficiency with low basal gonadotropin concentrations and poor response to gonadotropin-releasing hormone (GNRH; 152760) stimulation. There was no evidence of learning difficulties. </p><p>In a girl and 2 boys with bilateral clinical anophthalmia or severe microphthalmia, Schneider et al. (2009) identified the 70del20 mutation in the SOX2 gene. All 3 patients had developmental delay. Neuroimaging showed a hamartoma of the tuber cinereum in the 2-year-old girl, but was normal in the other 2 patients; none had pituitary anomalies. The 2 boys displayed genital anomalies, including micropenis, cryptorchidism, and foreskin adhesion. Other features seen in the 2 boys included a heart murmur in 1 patient and 2-3 toe syndactyly, febrile seizures, and mild pectus excavatum in the other. The girl had a half-sister with unilateral clinical anophthalmia and mental retardation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 MICROPHTHALMIA, SYNDROMIC 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX2, 1-BP INS, 60G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122803,
|
|
|
|
|
|
|
|
ClinVar: RCV000346070, RCV002307477
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 13-year-old girl with bilateral clinical anophthalmia, learning difficulties, spastic diplegia, and a history of esophageal atresia (MCOPS3; 206900), previously reported by Morini et al. (2005), Kelberman et al. (2006) identified heterozygosity for a 1-bp insertion (60insG) in the SOX2 gene, predicted to result in a truncation at codon 95 that completely removes the HMG box. Pelvic ultrasound revealed small ovaries and an infantile uterus, suggesting a diagnosis of hypogonadotropic hypogonadism. Brain MRI revealed hippocampal abnormalities with anterior pituitary hypoplasia, hypothalamic hamartoma, small corpus callosum, generalized reduction of white matter, and absent optic nerves. Functional analysis of the mutant protein revealed impaired nuclear localization, DNA binding, and transcriptional activation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 OPTIC NERVE HYPOPLASIA AND ABNORMALITIES OF THE CENTRAL NERVOUS SYSTEM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX2, GLY130ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918652,
|
|
|
|
|
|
gnomAD: rs121918652,
|
|
|
|
|
|
ClinVar: RCV000013673, RCV003227462
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 11-year-old girl with roving eye movements, severe visual impairment, bilateral optic nerve hypoplasia, developmental delay, short stature, and spastic diplegia (see 206900), Kelberman et al. (2006) identified heterozygosity for a 389G-C transversion in the SOX2 gene, resulting in a gly130-to-ala (G130A) substitution. Brain MRI revealed an absent septum pellucidum, bilateral optic nerve hypoplasia, bilateral schizencephaly, right porencephalic cyst, and normal anterior and posterior pituitary. A brother died at age 11 years with hydranencephaly. The mutation was inherited from her phenotypically normal father; the mutation was not found in 100 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 OPTIC NERVE HYPOPLASIA AND ABNORMALITIES OF THE CENTRAL NERVOUS SYSTEM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX2, ALA191THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104893808,
|
|
|
|
|
|
gnomAD: rs104893808,
|
|
|
|
|
|
ClinVar: RCV000013674, RCV000624040, RCV002513019
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 2-year-old girl who was hypoglycemic at birth and noted to have roving eye movements and bilateral optic nerve hypoplasia (see 206900), Kelberman et al. (2006) identified heterozygosity for a 571G-A transition in the SOX2 gene, resulting in an ala191-to-thr (A191T) substitution. Brain MRI revealed an absent septum pellucidum, small optic chiasm, absent infundibulum, severe hypoplasia of the anterior pituitary, and an ectopic or undescended posterior pituitary. Endocrine evaluation revealed deficiencies in growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone. The mutation was inherited from her phenotypically normal father; the mutation was not found in 100 control chromosomes. </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>.0014 MICROPHTHALMIA, SYNDROMIC 3</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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SOX2, 17-BP DEL, NT70
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<br />
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SNP: rs1553862927,
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ClinVar: RCV000622595, RCV002307563, RCV004719905
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 female sibs with syndromid microphthalmia (MCOPS3; 206900), 1 of whom was previously reported by Menetrey et al. (2002), Chassaing et al. (2007) identified heterozygosity for a 17-bp deletion (70del17) in the SOX2 gene, predicted to cause a frameshift resulting in a premature termination signal at codon 66. The first sib had bilateral anophthalmia and esophageal atresia. During the mother's subsequent pregnancy, the fetus showed severe and progressive triventricular hydrocephalus on ultrasound, and the pregnancy was interrupted. Autopsy showed stenosis of the Sylvian aqueduct, and hypoplasia of the corpus callosum, but age-appropriate ocular length and normal external and microscopic ocular examination. The mother was found to have germinal mosaicism for the mutation, estimated at approximately 3%. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0015 MICROPHTHALMIA, SYNDROMIC 3</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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SOX2, 1-BP DEL, 551C
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<br />
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SNP: rs587776776,
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ClinVar: RCV000013676
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sisters with bilateral clinical anophthalmia/microphthalmia and brain anomalies (MCOPS3; 206900), Schneider et al. (2008) identified heterozygosity for a 1-bp deletion (551delC) in the SOX2 gene, predicted to cause a frameshift and premature termination resulting in a nonfunctional protein. The unaffected mother, who had 2 healthy older children, was found to have a reduced signal for the deletion in peripheral blood and buccal cell DNA, confirming somatic mosaicism; the mutation was not found in the maternal grandparents. </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>.0016 MICROPHTHALMIA, SYNDROMIC 3</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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SOX2, 2-BP INS, 59GG
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<br />
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SNP: rs398122803,
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ClinVar: RCV000022771
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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 6-month-old Italian boy with clinical anophthalmia and severe microphthalmia of the right and left eyes, respectively, associated with micropenis (MCOPS3; 206900), Pedace et al. (2009) identified heterozygosity for a de novo 2-bp insertion (60insGG) in the SOX2 gene, causing a frameshift resulting in a premature termination codon that was predicted to cause loss of 94% of the encoded protein. The mutation was not detected in the patient's unaffected second-cousin parents or in his unaffected dizygotic twin, and was not found in 200 control chromosomes. Repeated endocrinologic evaluation and brain MRI in this patient did not reveal any morphologic or functional anomaly of the hypothalamic-pituitary axis. </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>.0017 MICROPHTHALMIA, SYNDROMIC 3</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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SOX2, LEU82TER
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<br />
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SNP: rs387906688,
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ClinVar: RCV000022772
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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 21-year-old Japanese man with bilateral clinical anophthalmia, hypogonadotropic hypogonadism, seizures, spastic diplegia, intellectual disability, and dental anomalies including multiple supernumerary impacted teeth, Numakura et al. (2010) identified heterozygosity for a 245T-A transversion in the SOX2 gene, resulting in a leu82-to-ter (L82X) substitution, predicted to produce a protein truncated within the HMG domain that would lack DNA-binding and transactivation activity. The patient's mother did not carry the mutation; DNA from the father was not available. </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>.0018 MICROPHTHALMIA, SYNDROMIC 3</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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SOX2, PHE48TER
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<br />
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SNP: rs398122915,
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ClinVar: RCV000033025
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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 male infant born with bilateral clinical anophthalmia who was referred for evaluation of micropenis (MCOPS3; 206900), Alatzoglou et al. (2011) identified heterozygosity for a 143TC-AA change in the SOX2 gene, resulting in a phe48-to-ter (F48X) substitution that was predicted to generate a truncated protein lacking most of the HMG domain and the C-terminal domain. DNA from the parents was unavailable. Immunostaining of transfected HEK293T cells showed mainly cytoplasmic localization of the mutant compared to the nuclear localization of wildtype protein, and luciferase expression studies showed only a 1.59-fold activation of the basal reporter activity with the F48X mutant compared to a 3.31-fold increase with wildtype. In addition, the mutant failed to suppress beta-catenin (116806) transcriptional activity in vitro, whereas it was significantly reduced by wildtype SOX2. Examination at 17 months of age revealed a stretched penile length of 2.5 cm and a hypoplastic scrotum with testes of 0.5 to 1.0 ml palpable high in the scrotal sacs. Endocrine evaluation showed low IGF1 (147440), and the testosterone response to a 3-week hCG test was consistent with hypogonadotropic hypogonadism. MRI at 17 months of age revealed a pituitary mass with a cystic component extending to the suprasellar area, and review of an MRI from the neonatal period, which was thought to have been normal apart from absent prechiasmatic optic nerves, showed that the mass had been present at that stage. A follow-up MRI at 32 months of age demonstrated only a modest increase in size of the mass. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 MICROPHTHALMIA, SYNDROMIC 3</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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SOX2, 1-BP DEL, 837C
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<br />
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SNP: rs398122916,
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gnomAD: rs398122916,
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ClinVar: RCV000033026
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In an 8-year-old boy with bilateral clinical anophthalmia and endocrinologic abnormalities (MCOPS3; 206900) and his sister who had only unilateral microphthalmia, Stark et al. (2011) identified heterozygosity for a 1-bp deletion (837delC) in the SOX2 gene, predicted to cause a frameshift and addition of 90 abnormal C-terminal residues (Gly208AlafsTer91). The boy had transient growth and growth hormone disturbances in infancy, but was not dysmorphic and had descended testes with a normal phallus; subsequently his growth normalized and pituitary function was normal on yearly monitoring. MRI of the brain at 1 year of age showed no eye remnants and absent optic nerves, an intact corpus callosum and a normal pituitary, but a dysplastic right hippocampus. His 8-month-old sister had left microphthalmia and a large left retinal coloboma, but no associated anomalies or dysmorphic features. Their mother, who had been evaluated at 18 years of age for primary amenorrhea and limited development of secondary sexual characteristics and was diagnosed with isolated hypogonadotropic hypogonadism, had a normal sense of smell, no dysmorphism, and a normal ophthalmologic examination. Sequencing results from the mother's lymphocyte DNA showed the presence of the mutation but at lower levels compared to her children, suggesting possible mosaicism. The unaffected father's sequencing results were normal. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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|
</span>
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</h4>
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Alatzoglou, K. S., Andoniadou, C. L., Kelberman, D., Buchanan, C. R., Crolla, J., Arriazu, M. C., Roubicek, M., Moncet, D., Martinez-Barbera, J. P., Dattani, M. T.
|
|
<strong>SOX2 haploinsufficiency is associated with slow progressing hypothalamo-pituitary tumours.</strong>
|
|
Hum. Mutat. 32: 1376-1380, 2011.
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[PubMed: 21919124]
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[Full Text: https://doi.org/10.1002/humu.21606]
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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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Bass, A. J., Watanabe, H., Mermel, C. H., Yu, S., Perner, S., Verhaak, R. G., Kim, S. Y., Wardwell, L., Tamayo, P., Gat-Viks, I., Ramos, A. H., Woo, M. S., and 36 others.
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|
<strong>SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas.</strong>
|
|
Nature Genet. 41: 1238-1242, 2009.
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[PubMed: 19801978]
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[Full Text: https://doi.org/10.1038/ng.465]
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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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Boumahdi, S., Driessens, G., Lapouge, G., Rorive, S., Nassar, D., Le Mercier, M., Delatte, B., Caauwe, A., Lenglez, S., Nkusi, E., Brohee, S., Salmon, I., Dubois, C., del Marmol, V., Fuks, F., Beck, B., Blanpain, C.
|
|
<strong>SOX2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma.</strong>
|
|
Nature 511: 246-250, 2014.
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[PubMed: 24909994]
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[Full Text: https://doi.org/10.1038/nature13305]
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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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Bylund, M., Andersson, E., Novitch, B. G., Muhr, J.
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|
<strong>Vertebrate neurogenesis is counteracted by Sox1-3 activity.</strong>
|
|
Nature Neurosci. 6: 1162-1168, 2003.
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[PubMed: 14517545]
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[Full Text: https://doi.org/10.1038/nn1131]
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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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Chassaing, N., Davis, E. E., McKnight, K. L., Niederriter, A. R., Causse, A., David, V., Desmaison, A., Lamarre, S., Vincent-Delorme, C., Pasquier, L., Coubes, C., Lacombe, D., Rossi, M., Dufier, J.-L., Dollfus, H., Kaplan, J., Katsanis, N., Etchevers, H. C., Faguer, S., Calvas, P.
|
|
<strong>Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network.</strong>
|
|
Genome Res. 26: 474-485, 2016.
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[PubMed: 26893459]
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[Full Text: https://doi.org/10.1101/gr.196048.115]
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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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Chassaing, N., Gilbert-Dussardier, B., Nicot, F., Fermeaux, V., Encha-Razavi, F., Fiorenza, M., Toutain, A., Calvas, P.
|
|
<strong>Germinal mosaicism and familial recurrence of a SOX2 mutation with highly variable phenotypic expression extending from AEG syndrome to absence of ocular involvement.</strong>
|
|
Am. J. Med. Genet. 143A: 289-291, 2007.
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|
[PubMed: 17219395]
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[Full Text: https://doi.org/10.1002/ajmg.a.31524]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Chitayat, D., Babul, R., Silver, M. M., Jay, V., Teshima, I. E., Babyn, P., Becker, L. E.
|
|
<strong>Terminal deletion of the long arm of chromosome 3 [46,XX,del(3)(q27-qter)].</strong>
|
|
Am. J. Med. Genet. 61: 45-48, 1996.
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|
|
[PubMed: 8741917]
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|
[Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960102)61:1<45::AID-AJMG9>3.0.CO;2-W]
|
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Danno, H., Michiue, T., Hitachi, K., Yukita, A., Ishiura, S., Asashima, M.
|
|
<strong>Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression.</strong>
|
|
Proc. Nat. Acad. Sci. 105: 5408-5413, 2008.
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|
[PubMed: 18385377]
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[Full Text: https://doi.org/10.1073/pnas.0710954105]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Dodonova, S. O., Zhu, F., Dienemann, C., Taipale, J., Cramer, P.
|
|
<strong>Nucleosome-bound SOX2 and SOX11 structures elucidate pioneer factor function.</strong>
|
|
Nature 580: 669-672, 2020.
|
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|
[PubMed: 32350470]
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|
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[Full Text: https://doi.org/10.1038/s41586-020-2195-y]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Dong, S., Leung, K. K. H., Pelling, A. L., Lee, P. Y. T., Tang, A. S. P., Heng, H. H. Q., Tsui, L. C., Tease, C., Fisher, G., Steel, K. P., Cheah, K. S. E.
|
|
<strong>Circling, deafness, and yellow coat displayed by yellow submarine (Ysb) and light coat and circling (Lcc) mice with mutations on chromosome 3.</strong>
|
|
Genomics 79: 777-784, 2002.
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|
[PubMed: 12036291]
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[Full Text: https://doi.org/10.1006/geno.2002.6783]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Driggers, R. W., Macri, C. J., Greenwald, J., Carpenter, D., Avallone, J., Howard-Peebles, P. N., Levin, S. W.
|
|
<strong>Isolated bilateral anophthalmia in a girl with an apparently balanced de novo translocation: 46,XX,t(3;11)(q27;p11.2).</strong>
|
|
Am. J. Med. Genet. 87: 201-202, 1999.
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|
[PubMed: 10564870]
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[Full Text: https://doi.org/10.1002/(sici)1096-8628(19991126)87:3<201::aid-ajmg1>3.0.co;2-h]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Engelen, E., Akinci, U., Bryne, J. C., Hou, J., Gontan, C., Moen, M., Szumska, D., Kockx, C., van IJcken, W., Dekkers, D. H. W., Demmers, J., Rijkers, E.-J., Bhattacharya, S., Philipsen, S., Pevny, L. H., Grosveld, F. G., Rottier, R. J., Lenhard, B., Poot, R. A.
|
|
<strong>Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes.</strong>
|
|
Nature Genet. 43: 607-611, 2011.
|
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|
|
[PubMed: 21532573]
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[Full Text: https://doi.org/10.1038/ng.825]
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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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Faivre, L., Williamson, K. A., Faber, V., Laurent, N., Grimaldi, M., Thauvin-Robinet, C., Durand, C., Mugneret, F., Gouyon, J.-B., Bron, A., Huet, F., Hayward, C., van Heyningen, V., FitzPatrick, D. R.
|
|
<strong>Recurrence of SOX2 anophthalmia syndrome with gonosomal mosaicism in a phenotypically normal mother. (Letter)</strong>
|
|
Am. J. Med. Genet. 140A: 636-639, 2006.
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|
[PubMed: 16470798]
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Tay, Y., Zhang, J., Thomson, A. M., Lim, B., Rigoutsos, I.
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Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger, K., Bernstein, B. E., Jaenisch, R.
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<strong>In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state.</strong>
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Nature 448: 318-324, 2007.
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Williamson, K. A., Hever, A. M., Rainger, J., Rogers, R. C., Magee, A., Fiedler, Z., Keng, W. T., Sharkey, F. H., McGill, N., Hill, C. J., Schneider, A., Messina, M., Turnpenny, P. D., Fantes, J. A., van Heyningen, V., FitzPatrick, D. R.
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<strong>Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome.</strong>
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Hum. Molec. Genet. 15: 1413-1422, 2006. Note: Erratum: Hum. Molec. Genet. 15: 2030 only, 2006.
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Yu, H., Kunarso, G., Hong, F. H., Stanton, L. W.
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Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., Slukvin, I. I., Thomson, J. A.
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<strong>Induced pluripotent stem cell lines derived from human somatic cells.</strong>
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Zenteno, J. C., Gascon-Guzman, G., Tovilla-Canales, J. L.
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<strong>Bilateral anophthalmia and brain malformations caused by a 20-bp deletion in the SOX2 gene. (Letter)</strong>
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Zenteno, J. C., Perez-Cano, H. J., Aguinaga, M.
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Zhang, C., Leng, F., Saxena, L., Hoang, N., Yu, J., Alejo, S., Lee, L., Qi, D., Lu, F., Sun, H., Zhang, H.
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Ada Hamosh - updated : 06/08/2020<br>Bao Lige - updated : 04/08/2020<br>Bao Lige - updated : 03/22/2019<br>Patricia A. Hartz - updated : 04/01/2016<br>Ada Hamosh - updated : 8/28/2014<br>Ada Hamosh - updated : 12/5/2013<br>Marla J. F. O'Neill - updated : 11/21/2012<br>Marla J. F. O'Neill - updated : 11/20/2012<br>Marla J. F. O'Neill - updated : 6/12/2012<br>Marla J. F. O'Neill - updated : 9/22/2011<br>Patricia A. Hartz - updated : 8/31/2011<br>Ada Hamosh - updated : 6/29/2011<br>Marla J. F. O'Neill - updated : 4/15/2011<br>Ada Hamosh - updated : 1/7/2011<br>Ada Hamosh - updated : 2/16/2010<br>Ada Hamosh - updated : 1/12/2010<br>Marla J. F. O'Neill - updated : 8/31/2009<br>Ada Hamosh - updated : 4/28/2009<br>John A. Phillips, III - updated : 1/14/2009<br>Ada Hamosh - updated : 12/30/2008<br>Ada Hamosh - updated : 11/26/2008<br>Marla J. F. O'Neill - updated : 6/6/2008<br>Patricia A. Hartz - updated : 3/3/2008<br>Patricia A. Hartz - updated : 2/7/2008<br>Ada Hamosh - updated : 1/23/2008<br>Ada Hamosh - updated : 8/29/2007<br>Marla J. F. O'Neill - updated : 7/2/2007<br>Marla J. F. O'Neill - updated : 1/19/2007<br>Patricia A. Hartz - updated : 11/1/2006<br>Marla J. F. O'Neill - updated : 10/25/2006<br>Victor A. McKusick - updated : 9/13/2006<br>Marla J. F. O'Neill - updated : 7/27/2006<br>Patricia A. Hartz - updated : 6/23/2006<br>Marla J. F. O'Neill - updated : 6/20/2006<br>Marla J. F. O'Neill - updated : 4/26/2006<br>Marla J. F. O'Neill - updated : 4/20/2006<br>Marla J. F. O'Neill - updated : 11/7/2005<br>Marla J. F. O'Neill - updated : 5/23/2005<br>Ada Hamosh - updated : 5/3/2005<br>Cassandra L. Kniffin - updated : 10/3/2003<br>Victor A. McKusick - updated : 3/19/2003<br>Victor A. McKusick - updated : 8/18/1999
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Victor A. McKusick : 4/14/1994
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