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Entry
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- *608160 - SRY-BOX 9; SOX9
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*608160</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/608160">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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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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<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=ENSG00000125398;t=ENST00000245479" 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=6662" 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=608160" 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 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=ENSG00000125398;t=ENST00000245479" 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_000346" 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_000346" 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=608160" 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=06427&isoform_id=06427_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/SOX9" 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/758103,807060,1351096,4557853,14044055,30582589,33991649,60496331,119609508,194380472,527316674,556559922,556559924,556559926,556559928,556559930,556559934,556559936,556559938,556559940,556559942,556559944,556559946,922664347,922664349,2125807395" 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/P48436" 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=6662" 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=ENSG00000125398;t=ENST00000245479" 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=SOX9" 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=SOX9" 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+6662" 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/SOX9" 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:6662" 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/6662" 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=chr17&hgg_gene=ENST00000245479.3&hgg_start=72121020&hgg_end=72126416&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:11204" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11204" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/sox9" 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=608160[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=608160[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/SOX9/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/ENSG00000125398" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=SOX9" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=SOX9" 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=SOX9" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SOX9&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/PA36041" 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:11204" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0024288.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:98371" 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/SOX9#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:98371" 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/6662/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002694/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=6662" 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://zfin.org/ZDB-GENE-001103-1" 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">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:6662" 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=SOX9&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> 74928006<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>
|
|
608160
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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SRY-BOX 9; SOX9
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
SRY-RELATED HMG-BOX GENE 9
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
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</span>
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</p>
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</div>
|
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<div>
|
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<span class="h3 mim-font">
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|
XXSR, INCLUDED
|
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</span>
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</div>
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<div>
|
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<span class="h4 mim-font">
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|
XYSR, INCLUDED<br />
|
|
TESTIS-SPECIFIC ENHANCER OF SOX9, INCLUDED; TES, INCLUDED<br />
|
|
TESTIS-SPECIFIC ENHANCER OF SOX9 CORE, INCLUDED; TESCO, INCLUDED<br />
|
|
REGULATORY ELEMENT, ENHANCER, 13, INCLUDED; ENH13, INCLUDED
|
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</span>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SOX9" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SOX9</a></em></strong>
|
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</span>
|
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</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/17/894?start=-3&limit=10&highlight=894">17q24.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr17:72121020-72126416&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'})">17:72,121,020-72,126,416</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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</span>
|
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</p>
|
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</div>
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<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
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=278850,616425,114290,114290,114290" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="5">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/17/894?start=-3&limit=10&highlight=894">
|
|
17q24.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
46XX sex reversal 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/278850"> 278850 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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<p>SOX9 is a transcription factor essential for both sex and skeletal development. Transient expression of the Y chromosome gene SRY (<a href="/entry/480000">480000</a>) initiates a cascade of gene interactions orchestrated by SOX9, leading to the formation of testes from bipotential gonads (summary by <a href="#13" class="mim-tip-reference" title="Cox, J. J., Willatt, L., Homfray, T., Woods, C. G. <strong>A SOX9 duplication and familial 46,XX developmental testicular disorder. (Letter)</strong> New Eng. J. Med. 364: 91-93, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21208124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21208124</a>] [<a href="https://doi.org/10.1056/NEJMc1010311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21208124">Cox et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21208124" 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="#16" class="mim-tip-reference" title="Foster, J. W., Dominguez-Steglich, M. A., Guioli, S., Kwok, C., Weller, P. A., Stevanovic, M., Weissenbach, J., Mansour, S., Young, I. D., Goodfellow, P. N., Brook, J. D., Schafer, A. J. <strong>Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.</strong> Nature 372: 525-530, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7990924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7990924</a>] [<a href="https://doi.org/10.1038/372525a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7990924">Foster et al. (1994)</a> constructed a high-resolution map across a 20-Mb region spanning chromosome 17q24.1-q25.1 that was identified by <a href="#62" class="mim-tip-reference" title="Tommerup, N., Schempp, W., Meinecke, P., Pedersen, S., Bolund, L., Brandt, C., Goodpasture, C., Guldberg, P., Held, K., Reinwein, H., Saugstad, O. D., Scherer, G., Skjeldal, O., Toder, R., Westvik, J., van der Hagen, C. B., Wolf, U. <strong>Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to 17q24.3-q25.1.</strong> Nature Genet. 4: 170-174, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8348155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8348155</a>] [<a href="https://doi.org/10.1038/ng0693-170" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8348155">Tommerup et al. (1993)</a> as containing the locus for campomelic dysplasia (CMPD; <a href="/entry/114290">114290</a>). Using this map and a translocation chromosome breakpoint from a sex-reversed patient with campomelic dysplasia (see <a href="/entry/114290">114290</a>) previously reported by <a href="#77" class="mim-tip-reference" title="Young, I. D., Zuccollo, J. M., Maltby, E. L., Broderick, N. J. <strong>Campomelic dysplasia associated with a de novo 2q;17q reciprocal translocation.</strong> J. Med. Genet. 29: 251-252, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1583645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1583645</a>] [<a href="https://doi.org/10.1136/jmg.29.4.251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1583645">Young et al. (1992)</a>, <a href="#16" class="mim-tip-reference" title="Foster, J. W., Dominguez-Steglich, M. A., Guioli, S., Kwok, C., Weller, P. A., Stevanovic, M., Weissenbach, J., Mansour, S., Young, I. D., Goodfellow, P. N., Brook, J. D., Schafer, A. J. <strong>Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.</strong> Nature 372: 525-530, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7990924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7990924</a>] [<a href="https://doi.org/10.1038/372525a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7990924">Foster et al. (1994)</a> identified an SRY (<a href="/entry/480000">480000</a>)-related gene, SOX9, located 88 kb distal to the translocation breakpoint. The gene is predicted to encode a 509-amino acid polypeptide containing an SRY homology domain. The isolated cDNA corresponded to 3.9 kb of the transcript, but Northern blot analysis detected a 4.5-kb transcript in adult testes, adult heart, and fetal brain. The SOX9 protein HMG box domain at amino acids 104-182 showed 71% similarity with the SRY HMG box, and the C-terminal third of the protein has a proline- and glutamine-rich region similar to activation domains present in some transcription factors. The genomic arrangement of SOX9 is such that the 5-prime end is oriented toward the centromere of chromosome 17 and closest to the breakpoint. It is possible that 1 or more exons are present 5-prime to the known exons and that these are disrupted by the translocation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1583645+7990924+8348155" 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 a fragment derived from mouse SOX9, <a href="#68" class="mim-tip-reference" title="Wagner, T., Wirth, J., Meyer, J., Zabel, B., Held, M., Zimmer, J., Pasantes, J., Dagna Bricarelli, F., Keutel, J., Hustert, E., Wolf, U., Tommerup, N., Schempp, W., Scherer, G. <strong>Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.</strong> Cell 79: 1111-1120, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001137</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90041-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8001137">Wagner et al. (1994)</a> isolated human SOX9 from a human fetal cDNA brain library. The cDNA was found to encode a 509-amino acid protein with a predicted molecular mass of 56 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8001137" 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 immunofluorescence analysis, <a href="#53" class="mim-tip-reference" title="Schmidt, K., Glaser, G.,, Wernig, A., Wegner, M., Rosorius, O. <strong>Sox8 is a specific marker for muscle satellite cells and inhibits myogenesis.</strong> J. Biol. Chem. 278: 29769-29775, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12782625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12782625</a>] [<a href="https://doi.org/10.1074/jbc.M301539200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12782625">Schmidt et al. (2003)</a> showed that Sox8 (<a href="/entry/605923">605923</a>) and Sox9 localized to nuclei of undifferentiated C2C12 mouse myoblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12782625" 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>By immunohistochemical analysis of adult human and mouse tissues, <a href="#17" class="mim-tip-reference" title="Furuyama, K., Kawaguchi, Y., Akiyama, H., Horiguchi, M., Kodama, S., Kuhara, T., Hosokawa, S., Elbahrawy, A., Soeda, T., Koizumi, M., Masui, T., Kawaguchi, M., Takaori, K., Doi, R., Nishi, E., Kakinoki, R., Deng, J. M., Behringer, R. R., Nakamura, T., Uemoto, S. <strong>Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine.</strong> Nature Genet. 43: 34-41, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21113154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21113154</a>] [<a href="https://doi.org/10.1038/ng.722" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21113154">Furuyama et al. (2011)</a> found that SOX9 was expressed in hepatic bile duct, duodenal crypt, and pancreatic duct. In mouse, Sox9 was detected in extrahepatic biliary tract epithelia, including the common bile duct, duodenal papilla, and gallbladder. Sox9 was detected broadly in primitive gut epithelial cells in developing mouse at embryonic days 13.5 and 16.5 and was restricted to crypt at embryonic day 18.5. In pancreas, Sox9 was expressed in epithelial cells at embryonic day 13.5 and was confined to duct cells and was not present in differentiated cells at embryonic days 16.5 and 18.5. Sox9 was detected in extrahepatic bile duct, but not in hepatocytes, at embryonic day 13.5 and was expressed in intrahepatic bile duct at embryonic day 16.5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21113154" 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="Fantauzzo, K. A., Kurban, M., Levy, B., Christiano, A. M. <strong>Trps1 and its target gene Sox9 regulate epithelial proliferation in the developing hair follicle and are associated with hypertrichosis.</strong> PLoS Genet. 8: e1003002, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23133399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23133399</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23133399[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1003002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23133399">Fantauzzo et al. (2012)</a> used immunofluorescence analysis to examine expression of Sox9 during vibrissae follicle morphogenesis in mice. At embryonic day (E) 12.5, Sox9 was expressed throughout the whisker pad epidermis, with increased expression in the suprabasal layers of the epithelial placode. By the peg stage at E14.5, Sox9 was expressed throughout the epithelial compartment of the downgrowing follicle, with the exception of the matrix cells. From E16.5 to E18.5, Sox9 continued to be expressed throughout the follicle epithelium, with increased expression in the matrix and the inner and outer root sheath layers. By postnatal day 0, Sox9 expression was restricted to the outer root sheath cells along the length of the follicle. In addition, faint expression was also detected in the dermal papilla as early as E14.5, as well as in the dermal cells of the collagen capsule surrounding the developing vibrissae follicles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23133399" 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="#16" class="mim-tip-reference" title="Foster, J. W., Dominguez-Steglich, M. A., Guioli, S., Kwok, C., Weller, P. A., Stevanovic, M., Weissenbach, J., Mansour, S., Young, I. D., Goodfellow, P. N., Brook, J. D., Schafer, A. J. <strong>Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.</strong> Nature 372: 525-530, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7990924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7990924</a>] [<a href="https://doi.org/10.1038/372525a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7990924">Foster et al. (1994)</a> localized the SOX9 gene to chromosome 17q24. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7990924" 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="#68" class="mim-tip-reference" title="Wagner, T., Wirth, J., Meyer, J., Zabel, B., Held, M., Zimmer, J., Pasantes, J., Dagna Bricarelli, F., Keutel, J., Hustert, E., Wolf, U., Tommerup, N., Schempp, W., Scherer, G. <strong>Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.</strong> Cell 79: 1111-1120, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001137</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90041-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8001137">Wagner et al. (1994)</a> cited evidence that the murine Sox9 gene is on chromosome 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8001137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Role in Chondrogenesis</em></strong></p><p>
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During chondrogenesis in the mouse, Sox9 is coexpressed with Col2a1 (<a href="/entry/120140">120140</a>), the gene encoding type II collagen, the major cartilage matrix protein. COL2A1 is therefore a candidate regulatory target of SOX9. Regulatory sequences required for chondrocyte-specific expression of the COL2A1 gene have been localized to conserved sequences in the first intron in rats, mice, and humans. <a href="#4" class="mim-tip-reference" title="Bell, D. M., Leung, K. K. H., Wheatley, S. C., Ng, L. J., Zhou, S., Ling, K. W., Sham, M. H., Koopman, P., Tam, P. P. L., Cheah, K. S. E. <strong>SOX9 directly regulates the type-II collagen gene.</strong> Nature Genet. 16: 174-178, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9171829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9171829</a>] [<a href="https://doi.org/10.1038/ng0697-174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9171829">Bell et al. (1997)</a> showed that SOX9 protein binds specifically to sequences in the first intron of human COL2A1. Mutation of these sequences abolished SOX9 binding and chondrocyte-specific expression of a COL2A1-driven reporter gene (COL2A1-lacZ) in transgenic mice. Furthermore, ectopic expression of Sox9 transactivated both a COL2A1-driven reporter gene and the endogenous Col2a1 gene in transgenic mice. These results demonstrated that COL2A1 expression is directly regulated by SOX9 protein in vivo and implicated abnormal regulation of COL2A1 during chondrogenesis as a cause of the skeletal abnormalities associated with campomelic dysplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9171829" 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="#40" class="mim-tip-reference" title="Murakami, S., Kan, M., McKeehan, W. L., de Crombrugghe, B. <strong>Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway.</strong> Proc. Nat. Acad. Sci. 97: 1113-1118, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655493</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10655493[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.97.3.1113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655493">Murakami et al. (2000)</a> showed that expression of SOX9 is upregulated by fibroblast growth factors (FGFs; see <a href="/entry/601513">601513</a>) in primary chondrocytes and in SOX9-expressing mesenchymal cells. They further presented evidence that FGF stimulation of SOX9 expression is mediated by the mitogen-activated protein kinase (MAPK) cascade (see <a href="/entry/176948">176948</a>), a signal transduction pathway that is activated by growth factors such as FGF. The data strongly suggested that FGF and the MAPK pathway play an important role in the regulation of SOX9 expression during chondrocyte differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10655493" 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="#23" class="mim-tip-reference" title="Huang, W., Chung, U., Kronenberg, H. M., de Crombrugghe, B. <strong>The chondrogenic transcription factor Sox9 is a target of signaling by the parathyroid hormone-related peptide in the growth plate of endochondral bones.</strong> Proc. Nat. Acad. Sci. 98: 160-165, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11120880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11120880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11120880[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.98.1.160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11120880">Huang et al. (2001)</a> showed that the chondrogenic transcription factor SOX9 is a target of signaling by the parathyroid hormone-related peptide (PTHRP; <a href="/entry/168470">168470</a>) in the growth plate of endochondral bones. PTHRP strongly increased the phosphorylation of SOX9 and increased the SOX9-dependent activity of chondrocyte-specific enhancers in the gene for type II collagen (COL2A1) in transient transfection experiments. This increased enhancer activity did not occur with a SOX9 mutant harboring serine-to-alanine substitutions in its 2 consensus protein kinase A phosphorylation sites. Since SOX9 is a target of PTHRP signaling in prehypertrophic chondrocytes in the growth plate, <a href="#23" class="mim-tip-reference" title="Huang, W., Chung, U., Kronenberg, H. M., de Crombrugghe, B. <strong>The chondrogenic transcription factor Sox9 is a target of signaling by the parathyroid hormone-related peptide in the growth plate of endochondral bones.</strong> Proc. Nat. Acad. Sci. 98: 160-165, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11120880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11120880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11120880[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.98.1.160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11120880">Huang et al. (2001)</a> hypothesized that SOX9 mediates at least some effects of PTHRP in the growth plate and that the PTHRP-dependent increased transcriptional activity of SOX9 helps maintain the chondrocyte phenotype of cells in the prehypertrophic zone and inhibits their maturation to hypertrophic chondrocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11120880" 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>Komeda miniature rat Ishikawa (KMI) is a naturally occurring rat mutant that grows normally until 3 to 4 weeks of age, but then gradually develops longitudinal growth retardation without other organ abnormalities. <a href="#12" class="mim-tip-reference" title="Chikuda, H., Kugimiya, F., Hoshi, K., Ikeda, T., Ogasawara, T., Shimoaka, T., Kawano, H., Kamekura, S., Tsuchida, A., Yokoi, N., Nakamura, K., Komeda, K., Chung, U., Kawaguchi, H. <strong>Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.</strong> Genes Dev. 18: 2418-2429, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466490</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15466490[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.1224204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466490">Chikuda et al. (2004)</a> found that expression of Sox9, which is normally downregulated in postmitotic chondrocytes, persisted in the nuclei of KMI growth plate chondrocytes. They determined that KMI rats have a deletion in the cGKII gene (PRKG2; <a href="/entry/601591">601591</a>) that results in a truncated protein lacking the kinase domain. Transfection experiments in human cells revealed that cGKII phosphorylates SOX9 on ser181 and attenuates SOX9 function by inhibiting its nuclear entry. Furthermore, the impaired differentiation of cultured KMI chondrocytes was restored by silencing Sox9 by RNA interference. <a href="#12" class="mim-tip-reference" title="Chikuda, H., Kugimiya, F., Hoshi, K., Ikeda, T., Ogasawara, T., Shimoaka, T., Kawano, H., Kamekura, S., Tsuchida, A., Yokoi, N., Nakamura, K., Komeda, K., Chung, U., Kawaguchi, H. <strong>Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.</strong> Genes Dev. 18: 2418-2429, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466490</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15466490[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.1224204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15466490">Chikuda et al. (2004)</a> concluded that cGKII is a molecular switch that couples the cessation of proliferation and the start of hypertrophic chondrocyte differentiation through attenuating SOX9 function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15466490" 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="#64" class="mim-tip-reference" title="van Gastel, N., Stegen, S., Eelen, G., Schoors, S., Carlier, A., Daniels, V. W., Baryawno, N., Przybylski, D., Depypere, M., Stiers, P.-J., Lambrechts, D., Van Looveren, R., and 12 others. <strong>Lipid availability determines fate of skeletal progenitor cells via SOX9.</strong> Nature 579: 111-117, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32103177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32103177</a>] [<a href="https://doi.org/10.1038/s41586-020-2050-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32103177">Van Gastel et al. (2020)</a> showed that obstruction of vascular invasion during bone healing favors chondrogenic over osteogenic differentiation of skeletal progenitor cells. Unexpectedly, this process is driven by a decreased availability of extracellular lipids. When lipids are scarce, skeletal progenitors activate FOXO transcription factors (e.g., FOXO1, <a href="/entry/136533">136533</a>), which bind to the SOX9 promoter and increase its expression. Besides initiating chondrogenesis, SOX9 acts as a regulator of cellular metabolism by suppressing oxidation of fatty acids, and thus adapts the cells to an avascular life. <a href="#64" class="mim-tip-reference" title="van Gastel, N., Stegen, S., Eelen, G., Schoors, S., Carlier, A., Daniels, V. W., Baryawno, N., Przybylski, D., Depypere, M., Stiers, P.-J., Lambrechts, D., Van Looveren, R., and 12 others. <strong>Lipid availability determines fate of skeletal progenitor cells via SOX9.</strong> Nature 579: 111-117, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32103177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32103177</a>] [<a href="https://doi.org/10.1038/s41586-020-2050-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32103177">Van Gastel et al. (2020)</a> concluded that their results defined lipid scarcity as an important determinant of chondrogenic commitment, revealed a role for FOXO transcription factors during lipid starvation, and identified SOX9 as a critical metabolic mediator. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32103177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role in Sex Determination</em></strong></p><p>
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<a href="#38" class="mim-tip-reference" title="Morais da Silva, S., Hacker, A., Harley, V., Goodfellow, P., Swain, A., Lovell-Badge, R. <strong>Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birds.</strong> Nature Genet. 14: 62-68, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782821</a>] [<a href="https://doi.org/10.1038/ng0996-62" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782821">Morais da Silva et al. (1996)</a> found that, consistent with its role in sex determination, SOX9 expression closely follows differentiation of Sertoli cells in the mouse testis, in experimental sex reversal when fetal ovaries are grafted to adult kidneys, and in the chick where there is no evidence for an Sry gene (<a href="/entry/480000">480000</a>). The results suggested to the authors that SOX9 plays an essential role in sex determination, possibly immediately downstream of SRY in mammals, and that it functions as a critical Sertoli cell differentiation factor, perhaps in all vertebrates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782821" 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 most mammals, male development is triggered by the transient expression of the SRY gene on the Y chromosome, which initiates a cascade of gene interactions ultimately leading to the formation of a testis from the indifferent fetal gonad. Several genes, in particular SOX9, have a crucial role in this pathway. <a href="#8" class="mim-tip-reference" title="Bishop, C. E., Whitworth, D. J., Qin, Y., Agoulnik, A. I., Agoulnik, I. U., Harrison, W. R., Behringer, R. R., Overbeek, P. A. <strong>A transgenic insertion upstream of Sox9 is associated with dominant XX sex reversal in the mouse.</strong> Nature Genet. 26: 490-494, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11101852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11101852</a>] [<a href="https://doi.org/10.1038/82652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11101852">Bishop et al. (2000)</a> described a dominant insertion mutation, Odsex (Ods), in which XX mice carrying a 150-kb deletion approximately 1 Mb upstream of Sox9 developed as sterile XX males lacking Sry. During embryogenesis, wildtype XX fetal gonads downregulated Sox9 expression, whereas XY and XX Ods/+ fetal gonads upregulated and maintained its expression. <a href="#8" class="mim-tip-reference" title="Bishop, C. E., Whitworth, D. J., Qin, Y., Agoulnik, A. I., Agoulnik, I. U., Harrison, W. R., Behringer, R. R., Overbeek, P. A. <strong>A transgenic insertion upstream of Sox9 is associated with dominant XX sex reversal in the mouse.</strong> Nature Genet. 26: 490-494, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11101852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11101852</a>] [<a href="https://doi.org/10.1038/82652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11101852">Bishop et al. (2000)</a> proposed that the Ods mutation removed a long-range, gonad-specific regulatory element that mediates the repression of Sox9 expression in XX fetal gonads. This repression would normally be antagonized by Sry protein in XY embryos. The data were considered consistent with Sox9 being a direct downstream target of Sry and provided genetic evidence to support a general repressor model of sex determination in mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11101852" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The Ods mouse phenotype, described by <a href="#8" class="mim-tip-reference" title="Bishop, C. E., Whitworth, D. J., Qin, Y., Agoulnik, A. I., Agoulnik, I. U., Harrison, W. R., Behringer, R. R., Overbeek, P. A. <strong>A transgenic insertion upstream of Sox9 is associated with dominant XX sex reversal in the mouse.</strong> Nature Genet. 26: 490-494, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11101852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11101852</a>] [<a href="https://doi.org/10.1038/82652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11101852">Bishop et al. (2000)</a>, consists of female-to-male sex reversal in XX Ods/+ mice and a characteristic eye phenotype of microphthalmia with cataracts. The mutation arose in a transgenic line of mice carrying a tyrosinase (TYR; <a href="/entry/606933">606933</a>) minigene driven by the dopachrome tautomerase (DCT; <a href="/entry/191275">191275</a>) promoter region. The minigene integrated 1 Mb upstream of Sox9 and was accompanied by a deletion of 134 kb. Ods causes sex reversal in the absence of Sry by upregulating Sox9 expression and maintaining a male pattern of Sox9 expression in XX Ods/+ embryonic gonads. <a href="#50" class="mim-tip-reference" title="Qin, Y., Kong, L., Poirier, C., Truong, C., Overbeek, P. A., Bishop, C. E. <strong>Long-range activation of Sox9 in Odd Sex (Ods) mice.</strong> Hum. Molec. Genet. 13: 1213-1218, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115764/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115764</a>] [<a href="https://doi.org/10.1093/hmg/ddh141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115764">Qin et al. (2004)</a> reported that the 134-kb deletion alone was insufficient to cause sex reversal. Rather, the Dct promoter was capable of acting over a distance of 1 Mb to induce inappropriate expression of Sox9 in the retinal pigmented epithelium of the eye, causing the observed microphthalmia. In addition, it induced Sox9 expression in the melanocytes where it caused pigmentation defects. <a href="#50" class="mim-tip-reference" title="Qin, Y., Kong, L., Poirier, C., Truong, C., Overbeek, P. A., Bishop, C. E. <strong>Long-range activation of Sox9 in Odd Sex (Ods) mice.</strong> Hum. Molec. Genet. 13: 1213-1218, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115764/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115764</a>] [<a href="https://doi.org/10.1093/hmg/ddh141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115764">Qin et al. (2004)</a> proposed that Ods sex reversal may be due to the Dct promoter element interacting with gonad-specific enhancer elements to produce the observed male pattern expression of Sox9 in the embryonic gonads. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11101852+15115764" 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 mammals, male sex determination starts when the Y chromosome Sry gene is expressed within the undetermined male gonad. One of the earliest effects of SRY expression is to induce upregulation of SOX9 gene expression in the developing gonad. SOX9, like SRY, contains a high mobility group domain and is sufficient to induce testis differentiation in transgenic XX mice. Before sexual differentiation, SOX9 protein is initially found in the cytoplasm of undifferentiated gonads from both sexes. At the time of testis differentiation and anti-mullerian hormone (AMH; <a href="/entry/600957">600957</a>) expression, it becomes localized to the nuclear compartment in males, whereas it is downregulated in females. <a href="#18" class="mim-tip-reference" title="Gasca, S., Canizares, J., de Santa Barbara, P., Mejean, C., Poulat, F., Berta, P., Boizet-Bonhoure, B. <strong>A nuclear export signal within the high mobility group domain regulates the nucleocytoplasmic translocation of SOX9 during sexual determination.</strong> Proc. Nat. Acad. Sci. 99: 11199-11204, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12169669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12169669</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12169669[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.172383099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12169669">Gasca et al. (2002)</a> used NIH 3T3 cells as a model to examine the regulation of SOX9 nucleocytoplasmic shuttling. SOX9-transfected cells expressed nuclear and cytoplasmic SOX9, whereas transfected cells treated with the nuclear export inhibitor leptomycin B displayed an exclusive nuclear localization of SOX9. By using SOX9 deletion constructs in GFP fusion proteins, <a href="#18" class="mim-tip-reference" title="Gasca, S., Canizares, J., de Santa Barbara, P., Mejean, C., Poulat, F., Berta, P., Boizet-Bonhoure, B. <strong>A nuclear export signal within the high mobility group domain regulates the nucleocytoplasmic translocation of SOX9 during sexual determination.</strong> Proc. Nat. Acad. Sci. 99: 11199-11204, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12169669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12169669</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12169669[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.172383099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12169669">Gasca et al. (2002)</a> identified a functional nuclear export signal sequence between amino acids 134 and 147 of the SOX9 high mobility group box. More strikingly, they showed that inhibiting nuclear export with leptomycin B in mouse XX gonads cultured in vitro induced a sex reversal phenotype characterized by nuclear SOX9 and anti-mullerian hormone expression. These results indicated that the SOX9 nuclear export signal is essential for SOX9 sex-specific subcellular localization and could be part of a regulatory switch that represses (in females) or triggers (in males) male-specific sexual differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12169669" 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>To test whether SOX9 was sufficient to generate a fully fertile male in the absence of Sry, <a href="#49" class="mim-tip-reference" title="Qin, Y., Bishop, C. E. <strong>Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry.</strong> Hum. Molec. Genet. 14: 1221-1229, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15790596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15790596</a>] [<a href="https://doi.org/10.1093/hmg/ddi133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15790596">Qin and Bishop (2005)</a> constructed XY(Sry-) Ods/+ male mice, in which the male phenotype is controlled autosomally by the Ods mutation. Mice gradually became infertile by 5 to 6 months of life. XY(Sry-) Ods/+ males also failed to establish the correct male-specific pattern of vascularization at the time of sex determination. Increasing the amount of SOX9 by producing homozygous XY(Sry-) Ods/Ods males completely rescued the phenotype and restored correct vascular patterning and long-term fertility. <a href="#49" class="mim-tip-reference" title="Qin, Y., Bishop, C. E. <strong>Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry.</strong> Hum. Molec. Genet. 14: 1221-1229, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15790596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15790596</a>] [<a href="https://doi.org/10.1093/hmg/ddi133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15790596">Qin and Bishop (2005)</a> showed that activation of SOX9 in the gonad was sufficient to trigger all the downstream events needed for the development of a fully fertile male, and they provided additional evidence that Sox9 may downregulate Wnt4 (<a href="/entry/603490">603490</a>) expression in the gonad. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15790596" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role in Muscle Development</em></strong></p><p>
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<a href="#53" class="mim-tip-reference" title="Schmidt, K., Glaser, G.,, Wernig, A., Wegner, M., Rosorius, O. <strong>Sox8 is a specific marker for muscle satellite cells and inhibits myogenesis.</strong> J. Biol. Chem. 278: 29769-29775, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12782625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12782625</a>] [<a href="https://doi.org/10.1074/jbc.M301539200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12782625">Schmidt et al. (2003)</a> found that expression of mouse Sox8 and Sox9 was downregulated during myogenesis. Overexpression of Sox8 or Sox9 inhibited myotube formation of C2C12 cells and decreased expression of Myod (MYOD1; <a href="/entry/159970">159970</a>), an early marker of myogenic differentiation. In addition, overexpression of Sox8 or Sox9 negatively regulated the myogenin (MYOG; <a href="/entry/159980">159980</a>) promoter and repressed Myod-dependent myogenin expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12782625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Transcription Factor Activity</em></strong></p><p>
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By cell transfection experiments, <a href="#59" class="mim-tip-reference" title="Sudbeck, P., Schmitz, M. L., Baeuerle, P. A., Scherer, G. <strong>Sex reversal by loss of the C-terminal transactivation domain of human SOX9.</strong> Nature Genet. 13: 230-232, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640233</a>] [<a href="https://doi.org/10.1038/ng0696-230" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8640233">Sudbeck et al. (1996)</a> showed that SOX9 can transactivate transcription from a reporter plasmid through the motif AACAAAG, a sequence recognized by other HMG domain transcription factors. By fusing all or part of SOX9 to the DNA-binding domain of yeast Gal4, the transactivating function was mapped to a transcription activation domain at the C terminus of SOX9. With 1 exception, all SOX9 nonsense and frameshift mutations in patients with campomelic dysplasia and sex reversal lead to truncation of this domain, suggesting to <a href="#59" class="mim-tip-reference" title="Sudbeck, P., Schmitz, M. L., Baeuerle, P. A., Scherer, G. <strong>Sex reversal by loss of the C-terminal transactivation domain of human SOX9.</strong> Nature Genet. 13: 230-232, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640233</a>] [<a href="https://doi.org/10.1038/ng0696-230" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8640233">Sudbeck et al. (1996)</a> that impairment of gonadal and skeletal development in these cases results, at least in part, from loss of the transactivation of genes downstream of SOX9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8640233" 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>By yeast 2-hybrid analysis of a human embryo cDNA expression library, <a href="#79" class="mim-tip-reference" title="Zhou, R., Bonneaud, N., Yuan, C.-X., de Santa Barbara, P., Boizet, B., Schomber, T., Scherer, G., Roeder, R. G., Poulat, F., Berta, P. <strong>SOX9 interacts with a component of the human thyroid hormone receptor-associated protein complex.</strong> Nucleic Acids Res. 30: 3245-3252, 2002. Note: Erratum: Nucleic Acids Res. 30: 3917 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12136106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12136106</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12136106[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/10.1093/nar/gkf443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12136106">Zhou et al. (2002)</a> found that the transcription activation domain of SOX9 interacted with the proline-, glutamine-, and leucine-rich (PQL) domain of TRAP230 (MED12; <a href="/entry/300188">300188</a>), a component of the thyroid hormone receptor-associated protein (TRAP) complex. In vitro and in vivo assays confirmed that the proteins interact endogenously and associate with several other TRAP complex proteins in HeLa cell nuclear lysates. SOX9 and TRAP230 colocalized in nuclei of cultured human embryo chondrocytes. The isolated PQL domain of TRAP230 acted as a dominant-negative inhibitor of SOX9 activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12136106" 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="#63" class="mim-tip-reference" title="Tsuda, M., Takahashi, S., Takahashi, Y., Asahara, H. <strong>Transcriptional co-activators CREB-binding protein and p300 regulate chondrocyte-specific gene expression via association with Sox9.</strong> J. Biol. Chem. 278: 27224-27229, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12732631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12732631</a>] [<a href="https://doi.org/10.1074/jbc.M303471200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12732631">Tsuda et al. (2003)</a> found that SOX9 used CBP (CREBBP; <a href="/entry/600140">600140</a>) and p300 (EP300; <a href="/entry/602700">602700</a>) as transcriptional coactivators. SOX9 bound CBP and p300 in vitro and in vivo, and both coactivators enhanced SOX9-dependent COL2A1 promoter activity. Disruption of the CBP-SOX9 complex inhibited COL2A1 mRNA expression and differentiation of human mesenchymal stem cells into chondrocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12732631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Blache, P., van de Wetering, M., Duluc, I., Domon, C., Berta, P., Freund, J.-N., Clevers, H., Jay, P. <strong>SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes.</strong> J. Cell Biol. 166: 37-47, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15240568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15240568</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15240568[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/10.1083/jcb.200311021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15240568">Blache et al. (2004)</a> found that Sox9 was expressed in fetal mouse intestinal epithelium. Expression of Sox9 was dependent on activity of the Wnt (see <a href="/entry/164820">164820</a>) pathway. In human colon-derived epithelial cells, <a href="#9" class="mim-tip-reference" title="Blache, P., van de Wetering, M., Duluc, I., Domon, C., Berta, P., Freund, J.-N., Clevers, H., Jay, P. <strong>SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes.</strong> J. Cell Biol. 166: 37-47, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15240568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15240568</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15240568[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/10.1083/jcb.200311021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15240568">Blache et al. (2004)</a> demonstrated that SOX9 transcriptionally repressed the expression of CDX2 (<a href="/entry/600297">600297</a>) and MUC2 (<a href="/entry/158370">158370</a>), genes expressed in the villus compartment encoding markers of differentiated cells. <a href="#9" class="mim-tip-reference" title="Blache, P., van de Wetering, M., Duluc, I., Domon, C., Berta, P., Freund, J.-N., Clevers, H., Jay, P. <strong>SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes.</strong> J. Cell Biol. 166: 37-47, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15240568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15240568</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15240568[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/10.1083/jcb.200311021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15240568">Blache et al. (2004)</a> hypothesized that SOX9 function might contribute to the Wnt-dependent maintenance of an undifferentiated progenitor phenotype in the intestinal epithelium by repressing differentiation genes such as CDX2 and MUC2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15240568" 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>By expression of Sox9 or Sox10 (<a href="/entry/602229">602229</a>) in early Xenopus embryos, <a href="#60" class="mim-tip-reference" title="Taylor, K. M., LaBonne, C. <strong>SoxE factors function equivalently during neural crest and inner ear development and their activity is regulated by SUMOylation.</strong> Dev. Cell 9: 593-603, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16256735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16256735</a>] [<a href="https://doi.org/10.1016/j.devcel.2005.09.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16256735">Taylor and LaBonne (2005)</a> found that each factor could direct the formation of neural crest precursors and the development of a range of neural crest derivatives. They detected no differences in the activities of Sox9 and Sox10 in these assays. They identified Sumo1 (<a href="/entry/601912">601912</a>) and Ubc9 (UBE2I; <a href="/entry/601661">601661</a>) as Sox-interacting proteins that play a role in regulating the function of Sox9 and Sox10 during neural crest and inner ear development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16256735" 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>By analyzing embryonic Sox9-null mice and using gain-of-function experiments, <a href="#11" class="mim-tip-reference" title="Cheung, M., Chaboissier, M.-C., Mynett, A., Hirst, E., Schedl, A., Briscoe, J. <strong>The transcriptional control of trunk neural crest induction, survival, and delamination.</strong> Dev. Cell 8: 179-192, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15691760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15691760</a>] [<a href="https://doi.org/10.1016/j.devcel.2004.12.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15691760">Cheung et al. (2005)</a> determined that specification of trunk neural crest cells involves the coordinated activity of Sox9, Foxd3 (<a href="/entry/611539">611539</a>), and Slug (SNAI2; <a href="/entry/602150">602150</a>). Each transcription factor appeared to regulate the acquisition of distinct neural crest cell properties, while the combined expression of Sox9, Slug, and Foxd3 induced cells to manifest all the principal transcriptional and morphologic characteristics of neural crest cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15691760" 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>Prostaglandin D2 (<a href="/entry/176803">176803</a>) contributes to the development of the testis by recruiting cells of the supporting cell lineage to a Sertoli cell fate. <a href="#72" class="mim-tip-reference" title="Wilhelm, D., Hiramatsu, R., Mizusaki, H., Widjaja, L., Combes, A. N., Kanai, Y., Koopman, P. <strong>SOX9 regulates prostaglandin D synthase gene transcription in vivo to ensure testis development.</strong> J. Biol. Chem. 282: 10553-10560, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17277314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17277314</a>] [<a href="https://doi.org/10.1074/jbc.M609578200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17277314">Wilhelm et al. (2007)</a> found that Pgds was expressed in embryonic mouse Sertoli cells immediately after the onset of Sry and Sox9 expression. Pgds upregulation was mediated by Sox9, but not Sry, and required the binding of dimeric Sox9 to a paired SOX recognition site within the Pgds 5-prime flanking region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17277314" 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="#78" class="mim-tip-reference" title="Zalzali, H., Naudin, C., Bastide, P., Quittau-Prevostel, C., Yaghi, C., Poulat, F., Jay, P., Blache, P. <strong>CEACAM1, a SOX9 direct transcriptional target identified in the colon epithelium.</strong> Oncogene 27: 7131-7138, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18794798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18794798</a>] [<a href="https://doi.org/10.1038/onc.2008.331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18794798">Zalzali et al. (2008)</a> found that expression of epitope-tagged SOX9 in human colonic carcinoma cells upregulated the expression of CEACAM1 (<a href="/entry/109770">109770</a>). Conversely, Sox9-deficient mice showed reduced Ceacam1 expression in colon. The promoter regions of mouse, rat, and human CEACAM1 contain SOX9-binding motifs despite no other significant sequence homology, and chromatin immunoprecipitation analysis confirmed that SOX9 bound the human CEACAM1 promoter. In addition, the histone acetyltransferase p300 enhanced transactivation of CEACAM1 by the rat and human CEACAM1 promoters. <a href="#78" class="mim-tip-reference" title="Zalzali, H., Naudin, C., Bastide, P., Quittau-Prevostel, C., Yaghi, C., Poulat, F., Jay, P., Blache, P. <strong>CEACAM1, a SOX9 direct transcriptional target identified in the colon epithelium.</strong> Oncogene 27: 7131-7138, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18794798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18794798</a>] [<a href="https://doi.org/10.1038/onc.2008.331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18794798">Zalzali et al. (2008)</a> concluded that SOX9 regulates CEACAM1 expression in colon epithelium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18794798" 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="Adam, R. C., Yang, H., Rockowitz, S., Larsen, S. B., Nikolova, M., Oristian, D. S., Polak, L., Kadaja, M., Asare, A., Zheng, D., Fuchs, E. <strong>Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice.</strong> Nature 521: 366-370, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25799994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25799994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25799994[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/nature14289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25799994">Adam et al. (2015)</a> identified SOX9 as a crucial chromatin rheostat of hair follicle stem cell superenhancers, and provided functional evidence that superenhancers are dynamic, dense transcription factor-binding platforms that are acutely sensitive to pioneer master regulators whose levels define not only spatial and temporal features of lineage-status but also stemness, plasticity in transitional states, and differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25799994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Regulatory Elements</em></strong></p><p>
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SOX9 is expressed during chondrocyte differentiation and is upregulated in male and downregulated in female genital ridges during sex differentiation. To study the sex- and tissue-specific regulation of SOX9, <a href="#24" class="mim-tip-reference" title="Kanai, Y., Koopman, P. <strong>Structural and functional characterization of the mouse Sox9 promoter: implications for campomelic dysplasia.</strong> Hum. Molec. Genet. 8: 691-696, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072439</a>] [<a href="https://doi.org/10.1093/hmg/8.4.691" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10072439">Kanai and Koopman (1999)</a> defined the transcription start site and characterized the Sox9 promoter region in the mouse. The Sox9 proximal promoter shows moderately high nucleotide similarity between mouse and human. Transient transfection experiments using various deletion constructs at the 6.8-kb upstream region of the mouse Sox9 gene fused to a luciferase reporter showed that the interval between 193 and 73 bp from the transcription start site was essential for maximal promoter activity in cell lines and in primary male and female gonadal somatic cells and liver cells isolated from mouse embryos 13.5 days postcoitum. This minimal promoter region was shown by DNase I hypersensitive site assay to be in an 'open' state of chromatin structure in gonads of both sexes, but not in the liver. Promoter activity was higher in testis than in ovary and liver, but deletion of the region from -193 to -73 bp abolished this difference. <a href="#24" class="mim-tip-reference" title="Kanai, Y., Koopman, P. <strong>Structural and functional characterization of the mouse Sox9 promoter: implications for campomelic dysplasia.</strong> Hum. Molec. Genet. 8: 691-696, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072439</a>] [<a href="https://doi.org/10.1093/hmg/8.4.691" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10072439">Kanai and Koopman (1999)</a> concluded that the proximal promoter region is in part responsible for the sex- and tissue-specific expression of the SOX9 gene, and that more distal positive and negative elements contribute to its regulation in vivo, consistent with the observation that translocations upstream from the SOX9 gene can result in campomelic dysplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10072439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Bien-Willner, G. A., Stankiewicz, P., Lupski, J. R. <strong>SOX9cre1, a cis-acting regulatory element located 1.1 Mb upstream of SOX9, mediates its enhancement through the SHH pathway.</strong> Hum. Molec. Genet. 16: 1143-1156, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17409199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17409199</a>] [<a href="https://doi.org/10.1093/hmg/ddm061" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17409199">Bien-Willner et al. (2007)</a> identified a 2.1-kb cis-acting regulatory element 1.1 Mb upstream of the SOX9 gene, called SOX9cre1. This element increased the activity of a minimal SOX9 promoter in reporter constructs in a dose-dependent manner. The enhancer effect was also tissue-specific and was observed in human chondrosarcoma cell lines, but not in HeLa cells. SOX9cre1 contains a GLI1 (<a href="/entry/165220">165220</a>)-binding element, suggesting that SOX9 has a role in hedgehog (SHH; <a href="/entry/600725">600725</a>) signaling. Stimulation of primary human chondrocytes in culture with SHH increased endogenous SOX9 expression 3-fold. EMSA and chromatin immunoprecipitation studies showed a direct interaction between GLI1 and the putative GLI1-binding site in SOX9cre1. <a href="#7" class="mim-tip-reference" title="Bien-Willner, G. A., Stankiewicz, P., Lupski, J. R. <strong>SOX9cre1, a cis-acting regulatory element located 1.1 Mb upstream of SOX9, mediates its enhancement through the SHH pathway.</strong> Hum. Molec. Genet. 16: 1143-1156, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17409199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17409199</a>] [<a href="https://doi.org/10.1093/hmg/ddm061" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17409199">Bien-Willner et al. (2007)</a> concluded that SHH regulates SOX9 expression in human chondrocytes and chondrosarcomas via GLI1 binding to a far upstream enhancer region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17409199" 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="Sekido, R., Lovell-Badge, R. <strong>Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer.</strong> Nature 453: 930-934, 2008. Note: Erratum: Nature 456: 824 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18454134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18454134</a>] [<a href="https://doi.org/10.1038/nature06944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18454134">Sekido and Lovell-Badge (2008)</a> demonstrated that SRY (<a href="/entry/480000">480000</a>) binds to multiple elements within a Sox9 gonad-specific enhancer that they called TESCO (testis-specific enhancer of Sox9 core) in mice, and that it does so along with steroidogenic factor-1 (SF1), an orphan nuclear receptor encoded by the gene Nr5a1 (<a href="/entry/184757">184757</a>). Mutation, cotransfection, and sex-reversal studies all pointed to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate SOX9; then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. <a href="#54" class="mim-tip-reference" title="Sekido, R., Lovell-Badge, R. <strong>Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer.</strong> Nature 453: 930-934, 2008. Note: Erratum: Nature 456: 824 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18454134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18454134</a>] [<a href="https://doi.org/10.1038/nature06944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18454134">Sekido and Lovell-Badge (2008)</a> concluded that their results permitted further characterization of the molecular mechanisms regulating sex determination, their evolution, and their failure in cases of sex reversal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18454134" 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>After identifying 7 consensus GATA-binding sites within 3 kb of the transcriptional start site of SOX9, <a href="#15" class="mim-tip-reference" title="Fantauzzo, K. A., Kurban, M., Levy, B., Christiano, A. M. <strong>Trps1 and its target gene Sox9 regulate epithelial proliferation in the developing hair follicle and are associated with hypertrichosis.</strong> PLoS Genet. 8: e1003002, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23133399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23133399</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23133399[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1003002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23133399">Fantauzzo et al. (2012)</a> performed endogenous chromatin immunoprecipitation experiments in HEK293T cells and observed that TRPS1 (<a href="/entry/604386">604386</a>) bound up to 5 of those sites in the SOX9 promoter. Luciferase reporter promoter assays demonstrated that TRPS1 represses SOX9 transcription in a dose-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23133399" 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 in vivo high-throughput chromatin accessibility techniques, transgenic assays, and genome editing, <a href="#20" class="mim-tip-reference" title="Gonen, N., Futtner, C. R., Wood, S., Garcia-Moreno, S. A., Salamone, I. M., Samson, S. C., Sekido, R., Poulat, F., Maatouk, D. M., Lovell-Badge, R. <strong>Sex reversal following deletion of a single distal enhancer of Sox9.</strong> Science 360: 1469-1473, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29903884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29903884</a>] [<a href="https://doi.org/10.1126/science.aas9408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29903884">Gonen et al. (2018)</a> detected several novel gonadal regulatory elements in the 2-megabase gene desert upstream of Sox9. Although others are redundant, enhancer-13 (Enh13), a 557-basepair element located 565 kilobases 5-prime from the transcriptional start site, is essential to initiate mouse testis development; its deletion results in XY females with Sox9 transcript levels equivalent to those in XX gonads. <a href="#20" class="mim-tip-reference" title="Gonen, N., Futtner, C. R., Wood, S., Garcia-Moreno, S. A., Salamone, I. M., Samson, S. C., Sekido, R., Poulat, F., Maatouk, D. M., Lovell-Badge, R. <strong>Sex reversal following deletion of a single distal enhancer of Sox9.</strong> Science 360: 1469-1473, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29903884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29903884</a>] [<a href="https://doi.org/10.1126/science.aas9408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29903884">Gonen et al. (2018)</a> concluded that their data are consistent with the time-sensitive activity of SRY and indicate a strict order of enhancer usage. Enh13 is conserved and embedded within the 32.5-kilobase SR XY region, whose deletion in humans is associated with XY sex reversal, suggesting that it is also critical in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29903884" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role in Pigmentation</em></strong></p><p>
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<a href="#43" class="mim-tip-reference" title="Passeron, T., Valencia, J. C., Bertolotto, C., Hoashi, T., Le Pape, E., Takahashi, K., Ballotti, R., Hearing, V. J. <strong>SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation.</strong> Proc. Nat. Acad. Sci. 104: 13984-13989, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17702866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17702866</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17702866[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.0705117104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17702866">Passeron et al. (2007)</a> detected SOX9 mRNA and protein in normal human melanocytes in vitro and in vivo. Ultraviolet B exposure upregulated SOX9 expression and nuclear accumulation, and upregulation was mediated by cAMP and protein kinase A (see <a href="/entry/176911">176911</a>). Agouti signal protein (ASIP; <a href="/entry/600201">600201</a>), which decreases pigmentation and antagonizes the alpha-MSH (<a href="/entry/176830">176830</a>) signaling pathway, downregulated SOX9 expression. SOX9 regulated the MITF (<a href="/entry/156845">156845</a>) and DCT (<a href="/entry/191275">191275</a>) promoters. Overexpression of SOX9 increased MITF, DCT, and TYR (<a href="/entry/606933">606933</a>) proteins, which led to increased melanin production in cells. <a href="#43" class="mim-tip-reference" title="Passeron, T., Valencia, J. C., Bertolotto, C., Hoashi, T., Le Pape, E., Takahashi, K., Ballotti, R., Hearing, V. J. <strong>SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation.</strong> Proc. Nat. Acad. Sci. 104: 13984-13989, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17702866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17702866</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17702866[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.0705117104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17702866">Passeron et al. (2007)</a> concluded that SOX9 has a role in pigmentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17702866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role in Organ Maintenance</em></strong></p><p>
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Using lineage analysis, <a href="#17" class="mim-tip-reference" title="Furuyama, K., Kawaguchi, Y., Akiyama, H., Horiguchi, M., Kodama, S., Kuhara, T., Hosokawa, S., Elbahrawy, A., Soeda, T., Koizumi, M., Masui, T., Kawaguchi, M., Takaori, K., Doi, R., Nishi, E., Kakinoki, R., Deng, J. M., Behringer, R. R., Nakamura, T., Uemoto, S. <strong>Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine.</strong> Nature Genet. 43: 34-41, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21113154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21113154</a>] [<a href="https://doi.org/10.1038/ng.722" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21113154">Furuyama et al. (2011)</a> showed that Sox9-negative mouse hepatocytes arose from a Sox9-positive precursor pool. These Sox9-positive precursors were involved in liver regeneration following hepatic injury. Embryonic pancreatic Sox9-expressing cells differentiated into all types of mature cells, but their capacity for endocrine differentiation diminished shortly after birth, when endocrine cells detached from the epithelial lining of the ducts and formed the islets of Langerhans. Since SOX9 was expressed in proliferating intestinal crypt cells and in hepatic and pancreatic duct in the adult, <a href="#17" class="mim-tip-reference" title="Furuyama, K., Kawaguchi, Y., Akiyama, H., Horiguchi, M., Kodama, S., Kuhara, T., Hosokawa, S., Elbahrawy, A., Soeda, T., Koizumi, M., Masui, T., Kawaguchi, M., Takaori, K., Doi, R., Nishi, E., Kakinoki, R., Deng, J. M., Behringer, R. R., Nakamura, T., Uemoto, S. <strong>Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine.</strong> Nature Genet. 43: 34-41, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21113154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21113154</a>] [<a href="https://doi.org/10.1038/ng.722" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21113154">Furuyama et al. (2011)</a> concluded that SOX9 is involved in the continuous supply of cells from the progenitor pool. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21113154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role in Cancer</em></strong></p><p>
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<a href="#70" class="mim-tip-reference" title="Wang, H., Leav, I., Ibaragi, S., Wegner, M., Hu, G., Lu, M. L., Balk, S. P., Yuan, X. <strong>SOX9 is expressed in human fetal prostate epithelium and enhances prostate cancer invasion.</strong> Cancer Res. 68: 1625-1630, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18339840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18339840</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-07-5915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18339840">Wang et al. (2008)</a> noted that, in adult prostate, SOX9 expression is restricted to basal epithelium. By immunohistochemical analysis of human fetal prostate, they found that SOX9 was initially expressed in prostate epithelium at 19 weeks gestation. By 22.5 weeks, expression was more pronounced at the tip of the branching prostate gland that was expanding into the surrounding stroma. In xenografts of human prostate cancer cell lines, SOX9 overexpression enhanced tumor growth, whereas knockdown of SOX9 via small interfering RNA suppressed tumor growth. <a href="#70" class="mim-tip-reference" title="Wang, H., Leav, I., Ibaragi, S., Wegner, M., Hu, G., Lu, M. L., Balk, S. P., Yuan, X. <strong>SOX9 is expressed in human fetal prostate epithelium and enhances prostate cancer invasion.</strong> Cancer Res. 68: 1625-1630, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18339840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18339840</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-07-5915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18339840">Wang et al. (2008)</a> concluded that during normal development SOX9 allows the prostate epithelium to outgrow into the mesenchyme and then provides basal cell support for development and maintenance of the luminal epithelium. They suggested that these functions of SOX9 are subverted in prostate cancer to support tumor growth and invasion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18339840" 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="#44" class="mim-tip-reference" title="Passeron, T., Valencia, J. C., Namiki, T., Vieira, W. D., Passeron, H., Miyamura, Y., Hearing, V. J. <strong>Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid.</strong> J. Clin. Invest. 119: 954-963, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19273910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19273910</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19273910[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/JCI34015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19273910">Passeron et al. (2009)</a> found weak or absent SOX9 expression in 37 (95%) of 39 melanoma (<a href="/entry/155600">155600</a>) specimens. SOX9 expression was positive in normal skin areas, but weak or negative in 18 (81.8%) of 22 nevi, in 54 (96.4%) of 56 primary melanomas, and in 100% (20 of 20) metastatic melanomas. Thus, SOX9 expression decreased as melanocytic cells progressed from the normal condition to the premalignant (nevi) to the transformed state, and was completely negative in the most advanced (metastatic) state of malignancy. SOX9 functioned by binding the CDKN1A (<a href="/entry/116899">116899</a>) promoter, which resulted in strong suppression of cell growth in vivo. SOX9 also decreased PRAME (<a href="/entry/606021">606021</a>) protein levels in melanoma cells and restored sensitivity to retinoic acid. SOX9 overexpression in melanoma cell lines inhibited tumorigenicity both in mice and in a human ex vivo model of melanoma. Treatment of melanoma cell lines with PGD2 (<a href="/entry/176803">176803</a>) increased SOX9 expression and restored sensitivity to retinoic acid. Combined treatment with PGD2 and retinoic acid substantially decreased tumor growth in human ex vivo and mouse in vivo models of melanoma. These results provided insight into the pathophysiology of melanoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19273910" 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="#69" class="mim-tip-reference" title="Wang, G., Lunardi, A., Zhang, J., Chen, Z., Ala, U., Webster, K. A., Tay, Y., Gonzalez-Billalabeitia, E., Egia, A., Shaffer, D. R., Carver, B., Liu, X.-S., Taulli, R., Kuo, W. P., Nardella, C., Signoretti, S., Cordon-Cardo, C., Gerald, W. L., Pandolfi, P. P. <strong>Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion.</strong> Nature Genet. 45: 739-746, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23727861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23727861</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23727861[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.2654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23727861">Wang et al. (2013)</a> showed that ZBTB7A (<a href="/entry/605878">605878</a>) physically interacts with SOX9 during prostate tumorigenesis and functionally antagonizes its transcriptional activity on key target genes such as MIA (<a href="/entry/601340">601340</a>), which is involved in tumor cell invasion, and H19 (<a href="/entry/103280">103280</a>), a long noncoding RNA precursor for an RB (see <a href="/entry/614041">614041</a>)-targeting microRNA (MIR675; <a href="/entry/615509">615509</a>). These and other results showed that the oncosuppressive function of ZBTB7A directly impinges on the oncogenic activity of SOX9 and that ZBTB7A loss in the prostate favors senescence bypass, increased proliferation rate, resistance to apoptosis, and greater invasive potential. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23727861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Effects of Chromosomal Translocations on SOX9</em></strong></p><p>
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Many patients with campomelic dysplasia have chromosomal translocations involving regions surrounding or including the SOX9 gene. <a href="#68" class="mim-tip-reference" title="Wagner, T., Wirth, J., Meyer, J., Zabel, B., Held, M., Zimmer, J., Pasantes, J., Dagna Bricarelli, F., Keutel, J., Hustert, E., Wolf, U., Tommerup, N., Schempp, W., Scherer, G. <strong>Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.</strong> Cell 79: 1111-1120, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001137</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90041-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8001137">Wagner et al. (1994)</a> found that the 17q breakpoints in 3 campomelic dysplasia patients with translocations mapped 50 kb or more from the SOX9 gene. <a href="#73" class="mim-tip-reference" title="Wirth, J., Wagner, T., Meyer, J., Pfeiffer, R. A., Tietze, H.-U., Schempp, W., Scherer, G. <strong>Translocation breakpoints in three patients with campomelic dysplasia and autosomal sex reversal map more than 130 kb from SOX9.</strong> Hum. Genet. 97: 186-193, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8566951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8566951</a>] [<a href="https://doi.org/10.1007/BF02265263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8566951">Wirth et al. (1996)</a> showed that the breakpoints in 2 affected patients reported by <a href="#68" class="mim-tip-reference" title="Wagner, T., Wirth, J., Meyer, J., Zabel, B., Held, M., Zimmer, J., Pasantes, J., Dagna Bricarelli, F., Keutel, J., Hustert, E., Wolf, U., Tommerup, N., Schempp, W., Scherer, G. <strong>Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.</strong> Cell 79: 1111-1120, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001137</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90041-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8001137">Wagner et al. (1994)</a> were more than 130 kb 5-prime of SOX9, as was the breakpoint in a third patient with CMPD and a de novo t(6;17) translocation. The last patient was a phenotypic female with XY sex chromosome constitution, as were the 3 previously described CMPD translocation cases. <a href="#73" class="mim-tip-reference" title="Wirth, J., Wagner, T., Meyer, J., Pfeiffer, R. A., Tietze, H.-U., Schempp, W., Scherer, G. <strong>Translocation breakpoints in three patients with campomelic dysplasia and autosomal sex reversal map more than 130 kb from SOX9.</strong> Hum. Genet. 97: 186-193, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8566951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8566951</a>] [<a href="https://doi.org/10.1007/BF02265263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8566951">Wirth et al. (1996)</a> reviewed the mechanisms by which translocation breakpoints upstream from the SOX9 gene can result in defective expression during embryonic development. In their study, <a href="#73" class="mim-tip-reference" title="Wirth, J., Wagner, T., Meyer, J., Pfeiffer, R. A., Tietze, H.-U., Schempp, W., Scherer, G. <strong>Translocation breakpoints in three patients with campomelic dysplasia and autosomal sex reversal map more than 130 kb from SOX9.</strong> Hum. Genet. 97: 186-193, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8566951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8566951</a>] [<a href="https://doi.org/10.1007/BF02265263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8566951">Wirth et al. (1996)</a> investigated whether there was any difference in the expression of SOX9 alleles on the normal versus the translocation chromosome. No significant difference was found in the study of a lymphoblastoid cell line; however, they pointed out that this may not accurately reflect the situation of regulated expression of SOX9 during embryonic development. It had not been possible to analyze SOX9 expression in embryonic tissue from CMPD translocation cases. In a note added in proof, they referred to 3 additional de novo translocation or inversion cases involving the distal 17q in patients with CMPD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8566951+8001137" 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>Because chromosomal breakpoints map 50 kb or more from the SOX9 gene and CMPD may be a contiguous gene syndrome (<a href="#52" class="mim-tip-reference" title="Schmickel, R. D. <strong>Contiguous gene syndromes: a component of recognizable syndromes.</strong> J. Pediat. 109: 231-241, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3016222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3016222</a>] [<a href="https://doi.org/10.1016/s0022-3476(86)80377-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3016222">Schmickel, 1986</a>), <a href="#41" class="mim-tip-reference" title="Ninomiya, S., Isomura, M., Narahara, K., Seino, Y., Nakamura, Y. <strong>Isolation of a testis-specific cDNA on chromosome 17q from a region adjacent to the breakpoint of t(12;17) observed in a patient with acampomelic campomelic dysplasia and sex reversal.</strong> Hum. Molec. Genet. 5: 69-72, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8789441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8789441</a>] [<a href="https://doi.org/10.1093/hmg/5.1.69" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8789441">Ninomiya et al. (1996)</a> cloned the breakpoint in the patient in search of a second gene associated with this syndrome. They isolated a cDNA adjacent to the breakpoint. Specific expression of this gene in testis suggested its candidacy for some role in CMPD and/or sex reversal. The mRNA, approximately 3.7 kb long, was expressed in testis as demonstrated by Northern blot analysis. However, they were unable to find any long open reading frame (ORF) in the 3.5-kb cDNA sequence or to detect any peptide following an in vitro translation experiment using RNA transcribed from this cDNA. Consequently, they speculated that the gene may play a critical role in differentiation or sex determination as a functional RNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3016222+8789441" 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>Whereas mutations in the ORF of SOX9 cause haploinsufficiency and campomelic dysplasia, the effects of translocations 5-prime to SOX9 were unclear and prompted <a href="#75" class="mim-tip-reference" title="Wunderle, V. M., Critcher, R., Hastie, N., Goodfellow, P. N., Schedl, A. <strong>Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia.</strong> Proc. Nat. Acad. Sci. 95: 10649-10654, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9724758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9724758</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9724758[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.18.10649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9724758">Wunderle et al. (1998)</a> to test whether these rearrangements also cause haploinsufficiency by altering spatial and temporal expression of SOX9. For this purpose, they generated mice transgenic for human SOX9-lacZ YACs containing variable amounts of DNA sequences upstream of SOX9. They showed that elements necessary for SOX9 expression during skeletal development are highly conserved between mouse and human and that a rearrangement upstream of SOX9, similar to those observed in campomelic dysplasia patients, leads to a substantial reduction of SOX9 expression, particularly in chondrogenic tissues. Thus, important regulatory elements are scattered over a large region upstream of SOX9 and explain how particular aspects of the CD phenotype are caused by chromosomal rearrangements 5-prime to SOX9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9724758" 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>As noted earlier, several campomelic dysplasia translocation and inversion cases have been described with breakpoints outside the coding region, mapping to locations more than 130 kb proximal to SOX9. These cases are generally less severely affected than cases with SOX9 coding region mutations, as borne out by 3 new translocation cases presented by <a href="#46" class="mim-tip-reference" title="Pfeifer, D., Kist, R., Dewar, K., Devon, K., Lander, E. S., Birren, B., Korniszewski, L., Back, E., Scherer, G. <strong>Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region.</strong> Am. J. Hum. Genet. 65: 111-124, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364523</a>] [<a href="https://doi.org/10.1086/302455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364523">Pfeifer et al. (1999)</a>. They cloned the region extending 1.2 Mb upstream of the SOX9 gene in overlapping BAC and PAC clones and established a restriction map with rare-cutter enzymes. With STS-content mapping in somatic cell hybrids, as well as with FISH, they mapped precisely the breakpoints of 3 new and 3 previously described CMPD cases. The 6 CMPD breakpoints mapped to an interval 140 to 950 kb proximal to the SOX9 gene. With exon trapping, they isolated 5 potential exons from a YAC that spanned the region, 4 of which could be placed in the contig in the vicinity of the breakpoints. These potential exons showed the same transcriptional orientation, but only 2 had an ORF. <a href="#46" class="mim-tip-reference" title="Pfeifer, D., Kist, R., Dewar, K., Devon, K., Lander, E. S., Birren, B., Korniszewski, L., Back, E., Scherer, G. <strong>Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region.</strong> Am. J. Hum. Genet. 65: 111-124, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364523</a>] [<a href="https://doi.org/10.1086/302455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364523">Pfeifer et al. (1999)</a> failed to detect expression of these fragments in several human and mouse cDNA libraries, as well as on Northern blots. Genomic sequence totaling 1,063 kb from the SOX9 5-prime flanking region was determined and analyzed, but no genes or transcripts could be identified. Together, these data suggested that chromosomal rearrangements most likely removed one or more cis-regulatory elements from the extended SOX9 control region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role in Limb Development</em></strong></p><p>
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By combining experiments and modeling, <a href="#51" class="mim-tip-reference" title="Raspopovic, J., Marcon, L., Russo, L., Sharpe, J. <strong>Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients.</strong> Science 345: 566-570, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25082703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25082703</a>] [<a href="https://doi.org/10.1126/science.1252960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25082703">Raspopovic et al. (2014)</a> revealed evidence that a Turing network implemented by BMP2 (<a href="/entry/112261">112261</a>), SOX9, and Wnt (see <a href="/entry/164820">164820</a>) drives digit specification during development. <a href="#51" class="mim-tip-reference" title="Raspopovic, J., Marcon, L., Russo, L., Sharpe, J. <strong>Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients.</strong> Science 345: 566-570, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25082703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25082703</a>] [<a href="https://doi.org/10.1126/science.1252960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25082703">Raspopovic et al. (2014)</a> developed a realistic 2-dimensional simulation of digit patterning and showed that this network, when modulated by morphogen gradients, recapitulates the expression patterns of SOX9 in the wildtype and in perturbation experiments. <a href="#51" class="mim-tip-reference" title="Raspopovic, J., Marcon, L., Russo, L., Sharpe, J. <strong>Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients.</strong> Science 345: 566-570, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25082703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25082703</a>] [<a href="https://doi.org/10.1126/science.1252960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25082703">Raspopovic et al. (2014)</a> concluded that their systems biology approach revealed how a combination of growth, morphogen gradients, and a self-organizing Turing network can achieve robust and reproducible pattern formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25082703" 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="#21" class="mim-tip-reference" title="Gordon, C. T., Tan, T. Y., Benko, S., FitzPatrick, D., Lyonnet, S., Farlie, P. G. <strong>Long-range regulation at the SOX9 locus in development and disease.</strong> J. Med. Genet. 46: 649-656, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19473998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19473998</a>] [<a href="https://doi.org/10.1136/jmg.2009.068361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19473998">Gordon et al. (2009)</a> reviewed the spectrum of lesions surrounding the SOX9 gene, noting that translocation breakpoints upstream of SOX9 can be clustered into 3 groups, with a trend towards less severe skeletal phenotypes as the distance of each cluster from the SOX9 gene increases. The authors stated that the identification of novel lesions surrounding SOX9 supported the existence of tissue-specific enhancers acting over a long distance to regulate SOX9 expression during craniofacial development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19473998" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Campomelic Dysplasia with or without Sex Reversal</em></strong></p><p>
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In 6 of 9 patients with campomelic dysplasia (<a href="/entry/114290">114290</a>), <a href="#16" class="mim-tip-reference" title="Foster, J. W., Dominguez-Steglich, M. A., Guioli, S., Kwok, C., Weller, P. A., Stevanovic, M., Weissenbach, J., Mansour, S., Young, I. D., Goodfellow, P. N., Brook, J. D., Schafer, A. J. <strong>Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.</strong> Nature 372: 525-530, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7990924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7990924</a>] [<a href="https://doi.org/10.1038/372525a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7990924">Foster et al. (1994)</a> identified mutations in single alleles of the SOX9 gene. The 3 mutations described in detail would be expected to destroy gene function; 2 caused frameshifts that led to premature chain termination and loss of one-third of the protein (<a href="#0002">608160.0002</a>, <a href="#0003">608160.0003</a>), and 1 caused a premature termination that truncated the protein at 40% of its predicted length (<a href="#0001">608160.0001</a>). Both parents of 2 of the patients did not have the mutation. The de novo appearance of a mutation in a sex-reversed campomelic patient established that alterations in SOX9 caused both abnormalities. The findings indicated that SOX9 is involved in both bone formation and control of testis development. <a href="#16" class="mim-tip-reference" title="Foster, J. W., Dominguez-Steglich, M. A., Guioli, S., Kwok, C., Weller, P. A., Stevanovic, M., Weissenbach, J., Mansour, S., Young, I. D., Goodfellow, P. N., Brook, J. D., Schafer, A. J. <strong>Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.</strong> Nature 372: 525-530, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7990924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7990924</a>] [<a href="https://doi.org/10.1038/372525a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7990924">Foster et al. (1994)</a> suggested that campomelic dysplasia is an autosomal dominant disorder, as they did not detect mutations in both SOX9 alleles of any patient. Dominance appeared to be due to haploinsufficiency rather than gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7990924" 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="#68" class="mim-tip-reference" title="Wagner, T., Wirth, J., Meyer, J., Zabel, B., Held, M., Zimmer, J., Pasantes, J., Dagna Bricarelli, F., Keutel, J., Hustert, E., Wolf, U., Tommerup, N., Schempp, W., Scherer, G. <strong>Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.</strong> Cell 79: 1111-1120, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001137</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90041-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8001137">Wagner et al. (1994)</a> likewise identified inactivating mutations in 1 SOX9 allele in nontranslocation CMPD-SOX9 cases pointing to haploinsufficiency for SOX9 as the cause of both campomelic dysplasia and autosomal XY sex reversal (see <a href="#0005">608160.0005</a>). The 17q breakpoints in 3 translocation cases mapped 50 kb or more from SOX9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8001137" 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="#28" class="mim-tip-reference" title="Kwok, C., Weller, P. A., Guioli, S., Foster, J. W., Mansour, S., Zuffardi, O., Punnett, H. H., Dominguez-Steglich, M. A., Brook, J. D., Young, I. D., Goodfellow, P. N., Schafer, A. J. <strong>Mutations in SOX9, the gene responsible for campomelic dysplasia and autosomal sex reversal.</strong> Am. J. Hum. Genet. 57: 1028-1036, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7485151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7485151</a>]" pmid="7485151">Kwok et al. (1995)</a> analyzed the SOX9 gene in 9 patients with campomelic dysplasia, 2 of whom had chromosome 17 rearrangements, and identified heterozygosity for 2 missense mutations, 3 frameshift mutations, and a splice site mutation, respectively, in 6 of the patients with no cytologically detectable chromosomal aberrations. An identical frameshift mutation (<a href="#0013">608160.0013</a>) was found in 2 unrelated 46,XY patients, 1 exhibiting a male phenotype and the other displaying a female phenotype (XY sex reversal). <a href="#28" class="mim-tip-reference" title="Kwok, C., Weller, P. A., Guioli, S., Foster, J. W., Mansour, S., Zuffardi, O., Punnett, H. H., Dominguez-Steglich, M. A., Brook, J. D., Young, I. D., Goodfellow, P. N., Schafer, A. J. <strong>Mutations in SOX9, the gene responsible for campomelic dysplasia and autosomal sex reversal.</strong> Am. J. Hum. Genet. 57: 1028-1036, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7485151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7485151</a>]" pmid="7485151">Kwok et al. (1995)</a> noted that these results were consistent with the hypothesis that CMPD results from haploinsufficiency of SOX9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7485151" 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>Prompted by the observation that mutations of the SOX9 gene can cause campomelic dysplasia with 46,XY sex reversal, <a href="#27" class="mim-tip-reference" title="Kwok, C., Goodfellow, P. N., Hawkins, J. R. <strong>Evidence to exclude SOX9 as a candidate gene for XY sex reversal without skeletal malformation.</strong> J. Med. Genet. 33: 800-801, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8880588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8880588</a>] [<a href="https://doi.org/10.1136/jmg.33.9.800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8880588">Kwok et al. (1996)</a> examined the entire coding region of the SOX9 gene in 30 46,XY patients with abnormalities of sexual development but without any skeletal abnormalities. Of the 30 patients, gonadal dysgenesis was diagnosed in 12 and partial gonadal dysgenesis in 14. Except for a C-to-T polymorphism at nucleotide 507 in 1 person, no other abnormalities of the SOX9 were found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8880588" 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="#55" class="mim-tip-reference" title="Sock, E., Pagon, R. A., Keymolen, K., Lissens, W., Wegner, M., Scherer, G. <strong>Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia.</strong> Hum. Molec. Genet. 12: 1439-1447, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12783851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12783851</a>] [<a href="https://doi.org/10.1093/hmg/ddg158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12783851">Sock et al. (2003)</a> presented 2 CMPD patients with de novo mutations in a conserved region preceding the HMG domain of SOX9. A long-term survivor with the acampomelic form of CMPD had an ala76-to-glu amino acid substitution (<a href="#0009">608160.0009</a>), while a severely affected CMPD patient had an in-frame deletion of amino acid residues 66 through 75 (<a href="#0010">608160.0010</a>). The conserved domain functions in the related transcription factor SOX10 as a DNA-dependent dimerization domain. The authors demonstrated that like SOX10, SOX9 binds cooperatively as a dimer to response elements in regulatory regions of some target genes such as the cartilage genes COL11A2 (<a href="/entry/120290">120290</a>) and cartilage-derived retinoic acid-sensitive protein (MIA/CDRAP; <a href="/entry/601340">601340</a>). Dimerization and the resulting capacity to activate promoters via dimeric binding sites was lost in both mutant SOX9 proteins while other features involved in SOX9 function remained unaltered. The authors concluded that the dimerization domain is a third domain essential for SOX9 function during chondrogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12783851" 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-year-old 46,XY girl with acampomelic campomelic dysplasia and complete sex reversal and her mildly affected mother, <a href="#31" class="mim-tip-reference" title="Lecointre, C., Pichon, O., Hamel, A., Heloury, Y., Michel-Calemard, L., Morel, Y., David, A., Le Caignec, C. <strong>Familial acampomelic form of campomelic dysplasia caused by a 960 kb deletion upstream of SOX9.</strong> Am. J. Med. Genet. 149A: 1183-1189, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19449405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19449405</a>] [<a href="https://doi.org/10.1002/ajmg.a.32830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19449405">Lecointre et al. (2009)</a> identified heterozygosity for a 960-kb deletion upstream of the SOX9 gene (<a href="#0015">608160.0015</a>). The authors stated that this deletion narrowed the minimum critical region and reduced the number of highly conserved sequence elements responsible for acampomelic campomelic dysplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19449405" 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 10-year-old Japanese boy with mild campomelic dysplasia, <a href="#35" class="mim-tip-reference" title="Matsushita, M., Kitoh, H., Kaneko, H., Mishima, K., Kadono, I., Ishiguro, N., Nishimura, G. <strong>A novel SOX9 H169Q mutation in a family with overlapping phenotype of mild campomelic dysplasia and small patella syndrome.</strong> Am. J. Med. Genet. 161A: 2528-2534, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24038782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24038782</a>] [<a href="https://doi.org/10.1002/ajmg.a.36134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24038782">Matsushita et al. (2013)</a> identified a heterozygous missense mutation in SOX9 (H169Q; <a href="#0021">608160.0021</a>) that was inherited from his mother, who showed minimal clinical findings of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24038782" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Pierre Robin Sequence</em></strong></p><p>
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<a href="#5" class="mim-tip-reference" title="Benko, S., Fantes, J. A., Amiel, J., Kleinjan, D.-J., Thomas, S., Ramsay, J., Jamshidi, N., Essafi, A., Heaney, S., Gordon, C. T., McBride, D., Golzio, C., and 20 others. <strong>Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence.</strong> Nature Genet. 41: 359-364, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19234473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19234473</a>] [<a href="https://doi.org/10.1038/ng.329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19234473">Benko et al. (2009)</a> reported several lines of evidence for the existence of a 17q24 locus underlying isolated Pierre Robin sequence (<a href="/entry/261800">261800</a>), including linkage analysis results, a clustering of translocation breakpoints 1.06 to 1.23 Mb upstream of the SOX9 gene, and microdeletions that were approximately 1.5 Mb centromeric and 1.5 Mb telomeric of SOX9. They identified a heterozygous point mutation in an evolutionarily conserved region of DNA with in vitro and in vivo features of a developmental enhancer; the mutation abrogated the in vitro enhancer function and altered binding of the transcription factor MSX1 (<a href="/entry/142983">142983</a>) compared to wildtype. In the developing mouse mandible, the 3-Mb region bounded by the microdeletions showed a regionally specific chromatin decompaction in cells expressing SOX9. <a href="#5" class="mim-tip-reference" title="Benko, S., Fantes, J. A., Amiel, J., Kleinjan, D.-J., Thomas, S., Ramsay, J., Jamshidi, N., Essafi, A., Heaney, S., Gordon, C. T., McBride, D., Golzio, C., and 20 others. <strong>Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence.</strong> Nature Genet. 41: 359-364, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19234473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19234473</a>] [<a href="https://doi.org/10.1038/ng.329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19234473">Benko et al. (2009)</a> concluded that some cases of Pierre Robin sequence may result from developmental misexpression of SOX9 due to disruption of very-long-range cis-regulatory elements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19234473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Cooks Syndrome</em></strong></p><p>
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In affected members of 4 unrelated families with a phenotype consistent with Cooks syndrome (<a href="/entry/106995">106995</a>), <a href="#26" class="mim-tip-reference" title="Kurth, I., Klopocki, E., Stricker, S., van Oosterwijk, J., Vanek, S., Altmann, J., Santos, H. G., van Harssel, J. J. T., de Ravel, T., Wilkie, A. O. M., Gal, A., Mundlos, S. <strong>Duplications of noncoding elements 5-prime of SOX9 are associated with brachydactyly-anonychia. (Letter)</strong> Nature Genet. 41: 862-863, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19639023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19639023</a>] [<a href="https://doi.org/10.1038/ng0809-862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19639023">Kurth et al. (2009)</a> identified overlapping duplications in a 2-Mb interval on chromosome 17q24.3, with a minimal critical area of 1.2 Mb. The region encompassed a large gene desert between KCNJ2 (<a href="/entry/600681">600681</a>) and SOX9. The duplications were confirmed by quantitative PCR and were not detected in more than 400 control DNA samples. The duplications occurred de novo in 2 families. <a href="#26" class="mim-tip-reference" title="Kurth, I., Klopocki, E., Stricker, S., van Oosterwijk, J., Vanek, S., Altmann, J., Santos, H. G., van Harssel, J. J. T., de Ravel, T., Wilkie, A. O. M., Gal, A., Mundlos, S. <strong>Duplications of noncoding elements 5-prime of SOX9 are associated with brachydactyly-anonychia. (Letter)</strong> Nature Genet. 41: 862-863, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19639023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19639023</a>] [<a href="https://doi.org/10.1038/ng0809-862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19639023">Kurth et al. (2009)</a> suggested that the duplications involved putative regulatory elements of SOX9 and may induce SOX9 misexpression and/or overexpression at specific time points during development, resulting in abnormal digit and nail development. In mouse embryo, Sox9 was strongly expressed in the distal mesenchymal condensations that develop into terminal phalanges. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19639023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>46,XX Sex Reversal 2</em></strong></p><p>
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In a family with 46,XX testicular disorder of sex development (SRXX2; <a href="/entry/278850">278850</a>) in which 3 adult males (2 brothers and a paternal uncle) were determined to be female according to karyotype (46,XX) and were negative for the SRY gene, <a href="#13" class="mim-tip-reference" title="Cox, J. J., Willatt, L., Homfray, T., Woods, C. G. <strong>A SOX9 duplication and familial 46,XX developmental testicular disorder. (Letter)</strong> New Eng. J. Med. 364: 91-93, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21208124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21208124</a>] [<a href="https://doi.org/10.1056/NEJMc1010311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21208124">Cox et al. (2011)</a> identified a heterozygous 178-kb duplication 600 kb upstream of SOX9 (<a href="#0014">608160.0014</a>). The duplication was arranged in tandem in wildtype orientation, and the joining points of the duplicated segments were uncorrupted. All affected family members carried the duplication in heterozygosity as did the proband's healthy, fertile 46,XY father. Affected individuals were infertile with azoospermia. In 2 men the testes had been removed and prostheses placed during their 20s because of testicular pain secondary to testosterone replacement. Histologic exams showed the presence of Leydig and Sertoli cells, severely diminished and atrophied seminiferous tubules, and no spermatogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21208124" 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 two 46,XX SRY-negative Italian brothers, who were phenotypically normal males but had hypotrophic testes and azoospermia, <a href="#66" class="mim-tip-reference" title="Vetro, A., Ciccone, R., Giorda, R., Patricelli, M. G., Della Mina, E., Forlino, A., Zuffardi, O. <strong>XX males SRY negative: a confirmed cause of infertility.</strong> J. Med. Genet. 48: 710-712, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21653197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21653197</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21653197">Vetro et al. (2011)</a> identified heterozygosity for a 96-kb triplication located 500 kb upstream of the SOX9 gene (<a href="#0016">608160.0016</a>) that was not present in their 2 fertile sisters and mother. The 2 brothers shared the same paternal haplotype for the SOX9 region, supporting the possibility that their deceased unaffected father was the carrier of the triplication. <a href="#66" class="mim-tip-reference" title="Vetro, A., Ciccone, R., Giorda, R., Patricelli, M. G., Della Mina, E., Forlino, A., Zuffardi, O. <strong>XX males SRY negative: a confirmed cause of infertility.</strong> J. Med. Genet. 48: 710-712, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21653197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21653197</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21653197">Vetro et al. (2011)</a> stated that this was the shortest region of amplification upstream of SOX9 reported to be associated with 46,XX SRY-negative infertile males, and noted that, like the duplication reported by <a href="#13" class="mim-tip-reference" title="Cox, J. J., Willatt, L., Homfray, T., Woods, C. G. <strong>A SOX9 duplication and familial 46,XX developmental testicular disorder. (Letter)</strong> New Eng. J. Med. 364: 91-93, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21208124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21208124</a>] [<a href="https://doi.org/10.1056/NEJMc1010311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21208124">Cox et al. (2011)</a>, the triplication did not seem to have any effect on the XY background. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21208124+21653197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a cohort of 14 cases of 46,XX patients with a disorder of sex development (DSD), <a href="#6" class="mim-tip-reference" title="Benko, S., Gordon, C. T., Mallet, D., Sreenivasan, R., Thauvin-Robinet, C., Brendehaug, A., Thomas, S., Bruland, O., David, M., Nicolino, M., Labalme, A., Sanlaville, D., and 12 others. <strong>Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.</strong> J. Med. Genet. 48: 825-830, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22051515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22051515</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22051515">Benko et al. (2011)</a> used MLPA and quantitative PCR to screen for copy number variation (CNV) in the SOX9 proximal gene desert and identified heterozygosity for 3 different duplications in 3 unrelated SRY-negative patients (see, e.g., <a href="#0017">608160.0017</a>). <a href="#6" class="mim-tip-reference" title="Benko, S., Gordon, C. T., Mallet, D., Sreenivasan, R., Thauvin-Robinet, C., Brendehaug, A., Thomas, S., Bruland, O., David, M., Nicolino, M., Labalme, A., Sanlaville, D., and 12 others. <strong>Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.</strong> J. Med. Genet. 48: 825-830, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22051515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22051515</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22051515">Benko et al. (2011)</a> stated that the region of overlap among these genomic alterations and a deletion in a family with 46,XY DSD reveals a minimal noncoding 78-kb sex-determining region ('RevSex') located in a gene desert approximately 517 to 595 kb upstream of the SOX9 promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22051515" 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>By performing CNV analysis in a cohort of 19 cases of SRY-negative 46,XX testicular or ovotesticular DSD, <a href="#25" class="mim-tip-reference" title="Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others. <strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong> J. Med. Genet. 52: 240-247, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25604083">Kim et al. (2015)</a> identified 3 unrelated individuals with heterozygous duplications upstream of the SOX9 gene, 1 of which was shown to be paternally inherited. The 3 duplications and previously reported SOX9 upstream duplication/triplication cases shared a common 68-kb duplicated region, located 516 to 584 kb upstream of SOX9, which <a href="#25" class="mim-tip-reference" title="Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others. <strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong> J. Med. Genet. 52: 240-247, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25604083">Kim et al. (2015)</a> designated XXSR for 'XX sex-reversal region,' noting that it was largely identical with the 78-kb RevSex region. The authors also defined a distinct 32.5-kb XY sex-reversal region (XYSR) upstream of the SOX9 gene, based on 46,XY patients with deletions (see SRXY10, <a href="/entry/616425">616425</a>). <a href="#25" class="mim-tip-reference" title="Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others. <strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong> J. Med. Genet. 52: 240-247, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25604083">Kim et al. (2015)</a> stated that the XYSR and XXSR intervals do not overlap, being separated by 23 kb, and proposed that each harbors a differently-acting gonad-specific regulatory element. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25604083" 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="#76" class="mim-tip-reference" title="Xia, X.-Y., Zhang, C., Li, T.-F., Wu, Q.-Y., Li, N., Li, W.-W., Cui, Y.-X., Li, X.-J., Shi, Y.-C. <strong>A duplication upstream of SOX9 was not positively correlated with the SRY-negative 46,XX testicular disorder of sex development: a case report and literature review.</strong> Molec. Med. Rep. 12: 5659-5664, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26260363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26260363</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26260363[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/10.3892/mmr.2015.4202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26260363">Xia et al. (2015)</a> reported a 46,XX male with an approximately 88-kb duplication in a region upstream of SOX9 (chr17:67,024,087-67,112,435; GRCh37). Because the duplication was also present in his unaffected mother, <a href="#76" class="mim-tip-reference" title="Xia, X.-Y., Zhang, C., Li, T.-F., Wu, Q.-Y., Li, N., Li, W.-W., Cui, Y.-X., Li, X.-J., Shi, Y.-C. <strong>A duplication upstream of SOX9 was not positively correlated with the SRY-negative 46,XX testicular disorder of sex development: a case report and literature review.</strong> Molec. Med. Rep. 12: 5659-5664, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26260363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26260363</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26260363[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/10.3892/mmr.2015.4202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26260363">Xia et al. (2015)</a> suggested that it represented a polymorphism and was not a direct cause of the 46,XX testicular DSD. The authors concluded that other genetic or environmental factors are significant in the regulation of DSD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26260363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>46,XY Sex Reversal 10</em></strong></p><p>
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In a cohort of 46,XY patients with DSD, including 29 with complete female phenotype and 118 with undermasculinized external genitalia, <a href="#6" class="mim-tip-reference" title="Benko, S., Gordon, C. T., Mallet, D., Sreenivasan, R., Thauvin-Robinet, C., Brendehaug, A., Thomas, S., Bruland, O., David, M., Nicolino, M., Labalme, A., Sanlaville, D., and 12 others. <strong>Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.</strong> J. Med. Genet. 48: 825-830, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22051515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22051515</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22051515">Benko et al. (2011)</a> used MLPA and quantitative PCR to screen for CNV in the SOX9 proximal gene desert. They identified 2 46,XY cousins, 1 with a normal external female phenotype and the other with severe ambiguous and asymmetric external genitalia (SRXY10; <a href="/entry/616425">616425</a>), who were heterozygous for an approximately 240-kb deletion (<a href="#0018">608160.0018</a>) between 405 and 645 kb upstream of the SOX9 transcription start site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22051515" 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>By performing CNV analysis in 100 patients with SRY-positive 46,XY nonsyndromic partial or complete gonadal dysgenesis, <a href="#25" class="mim-tip-reference" title="Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others. <strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong> J. Med. Genet. 52: 240-247, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25604083">Kim et al. (2015)</a> identified 4 unrelated individuals with heterozygous deletions upstream of the SOX9 gene, including a patient from the family originally reported by <a href="#19" class="mim-tip-reference" title="German, J., Simpson, J. L., Chaganti, R. S. K. <strong>Genetically determined sex-reversal in 46,XY humans.</strong> Science 202: 53-56, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/567843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">567843</a>] [<a href="https://doi.org/10.1126/science.567843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="567843">German et al. (1978)</a> (<a href="#0019">608160.0019</a>) and a patient from the family studied by <a href="#33" class="mim-tip-reference" title="Mann, J. R., Corkery, J. J., Fisher, H. J. W., Cameron, A. H., Mayerova, A., Wolf, U., Kennaugh, A. A., Woolley, V. <strong>The X-linked recessive form of XY gonadal dysgenesis with a high incidence of gonadal germ cell tumours: clinical and genetic studies.</strong> J. Med. Genet. 20: 264-270, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6620326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6620326</a>] [<a href="https://doi.org/10.1136/jmg.20.4.264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6620326">Mann et al. (1983)</a> (<a href="#0020">608160.0020</a>). Both of the latter deletions segregated with disease in the respective families. Together, the 4 deletions defined a 32.5-kb interval, which <a href="#25" class="mim-tip-reference" title="Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others. <strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong> J. Med. Genet. 52: 240-247, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25604083">Kim et al. (2015)</a> designated XYSR for 'XY sex-reversal region,' noting that it overlapped with previously described SOX9 upstream deletions but not with the RevSex region. The authors also identified a distinct 68-kb XX sex-reversal region (XXSR) upstream of the SOX9 gene, based on 46,XX patients with duplications (see <a href="/entry/278850">278850</a>), that was largely identical to the RevSex region. <a href="#25" class="mim-tip-reference" title="Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others. <strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong> J. Med. Genet. 52: 240-247, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25604083">Kim et al. (2015)</a> stated that the XYSR and XXSR intervals do not overlap, being separated by 23 kb, and proposed that each harbors a differently-acting gonad-specific regulatory element. Testing of XYSR subfragments in cell transfection and transgenic experiments revealed a 1.9-kb SRY-responsive subfragment, designated F8, that drives expression specifically in Sertoli-like cells and contains consensus binding sites for SRY and WT1 (<a href="/entry/607102">607102</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25604083+567843+6620326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Hypertrichosis, Congenital Generalized, with or without Gingival Hyperplasia</em></strong></p><p>
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For discussion of the relationship between microdeletion or microduplication upstream of SOX9 and congenital generalized hypertrichosis with or without gingival hyperplasia, see HTC3 (<a href="/entry/135400">135400</a>).</p>
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<p><a href="#65" class="mim-tip-reference" title="Velagaleti, G. V. N., Bien-Willner, G. A., Northrup, J. K., Lockhart, L. H., Hawkins, J. C., Jalal, S. M., Withers, M., Lupski, J. R., Stankiewicz, P. <strong>Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia.</strong> Am. J. Hum. Genet. 76: 652-662, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15726498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15726498</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15726498[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/429252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15726498">Velagaleti et al. (2005)</a> presented a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with mild CMPD with Pierre Robin sequence (<a href="/entry/602196">602196</a>). They identified both chromosome breakpoints by FISH and sequenced them using a somatic cell hybrid. They found that the 17q24.3 breakpoint mapped approximately 900 kb upstream of SOX9, which was within the same BAC clone as the breakpoints of 2 other reported patients with mild CMPD. They also reported a prenatal identification of CMPD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype. The 17q breakpoint mapped approximately 1.3 Mb downstream of SOX9, making this the longest-range position effect found to that time in the field of human genetics and the first report of a patient with CMPD with the chromosome breakpoint mapping 3-prime of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, they identified a candidate upstream cis-regulatory element, SOX9cre1 (SOX9 conserved regulatory element-1). <a href="#65" class="mim-tip-reference" title="Velagaleti, G. V. N., Bien-Willner, G. A., Northrup, J. K., Lockhart, L. H., Hawkins, J. C., Jalal, S. M., Withers, M., Lupski, J. R., Stankiewicz, P. <strong>Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia.</strong> Am. J. Hum. Genet. 76: 652-662, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15726498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15726498</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15726498[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/429252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15726498">Velagaleti et al. (2005)</a> provided evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15726498" 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="#22" class="mim-tip-reference" title="Hill-Harfe, K. L., Kaplan, L., Stalker, H. J., Zori, R. T., Pop, R., Scherer, G., Wallace, M. R. <strong>Fine mapping of chromosome 17 translocation breakpoints greater than 900 Kb upstream of SOX9 in acampomelic campomelic dysplasia and a mild, familial skeletal dysplasia.</strong> Am. J. Hum. Genet. 76: 663-671, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15717285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15717285</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15717285[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/429254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15717285">Hill-Harfe et al. (2005)</a> presented fine mapping of chromosome 17 translocation breakpoints upstream of SOX9 associated with skeletal dysplasias. The breakpoint in this case was the most proximal to the SOX9 gene identified up to that time. Their family F had been reported by <a href="#56" class="mim-tip-reference" title="Stalker, H. J., Zori, R. T. <strong>Variable expression of rib, pectus, and scapular anomalies with Robin-type cleft palate in a 5-generation family: a new syndrome?</strong> Am. J. Med. Genet. 73: 247-250, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9415678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9415678</a>]" pmid="9415678">Stalker and Zori (1997)</a> and <a href="#57" class="mim-tip-reference" title="Stalker, H., Zori, R., Wallace, M., Hill-Harfe, K., Kaplan, L. <strong>Reply to Unger: the mildest form of campomelic dysplasia. (Letter)</strong> Am. J. Med. Genet. 132A: 114-115, 2005."None>Stalker et al. (2005)</a>; see Pierre Robin sequence with pectus excavatum and rib and scapular anomalies (<a href="/entry/602196">602196</a>). Pierre Robin sequence, hypoplastic scapulae, and 11 pairs of ribs are the primary features in family F and are nearly universal in both mild and severe forms of CMPD. However, <a href="#22" class="mim-tip-reference" title="Hill-Harfe, K. L., Kaplan, L., Stalker, H. J., Zori, R. T., Pop, R., Scherer, G., Wallace, M. R. <strong>Fine mapping of chromosome 17 translocation breakpoints greater than 900 Kb upstream of SOX9 in acampomelic campomelic dysplasia and a mild, familial skeletal dysplasia.</strong> Am. J. Hum. Genet. 76: 663-671, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15717285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15717285</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15717285[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/429254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15717285">Hill-Harfe et al. (2005)</a> considered this case to represent either an etiologically distinct disorder or a mild form of CMPD because many other features of CMPD were not present. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9415678+15717285" 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="#32" class="mim-tip-reference" title="Leipoldt, M., Erdel, M., Bien-Willner, G. A., Smyk, M., Theurl, M., Yatsenko, S. A., Lupski, J. R., Lane, A. H., Shanske, A. L., Stankiewicz, P., Scherer, G. <strong>Two novel translocation breakpoints upstream of SOX9 define borders of the proximal and distal breakpoint cluster region in campomelic dysplasia.</strong> Clin. Genet. 71: 67-75, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17204049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17204049</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00736.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17204049">Leipoldt et al. (2007)</a> reported a patient with characteristic symptoms of CMPD and a 46,XY,t(1;17)(q42.1;q24.3) karyotype in whom they mapped the 17q breakpoint 375 kb upstream from SOX9 using standard and high-resolution fiber FISH. Another patient with a 46,X,t(Y;17)(q11.2;q24.3) karyotype had the acampomelic form of CMPD and complete XY sex reversal; using FISH and somatic cell hybrid analysis, the authors mapped the 17q breakpoint 789 kb from SOX9. Combining their data with previously published CMPD translocation breakpoints, <a href="#32" class="mim-tip-reference" title="Leipoldt, M., Erdel, M., Bien-Willner, G. A., Smyk, M., Theurl, M., Yatsenko, S. A., Lupski, J. R., Lane, A. H., Shanske, A. L., Stankiewicz, P., Scherer, G. <strong>Two novel translocation breakpoints upstream of SOX9 define borders of the proximal and distal breakpoint cluster region in campomelic dysplasia.</strong> Clin. Genet. 71: 67-75, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17204049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17204049</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00736.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17204049">Leipoldt et al. (2007)</a> defined 2 clusters upstream of the SOX9 gene: a proximal cluster of breakpoints between 50 and 375 kb upstream and a distal cluster of breakpoints between 789 and 932 kb upstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17204049" 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="#45" class="mim-tip-reference" title="Patel, M., Dorman, K. S., Zhang, Y.-H., Huang, B.-L., Arnold, A. P., Sinsheimer, J. S., Vilain, E., McCabe, E. R. B. <strong>Primate DAX1, SRY, and SOX9: evolutionary stratification of sex-determination pathway.</strong> Am. J. Hum. Genet. 68: 275-280, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11112659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11112659</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11112659[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/316932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11112659">Patel et al. (2001)</a> examined the molecular evolution of DAX1 (<a href="/entry/300473">300473</a>), SRY (<a href="/entry/480000">480000</a>), and SOX9 genes involved in mammalian sex determination in 6 primate species. DAX1 and SRY were added to the X and Y chromosomes, respectively, during mammalian evolution, whereas SOX9 remained autosomal. They determined the genomic sequences of DAX1, SRY, and SOX9 in all 6 species, and calculated K(a), the number of nonsynonymous substitutions per nonsynonymous site, and compared this with the K(s), the number of synonymous substitutions per synonymous site. Phylogenetic trees were constructed by means of the DAX1, SRY, and SOX9 coding sequences, and phylogenetic analysis was performed using maximum likelihood. Overall measures of gene and protein similarity were closer for DAX1 and SOX9, but DAX1 exhibited nonsynonymous amino acid substitutions at an accelerated frequency relative to synonymous changes, similar to SRY and significantly higher than SOX9. <a href="#45" class="mim-tip-reference" title="Patel, M., Dorman, K. S., Zhang, Y.-H., Huang, B.-L., Arnold, A. P., Sinsheimer, J. S., Vilain, E., McCabe, E. R. B. <strong>Primate DAX1, SRY, and SOX9: evolutionary stratification of sex-determination pathway.</strong> Am. J. Hum. Genet. 68: 275-280, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11112659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11112659</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11112659[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/316932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11112659">Patel et al. (2001)</a> concluded that, at the protein level, DAX1 and SRY are under less selective pressure to remain conserved than SOX9, and, therefore, diverge more across species than does SOX9. These results were consistent with evolutionary stratification of the mammalian sex determination pathway, analogous to that for sex chromosomes which may be evolving by punctuated sequential events (Lahn and Page (<a href="#29" class="mim-tip-reference" title="Lahn, B. T., Page, D. C. <strong>Functional coherence of the human Y chromosome.</strong> Science 278: 675-680, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9381176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9381176</a>] [<a href="https://doi.org/10.1126/science.278.5338.675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9381176">1997</a>, <a href="#30" class="mim-tip-reference" title="Lahn, B. T., Page, D. C. <strong>Four evolutionary strata on the human X chromosome.</strong> Science 286: 964-967, 1999. Note: Erratum: Science 286: 2273 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10542153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10542153</a>] [<a href="https://doi.org/10.1126/science.286.5441.964" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10542153">1999</a>)). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10542153+9381176+11112659" 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>Sex determination in many reptiles, including the American alligator, is determined by temperature rather than by sex chromosomes as is the case in mammals and birds. Using incubation temperatures favorable to male or female development, <a href="#71" class="mim-tip-reference" title="Western, P. S., Harry, J. L., Graves, J. A. M., Sinclair, A. H. <strong>Temperature-dependent sex determination: upregulation of SOX9 expression after commitment to male development.</strong> Dev. Dyn. 214: 171-177, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10090144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10090144</a>] [<a href="https://doi.org/10.1002/(SICI)1097-0177(199903)214:3<171::AID-AJA1>3.0.CO;2-S" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10090144">Western et al. (1999)</a> showed that Sox9 expression in alligator embryos was male- and testis- specific, occurred near the end of the 10-day temperature-sensitive period, and was coincident with structural organization of the testis. The late timing of Sox9 expression suggests that Sox9 is unlikely to directly induce the differentiation of the supporting cell lineage into mature Sertoli cells in alligators. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10090144" 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>Studying the expression of mouse Sox9 during embryogenesis, <a href="#74" class="mim-tip-reference" title="Wright, E., Hargrave, M. R., Christiansen, J., Cooper, L., Kun, J., Evans, T., Gangadharan, U., Greenfield, A., Koopman, P. <strong>The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos.</strong> Nature Genet. 9: 15-20, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7704017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7704017</a>] [<a href="https://doi.org/10.1038/ng0195-15" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7704017">Wright et al. (1995)</a> found that the gene is expressed predominantly in mesenchymal condensations throughout the embryo before and during the deposition of cartilage, consistent with a primary role in skeletal formation. The expression pattern and chromosomal location of Sox9 suggested that it may be the gene defective in the mouse skeletal mutant 'Tail-short,' a potential animal model for campomelic dysplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7704017" 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>To analyze Sox9 function during sex determination in mice, <a href="#67" class="mim-tip-reference" title="Vidal, V. P. I., Chaboissier, M.-C., de Rooij, D. G., Schedl, A. <strong>Sox9 induces testis development in XX transgenic mice.</strong> Nature Genet. 28: 216-217, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431689</a>] [<a href="https://doi.org/10.1038/90046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431689">Vidal et al. (2001)</a> ectopically expressed this gene in XX gonads. They showed that Sox9 is sufficient to induce testis formation in mice, indicating that it can substitute for the sex-determining gene Sry. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431689" 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="Akiyama, H., Chaboissier, M.-C., Martin, J. F., Schedl, A., de Crombrugghe, B. <strong>The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6.</strong> Genes Dev. 16: 2813-2828, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12414734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12414734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12414734[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.1017802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12414734">Akiyama et al. (2002)</a> conditionally deleted the Sox9 gene in mice to examine its contribution at different steps in chondrocyte differentiation. Inactivation of Sox9 in limb buds before mesenchymal condensations resulted in complete absence of cartilage and bone and loss of Sox5 (<a href="/entry/604975">604975</a>), Sox6 (<a href="/entry/607257">607257</a>), and Runx2 (<a href="/entry/600211">600211</a>) expression. Markers for the different axes of limb development were unaffected. Apoptotic domains within the developing limbs were expanded, suggesting that Sox9 suppresses apoptosis. Deletion of Sox9 expression after mesenchymal condensations resulted in a severe generalized chondrodysplasia. Most cells arrested as condensed mesenchymal cells and did not undergo overt differentiation into chondrocytes. Chondrocyte proliferation was inhibited, expression of genes associated with chondrocyte proliferation was downregulated, and joint formation was defective. <a href="#3" class="mim-tip-reference" title="Akiyama, H., Chaboissier, M.-C., Martin, J. F., Schedl, A., de Crombrugghe, B. <strong>The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6.</strong> Genes Dev. 16: 2813-2828, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12414734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12414734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12414734[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.1017802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12414734">Akiyama et al. (2002)</a> concluded that SOX9 is needed to prevent conversion of proliferating chondrocytes into hypertrophic chondrocytes and that SOX9 is required during sequential steps of the chondrocyte differentiation pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12414734" 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>SOX9 has essential roles in endochondral bone formation during axial and appendicular skeletogenesis. Because SOX9 is also expressed in neural crest cells, <a href="#39" class="mim-tip-reference" title="Mori-Akiyama, Y., Akiyama, H., Rowitch, D. H., de Crombrugghe, B. <strong>Sox9 is required for determination of the chondrogenic cell lineage in the cranial neural crest.</strong> Proc. Nat. Acad. Sci. 100: 9360-9365, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12878728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12878728</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12878728[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.1631288100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12878728">Mori-Akiyama et al. (2003)</a> studied its function in neural crest. As many craniofacial skeletal elements are derived from cranial neural crest cells, the authors hypothesized that deletion of Sox9 in cranial neural crest cells of mice using the Cre recombinase/loxP recombination system would affect craniofacial development. They found that inactivation of Sox9 in neural crest resulted in a complete absence of cartilages and endochondral bones derived from the cranial neural crest. In contrast, all of the mesodermal skeletal elements and intramembranous bones were essentially conserved. Migration and localization of the Sox9 null mutant cranial neural crest cells were normal. In mouse embryo chimeras, Sox9 null mutant cells migrated to their correct location in endochondral skeletal elements; however, the deficient cranial neural crest cells were unable to contribute chondrogenic mesenchymal condensations. <a href="#39" class="mim-tip-reference" title="Mori-Akiyama, Y., Akiyama, H., Rowitch, D. H., de Crombrugghe, B. <strong>Sox9 is required for determination of the chondrogenic cell lineage in the cranial neural crest.</strong> Proc. Nat. Acad. Sci. 100: 9360-9365, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12878728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12878728</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12878728[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.1631288100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12878728">Mori-Akiyama et al. (2003)</a> suggested that these cells changed their cell fate and acquired the ability to differentiate into osteoblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12878728" 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="#58" class="mim-tip-reference" title="Stolt, C. C., Lommes, P., Sock, E., Chaboissier, M.-C., Schedl, A., Wegner, M. <strong>The Sox9 transcription factor determines glial fate choice in the developing spinal cord.</strong> Genes Dev. 17: 1677-1689, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12842915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12842915</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12842915[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.259003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12842915">Stolt et al. (2003)</a> ablated Sox9 from mouse neural stem cells to study its role in the switch from neurogenesis to gliogenesis during spinal cord development. Mutant mice exhibited an early and dramatic reduction in progenitors of the myelin-forming oligodendrocytes, but oligodendrocyte progenitor numbers recovered at later stages of development. Astrocyte numbers were severely reduced and did not recover at later stages. <a href="#58" class="mim-tip-reference" title="Stolt, C. C., Lommes, P., Sock, E., Chaboissier, M.-C., Schedl, A., Wegner, M. <strong>The Sox9 transcription factor determines glial fate choice in the developing spinal cord.</strong> Genes Dev. 17: 1677-1689, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12842915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12842915</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12842915[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.259003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12842915">Stolt et al. (2003)</a> concluded that SOX9 is a major molecular component of the neuron-glia switch in developing spinal cord. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12842915" 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="Airik, R. Trowe, M.-O., Foik, A., Farin, H. F., Petry, M., Schuster-Gossler, K., Schweizer, M., Scherer, G., Kist, R., Kispert, A. <strong>Hydroureternephrosis due to loss of Sox9-regulated smooth muscle cell differentiation of the ureteric mesenchyme.</strong> Hum. Molec. Genet. 19: 4918-4929, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20881014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20881014</a>] [<a href="https://doi.org/10.1093/hmg/ddq426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20881014">Airik et al. (2010)</a> found that targeted Sox9 deletion in mouse ureteric mesenchyme resulted in hydroureter and hydronephrosis, concomitant with small muscle cell deficiency and changes in the composition of uretic extracellular matrix. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20881014" 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>21 Selected Examples</a>):</strong>
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<div id="mimAllelicVariantsFold" class="collapse in mimTextToggleFold">
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<a href="/allelicVariants/608160" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=608160[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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<strong>.0001 CAMPOMELIC DYSPLASIA</strong>
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SOX9, 583C-T
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1480235826 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1480235826;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=rs1480235826" 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=rs1480235826" 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=RCV000002612" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002612" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002612</a>
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<p>In a 46,XX female with typical features of campomelic dysplasia (<a href="/entry/114290">114290</a>), <a href="#16" class="mim-tip-reference" title="Foster, J. W., Dominguez-Steglich, M. A., Guioli, S., Kwok, C., Weller, P. A., Stevanovic, M., Weissenbach, J., Mansour, S., Young, I. D., Goodfellow, P. N., Brook, J. D., Schafer, A. J. <strong>Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.</strong> Nature 372: 525-530, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7990924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7990924</a>] [<a href="https://doi.org/10.1038/372525a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7990924">Foster et al. (1994)</a> found a 583C-T transition in the SOX9 gene, resulting in a premature stop codon at amino acid position 195 (195X) of the predicted 509-amino acid sequence. The mutation was not found in either parent and was also absent in DNA samples from over 100 unaffected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7990924" 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 id="0002" class="mim-anchor"></a>
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<strong>.0002 CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL</strong>
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</h4>
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SOX9, 1-BP INS, 783G
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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> rs1274036689 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1274036689;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/rs1274036689?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=rs1274036689" 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=rs1274036689" 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=RCV000002613 OR RCV002512682" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002613, RCV002512682" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002613...</a>
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<p>In a 46,XY female with typical features of campomelic dysplasia (see <a href="/entry/114290">114290</a>), <a href="#16" class="mim-tip-reference" title="Foster, J. W., Dominguez-Steglich, M. A., Guioli, S., Kwok, C., Weller, P. A., Stevanovic, M., Weissenbach, J., Mansour, S., Young, I. D., Goodfellow, P. N., Brook, J. D., Schafer, A. J. <strong>Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.</strong> Nature 372: 525-530, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7990924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7990924</a>] [<a href="https://doi.org/10.1038/372525a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7990924">Foster et al. (1994)</a> identified a single G insertion in a series of 6 Gs (nucleotides 783-788) contained within codons 261-263 of SOX9. The resulting frameshift introduced a premature stop codon such that a 294-amino acid truncated protein would be translated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7990924" 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 id="0003" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0003 CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL</strong>
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</h4>
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<span class="mim-text-font">
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<div style="float: left;">
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SOX9, 4-BP INS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2143251627 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2143251627;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=rs2143251627" 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=rs2143251627" 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=RCV000002614" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002614" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002614</a>
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</span>
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<span class="mim-text-font">
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<p>In a 46,XY female fetus aborted at 17 weeks because of ultrasound findings of short limbs and cystic hygroma and with clinical findings consistent with campomelic dysplasia (see <a href="/entry/114290">114290</a>), including 7 pairs of ribs, <a href="#16" class="mim-tip-reference" title="Foster, J. W., Dominguez-Steglich, M. A., Guioli, S., Kwok, C., Weller, P. A., Stevanovic, M., Weissenbach, J., Mansour, S., Young, I. D., Goodfellow, P. N., Brook, J. D., Schafer, A. J. <strong>Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.</strong> Nature 372: 525-530, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7990924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7990924</a>] [<a href="https://doi.org/10.1038/372525a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7990924">Foster et al. (1994)</a> found a 4-bp insertion following amino acid 286 (nucleotide 858) of the predicted protein sequence. The frameshift introduced a premature stop with a predicted translation of a 294-amino acid truncated protein as in the patient described in <a href="#0002">608160.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7990924" 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 id="0004" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0004 CAMPOMELIC DYSPLASIA</strong>
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</span>
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<span class="mim-text-font">
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CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL, INCLUDED
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</span>
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<span class="mim-text-font">
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SOX9, 1-BP INS, 1096C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776541 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776541;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=rs587776541" 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=rs587776541" 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=RCV000002615 OR RCV000002616" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002615, RCV000002616" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002615...</a>
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<p><a href="#10" class="mim-tip-reference" title="Cameron, F. J., Hageman, R. M., Cooke-Yarborough, C., Kwok, C., Goodwin, L. L., Sillence, D. O., Sinclair, A. H. <strong>A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal.</strong> Hum. Molec. Genet. 5: 1625-1630, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8894698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8894698</a>] [<a href="https://doi.org/10.1093/hmg/5.10.1625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8894698">Cameron et al. (1996)</a> reported a family in which there were 3 patients affected with campomelic dysplasia (<a href="/entry/114290">114290</a>). Two of the patients showed 46,XY sex reversal (see <a href="/entry/114290">114290</a>). The gonadal phenotype varied widely among the 3 affected sibs. The proband had 46,XY true hermaphroditism with ambiguous external genitalia. The other 2 sibs were 46,XY and 46,XX and both had bilateral ovaries with normal female genitalia. A 1-bp insertion (cytidine) at nucleotide position 1096 was detected in the affected children. Mutational analysis revealed wildtype SOX9 nucleotide sequence in the parental somatic cells but detected gonadal mosaicism for the mutation in the father's germ cells. <a href="#10" class="mim-tip-reference" title="Cameron, F. J., Hageman, R. M., Cooke-Yarborough, C., Kwok, C., Goodwin, L. L., Sillence, D. O., Sinclair, A. H. <strong>A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal.</strong> Hum. Molec. Genet. 5: 1625-1630, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8894698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8894698</a>] [<a href="https://doi.org/10.1093/hmg/5.10.1625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8894698">Cameron et al. (1996)</a> noted that incomplete penetrance or stochastic environmental factors could account for the variable phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8894698" 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 id="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL</strong>
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SOX9, TYR440TER
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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> rs80338688 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338688;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/rs80338688?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=rs80338688" 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=rs80338688" 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=RCV000002617 OR RCV000020283 OR RCV000321802 OR RCV002276527" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002617, RCV000020283, RCV000321802, RCV002276527" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002617...</a>
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<p><a href="#68" class="mim-tip-reference" title="Wagner, T., Wirth, J., Meyer, J., Zabel, B., Held, M., Zimmer, J., Pasantes, J., Dagna Bricarelli, F., Keutel, J., Hustert, E., Wolf, U., Tommerup, N., Schempp, W., Scherer, G. <strong>Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.</strong> Cell 79: 1111-1120, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001137</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90041-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8001137">Wagner et al. (1994)</a> reported a de novo nonsense mutation within codon 440 (Y440X; TAC-TAG) in a sex-reversed XY female with campomelic dysplasia (see <a href="/entry/114290">114290</a>) who survived for 4 years (<a href="#14" class="mim-tip-reference" title="Ebensperger, C., Jager, R. J., Lattermann, U., Dagna Bricarelli, F., Keutel, J., Lindsten, J., Rehder, H., Muller, U., Wolf, U. <strong>No evidence of mutations in four candidate genes for male sex determination/differentiation in sex-reversed XY females with campomelic dysplasia.</strong> Ann. Genet. 34: 233-238, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1809232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1809232</a>]" pmid="1809232">Ebensperger et al., 1991</a>). <a href="#36" class="mim-tip-reference" title="Meyer, J., Sudbeck, P., Held, M., Wagner, T., Schmitz, M. L., Bricarelli, F. D., Eggermont, E., Friedrich, U., Haas, O. A., Kobelt, A., Leroy, J. G., van Maldergem, L., Michel, E., Mitulla, B., Pfeiffer, R. A., Schinzel, A., Schmidt, H., Scherer, G. <strong>Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations.</strong> Hum. Molec. Genet. 6: 91-98, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9002675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9002675</a>] [<a href="https://doi.org/10.1093/hmg/6.1.91" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9002675">Meyer et al. (1997)</a> identified the same de novo stop codon mutation in a karyotypic and phenotypic female who was still alive at the age of 10 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8001137+1809232+9002675" 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 campomelic dysplasia and XY sex reversal, <a href="#47" class="mim-tip-reference" title="Pop, R., Zaragoza, M. V., Gaudette, M., Dohrmann, U., Scherer, G. <strong>A homozygous nonsense mutation in SOX9 in the dominant disorder campomelic dysplasia: a case of mitotic gene conversion.</strong> Hum. Genet. 117: 43-53, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15806394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15806394</a>] [<a href="https://doi.org/10.1007/s00439-005-1295-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15806394">Pop et al. (2005)</a> identified homozygosity for the Y440X mutation. Neither parent carried the mutation; analysis of intragenic SNPs suggested that the homozygous mutation arose by a mitotic gene conversion event involving exchange of at least 440 nucleotides and at most 2,208 nucleotides between a de novo mutant maternal allele and a wildtype paternal allele. The patient also had somatic mosaicism, with homozygous mutant cells constituting about 80% of the leukocyte cell population, whereas about 20% were heterozygous mutant cells; she died at the age of 3 months due to progressive respiratory compromise. Transient cotransfection experiments in mouse neuro2a cells demonstrated that the Y440X mutant retained some transactivation capacity on authentic SOX9-responsive promoters/enhancers, ranging from 5 to 22% of wildtype activity. <a href="#47" class="mim-tip-reference" title="Pop, R., Zaragoza, M. V., Gaudette, M., Dohrmann, U., Scherer, G. <strong>A homozygous nonsense mutation in SOX9 in the dominant disorder campomelic dysplasia: a case of mitotic gene conversion.</strong> Hum. Genet. 117: 43-53, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15806394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15806394</a>] [<a href="https://doi.org/10.1007/s00439-005-1295-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15806394">Pop et al. (2005)</a> suggested that this is a hypomorphic rather than a complete loss-of-function allele, which may account for the milder phenotype and longer survival seen in some patients with this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15806394" 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">rs104894647 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894647;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=rs104894647" 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=rs104894647" 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=RCV000002618 OR RCV003497831" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002618, RCV003497831" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002618...</a>
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<p>Acampomelic campomelic dysplasia (see <a href="/entry/114290">114290</a>) is a rare variant of the more commonly encountered campomelic dysplasia, characterized by absence of long bone curvature. <a href="#61" class="mim-tip-reference" title="Thong, M.-K., Scherer, G., Kozlowski, K., Haan, E., Morris, L. <strong>Acampomelic campomelic dysplasia with SOX9 mutation.</strong> Am. J. Med. Genet. 93: 421-425, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10951468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10951468</a>]" pmid="10951468">Thong et al. (2000)</a> described a patient with acampomelic dysplasia with a de novo heterozygous mutation in the SOX9 gene, resulting in a lys173-to-glu (K173E) substitution. The mutation was located within the DNA binding HMG (high mobility group) domain of the SOX9 protein. The mutation was not present in the parents. The patient's antenatal period was uneventful, apart from renal pelvis dilatation detected at 19 weeks on ultrasound scan. Soon after birth he developed severe respiratory distress requiring ventilation for 2 weeks and continuous positive airway pressure via nasal prong thereafter. He developed recurrent chest infections and feeding difficulties. Oxygen supplementation was discontinued at 7 months. Physical examination showed rounded face, flat nasal bridge, micrognathia, midline cleft palate, long deep philtrum, and small mouth. The genital abnormalities consisted of bifid scrotum, perineal hypospadias, and undescended right testis. He had deep plantar creases, mild clinodactyly, small and hyperconvex nails, and limited elbow extension. The limbs were straight with no pretibial dimples. The karyotype was 46,XY. Skeletal survey at 7 weeks showed 11 pairs of gracile ribs, hypoplastic scapulas, dysplastic clavicles with broad medial aspects, and coronal clefts in the vertebral bodies T11, L1, and L2. The bodies of the iliac and pubic bones were hypoplastic with small sacrosciatic notches. The long bones were straight with mild shortness and flare of the metaphyses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10951468" 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">rs1598175249 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1598175249;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=rs1598175249" 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=rs1598175249" 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=RCV000002619" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002619" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002619</a>
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<p>In a patient with campomelic syndrome with autosomal sex reversal (see <a href="/entry/114290">114290</a>), <a href="#42" class="mim-tip-reference" title="Ninomiya, S., Yokoyama, Y., Teraoka, M., Mori, R., Inoue, C., Yamashita, S., Tamai, H., Funato, M., Seino, Y. <strong>A novel mutation (296 del G) of the SOX9 gene in a patient with campomelic syndrome and sex reversal.</strong> Clin. Genet. 58: 224-227, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11076045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11076045</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2000.580310.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11076045">Ninomiya et al. (2000)</a> identified a 1-bp deletion (296G), resulting in a frameshift upstream of the HMG box and a stop codon in the HMG domain of SOX9. The predicted truncated SOX9 protein contained 108 amino acids instead of the normal 509. Despite the marked change in the SOX9 protein, the patient had survived for 63 months, although requiring daily mechanical support of ventilation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11076045" 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 ACAMPOMELIC CAMPOMELIC DYSPLASIA</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">rs28940282 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940282;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=rs28940282" 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=rs28940282" 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=RCV000002620" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002620" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002620</a>
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<p>In a chromosomally normal boy with acampomelic campomelic dysplasia (see <a href="/entry/114290">114290</a>), <a href="#37" class="mim-tip-reference" title="Moog, U., Jansen, N. J. G., Scherer, G., Schrander-Stumpel, C. T. R. M. <strong>Acampomelic campomelic syndrome.</strong> Am. J. Med. Genet. 104: 239-245, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11754051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11754051</a>]" pmid="11754051">Moog et al. (2001)</a> identified a heterozygous 865C-T transition in the SOX9 gene, leading to a his165-to-tyr (H165Y) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11754051" 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">rs137853128 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853128;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=rs137853128" 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=rs137853128" 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=RCV000002621 OR RCV001266938" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002621, RCV001266938" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002621...</a>
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<p>In a long-term survivor with acampomelic campomelic dysplasia (see <a href="/entry/114290">114290</a>), <a href="#55" class="mim-tip-reference" title="Sock, E., Pagon, R. A., Keymolen, K., Lissens, W., Wegner, M., Scherer, G. <strong>Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia.</strong> Hum. Molec. Genet. 12: 1439-1447, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12783851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12783851</a>] [<a href="https://doi.org/10.1093/hmg/ddg158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12783851">Sock et al. (2003)</a> reported a C-to-A transversion in the SOX9 gene that resulted in an ala76-to-glu (A76E) amino acid substitution. Dimerization and the resulting capacity to activate promoters via dimeric binding sites was lost in the mutant SOX9 protein while other features involved in SOX9 function remained unaltered. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12783851" 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=RCV000002622" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002622" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002622</a>
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<p>In a patient with campomelic dysplasia (<a href="/entry/114290">114290</a>), <a href="#55" class="mim-tip-reference" title="Sock, E., Pagon, R. A., Keymolen, K., Lissens, W., Wegner, M., Scherer, G. <strong>Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia.</strong> Hum. Molec. Genet. 12: 1439-1447, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12783851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12783851</a>] [<a href="https://doi.org/10.1093/hmg/ddg158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12783851">Sock et al. (2003)</a> detected a 30-bp deletion in the SOX9 gene that removed amino acids 66 through 75 (delta66-75). The 30-bp deletion occurred between 2 hexanucleotide repeats, retaining 1 copy. The patient, a girl who died soon after birth from respiratory failure, had all the hallmarks of campomelic dysplasia, including bending of femora, tibiae, and fibulae. Additionally she showed the rare findings of absence of toenails and a broad gap between the first and second toes, combined with syndactyly between the second, third, and fourth toes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12783851" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137853129 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853129;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/rs137853129?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=rs137853129" 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=rs137853129" 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=RCV000002623" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002623" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002623</a>
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<p>In an infant with campomelic dysplasia (<a href="/entry/114290">114290</a>), <a href="#48" class="mim-tip-reference" title="Preiss, S., Argentaro, A., Clayton, A., John, A., Jans, D. A., Ogata, T., Nagai, T., Barroso, I., Schafer, A. J., Harley, V. R. <strong>Compound effects of point mutations causing campomelic dysplasia/autosomal sex reversal upon SOX9 structure, nuclear transport, DNA binding, and transcriptional activation.</strong> J. Biol. Chem. 276: 27864-27872, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11323423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11323423</a>] [<a href="https://doi.org/10.1074/jbc.M101278200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11323423">Preiss et al. (2001)</a> identified a heterozygous 462C-G transversion in the SOX9 gene, resulting in a phe154-to-leu (F154L) substitution. F154 is a highly conserved residue of helix 3 within the HMG domain. Fluorescence studies showed that the mutant F154L protein did not have significant changes in tertiary structure. In vitro functional expression studies demonstrated that the mutant protein had a significant loss of DNA-binding activity (5% of wildtype) and a loss of transcriptional activation activity (26% of wildtype). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11323423" 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 CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL</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">rs137853130 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853130;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=rs137853130" 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=rs137853130" 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=RCV000002624 OR RCV001851587" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002624, RCV001851587" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002624...</a>
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<p>In a patient with campomelic dysplasia with autosomal sex reversal (see <a href="/entry/114290">114290</a>), <a href="#48" class="mim-tip-reference" title="Preiss, S., Argentaro, A., Clayton, A., John, A., Jans, D. A., Ogata, T., Nagai, T., Barroso, I., Schafer, A. J., Harley, V. R. <strong>Compound effects of point mutations causing campomelic dysplasia/autosomal sex reversal upon SOX9 structure, nuclear transport, DNA binding, and transcriptional activation.</strong> J. Biol. Chem. 276: 27864-27872, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11323423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11323423</a>] [<a href="https://doi.org/10.1074/jbc.M101278200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11323423">Preiss et al. (2001)</a> identified a heterozygous 472G-A transition in the SOX9 gene, resulting in an ala158-to-thr (A158T) substitution. A158 is a highly conserved residue of helix 3 within the HMG domain. Fluorescence studies showed that the mutant A158T protein did not have significant changes in tertiary structure. In vitro functional expression studies demonstrated that the mutant protein had a 2-fold decrease in nuclear accumulation, a loss of DNA-binding activity (17% of wildtype), and a milder loss of transcriptional activation activity (62% of wildtype). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11323423" 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 CAMPOMELIC DYSPLASIA</strong>
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CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1598176785 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1598176785;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=rs1598176785" 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=rs1598176785" 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=RCV000002625 OR RCV000002626" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002625, RCV000002626" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002625...</a>
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<p>In a 46,XY patient with campomelic dysplasia (<a href="/entry/114290">114290</a>) and a 46,XY patient with campomelic dysplasia and autosomal sex reversal (see <a href="/entry/114290">114290</a>), <a href="#28" class="mim-tip-reference" title="Kwok, C., Weller, P. A., Guioli, S., Foster, J. W., Mansour, S., Zuffardi, O., Punnett, H. H., Dominguez-Steglich, M. A., Brook, J. D., Young, I. D., Goodfellow, P. N., Schafer, A. J. <strong>Mutations in SOX9, the gene responsible for campomelic dysplasia and autosomal sex reversal.</strong> Am. J. Hum. Genet. 57: 1028-1036, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7485151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7485151</a>]" pmid="7485151">Kwok et al. (1995)</a> identified heterozygosity for a 1-bp insertion (1103insA) in the SOX9 gene, causing a frameshift at codon 368 and resulting in an early termination signal at nucleotide 1671. The authors attributed the difference in sexual phenotype of these two 46,XY individuals to incomplete penetrance of the disease that might result from differences in genetic background. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7485151" 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 46,XX SEX REVERSAL 2</strong>
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SOX9, 178-KB DUP, UPSTREAM REGULATORY REGION
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000023686" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023686" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023686</a>
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<p><a href="#13" class="mim-tip-reference" title="Cox, J. J., Willatt, L., Homfray, T., Woods, C. G. <strong>A SOX9 duplication and familial 46,XX developmental testicular disorder. (Letter)</strong> New Eng. J. Med. 364: 91-93, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21208124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21208124</a>] [<a href="https://doi.org/10.1056/NEJMc1010311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21208124">Cox et al. (2011)</a> identified a family with 46,XX testicular disorder of sex development (SRXX2; <a href="/entry/278850">278850</a>) in which 3 adult males (2 brothers and a paternal uncle) were determined to be female according to karyotype and were negative for the SRY gene (<a href="/entry/480000">480000</a>). The proband and his uncle had an approximately 178-kb duplication 600 kb upstream of SOX9. The duplication was arranged in tandem in wildtype orientation, and the joining points of the duplicated segments were uncorrupted. All affected family members carried the duplication as did the proband's healthy, fertile 46,XY father. Of note, the 1.9-Mb region of chromosome 17 upstream of SOX9 contains no other genes and is evolutionarily highly conserved in mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21208124" 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>.0015 ACAMPOMELIC CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000032999" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032999" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032999</a>
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<p>In a 6-year-old 46,XY girl with acampomelic campomelic dysplasia and complete sex reversal (see <a href="/entry/114290">114290</a>), <a href="#31" class="mim-tip-reference" title="Lecointre, C., Pichon, O., Hamel, A., Heloury, Y., Michel-Calemard, L., Morel, Y., David, A., Le Caignec, C. <strong>Familial acampomelic form of campomelic dysplasia caused by a 960 kb deletion upstream of SOX9.</strong> Am. J. Med. Genet. 149A: 1183-1189, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19449405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19449405</a>] [<a href="https://doi.org/10.1002/ajmg.a.32830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19449405">Lecointre et al. (2009)</a> identified a heterozygous 960-kb deletion on chromosome 17q24, extending from -517 to -1,477 kb upstream of SOX9. The deletion was also present in her mildly affected mother, who was born with cleft palate and had mild microretrognathia, sandal gap, short great toes, and defective ischiopubic ossification; the unaffected father's DNA was normal. FISH analysis confirmed the presence of the deletion in the mother and daughter and its absence in the father; analysis of interphase nuclei in 3 different tissues from the mother demonstrated the presence of the deletion in 97 to 98.5% of nuclei, which suggested that the mother did not have somatic mosaicism. MLPA results were consistent with the interphase FISH analysis, again strongly suggesting that the mother was not mosaic for the deletion. <a href="#31" class="mim-tip-reference" title="Lecointre, C., Pichon, O., Hamel, A., Heloury, Y., Michel-Calemard, L., Morel, Y., David, A., Le Caignec, C. <strong>Familial acampomelic form of campomelic dysplasia caused by a 960 kb deletion upstream of SOX9.</strong> Am. J. Med. Genet. 149A: 1183-1189, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19449405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19449405</a>] [<a href="https://doi.org/10.1002/ajmg.a.32830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19449405">Lecointre et al. (2009)</a> stated that this deletion narrowed the minimum critical region and reduced the number of highly conserved sequence elements responsible for acampomelic campomelic dysplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19449405" 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 46,XX SEX REVERSAL 2</strong>
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SOX9, 96-KB TRIPLICATION, UPSTREAM REGULATORY REGION
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000173015" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000173015" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000173015</a>
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<p>In 2 46,XX SRY-negative Italian brothers (SRXX2; <a href="/entry/278850">278850</a>), who were phenotypically normal males but had hypotrophic testes and azoospermia, <a href="#66" class="mim-tip-reference" title="Vetro, A., Ciccone, R., Giorda, R., Patricelli, M. G., Della Mina, E., Forlino, A., Zuffardi, O. <strong>XX males SRY negative: a confirmed cause of infertility.</strong> J. Med. Genet. 48: 710-712, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21653197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21653197</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21653197">Vetro et al. (2011)</a> identified heterozygosity for a 96-kb triplication located 500 kb upstream of the SOX9 gene on chromosome 17. Array CGH and quantitative PCR analysis defined the proximal breakpoint of the triplication from 67,018,227 bp (normal) to 67,018,939 bp (triplicated), and the distal breakpoint from 67,114,737 bp (triplicated) to 67,119,234 bp (normal; NCBI36). The triplication was not present in their 2 fertile sisters and mother. The 2 brothers shared the same paternal haplotype for the SOX9 region, supporting the possibility that their deceased unaffected father was the carrier of the triplication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21653197" 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 46,XX SEX REVERSAL 2</strong>
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SOX9, 148-KB DUP, UPSTREAM REGULATORY REGION
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000173016" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000173016" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000173016</a>
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<p>In a 46,XX SRY-negative patient (SRXX2; <a href="/entry/278850">278850</a>), who was born with perineal hypospadias and asymmetric scrotum containing a normal testis on one side and an ovarian remnant with fallopian tube structures on the other, <a href="#6" class="mim-tip-reference" title="Benko, S., Gordon, C. T., Mallet, D., Sreenivasan, R., Thauvin-Robinet, C., Brendehaug, A., Thomas, S., Bruland, O., David, M., Nicolino, M., Labalme, A., Sanlaville, D., and 12 others. <strong>Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.</strong> J. Med. Genet. 48: 825-830, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22051515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22051515</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22051515">Benko et al. (2011)</a> identified heterozygosity for an approximately 148-kb tandem duplication of the region -595 to -447 kb upstream of SOX9 (chr17:69,521,863-69,670,036; GRCh37). The duplication, which was inherited from the unaffected father, was also present in 2 unaffected brothers but was not found in a healthy 46,XX sister or in the Database of Genomic Variants. The proband's unaffected father inherited the duplication from his unaffected mother, indicating incomplete penetrance. The patient had normal psychomotor and pubertal development, with normal testosterone levels, and displayed normal growth and bodily proportions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22051515" 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 46,XY SEX REVERSAL 10</strong>
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SOX9, 240-KB DEL, UPSTREAM REGULATORY REGION
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000173017" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000173017" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000173017</a>
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<p>In two 46,XY cousins, 1 with a normal external female phenotype and the other with severe ambiguous and asymmetric external genitalia (SRXY10; <a href="/entry/616425">616425</a>), <a href="#6" class="mim-tip-reference" title="Benko, S., Gordon, C. T., Mallet, D., Sreenivasan, R., Thauvin-Robinet, C., Brendehaug, A., Thomas, S., Bruland, O., David, M., Nicolino, M., Labalme, A., Sanlaville, D., and 12 others. <strong>Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.</strong> J. Med. Genet. 48: 825-830, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22051515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22051515</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22051515">Benko et al. (2011)</a> identified heterozygosity for an approximately 240-kb deletion between 405 and 645 kb upstream of the SOX9 transcription start site. The unaffected mothers of the 2 patients were sisters and carried the same deletion, which was not found in the Database of Genomic Variants; no dysmorphism or skeletal abnormalities were detected in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22051515" 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 id="0019" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0019 46,XY SEX REVERSAL 10</strong>
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SOX9, 577-KB DEL, UPSTREAM REGULATORY REGION
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000173018" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000173018" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000173018</a>
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<p>In two 46,XY sisters who exhibited unambiguously female genitalia but did not undergo breast development or menstruation at puberty (SRXY10; <a href="/entry/616425">616425</a>), <a href="#25" class="mim-tip-reference" title="Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others. <strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong> J. Med. Genet. 52: 240-247, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25604083">Kim et al. (2015)</a> identified heterozygosity for a 577-kb deletion extending from 132.1 to 709.0 kb upstream of the SOX9 gene. These individuals had been reported as patients III.10 and III.11 by <a href="#19" class="mim-tip-reference" title="German, J., Simpson, J. L., Chaganti, R. S. K. <strong>Genetically determined sex-reversal in 46,XY humans.</strong> Science 202: 53-56, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/567843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">567843</a>] [<a href="https://doi.org/10.1126/science.567843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="567843">German et al. (1978)</a>; <a href="#25" class="mim-tip-reference" title="Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others. <strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong> J. Med. Genet. 52: 240-247, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25604083">Kim et al. (2015)</a> referred to the family as DSD4. Pelvic surgery in the third decade of life revealed bilateral streak gonads in both sisters; an affected cousin (patient III.16) had bilateral gonadoblastoma (<a href="#19" class="mim-tip-reference" title="German, J., Simpson, J. L., Chaganti, R. S. K. <strong>Genetically determined sex-reversal in 46,XY humans.</strong> Science 202: 53-56, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/567843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">567843</a>] [<a href="https://doi.org/10.1126/science.567843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="567843">German et al., 1978</a>). No skeletal anomalies were reported in any of the affected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25604083+567843" 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>.0020 46,XY SEX REVERSAL 10</strong>
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SOX9, 136-KB DEL, UPSTREAM REGULATORY REGION
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000173019" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000173019" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000173019</a>
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<p>In a 46,XY individual with apparently normal female genitalia (SRXY10; <a href="/entry/616425">616425</a>), <a href="#25" class="mim-tip-reference" title="Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others. <strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong> J. Med. Genet. 52: 240-247, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25604083">Kim et al. (2015)</a> identified heterozygosity for a 136-kb deletion extending from 510 to 646 kb upstream of the SOX9 gene. This individual had been reported by <a href="#33" class="mim-tip-reference" title="Mann, J. R., Corkery, J. J., Fisher, H. J. W., Cameron, A. H., Mayerova, A., Wolf, U., Kennaugh, A. A., Woolley, V. <strong>The X-linked recessive form of XY gonadal dysgenesis with a high incidence of gonadal germ cell tumours: clinical and genetic studies.</strong> J. Med. Genet. 20: 264-270, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6620326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6620326</a>] [<a href="https://doi.org/10.1136/jmg.20.4.264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6620326">Mann et al. (1983)</a> as patient VI.2; <a href="#25" class="mim-tip-reference" title="Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others. <strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong> J. Med. Genet. 52: 240-247, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25604083">Kim et al. (2015)</a> referred to the family as DSD3. Due to a family history of gonadal germ cell tumors in affected individuals, the patient underwent prophylactic removal of the gonads at age 20 months; histology showed dysgenetic gonads with gonadoblastoma present in the right gonad. The deletion was also present in a 46,XY maternal great-aunt (patient IV.25), who underwent gonadectomy at 23.5 years of age, which revealed bilateral 'ovarian' dysgerminomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25604083+6620326" 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>.0021 CAMPOMELIC DYSPLASIA</strong>
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SOX9, HIS169GLN
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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> rs2229989 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2229989;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/rs2229989?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=rs2229989" 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=rs2229989" 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=RCV000224991 OR RCV000278794 OR RCV001266335" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000224991, RCV000278794, RCV001266335" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000224991...</a>
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<p>In a 10-year-old Japanese boy with mild campomelic dysplasia (CMPD; <a href="/entry/114290">114290</a>), <a href="#35" class="mim-tip-reference" title="Matsushita, M., Kitoh, H., Kaneko, H., Mishima, K., Kadono, I., Ishiguro, N., Nishimura, G. <strong>A novel SOX9 H169Q mutation in a family with overlapping phenotype of mild campomelic dysplasia and small patella syndrome.</strong> Am. J. Med. Genet. 161A: 2528-2534, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24038782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24038782</a>] [<a href="https://doi.org/10.1002/ajmg.a.36134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24038782">Matsushita et al. (2013)</a> identified heterozygosity for a c.507C-G transversion in exon 2 of the SOX9 gene, resulting in a his169-to-gln (H169Q) substitution at a highly conserved residue. The mutation was inherited from his very mildly affected mother. Functional analysis of H169Q as well as H169P, a mutation previously identified in a more severe CMPD case by <a href="#34" class="mim-tip-reference" title="Massardier, J., Roth, P., Michel-Calemard, L., Rudigoz, R. C., Bouvier, R., Dijoud, F., Amould, P., Combourieu, D., Gaucherand, P. <strong>Campomelic dysplasia: echographic suspicion in the first trimester of pregnancy and final diagnosis of two cases.</strong> Fetal Diag. Ther. 24: 452-457, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19033726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19033726</a>] [<a href="https://doi.org/10.1159/000176299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19033726">Massardier et al. (2008)</a>, demonstrated that both mutants had significantly reduced transactivation capacity compared to wildtype, but that the H169Q mutant retained more residual transactivation (46% of wildtype) than the H169P mutant (21%). <a href="#35" class="mim-tip-reference" title="Matsushita, M., Kitoh, H., Kaneko, H., Mishima, K., Kadono, I., Ishiguro, N., Nishimura, G. <strong>A novel SOX9 H169Q mutation in a family with overlapping phenotype of mild campomelic dysplasia and small patella syndrome.</strong> Am. J. Med. Genet. 161A: 2528-2534, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24038782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24038782</a>] [<a href="https://doi.org/10.1002/ajmg.a.36134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24038782">Matsushita et al. (2013)</a> suggested that retained SOX9 function might account for the extremely mild CMPD phenotype in the Japanese family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19033726+24038782" 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>REFERENCES</strong>
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[<a href="https://doi.org/10.1093/hmg/ddq426" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1101/gad.1017802" target="_blank">Full Text</a>]
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Bell, D. M., Leung, K. K. H., Wheatley, S. C., Ng, L. J., Zhou, S., Ling, K. W., Sham, M. H., Koopman, P., Tam, P. P. L., Cheah, K. S. E.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9171829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9171829</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9171829" 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/ng0697-174" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19234473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19234473</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19234473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddm061" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1083/jcb.200311021" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/5.10.1625" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15691760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15691760</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15691760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.devcel.2004.12.010" target="_blank">Full Text</a>]
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Chikuda, H., Kugimiya, F., Hoshi, K., Ikeda, T., Ogasawara, T., Shimoaka, T., Kawano, H., Kamekura, S., Tsuchida, A., Yokoi, N., Nakamura, K., Komeda, K., Chung, U., Kawaguchi, H.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15466490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15466490</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15466490[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=15466490" 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/10.1101/gad.1224204" target="_blank">Full Text</a>]
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Cox, J. J., Willatt, L., Homfray, T., Woods, C. G.
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<strong>A SOX9 duplication and familial 46,XX developmental testicular disorder. (Letter)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21208124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21208124</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21208124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMc1010311" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302455" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/nar/gkf443" target="_blank">Full Text</a>]
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</p>
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</ol>
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<a id="contributors" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<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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Bao Lige - updated : 11/20/2020
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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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Ada Hamosh - updated : 09/22/2020<br>Ada Hamosh - updated : 09/04/2018<br>Marla J. F. O'Neill - updated : 08/03/2016<br>Marla J. F. O'Neill - updated : 5/18/2016<br>Ada Hamosh - updated : 6/23/2015<br>Marla J. F. O'Neill - updated : 6/17/2015<br>Ada Hamosh - updated : 11/17/2014<br>Ada Hamosh - updated : 9/30/2014<br>Marla J. F. O'Neill - updated : 7/3/2014<br>Patricia A. Hartz - updated : 1/15/2014<br>Marla J. F. O'Neill - updated : 11/9/2012<br>Patricia A. Hartz - updated : 3/9/2011<br>Ada Hamosh - updated : 1/19/2011<br>Patricia A. Hartz - updated : 3/18/2010<br>Marla J. F. O'Neill - updated : 1/29/2010<br>Patricia A. Hartz - updated : 12/8/2009<br>Patricia A. Hartz - updated : 9/21/2009<br>Cassandra L. Kniffin - updated : 9/15/2009<br>Cassandra L. Kniffin - updated : 8/11/2009<br>Marla J. F. O'Neill - updated : 4/30/2009<br>Patricia A. Hartz - updated : 10/28/2008<br>Ada Hamosh - updated : 7/11/2008<br>George E. Tiller - updated : 5/19/2008<br>Patricia A. Hartz - updated : 2/29/2008<br>Marla J. F. O'Neill - updated : 3/9/2007<br>Marla J. F. O'Neill - updated : 10/30/2006<br>Patricia A. Hartz - updated : 12/20/2005<br>Patricia A. Hartz - updated : 11/9/2005<br>Cassandra L. Kniffin - updated : 9/7/2005<br>Marla J. F. O'Neill - updated : 7/5/2005<br>George E. Tiller - updated : 3/22/2005<br>Victor A. McKusick - updated : 3/11/2005<br>Patricia A. Hartz - updated : 2/23/2005<br>Patricia A. Hartz - updated : 12/9/2004<br>George E. Tiller - updated : 8/18/2004
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin : 10/10/2003
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</span>
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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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mgross : 11/20/2020
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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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alopez : 09/22/2020<br>alopez : 07/16/2019<br>alopez : 09/04/2018<br>alopez : 08/03/2016<br>alopez : 06/09/2016<br>alopez : 5/18/2016<br>alopez : 6/23/2015<br>alopez : 6/22/2015<br>mcolton : 6/17/2015<br>alopez : 11/17/2014<br>alopez : 9/30/2014<br>joanna : 9/2/2014<br>alopez : 7/8/2014<br>mcolton : 7/3/2014<br>mgross : 1/17/2014<br>mcolton : 1/15/2014<br>carol : 11/12/2012<br>terry : 11/9/2012<br>terry : 8/22/2012<br>carol : 6/4/2012<br>carol : 6/1/2011<br>mgross : 3/9/2011<br>terry : 3/9/2011<br>terry : 3/9/2011<br>alopez : 3/4/2011<br>alopez : 2/24/2011<br>alopez : 1/31/2011<br>terry : 1/19/2011<br>mgross : 3/22/2010<br>terry : 3/18/2010<br>wwang : 2/1/2010<br>terry : 1/29/2010<br>mgross : 1/25/2010<br>joanna : 1/25/2010<br>mgross : 1/4/2010<br>terry : 12/8/2009<br>carol : 9/22/2009<br>terry : 9/21/2009<br>wwang : 9/21/2009<br>ckniffin : 9/15/2009<br>carol : 8/19/2009<br>carol : 8/12/2009<br>ckniffin : 8/11/2009<br>wwang : 5/5/2009<br>terry : 4/30/2009<br>alopez : 2/9/2009<br>mgross : 10/28/2008<br>mgross : 10/28/2008<br>terry : 9/26/2008<br>alopez : 7/15/2008<br>terry : 7/11/2008<br>wwang : 5/22/2008<br>terry : 5/19/2008<br>wwang : 4/30/2008<br>mgross : 2/29/2008<br>carol : 7/26/2007<br>wwang : 3/13/2007<br>terry : 3/9/2007<br>wwang : 10/30/2006<br>wwang : 10/30/2006<br>wwang : 12/20/2005<br>mgross : 12/6/2005<br>terry : 11/9/2005<br>mgross : 9/7/2005<br>ckniffin : 9/7/2005<br>joanna : 9/6/2005<br>wwang : 7/11/2005<br>wwang : 7/8/2005<br>terry : 7/5/2005<br>wwang : 6/8/2005<br>terry : 5/23/2005<br>alopez : 3/22/2005<br>wwang : 3/18/2005<br>wwang : 3/15/2005<br>terry : 3/11/2005<br>mgross : 2/23/2005<br>mgross : 12/9/2004<br>alopez : 8/18/2004<br>carol : 2/23/2004<br>carol : 10/15/2003<br>ckniffin : 10/14/2003
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</span>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 608160
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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 9; SOX9
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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SRY-RELATED HMG-BOX GENE 9
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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<div>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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XXSR, INCLUDED
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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XYSR, INCLUDED<br />
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TESTIS-SPECIFIC ENHANCER OF SOX9, INCLUDED; TES, INCLUDED<br />
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TESTIS-SPECIFIC ENHANCER OF SOX9 CORE, INCLUDED; TESCO, INCLUDED<br />
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REGULATORY ELEMENT, ENHANCER, 13, INCLUDED; ENH13, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SOX9</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 74928006;
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</span>
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</p>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 17q24.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 17:72,121,020-72,126,416 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="5">
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<span class="mim-font">
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17q24.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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46XX sex reversal 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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278850
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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46XY sex reversal 10
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</span>
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</td>
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<td>
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<span class="mim-font">
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616425
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Acampomelic campomelic dysplasia
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</span>
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</td>
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<td>
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<span class="mim-font">
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114290
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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|
Campomelic dysplasia
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</span>
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</td>
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<td>
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<span class="mim-font">
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114290
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
|
Campomelic dysplasia with autosomal sex reversal
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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114290
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</h4>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
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<p>SOX9 is a transcription factor essential for both sex and skeletal development. Transient expression of the Y chromosome gene SRY (480000) initiates a cascade of gene interactions orchestrated by SOX9, leading to the formation of testes from bipotential gonads (summary by Cox et al., 2011). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
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<p>Foster et al. (1994) constructed a high-resolution map across a 20-Mb region spanning chromosome 17q24.1-q25.1 that was identified by Tommerup et al. (1993) as containing the locus for campomelic dysplasia (CMPD; 114290). Using this map and a translocation chromosome breakpoint from a sex-reversed patient with campomelic dysplasia (see 114290) previously reported by Young et al. (1992), Foster et al. (1994) identified an SRY (480000)-related gene, SOX9, located 88 kb distal to the translocation breakpoint. The gene is predicted to encode a 509-amino acid polypeptide containing an SRY homology domain. The isolated cDNA corresponded to 3.9 kb of the transcript, but Northern blot analysis detected a 4.5-kb transcript in adult testes, adult heart, and fetal brain. The SOX9 protein HMG box domain at amino acids 104-182 showed 71% similarity with the SRY HMG box, and the C-terminal third of the protein has a proline- and glutamine-rich region similar to activation domains present in some transcription factors. The genomic arrangement of SOX9 is such that the 5-prime end is oriented toward the centromere of chromosome 17 and closest to the breakpoint. It is possible that 1 or more exons are present 5-prime to the known exons and that these are disrupted by the translocation. </p><p>Using a fragment derived from mouse SOX9, Wagner et al. (1994) isolated human SOX9 from a human fetal cDNA brain library. The cDNA was found to encode a 509-amino acid protein with a predicted molecular mass of 56 kD. </p><p>Using immunofluorescence analysis, Schmidt et al. (2003) showed that Sox8 (605923) and Sox9 localized to nuclei of undifferentiated C2C12 mouse myoblasts. </p><p>By immunohistochemical analysis of adult human and mouse tissues, Furuyama et al. (2011) found that SOX9 was expressed in hepatic bile duct, duodenal crypt, and pancreatic duct. In mouse, Sox9 was detected in extrahepatic biliary tract epithelia, including the common bile duct, duodenal papilla, and gallbladder. Sox9 was detected broadly in primitive gut epithelial cells in developing mouse at embryonic days 13.5 and 16.5 and was restricted to crypt at embryonic day 18.5. In pancreas, Sox9 was expressed in epithelial cells at embryonic day 13.5 and was confined to duct cells and was not present in differentiated cells at embryonic days 16.5 and 18.5. Sox9 was detected in extrahepatic bile duct, but not in hepatocytes, at embryonic day 13.5 and was expressed in intrahepatic bile duct at embryonic day 16.5. </p><p>Fantauzzo et al. (2012) used immunofluorescence analysis to examine expression of Sox9 during vibrissae follicle morphogenesis in mice. At embryonic day (E) 12.5, Sox9 was expressed throughout the whisker pad epidermis, with increased expression in the suprabasal layers of the epithelial placode. By the peg stage at E14.5, Sox9 was expressed throughout the epithelial compartment of the downgrowing follicle, with the exception of the matrix cells. From E16.5 to E18.5, Sox9 continued to be expressed throughout the follicle epithelium, with increased expression in the matrix and the inner and outer root sheath layers. By postnatal day 0, Sox9 expression was restricted to the outer root sheath cells along the length of the follicle. In addition, faint expression was also detected in the dermal papilla as early as E14.5, as well as in the dermal cells of the collagen capsule surrounding the developing vibrissae follicles. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
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<p>By fluorescence in situ hybridization, Foster et al. (1994) localized the SOX9 gene to chromosome 17q24. </p><p>Wagner et al. (1994) cited evidence that the murine Sox9 gene is on chromosome 11. </p>
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<strong>Gene Function</strong>
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<p><strong><em>Role in Chondrogenesis</em></strong></p><p>
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During chondrogenesis in the mouse, Sox9 is coexpressed with Col2a1 (120140), the gene encoding type II collagen, the major cartilage matrix protein. COL2A1 is therefore a candidate regulatory target of SOX9. Regulatory sequences required for chondrocyte-specific expression of the COL2A1 gene have been localized to conserved sequences in the first intron in rats, mice, and humans. Bell et al. (1997) showed that SOX9 protein binds specifically to sequences in the first intron of human COL2A1. Mutation of these sequences abolished SOX9 binding and chondrocyte-specific expression of a COL2A1-driven reporter gene (COL2A1-lacZ) in transgenic mice. Furthermore, ectopic expression of Sox9 transactivated both a COL2A1-driven reporter gene and the endogenous Col2a1 gene in transgenic mice. These results demonstrated that COL2A1 expression is directly regulated by SOX9 protein in vivo and implicated abnormal regulation of COL2A1 during chondrogenesis as a cause of the skeletal abnormalities associated with campomelic dysplasia. </p><p>Murakami et al. (2000) showed that expression of SOX9 is upregulated by fibroblast growth factors (FGFs; see 601513) in primary chondrocytes and in SOX9-expressing mesenchymal cells. They further presented evidence that FGF stimulation of SOX9 expression is mediated by the mitogen-activated protein kinase (MAPK) cascade (see 176948), a signal transduction pathway that is activated by growth factors such as FGF. The data strongly suggested that FGF and the MAPK pathway play an important role in the regulation of SOX9 expression during chondrocyte differentiation. </p><p>Huang et al. (2001) showed that the chondrogenic transcription factor SOX9 is a target of signaling by the parathyroid hormone-related peptide (PTHRP; 168470) in the growth plate of endochondral bones. PTHRP strongly increased the phosphorylation of SOX9 and increased the SOX9-dependent activity of chondrocyte-specific enhancers in the gene for type II collagen (COL2A1) in transient transfection experiments. This increased enhancer activity did not occur with a SOX9 mutant harboring serine-to-alanine substitutions in its 2 consensus protein kinase A phosphorylation sites. Since SOX9 is a target of PTHRP signaling in prehypertrophic chondrocytes in the growth plate, Huang et al. (2001) hypothesized that SOX9 mediates at least some effects of PTHRP in the growth plate and that the PTHRP-dependent increased transcriptional activity of SOX9 helps maintain the chondrocyte phenotype of cells in the prehypertrophic zone and inhibits their maturation to hypertrophic chondrocytes. </p><p>Komeda miniature rat Ishikawa (KMI) is a naturally occurring rat mutant that grows normally until 3 to 4 weeks of age, but then gradually develops longitudinal growth retardation without other organ abnormalities. Chikuda et al. (2004) found that expression of Sox9, which is normally downregulated in postmitotic chondrocytes, persisted in the nuclei of KMI growth plate chondrocytes. They determined that KMI rats have a deletion in the cGKII gene (PRKG2; 601591) that results in a truncated protein lacking the kinase domain. Transfection experiments in human cells revealed that cGKII phosphorylates SOX9 on ser181 and attenuates SOX9 function by inhibiting its nuclear entry. Furthermore, the impaired differentiation of cultured KMI chondrocytes was restored by silencing Sox9 by RNA interference. Chikuda et al. (2004) concluded that cGKII is a molecular switch that couples the cessation of proliferation and the start of hypertrophic chondrocyte differentiation through attenuating SOX9 function. </p><p>Van Gastel et al. (2020) showed that obstruction of vascular invasion during bone healing favors chondrogenic over osteogenic differentiation of skeletal progenitor cells. Unexpectedly, this process is driven by a decreased availability of extracellular lipids. When lipids are scarce, skeletal progenitors activate FOXO transcription factors (e.g., FOXO1, 136533), which bind to the SOX9 promoter and increase its expression. Besides initiating chondrogenesis, SOX9 acts as a regulator of cellular metabolism by suppressing oxidation of fatty acids, and thus adapts the cells to an avascular life. Van Gastel et al. (2020) concluded that their results defined lipid scarcity as an important determinant of chondrogenic commitment, revealed a role for FOXO transcription factors during lipid starvation, and identified SOX9 as a critical metabolic mediator. </p><p><strong><em>Role in Sex Determination</em></strong></p><p>
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Morais da Silva et al. (1996) found that, consistent with its role in sex determination, SOX9 expression closely follows differentiation of Sertoli cells in the mouse testis, in experimental sex reversal when fetal ovaries are grafted to adult kidneys, and in the chick where there is no evidence for an Sry gene (480000). The results suggested to the authors that SOX9 plays an essential role in sex determination, possibly immediately downstream of SRY in mammals, and that it functions as a critical Sertoli cell differentiation factor, perhaps in all vertebrates. </p><p>In most mammals, male development is triggered by the transient expression of the SRY gene on the Y chromosome, which initiates a cascade of gene interactions ultimately leading to the formation of a testis from the indifferent fetal gonad. Several genes, in particular SOX9, have a crucial role in this pathway. Bishop et al. (2000) described a dominant insertion mutation, Odsex (Ods), in which XX mice carrying a 150-kb deletion approximately 1 Mb upstream of Sox9 developed as sterile XX males lacking Sry. During embryogenesis, wildtype XX fetal gonads downregulated Sox9 expression, whereas XY and XX Ods/+ fetal gonads upregulated and maintained its expression. Bishop et al. (2000) proposed that the Ods mutation removed a long-range, gonad-specific regulatory element that mediates the repression of Sox9 expression in XX fetal gonads. This repression would normally be antagonized by Sry protein in XY embryos. The data were considered consistent with Sox9 being a direct downstream target of Sry and provided genetic evidence to support a general repressor model of sex determination in mammals. </p><p>The Ods mouse phenotype, described by Bishop et al. (2000), consists of female-to-male sex reversal in XX Ods/+ mice and a characteristic eye phenotype of microphthalmia with cataracts. The mutation arose in a transgenic line of mice carrying a tyrosinase (TYR; 606933) minigene driven by the dopachrome tautomerase (DCT; 191275) promoter region. The minigene integrated 1 Mb upstream of Sox9 and was accompanied by a deletion of 134 kb. Ods causes sex reversal in the absence of Sry by upregulating Sox9 expression and maintaining a male pattern of Sox9 expression in XX Ods/+ embryonic gonads. Qin et al. (2004) reported that the 134-kb deletion alone was insufficient to cause sex reversal. Rather, the Dct promoter was capable of acting over a distance of 1 Mb to induce inappropriate expression of Sox9 in the retinal pigmented epithelium of the eye, causing the observed microphthalmia. In addition, it induced Sox9 expression in the melanocytes where it caused pigmentation defects. Qin et al. (2004) proposed that Ods sex reversal may be due to the Dct promoter element interacting with gonad-specific enhancer elements to produce the observed male pattern expression of Sox9 in the embryonic gonads. </p><p>In mammals, male sex determination starts when the Y chromosome Sry gene is expressed within the undetermined male gonad. One of the earliest effects of SRY expression is to induce upregulation of SOX9 gene expression in the developing gonad. SOX9, like SRY, contains a high mobility group domain and is sufficient to induce testis differentiation in transgenic XX mice. Before sexual differentiation, SOX9 protein is initially found in the cytoplasm of undifferentiated gonads from both sexes. At the time of testis differentiation and anti-mullerian hormone (AMH; 600957) expression, it becomes localized to the nuclear compartment in males, whereas it is downregulated in females. Gasca et al. (2002) used NIH 3T3 cells as a model to examine the regulation of SOX9 nucleocytoplasmic shuttling. SOX9-transfected cells expressed nuclear and cytoplasmic SOX9, whereas transfected cells treated with the nuclear export inhibitor leptomycin B displayed an exclusive nuclear localization of SOX9. By using SOX9 deletion constructs in GFP fusion proteins, Gasca et al. (2002) identified a functional nuclear export signal sequence between amino acids 134 and 147 of the SOX9 high mobility group box. More strikingly, they showed that inhibiting nuclear export with leptomycin B in mouse XX gonads cultured in vitro induced a sex reversal phenotype characterized by nuclear SOX9 and anti-mullerian hormone expression. These results indicated that the SOX9 nuclear export signal is essential for SOX9 sex-specific subcellular localization and could be part of a regulatory switch that represses (in females) or triggers (in males) male-specific sexual differentiation. </p><p>To test whether SOX9 was sufficient to generate a fully fertile male in the absence of Sry, Qin and Bishop (2005) constructed XY(Sry-) Ods/+ male mice, in which the male phenotype is controlled autosomally by the Ods mutation. Mice gradually became infertile by 5 to 6 months of life. XY(Sry-) Ods/+ males also failed to establish the correct male-specific pattern of vascularization at the time of sex determination. Increasing the amount of SOX9 by producing homozygous XY(Sry-) Ods/Ods males completely rescued the phenotype and restored correct vascular patterning and long-term fertility. Qin and Bishop (2005) showed that activation of SOX9 in the gonad was sufficient to trigger all the downstream events needed for the development of a fully fertile male, and they provided additional evidence that Sox9 may downregulate Wnt4 (603490) expression in the gonad. </p><p><strong><em>Role in Muscle Development</em></strong></p><p>
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Schmidt et al. (2003) found that expression of mouse Sox8 and Sox9 was downregulated during myogenesis. Overexpression of Sox8 or Sox9 inhibited myotube formation of C2C12 cells and decreased expression of Myod (MYOD1; 159970), an early marker of myogenic differentiation. In addition, overexpression of Sox8 or Sox9 negatively regulated the myogenin (MYOG; 159980) promoter and repressed Myod-dependent myogenin expression. </p><p><strong><em>Transcription Factor Activity</em></strong></p><p>
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By cell transfection experiments, Sudbeck et al. (1996) showed that SOX9 can transactivate transcription from a reporter plasmid through the motif AACAAAG, a sequence recognized by other HMG domain transcription factors. By fusing all or part of SOX9 to the DNA-binding domain of yeast Gal4, the transactivating function was mapped to a transcription activation domain at the C terminus of SOX9. With 1 exception, all SOX9 nonsense and frameshift mutations in patients with campomelic dysplasia and sex reversal lead to truncation of this domain, suggesting to Sudbeck et al. (1996) that impairment of gonadal and skeletal development in these cases results, at least in part, from loss of the transactivation of genes downstream of SOX9. </p><p>By yeast 2-hybrid analysis of a human embryo cDNA expression library, Zhou et al. (2002) found that the transcription activation domain of SOX9 interacted with the proline-, glutamine-, and leucine-rich (PQL) domain of TRAP230 (MED12; 300188), a component of the thyroid hormone receptor-associated protein (TRAP) complex. In vitro and in vivo assays confirmed that the proteins interact endogenously and associate with several other TRAP complex proteins in HeLa cell nuclear lysates. SOX9 and TRAP230 colocalized in nuclei of cultured human embryo chondrocytes. The isolated PQL domain of TRAP230 acted as a dominant-negative inhibitor of SOX9 activity. </p><p>Tsuda et al. (2003) found that SOX9 used CBP (CREBBP; 600140) and p300 (EP300; 602700) as transcriptional coactivators. SOX9 bound CBP and p300 in vitro and in vivo, and both coactivators enhanced SOX9-dependent COL2A1 promoter activity. Disruption of the CBP-SOX9 complex inhibited COL2A1 mRNA expression and differentiation of human mesenchymal stem cells into chondrocytes. </p><p>Blache et al. (2004) found that Sox9 was expressed in fetal mouse intestinal epithelium. Expression of Sox9 was dependent on activity of the Wnt (see 164820) pathway. In human colon-derived epithelial cells, Blache et al. (2004) demonstrated that SOX9 transcriptionally repressed the expression of CDX2 (600297) and MUC2 (158370), genes expressed in the villus compartment encoding markers of differentiated cells. Blache et al. (2004) hypothesized that SOX9 function might contribute to the Wnt-dependent maintenance of an undifferentiated progenitor phenotype in the intestinal epithelium by repressing differentiation genes such as CDX2 and MUC2. </p><p>By expression of Sox9 or Sox10 (602229) in early Xenopus embryos, Taylor and LaBonne (2005) found that each factor could direct the formation of neural crest precursors and the development of a range of neural crest derivatives. They detected no differences in the activities of Sox9 and Sox10 in these assays. They identified Sumo1 (601912) and Ubc9 (UBE2I; 601661) as Sox-interacting proteins that play a role in regulating the function of Sox9 and Sox10 during neural crest and inner ear development. </p><p>By analyzing embryonic Sox9-null mice and using gain-of-function experiments, Cheung et al. (2005) determined that specification of trunk neural crest cells involves the coordinated activity of Sox9, Foxd3 (611539), and Slug (SNAI2; 602150). Each transcription factor appeared to regulate the acquisition of distinct neural crest cell properties, while the combined expression of Sox9, Slug, and Foxd3 induced cells to manifest all the principal transcriptional and morphologic characteristics of neural crest cells. </p><p>Prostaglandin D2 (176803) contributes to the development of the testis by recruiting cells of the supporting cell lineage to a Sertoli cell fate. Wilhelm et al. (2007) found that Pgds was expressed in embryonic mouse Sertoli cells immediately after the onset of Sry and Sox9 expression. Pgds upregulation was mediated by Sox9, but not Sry, and required the binding of dimeric Sox9 to a paired SOX recognition site within the Pgds 5-prime flanking region. </p><p>Zalzali et al. (2008) found that expression of epitope-tagged SOX9 in human colonic carcinoma cells upregulated the expression of CEACAM1 (109770). Conversely, Sox9-deficient mice showed reduced Ceacam1 expression in colon. The promoter regions of mouse, rat, and human CEACAM1 contain SOX9-binding motifs despite no other significant sequence homology, and chromatin immunoprecipitation analysis confirmed that SOX9 bound the human CEACAM1 promoter. In addition, the histone acetyltransferase p300 enhanced transactivation of CEACAM1 by the rat and human CEACAM1 promoters. Zalzali et al. (2008) concluded that SOX9 regulates CEACAM1 expression in colon epithelium. </p><p>Adam et al. (2015) identified SOX9 as a crucial chromatin rheostat of hair follicle stem cell superenhancers, and provided functional evidence that superenhancers are dynamic, dense transcription factor-binding platforms that are acutely sensitive to pioneer master regulators whose levels define not only spatial and temporal features of lineage-status but also stemness, plasticity in transitional states, and differentiation. </p><p><strong><em>Regulatory Elements</em></strong></p><p>
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SOX9 is expressed during chondrocyte differentiation and is upregulated in male and downregulated in female genital ridges during sex differentiation. To study the sex- and tissue-specific regulation of SOX9, Kanai and Koopman (1999) defined the transcription start site and characterized the Sox9 promoter region in the mouse. The Sox9 proximal promoter shows moderately high nucleotide similarity between mouse and human. Transient transfection experiments using various deletion constructs at the 6.8-kb upstream region of the mouse Sox9 gene fused to a luciferase reporter showed that the interval between 193 and 73 bp from the transcription start site was essential for maximal promoter activity in cell lines and in primary male and female gonadal somatic cells and liver cells isolated from mouse embryos 13.5 days postcoitum. This minimal promoter region was shown by DNase I hypersensitive site assay to be in an 'open' state of chromatin structure in gonads of both sexes, but not in the liver. Promoter activity was higher in testis than in ovary and liver, but deletion of the region from -193 to -73 bp abolished this difference. Kanai and Koopman (1999) concluded that the proximal promoter region is in part responsible for the sex- and tissue-specific expression of the SOX9 gene, and that more distal positive and negative elements contribute to its regulation in vivo, consistent with the observation that translocations upstream from the SOX9 gene can result in campomelic dysplasia. </p><p>Bien-Willner et al. (2007) identified a 2.1-kb cis-acting regulatory element 1.1 Mb upstream of the SOX9 gene, called SOX9cre1. This element increased the activity of a minimal SOX9 promoter in reporter constructs in a dose-dependent manner. The enhancer effect was also tissue-specific and was observed in human chondrosarcoma cell lines, but not in HeLa cells. SOX9cre1 contains a GLI1 (165220)-binding element, suggesting that SOX9 has a role in hedgehog (SHH; 600725) signaling. Stimulation of primary human chondrocytes in culture with SHH increased endogenous SOX9 expression 3-fold. EMSA and chromatin immunoprecipitation studies showed a direct interaction between GLI1 and the putative GLI1-binding site in SOX9cre1. Bien-Willner et al. (2007) concluded that SHH regulates SOX9 expression in human chondrocytes and chondrosarcomas via GLI1 binding to a far upstream enhancer region. </p><p>Sekido and Lovell-Badge (2008) demonstrated that SRY (480000) binds to multiple elements within a Sox9 gonad-specific enhancer that they called TESCO (testis-specific enhancer of Sox9 core) in mice, and that it does so along with steroidogenic factor-1 (SF1), an orphan nuclear receptor encoded by the gene Nr5a1 (184757). Mutation, cotransfection, and sex-reversal studies all pointed to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate SOX9; then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. Sekido and Lovell-Badge (2008) concluded that their results permitted further characterization of the molecular mechanisms regulating sex determination, their evolution, and their failure in cases of sex reversal. </p><p>After identifying 7 consensus GATA-binding sites within 3 kb of the transcriptional start site of SOX9, Fantauzzo et al. (2012) performed endogenous chromatin immunoprecipitation experiments in HEK293T cells and observed that TRPS1 (604386) bound up to 5 of those sites in the SOX9 promoter. Luciferase reporter promoter assays demonstrated that TRPS1 represses SOX9 transcription in a dose-dependent manner. </p><p>Using in vivo high-throughput chromatin accessibility techniques, transgenic assays, and genome editing, Gonen et al. (2018) detected several novel gonadal regulatory elements in the 2-megabase gene desert upstream of Sox9. Although others are redundant, enhancer-13 (Enh13), a 557-basepair element located 565 kilobases 5-prime from the transcriptional start site, is essential to initiate mouse testis development; its deletion results in XY females with Sox9 transcript levels equivalent to those in XX gonads. Gonen et al. (2018) concluded that their data are consistent with the time-sensitive activity of SRY and indicate a strict order of enhancer usage. Enh13 is conserved and embedded within the 32.5-kilobase SR XY region, whose deletion in humans is associated with XY sex reversal, suggesting that it is also critical in humans. </p><p><strong><em>Role in Pigmentation</em></strong></p><p>
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Passeron et al. (2007) detected SOX9 mRNA and protein in normal human melanocytes in vitro and in vivo. Ultraviolet B exposure upregulated SOX9 expression and nuclear accumulation, and upregulation was mediated by cAMP and protein kinase A (see 176911). Agouti signal protein (ASIP; 600201), which decreases pigmentation and antagonizes the alpha-MSH (176830) signaling pathway, downregulated SOX9 expression. SOX9 regulated the MITF (156845) and DCT (191275) promoters. Overexpression of SOX9 increased MITF, DCT, and TYR (606933) proteins, which led to increased melanin production in cells. Passeron et al. (2007) concluded that SOX9 has a role in pigmentation. </p><p><strong><em>Role in Organ Maintenance</em></strong></p><p>
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Using lineage analysis, Furuyama et al. (2011) showed that Sox9-negative mouse hepatocytes arose from a Sox9-positive precursor pool. These Sox9-positive precursors were involved in liver regeneration following hepatic injury. Embryonic pancreatic Sox9-expressing cells differentiated into all types of mature cells, but their capacity for endocrine differentiation diminished shortly after birth, when endocrine cells detached from the epithelial lining of the ducts and formed the islets of Langerhans. Since SOX9 was expressed in proliferating intestinal crypt cells and in hepatic and pancreatic duct in the adult, Furuyama et al. (2011) concluded that SOX9 is involved in the continuous supply of cells from the progenitor pool. </p><p><strong><em>Role in Cancer</em></strong></p><p>
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Wang et al. (2008) noted that, in adult prostate, SOX9 expression is restricted to basal epithelium. By immunohistochemical analysis of human fetal prostate, they found that SOX9 was initially expressed in prostate epithelium at 19 weeks gestation. By 22.5 weeks, expression was more pronounced at the tip of the branching prostate gland that was expanding into the surrounding stroma. In xenografts of human prostate cancer cell lines, SOX9 overexpression enhanced tumor growth, whereas knockdown of SOX9 via small interfering RNA suppressed tumor growth. Wang et al. (2008) concluded that during normal development SOX9 allows the prostate epithelium to outgrow into the mesenchyme and then provides basal cell support for development and maintenance of the luminal epithelium. They suggested that these functions of SOX9 are subverted in prostate cancer to support tumor growth and invasion. </p><p>Passeron et al. (2009) found weak or absent SOX9 expression in 37 (95%) of 39 melanoma (155600) specimens. SOX9 expression was positive in normal skin areas, but weak or negative in 18 (81.8%) of 22 nevi, in 54 (96.4%) of 56 primary melanomas, and in 100% (20 of 20) metastatic melanomas. Thus, SOX9 expression decreased as melanocytic cells progressed from the normal condition to the premalignant (nevi) to the transformed state, and was completely negative in the most advanced (metastatic) state of malignancy. SOX9 functioned by binding the CDKN1A (116899) promoter, which resulted in strong suppression of cell growth in vivo. SOX9 also decreased PRAME (606021) protein levels in melanoma cells and restored sensitivity to retinoic acid. SOX9 overexpression in melanoma cell lines inhibited tumorigenicity both in mice and in a human ex vivo model of melanoma. Treatment of melanoma cell lines with PGD2 (176803) increased SOX9 expression and restored sensitivity to retinoic acid. Combined treatment with PGD2 and retinoic acid substantially decreased tumor growth in human ex vivo and mouse in vivo models of melanoma. These results provided insight into the pathophysiology of melanoma. </p><p>Wang et al. (2013) showed that ZBTB7A (605878) physically interacts with SOX9 during prostate tumorigenesis and functionally antagonizes its transcriptional activity on key target genes such as MIA (601340), which is involved in tumor cell invasion, and H19 (103280), a long noncoding RNA precursor for an RB (see 614041)-targeting microRNA (MIR675; 615509). These and other results showed that the oncosuppressive function of ZBTB7A directly impinges on the oncogenic activity of SOX9 and that ZBTB7A loss in the prostate favors senescence bypass, increased proliferation rate, resistance to apoptosis, and greater invasive potential. </p><p><strong><em>Effects of Chromosomal Translocations on SOX9</em></strong></p><p>
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Many patients with campomelic dysplasia have chromosomal translocations involving regions surrounding or including the SOX9 gene. Wagner et al. (1994) found that the 17q breakpoints in 3 campomelic dysplasia patients with translocations mapped 50 kb or more from the SOX9 gene. Wirth et al. (1996) showed that the breakpoints in 2 affected patients reported by Wagner et al. (1994) were more than 130 kb 5-prime of SOX9, as was the breakpoint in a third patient with CMPD and a de novo t(6;17) translocation. The last patient was a phenotypic female with XY sex chromosome constitution, as were the 3 previously described CMPD translocation cases. Wirth et al. (1996) reviewed the mechanisms by which translocation breakpoints upstream from the SOX9 gene can result in defective expression during embryonic development. In their study, Wirth et al. (1996) investigated whether there was any difference in the expression of SOX9 alleles on the normal versus the translocation chromosome. No significant difference was found in the study of a lymphoblastoid cell line; however, they pointed out that this may not accurately reflect the situation of regulated expression of SOX9 during embryonic development. It had not been possible to analyze SOX9 expression in embryonic tissue from CMPD translocation cases. In a note added in proof, they referred to 3 additional de novo translocation or inversion cases involving the distal 17q in patients with CMPD. </p><p>Because chromosomal breakpoints map 50 kb or more from the SOX9 gene and CMPD may be a contiguous gene syndrome (Schmickel, 1986), Ninomiya et al. (1996) cloned the breakpoint in the patient in search of a second gene associated with this syndrome. They isolated a cDNA adjacent to the breakpoint. Specific expression of this gene in testis suggested its candidacy for some role in CMPD and/or sex reversal. The mRNA, approximately 3.7 kb long, was expressed in testis as demonstrated by Northern blot analysis. However, they were unable to find any long open reading frame (ORF) in the 3.5-kb cDNA sequence or to detect any peptide following an in vitro translation experiment using RNA transcribed from this cDNA. Consequently, they speculated that the gene may play a critical role in differentiation or sex determination as a functional RNA. </p><p>Whereas mutations in the ORF of SOX9 cause haploinsufficiency and campomelic dysplasia, the effects of translocations 5-prime to SOX9 were unclear and prompted Wunderle et al. (1998) to test whether these rearrangements also cause haploinsufficiency by altering spatial and temporal expression of SOX9. For this purpose, they generated mice transgenic for human SOX9-lacZ YACs containing variable amounts of DNA sequences upstream of SOX9. They showed that elements necessary for SOX9 expression during skeletal development are highly conserved between mouse and human and that a rearrangement upstream of SOX9, similar to those observed in campomelic dysplasia patients, leads to a substantial reduction of SOX9 expression, particularly in chondrogenic tissues. Thus, important regulatory elements are scattered over a large region upstream of SOX9 and explain how particular aspects of the CD phenotype are caused by chromosomal rearrangements 5-prime to SOX9. </p><p>As noted earlier, several campomelic dysplasia translocation and inversion cases have been described with breakpoints outside the coding region, mapping to locations more than 130 kb proximal to SOX9. These cases are generally less severely affected than cases with SOX9 coding region mutations, as borne out by 3 new translocation cases presented by Pfeifer et al. (1999). They cloned the region extending 1.2 Mb upstream of the SOX9 gene in overlapping BAC and PAC clones and established a restriction map with rare-cutter enzymes. With STS-content mapping in somatic cell hybrids, as well as with FISH, they mapped precisely the breakpoints of 3 new and 3 previously described CMPD cases. The 6 CMPD breakpoints mapped to an interval 140 to 950 kb proximal to the SOX9 gene. With exon trapping, they isolated 5 potential exons from a YAC that spanned the region, 4 of which could be placed in the contig in the vicinity of the breakpoints. These potential exons showed the same transcriptional orientation, but only 2 had an ORF. Pfeifer et al. (1999) failed to detect expression of these fragments in several human and mouse cDNA libraries, as well as on Northern blots. Genomic sequence totaling 1,063 kb from the SOX9 5-prime flanking region was determined and analyzed, but no genes or transcripts could be identified. Together, these data suggested that chromosomal rearrangements most likely removed one or more cis-regulatory elements from the extended SOX9 control region. </p><p><strong><em>Role in Limb Development</em></strong></p><p>
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By combining experiments and modeling, Raspopovic et al. (2014) revealed evidence that a Turing network implemented by BMP2 (112261), SOX9, and Wnt (see 164820) drives digit specification during development. Raspopovic et al. (2014) developed a realistic 2-dimensional simulation of digit patterning and showed that this network, when modulated by morphogen gradients, recapitulates the expression patterns of SOX9 in the wildtype and in perturbation experiments. Raspopovic et al. (2014) concluded that their systems biology approach revealed how a combination of growth, morphogen gradients, and a self-organizing Turing network can achieve robust and reproducible pattern formation. </p>
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<strong>Molecular Genetics</strong>
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<p>Gordon et al. (2009) reviewed the spectrum of lesions surrounding the SOX9 gene, noting that translocation breakpoints upstream of SOX9 can be clustered into 3 groups, with a trend towards less severe skeletal phenotypes as the distance of each cluster from the SOX9 gene increases. The authors stated that the identification of novel lesions surrounding SOX9 supported the existence of tissue-specific enhancers acting over a long distance to regulate SOX9 expression during craniofacial development. </p><p><strong><em>Campomelic Dysplasia with or without Sex Reversal</em></strong></p><p>
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In 6 of 9 patients with campomelic dysplasia (114290), Foster et al. (1994) identified mutations in single alleles of the SOX9 gene. The 3 mutations described in detail would be expected to destroy gene function; 2 caused frameshifts that led to premature chain termination and loss of one-third of the protein (608160.0002, 608160.0003), and 1 caused a premature termination that truncated the protein at 40% of its predicted length (608160.0001). Both parents of 2 of the patients did not have the mutation. The de novo appearance of a mutation in a sex-reversed campomelic patient established that alterations in SOX9 caused both abnormalities. The findings indicated that SOX9 is involved in both bone formation and control of testis development. Foster et al. (1994) suggested that campomelic dysplasia is an autosomal dominant disorder, as they did not detect mutations in both SOX9 alleles of any patient. Dominance appeared to be due to haploinsufficiency rather than gain of function. </p><p>Wagner et al. (1994) likewise identified inactivating mutations in 1 SOX9 allele in nontranslocation CMPD-SOX9 cases pointing to haploinsufficiency for SOX9 as the cause of both campomelic dysplasia and autosomal XY sex reversal (see 608160.0005). The 17q breakpoints in 3 translocation cases mapped 50 kb or more from SOX9. </p><p>Kwok et al. (1995) analyzed the SOX9 gene in 9 patients with campomelic dysplasia, 2 of whom had chromosome 17 rearrangements, and identified heterozygosity for 2 missense mutations, 3 frameshift mutations, and a splice site mutation, respectively, in 6 of the patients with no cytologically detectable chromosomal aberrations. An identical frameshift mutation (608160.0013) was found in 2 unrelated 46,XY patients, 1 exhibiting a male phenotype and the other displaying a female phenotype (XY sex reversal). Kwok et al. (1995) noted that these results were consistent with the hypothesis that CMPD results from haploinsufficiency of SOX9. </p><p>Prompted by the observation that mutations of the SOX9 gene can cause campomelic dysplasia with 46,XY sex reversal, Kwok et al. (1996) examined the entire coding region of the SOX9 gene in 30 46,XY patients with abnormalities of sexual development but without any skeletal abnormalities. Of the 30 patients, gonadal dysgenesis was diagnosed in 12 and partial gonadal dysgenesis in 14. Except for a C-to-T polymorphism at nucleotide 507 in 1 person, no other abnormalities of the SOX9 were found. </p><p>Sock et al. (2003) presented 2 CMPD patients with de novo mutations in a conserved region preceding the HMG domain of SOX9. A long-term survivor with the acampomelic form of CMPD had an ala76-to-glu amino acid substitution (608160.0009), while a severely affected CMPD patient had an in-frame deletion of amino acid residues 66 through 75 (608160.0010). The conserved domain functions in the related transcription factor SOX10 as a DNA-dependent dimerization domain. The authors demonstrated that like SOX10, SOX9 binds cooperatively as a dimer to response elements in regulatory regions of some target genes such as the cartilage genes COL11A2 (120290) and cartilage-derived retinoic acid-sensitive protein (MIA/CDRAP; 601340). Dimerization and the resulting capacity to activate promoters via dimeric binding sites was lost in both mutant SOX9 proteins while other features involved in SOX9 function remained unaltered. The authors concluded that the dimerization domain is a third domain essential for SOX9 function during chondrogenesis. </p><p>In a 6-year-old 46,XY girl with acampomelic campomelic dysplasia and complete sex reversal and her mildly affected mother, Lecointre et al. (2009) identified heterozygosity for a 960-kb deletion upstream of the SOX9 gene (608160.0015). The authors stated that this deletion narrowed the minimum critical region and reduced the number of highly conserved sequence elements responsible for acampomelic campomelic dysplasia. </p><p>In a 10-year-old Japanese boy with mild campomelic dysplasia, Matsushita et al. (2013) identified a heterozygous missense mutation in SOX9 (H169Q; 608160.0021) that was inherited from his mother, who showed minimal clinical findings of the disease. </p><p><strong><em>Pierre Robin Sequence</em></strong></p><p>
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Benko et al. (2009) reported several lines of evidence for the existence of a 17q24 locus underlying isolated Pierre Robin sequence (261800), including linkage analysis results, a clustering of translocation breakpoints 1.06 to 1.23 Mb upstream of the SOX9 gene, and microdeletions that were approximately 1.5 Mb centromeric and 1.5 Mb telomeric of SOX9. They identified a heterozygous point mutation in an evolutionarily conserved region of DNA with in vitro and in vivo features of a developmental enhancer; the mutation abrogated the in vitro enhancer function and altered binding of the transcription factor MSX1 (142983) compared to wildtype. In the developing mouse mandible, the 3-Mb region bounded by the microdeletions showed a regionally specific chromatin decompaction in cells expressing SOX9. Benko et al. (2009) concluded that some cases of Pierre Robin sequence may result from developmental misexpression of SOX9 due to disruption of very-long-range cis-regulatory elements. </p><p><strong><em>Cooks Syndrome</em></strong></p><p>
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In affected members of 4 unrelated families with a phenotype consistent with Cooks syndrome (106995), Kurth et al. (2009) identified overlapping duplications in a 2-Mb interval on chromosome 17q24.3, with a minimal critical area of 1.2 Mb. The region encompassed a large gene desert between KCNJ2 (600681) and SOX9. The duplications were confirmed by quantitative PCR and were not detected in more than 400 control DNA samples. The duplications occurred de novo in 2 families. Kurth et al. (2009) suggested that the duplications involved putative regulatory elements of SOX9 and may induce SOX9 misexpression and/or overexpression at specific time points during development, resulting in abnormal digit and nail development. In mouse embryo, Sox9 was strongly expressed in the distal mesenchymal condensations that develop into terminal phalanges. </p><p><strong><em>46,XX Sex Reversal 2</em></strong></p><p>
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In a family with 46,XX testicular disorder of sex development (SRXX2; 278850) in which 3 adult males (2 brothers and a paternal uncle) were determined to be female according to karyotype (46,XX) and were negative for the SRY gene, Cox et al. (2011) identified a heterozygous 178-kb duplication 600 kb upstream of SOX9 (608160.0014). The duplication was arranged in tandem in wildtype orientation, and the joining points of the duplicated segments were uncorrupted. All affected family members carried the duplication in heterozygosity as did the proband's healthy, fertile 46,XY father. Affected individuals were infertile with azoospermia. In 2 men the testes had been removed and prostheses placed during their 20s because of testicular pain secondary to testosterone replacement. Histologic exams showed the presence of Leydig and Sertoli cells, severely diminished and atrophied seminiferous tubules, and no spermatogenesis. </p><p>In two 46,XX SRY-negative Italian brothers, who were phenotypically normal males but had hypotrophic testes and azoospermia, Vetro et al. (2011) identified heterozygosity for a 96-kb triplication located 500 kb upstream of the SOX9 gene (608160.0016) that was not present in their 2 fertile sisters and mother. The 2 brothers shared the same paternal haplotype for the SOX9 region, supporting the possibility that their deceased unaffected father was the carrier of the triplication. Vetro et al. (2011) stated that this was the shortest region of amplification upstream of SOX9 reported to be associated with 46,XX SRY-negative infertile males, and noted that, like the duplication reported by Cox et al. (2011), the triplication did not seem to have any effect on the XY background. </p><p>In a cohort of 14 cases of 46,XX patients with a disorder of sex development (DSD), Benko et al. (2011) used MLPA and quantitative PCR to screen for copy number variation (CNV) in the SOX9 proximal gene desert and identified heterozygosity for 3 different duplications in 3 unrelated SRY-negative patients (see, e.g., 608160.0017). Benko et al. (2011) stated that the region of overlap among these genomic alterations and a deletion in a family with 46,XY DSD reveals a minimal noncoding 78-kb sex-determining region ('RevSex') located in a gene desert approximately 517 to 595 kb upstream of the SOX9 promoter. </p><p>By performing CNV analysis in a cohort of 19 cases of SRY-negative 46,XX testicular or ovotesticular DSD, Kim et al. (2015) identified 3 unrelated individuals with heterozygous duplications upstream of the SOX9 gene, 1 of which was shown to be paternally inherited. The 3 duplications and previously reported SOX9 upstream duplication/triplication cases shared a common 68-kb duplicated region, located 516 to 584 kb upstream of SOX9, which Kim et al. (2015) designated XXSR for 'XX sex-reversal region,' noting that it was largely identical with the 78-kb RevSex region. The authors also defined a distinct 32.5-kb XY sex-reversal region (XYSR) upstream of the SOX9 gene, based on 46,XY patients with deletions (see SRXY10, 616425). Kim et al. (2015) stated that the XYSR and XXSR intervals do not overlap, being separated by 23 kb, and proposed that each harbors a differently-acting gonad-specific regulatory element. </p><p>Xia et al. (2015) reported a 46,XX male with an approximately 88-kb duplication in a region upstream of SOX9 (chr17:67,024,087-67,112,435; GRCh37). Because the duplication was also present in his unaffected mother, Xia et al. (2015) suggested that it represented a polymorphism and was not a direct cause of the 46,XX testicular DSD. The authors concluded that other genetic or environmental factors are significant in the regulation of DSD. </p><p><strong><em>46,XY Sex Reversal 10</em></strong></p><p>
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In a cohort of 46,XY patients with DSD, including 29 with complete female phenotype and 118 with undermasculinized external genitalia, Benko et al. (2011) used MLPA and quantitative PCR to screen for CNV in the SOX9 proximal gene desert. They identified 2 46,XY cousins, 1 with a normal external female phenotype and the other with severe ambiguous and asymmetric external genitalia (SRXY10; 616425), who were heterozygous for an approximately 240-kb deletion (608160.0018) between 405 and 645 kb upstream of the SOX9 transcription start site. </p><p>By performing CNV analysis in 100 patients with SRY-positive 46,XY nonsyndromic partial or complete gonadal dysgenesis, Kim et al. (2015) identified 4 unrelated individuals with heterozygous deletions upstream of the SOX9 gene, including a patient from the family originally reported by German et al. (1978) (608160.0019) and a patient from the family studied by Mann et al. (1983) (608160.0020). Both of the latter deletions segregated with disease in the respective families. Together, the 4 deletions defined a 32.5-kb interval, which Kim et al. (2015) designated XYSR for 'XY sex-reversal region,' noting that it overlapped with previously described SOX9 upstream deletions but not with the RevSex region. The authors also identified a distinct 68-kb XX sex-reversal region (XXSR) upstream of the SOX9 gene, based on 46,XX patients with duplications (see 278850), that was largely identical to the RevSex region. Kim et al. (2015) stated that the XYSR and XXSR intervals do not overlap, being separated by 23 kb, and proposed that each harbors a differently-acting gonad-specific regulatory element. Testing of XYSR subfragments in cell transfection and transgenic experiments revealed a 1.9-kb SRY-responsive subfragment, designated F8, that drives expression specifically in Sertoli-like cells and contains consensus binding sites for SRY and WT1 (607102). </p><p><strong><em>Hypertrichosis, Congenital Generalized, with or without Gingival Hyperplasia</em></strong></p><p>
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For discussion of the relationship between microdeletion or microduplication upstream of SOX9 and congenital generalized hypertrichosis with or without gingival hyperplasia, see HTC3 (135400).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Velagaleti et al. (2005) presented a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with mild CMPD with Pierre Robin sequence (602196). They identified both chromosome breakpoints by FISH and sequenced them using a somatic cell hybrid. They found that the 17q24.3 breakpoint mapped approximately 900 kb upstream of SOX9, which was within the same BAC clone as the breakpoints of 2 other reported patients with mild CMPD. They also reported a prenatal identification of CMPD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype. The 17q breakpoint mapped approximately 1.3 Mb downstream of SOX9, making this the longest-range position effect found to that time in the field of human genetics and the first report of a patient with CMPD with the chromosome breakpoint mapping 3-prime of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, they identified a candidate upstream cis-regulatory element, SOX9cre1 (SOX9 conserved regulatory element-1). Velagaleti et al. (2005) provided evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. </p><p>Hill-Harfe et al. (2005) presented fine mapping of chromosome 17 translocation breakpoints upstream of SOX9 associated with skeletal dysplasias. The breakpoint in this case was the most proximal to the SOX9 gene identified up to that time. Their family F had been reported by Stalker and Zori (1997) and Stalker et al. (2005); see Pierre Robin sequence with pectus excavatum and rib and scapular anomalies (602196). Pierre Robin sequence, hypoplastic scapulae, and 11 pairs of ribs are the primary features in family F and are nearly universal in both mild and severe forms of CMPD. However, Hill-Harfe et al. (2005) considered this case to represent either an etiologically distinct disorder or a mild form of CMPD because many other features of CMPD were not present. </p><p>Leipoldt et al. (2007) reported a patient with characteristic symptoms of CMPD and a 46,XY,t(1;17)(q42.1;q24.3) karyotype in whom they mapped the 17q breakpoint 375 kb upstream from SOX9 using standard and high-resolution fiber FISH. Another patient with a 46,X,t(Y;17)(q11.2;q24.3) karyotype had the acampomelic form of CMPD and complete XY sex reversal; using FISH and somatic cell hybrid analysis, the authors mapped the 17q breakpoint 789 kb from SOX9. Combining their data with previously published CMPD translocation breakpoints, Leipoldt et al. (2007) defined 2 clusters upstream of the SOX9 gene: a proximal cluster of breakpoints between 50 and 375 kb upstream and a distal cluster of breakpoints between 789 and 932 kb upstream. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Evolution</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Patel et al. (2001) examined the molecular evolution of DAX1 (300473), SRY (480000), and SOX9 genes involved in mammalian sex determination in 6 primate species. DAX1 and SRY were added to the X and Y chromosomes, respectively, during mammalian evolution, whereas SOX9 remained autosomal. They determined the genomic sequences of DAX1, SRY, and SOX9 in all 6 species, and calculated K(a), the number of nonsynonymous substitutions per nonsynonymous site, and compared this with the K(s), the number of synonymous substitutions per synonymous site. Phylogenetic trees were constructed by means of the DAX1, SRY, and SOX9 coding sequences, and phylogenetic analysis was performed using maximum likelihood. Overall measures of gene and protein similarity were closer for DAX1 and SOX9, but DAX1 exhibited nonsynonymous amino acid substitutions at an accelerated frequency relative to synonymous changes, similar to SRY and significantly higher than SOX9. Patel et al. (2001) concluded that, at the protein level, DAX1 and SRY are under less selective pressure to remain conserved than SOX9, and, therefore, diverge more across species than does SOX9. These results were consistent with evolutionary stratification of the mammalian sex determination pathway, analogous to that for sex chromosomes which may be evolving by punctuated sequential events (Lahn and Page (1997, 1999)). </p><p>Sex determination in many reptiles, including the American alligator, is determined by temperature rather than by sex chromosomes as is the case in mammals and birds. Using incubation temperatures favorable to male or female development, Western et al. (1999) showed that Sox9 expression in alligator embryos was male- and testis- specific, occurred near the end of the 10-day temperature-sensitive period, and was coincident with structural organization of the testis. The late timing of Sox9 expression suggests that Sox9 is unlikely to directly induce the differentiation of the supporting cell lineage into mature Sertoli cells in alligators. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Studying the expression of mouse Sox9 during embryogenesis, Wright et al. (1995) found that the gene is expressed predominantly in mesenchymal condensations throughout the embryo before and during the deposition of cartilage, consistent with a primary role in skeletal formation. The expression pattern and chromosomal location of Sox9 suggested that it may be the gene defective in the mouse skeletal mutant 'Tail-short,' a potential animal model for campomelic dysplasia. </p><p>To analyze Sox9 function during sex determination in mice, Vidal et al. (2001) ectopically expressed this gene in XX gonads. They showed that Sox9 is sufficient to induce testis formation in mice, indicating that it can substitute for the sex-determining gene Sry. </p><p>Akiyama et al. (2002) conditionally deleted the Sox9 gene in mice to examine its contribution at different steps in chondrocyte differentiation. Inactivation of Sox9 in limb buds before mesenchymal condensations resulted in complete absence of cartilage and bone and loss of Sox5 (604975), Sox6 (607257), and Runx2 (600211) expression. Markers for the different axes of limb development were unaffected. Apoptotic domains within the developing limbs were expanded, suggesting that Sox9 suppresses apoptosis. Deletion of Sox9 expression after mesenchymal condensations resulted in a severe generalized chondrodysplasia. Most cells arrested as condensed mesenchymal cells and did not undergo overt differentiation into chondrocytes. Chondrocyte proliferation was inhibited, expression of genes associated with chondrocyte proliferation was downregulated, and joint formation was defective. Akiyama et al. (2002) concluded that SOX9 is needed to prevent conversion of proliferating chondrocytes into hypertrophic chondrocytes and that SOX9 is required during sequential steps of the chondrocyte differentiation pathway. </p><p>SOX9 has essential roles in endochondral bone formation during axial and appendicular skeletogenesis. Because SOX9 is also expressed in neural crest cells, Mori-Akiyama et al. (2003) studied its function in neural crest. As many craniofacial skeletal elements are derived from cranial neural crest cells, the authors hypothesized that deletion of Sox9 in cranial neural crest cells of mice using the Cre recombinase/loxP recombination system would affect craniofacial development. They found that inactivation of Sox9 in neural crest resulted in a complete absence of cartilages and endochondral bones derived from the cranial neural crest. In contrast, all of the mesodermal skeletal elements and intramembranous bones were essentially conserved. Migration and localization of the Sox9 null mutant cranial neural crest cells were normal. In mouse embryo chimeras, Sox9 null mutant cells migrated to their correct location in endochondral skeletal elements; however, the deficient cranial neural crest cells were unable to contribute chondrogenic mesenchymal condensations. Mori-Akiyama et al. (2003) suggested that these cells changed their cell fate and acquired the ability to differentiate into osteoblasts. </p><p>Stolt et al. (2003) ablated Sox9 from mouse neural stem cells to study its role in the switch from neurogenesis to gliogenesis during spinal cord development. Mutant mice exhibited an early and dramatic reduction in progenitors of the myelin-forming oligodendrocytes, but oligodendrocyte progenitor numbers recovered at later stages of development. Astrocyte numbers were severely reduced and did not recover at later stages. Stolt et al. (2003) concluded that SOX9 is a major molecular component of the neuron-glia switch in developing spinal cord. </p><p>Airik et al. (2010) found that targeted Sox9 deletion in mouse ureteric mesenchyme resulted in hydroureter and hydronephrosis, concomitant with small muscle cell deficiency and changes in the composition of uretic extracellular matrix. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>21 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CAMPOMELIC DYSPLASIA</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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SOX9, 583C-T
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<br />
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SNP: rs1480235826,
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ClinVar: RCV000002612
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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 46,XX female with typical features of campomelic dysplasia (114290), Foster et al. (1994) found a 583C-T transition in the SOX9 gene, resulting in a premature stop codon at amino acid position 195 (195X) of the predicted 509-amino acid sequence. The mutation was not found in either parent and was also absent in DNA samples from over 100 unaffected individuals. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL</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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SOX9, 1-BP INS, 783G
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<br />
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SNP: rs1274036689,
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gnomAD: rs1274036689,
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ClinVar: RCV000002613, RCV002512682
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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 46,XY female with typical features of campomelic dysplasia (see 114290), Foster et al. (1994) identified a single G insertion in a series of 6 Gs (nucleotides 783-788) contained within codons 261-263 of SOX9. The resulting frameshift introduced a premature stop codon such that a 294-amino acid truncated protein would be translated. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL</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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SOX9, 4-BP INS
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<br />
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SNP: rs2143251627,
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ClinVar: RCV000002614
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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 46,XY female fetus aborted at 17 weeks because of ultrasound findings of short limbs and cystic hygroma and with clinical findings consistent with campomelic dysplasia (see 114290), including 7 pairs of ribs, Foster et al. (1994) found a 4-bp insertion following amino acid 286 (nucleotide 858) of the predicted protein sequence. The frameshift introduced a premature stop with a predicted translation of a 294-amino acid truncated protein as in the patient described in 608160.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 CAMPOMELIC DYSPLASIA</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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CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL, INCLUDED
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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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SOX9, 1-BP INS, 1096C
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<br />
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SNP: rs587776541,
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ClinVar: RCV000002615, RCV000002616
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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>Cameron et al. (1996) reported a family in which there were 3 patients affected with campomelic dysplasia (114290). Two of the patients showed 46,XY sex reversal (see 114290). The gonadal phenotype varied widely among the 3 affected sibs. The proband had 46,XY true hermaphroditism with ambiguous external genitalia. The other 2 sibs were 46,XY and 46,XX and both had bilateral ovaries with normal female genitalia. A 1-bp insertion (cytidine) at nucleotide position 1096 was detected in the affected children. Mutational analysis revealed wildtype SOX9 nucleotide sequence in the parental somatic cells but detected gonadal mosaicism for the mutation in the father's germ cells. Cameron et al. (1996) noted that incomplete penetrance or stochastic environmental factors could account for the variable phenotype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL</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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SOX9, TYR440TER
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<br />
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SNP: rs80338688,
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gnomAD: rs80338688,
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ClinVar: RCV000002617, RCV000020283, RCV000321802, RCV002276527
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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>Wagner et al. (1994) reported a de novo nonsense mutation within codon 440 (Y440X; TAC-TAG) in a sex-reversed XY female with campomelic dysplasia (see 114290) who survived for 4 years (Ebensperger et al., 1991). Meyer et al. (1997) identified the same de novo stop codon mutation in a karyotypic and phenotypic female who was still alive at the age of 10 years. </p><p>In a female infant with campomelic dysplasia and XY sex reversal, Pop et al. (2005) identified homozygosity for the Y440X mutation. Neither parent carried the mutation; analysis of intragenic SNPs suggested that the homozygous mutation arose by a mitotic gene conversion event involving exchange of at least 440 nucleotides and at most 2,208 nucleotides between a de novo mutant maternal allele and a wildtype paternal allele. The patient also had somatic mosaicism, with homozygous mutant cells constituting about 80% of the leukocyte cell population, whereas about 20% were heterozygous mutant cells; she died at the age of 3 months due to progressive respiratory compromise. Transient cotransfection experiments in mouse neuro2a cells demonstrated that the Y440X mutant retained some transactivation capacity on authentic SOX9-responsive promoters/enhancers, ranging from 5 to 22% of wildtype activity. Pop et al. (2005) suggested that this is a hypomorphic rather than a complete loss-of-function allele, which may account for the milder phenotype and longer survival seen in some patients with this mutation. </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>.0006 ACAMPOMELIC CAMPOMELIC DYSPLASIA</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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SOX9, LYS173GLU
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<br />
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SNP: rs104894647,
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ClinVar: RCV000002618, RCV003497831
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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>Acampomelic campomelic dysplasia (see 114290) is a rare variant of the more commonly encountered campomelic dysplasia, characterized by absence of long bone curvature. Thong et al. (2000) described a patient with acampomelic dysplasia with a de novo heterozygous mutation in the SOX9 gene, resulting in a lys173-to-glu (K173E) substitution. The mutation was located within the DNA binding HMG (high mobility group) domain of the SOX9 protein. The mutation was not present in the parents. The patient's antenatal period was uneventful, apart from renal pelvis dilatation detected at 19 weeks on ultrasound scan. Soon after birth he developed severe respiratory distress requiring ventilation for 2 weeks and continuous positive airway pressure via nasal prong thereafter. He developed recurrent chest infections and feeding difficulties. Oxygen supplementation was discontinued at 7 months. Physical examination showed rounded face, flat nasal bridge, micrognathia, midline cleft palate, long deep philtrum, and small mouth. The genital abnormalities consisted of bifid scrotum, perineal hypospadias, and undescended right testis. He had deep plantar creases, mild clinodactyly, small and hyperconvex nails, and limited elbow extension. The limbs were straight with no pretibial dimples. The karyotype was 46,XY. Skeletal survey at 7 weeks showed 11 pairs of gracile ribs, hypoplastic scapulas, dysplastic clavicles with broad medial aspects, and coronal clefts in the vertebral bodies T11, L1, and L2. The bodies of the iliac and pubic bones were hypoplastic with small sacrosciatic notches. The long bones were straight with mild shortness and flare of the metaphyses. </p>
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</span>
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</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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SOX9, 1-BP DEL, 296G
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|
<br />
|
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|
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SNP: rs1598175249,
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ClinVar: RCV000002619
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|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with campomelic syndrome with autosomal sex reversal (see 114290), Ninomiya et al. (2000) identified a 1-bp deletion (296G), resulting in a frameshift upstream of the HMG box and a stop codon in the HMG domain of SOX9. The predicted truncated SOX9 protein contained 108 amino acids instead of the normal 509. Despite the marked change in the SOX9 protein, the patient had survived for 63 months, although requiring daily mechanical support of ventilation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0008 ACAMPOMELIC CAMPOMELIC DYSPLASIA</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
SOX9, HIS165TYR
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<br />
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|
|
SNP: rs28940282,
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|
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ClinVar: RCV000002620
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|
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|
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|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a chromosomally normal boy with acampomelic campomelic dysplasia (see 114290), Moog et al. (2001) identified a heterozygous 865C-T transition in the SOX9 gene, leading to a his165-to-tyr (H165Y) substitution. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
|
|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 ACAMPOMELIC CAMPOMELIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX9, ALA76GLU
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|
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|
|
|
<br />
|
|
|
|
SNP: rs137853128,
|
|
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|
|
|
|
ClinVar: RCV000002621, RCV001266938
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a long-term survivor with acampomelic campomelic dysplasia (see 114290), Sock et al. (2003) reported a C-to-A transversion in the SOX9 gene that resulted in an ala76-to-glu (A76E) amino acid substitution. Dimerization and the resulting capacity to activate promoters via dimeric binding sites was lost in the mutant SOX9 protein while other features involved in SOX9 function remained unaltered. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CAMPOMELIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX9, 30-BP DEL
|
|
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|
|
|
<br />
|
|
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|
|
|
|
|
ClinVar: RCV000002622
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with campomelic dysplasia (114290), Sock et al. (2003) detected a 30-bp deletion in the SOX9 gene that removed amino acids 66 through 75 (delta66-75). The 30-bp deletion occurred between 2 hexanucleotide repeats, retaining 1 copy. The patient, a girl who died soon after birth from respiratory failure, had all the hallmarks of campomelic dysplasia, including bending of femora, tibiae, and fibulae. Additionally she showed the rare findings of absence of toenails and a broad gap between the first and second toes, combined with syndactyly between the second, third, and fourth toes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CAMPOMELIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX9, PHE154LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137853129,
|
|
|
|
|
|
gnomAD: rs137853129,
|
|
|
|
|
|
ClinVar: RCV000002623
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an infant with campomelic dysplasia (114290), Preiss et al. (2001) identified a heterozygous 462C-G transversion in the SOX9 gene, resulting in a phe154-to-leu (F154L) substitution. F154 is a highly conserved residue of helix 3 within the HMG domain. Fluorescence studies showed that the mutant F154L protein did not have significant changes in tertiary structure. In vitro functional expression studies demonstrated that the mutant protein had a significant loss of DNA-binding activity (5% of wildtype) and a loss of transcriptional activation activity (26% of wildtype). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX9, ALA158THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137853130,
|
|
|
|
|
|
|
|
ClinVar: RCV000002624, RCV001851587
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with campomelic dysplasia with autosomal sex reversal (see 114290), Preiss et al. (2001) identified a heterozygous 472G-A transition in the SOX9 gene, resulting in an ala158-to-thr (A158T) substitution. A158 is a highly conserved residue of helix 3 within the HMG domain. Fluorescence studies showed that the mutant A158T protein did not have significant changes in tertiary structure. In vitro functional expression studies demonstrated that the mutant protein had a 2-fold decrease in nuclear accumulation, a loss of DNA-binding activity (17% of wildtype), and a milder loss of transcriptional activation activity (62% of wildtype). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 CAMPOMELIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX9, 1-BP INS, 1103A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1598176785,
|
|
|
|
|
|
|
|
ClinVar: RCV000002625, RCV000002626
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 46,XY patient with campomelic dysplasia (114290) and a 46,XY patient with campomelic dysplasia and autosomal sex reversal (see 114290), Kwok et al. (1995) identified heterozygosity for a 1-bp insertion (1103insA) in the SOX9 gene, causing a frameshift at codon 368 and resulting in an early termination signal at nucleotide 1671. The authors attributed the difference in sexual phenotype of these two 46,XY individuals to incomplete penetrance of the disease that might result from differences in genetic background. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 46,XX SEX REVERSAL 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX9, 178-KB DUP, UPSTREAM REGULATORY REGION
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000023686
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Cox et al. (2011) identified a family with 46,XX testicular disorder of sex development (SRXX2; 278850) in which 3 adult males (2 brothers and a paternal uncle) were determined to be female according to karyotype and were negative for the SRY gene (480000). The proband and his uncle had an approximately 178-kb duplication 600 kb upstream of SOX9. The duplication was arranged in tandem in wildtype orientation, and the joining points of the duplicated segments were uncorrupted. All affected family members carried the duplication as did the proband's healthy, fertile 46,XY father. Of note, the 1.9-Mb region of chromosome 17 upstream of SOX9 contains no other genes and is evolutionarily highly conserved in mammals. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 ACAMPOMELIC CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX9, 960-KB DEL, UPSTREAM REGULATORY REGION
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000032999
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-year-old 46,XY girl with acampomelic campomelic dysplasia and complete sex reversal (see 114290), Lecointre et al. (2009) identified a heterozygous 960-kb deletion on chromosome 17q24, extending from -517 to -1,477 kb upstream of SOX9. The deletion was also present in her mildly affected mother, who was born with cleft palate and had mild microretrognathia, sandal gap, short great toes, and defective ischiopubic ossification; the unaffected father's DNA was normal. FISH analysis confirmed the presence of the deletion in the mother and daughter and its absence in the father; analysis of interphase nuclei in 3 different tissues from the mother demonstrated the presence of the deletion in 97 to 98.5% of nuclei, which suggested that the mother did not have somatic mosaicism. MLPA results were consistent with the interphase FISH analysis, again strongly suggesting that the mother was not mosaic for the deletion. Lecointre et al. (2009) stated that this deletion narrowed the minimum critical region and reduced the number of highly conserved sequence elements responsible for acampomelic campomelic dysplasia. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 46,XX SEX REVERSAL 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX9, 96-KB TRIPLICATION, UPSTREAM REGULATORY REGION
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000173015
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 46,XX SRY-negative Italian brothers (SRXX2; 278850), who were phenotypically normal males but had hypotrophic testes and azoospermia, Vetro et al. (2011) identified heterozygosity for a 96-kb triplication located 500 kb upstream of the SOX9 gene on chromosome 17. Array CGH and quantitative PCR analysis defined the proximal breakpoint of the triplication from 67,018,227 bp (normal) to 67,018,939 bp (triplicated), and the distal breakpoint from 67,114,737 bp (triplicated) to 67,119,234 bp (normal; NCBI36). The triplication was not present in their 2 fertile sisters and mother. The 2 brothers shared the same paternal haplotype for the SOX9 region, supporting the possibility that their deceased unaffected father was the carrier of the triplication. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 46,XX SEX REVERSAL 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX9, 148-KB DUP, UPSTREAM REGULATORY REGION
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000173016
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 46,XX SRY-negative patient (SRXX2; 278850), who was born with perineal hypospadias and asymmetric scrotum containing a normal testis on one side and an ovarian remnant with fallopian tube structures on the other, Benko et al. (2011) identified heterozygosity for an approximately 148-kb tandem duplication of the region -595 to -447 kb upstream of SOX9 (chr17:69,521,863-69,670,036; GRCh37). The duplication, which was inherited from the unaffected father, was also present in 2 unaffected brothers but was not found in a healthy 46,XX sister or in the Database of Genomic Variants. The proband's unaffected father inherited the duplication from his unaffected mother, indicating incomplete penetrance. The patient had normal psychomotor and pubertal development, with normal testosterone levels, and displayed normal growth and bodily proportions. </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 46,XY SEX REVERSAL 10</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SOX9, 240-KB DEL, UPSTREAM REGULATORY REGION
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<br />
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ClinVar: RCV000173017
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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 two 46,XY cousins, 1 with a normal external female phenotype and the other with severe ambiguous and asymmetric external genitalia (SRXY10; 616425), Benko et al. (2011) identified heterozygosity for an approximately 240-kb deletion between 405 and 645 kb upstream of the SOX9 transcription start site. The unaffected mothers of the 2 patients were sisters and carried the same deletion, which was not found in the Database of Genomic Variants; no dysmorphism or skeletal abnormalities were detected in the family. </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>.0019 46,XY SEX REVERSAL 10</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SOX9, 577-KB DEL, UPSTREAM REGULATORY REGION
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<br />
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ClinVar: RCV000173018
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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 two 46,XY sisters who exhibited unambiguously female genitalia but did not undergo breast development or menstruation at puberty (SRXY10; 616425), Kim et al. (2015) identified heterozygosity for a 577-kb deletion extending from 132.1 to 709.0 kb upstream of the SOX9 gene. These individuals had been reported as patients III.10 and III.11 by German et al. (1978); Kim et al. (2015) referred to the family as DSD4. Pelvic surgery in the third decade of life revealed bilateral streak gonads in both sisters; an affected cousin (patient III.16) had bilateral gonadoblastoma (German et al., 1978). No skeletal anomalies were reported in any of the affected individuals. </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>.0020 46,XY SEX REVERSAL 10</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SOX9, 136-KB DEL, UPSTREAM REGULATORY REGION
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<br />
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ClinVar: RCV000173019
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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 46,XY individual with apparently normal female genitalia (SRXY10; 616425), Kim et al. (2015) identified heterozygosity for a 136-kb deletion extending from 510 to 646 kb upstream of the SOX9 gene. This individual had been reported by Mann et al. (1983) as patient VI.2; Kim et al. (2015) referred to the family as DSD3. Due to a family history of gonadal germ cell tumors in affected individuals, the patient underwent prophylactic removal of the gonads at age 20 months; histology showed dysgenetic gonads with gonadoblastoma present in the right gonad. The deletion was also present in a 46,XY maternal great-aunt (patient IV.25), who underwent gonadectomy at 23.5 years of age, which revealed bilateral 'ovarian' dysgerminomas. </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>.0021 CAMPOMELIC DYSPLASIA</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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SOX9, HIS169GLN
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<br />
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SNP: rs2229989,
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gnomAD: rs2229989,
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ClinVar: RCV000224991, RCV000278794, RCV001266335
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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 10-year-old Japanese boy with mild campomelic dysplasia (CMPD; 114290), Matsushita et al. (2013) identified heterozygosity for a c.507C-G transversion in exon 2 of the SOX9 gene, resulting in a his169-to-gln (H169Q) substitution at a highly conserved residue. The mutation was inherited from his very mildly affected mother. Functional analysis of H169Q as well as H169P, a mutation previously identified in a more severe CMPD case by Massardier et al. (2008), demonstrated that both mutants had significantly reduced transactivation capacity compared to wildtype, but that the H169Q mutant retained more residual transactivation (46% of wildtype) than the H169P mutant (21%). Matsushita et al. (2013) suggested that retained SOX9 function might account for the extremely mild CMPD phenotype in the Japanese family. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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|
Adam, R. C., Yang, H., Rockowitz, S., Larsen, S. B., Nikolova, M., Oristian, D. S., Polak, L., Kadaja, M., Asare, A., Zheng, D., Fuchs, E.
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<strong>Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice.</strong>
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Nature 521: 366-370, 2015.
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[PubMed: 25799994]
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[Full Text: https://doi.org/10.1038/nature14289]
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<p class="mim-text-font">
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Airik, R. Trowe, M.-O., Foik, A., Farin, H. F., Petry, M., Schuster-Gossler, K., Schweizer, M., Scherer, G., Kist, R., Kispert, A.
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<strong>Hydroureternephrosis due to loss of Sox9-regulated smooth muscle cell differentiation of the ureteric mesenchyme.</strong>
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Hum. Molec. Genet. 19: 4918-4929, 2010.
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[PubMed: 20881014]
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<p class="mim-text-font">
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Akiyama, H., Chaboissier, M.-C., Martin, J. F., Schedl, A., de Crombrugghe, B.
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<strong>The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6.</strong>
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Genes Dev. 16: 2813-2828, 2002.
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[PubMed: 12414734]
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[Full Text: https://doi.org/10.1101/gad.1017802]
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<p class="mim-text-font">
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Bell, D. M., Leung, K. K. H., Wheatley, S. C., Ng, L. J., Zhou, S., Ling, K. W., Sham, M. H., Koopman, P., Tam, P. P. L., Cheah, K. S. E.
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|
<strong>SOX9 directly regulates the type-II collagen gene.</strong>
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|
Nature Genet. 16: 174-178, 1997.
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[PubMed: 9171829]
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[Full Text: https://doi.org/10.1038/ng0697-174]
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</p>
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<li>
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<p class="mim-text-font">
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Benko, S., Fantes, J. A., Amiel, J., Kleinjan, D.-J., Thomas, S., Ramsay, J., Jamshidi, N., Essafi, A., Heaney, S., Gordon, C. T., McBride, D., Golzio, C., and 20 others.
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<strong>Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence.</strong>
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Nature Genet. 41: 359-364, 2009.
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[PubMed: 19234473]
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[Full Text: https://doi.org/10.1038/ng.329]
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<p class="mim-text-font">
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Benko, S., Gordon, C. T., Mallet, D., Sreenivasan, R., Thauvin-Robinet, C., Brendehaug, A., Thomas, S., Bruland, O., David, M., Nicolino, M., Labalme, A., Sanlaville, D., and 12 others.
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<strong>Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.</strong>
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J. Med. Genet. 48: 825-830, 2011.
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[PubMed: 22051515]
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[Full Text: https://doi.org/10.1136/jmedgenet-2011-100255]
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<p class="mim-text-font">
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Bien-Willner, G. A., Stankiewicz, P., Lupski, J. R.
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<strong>SOX9cre1, a cis-acting regulatory element located 1.1 Mb upstream of SOX9, mediates its enhancement through the SHH pathway.</strong>
|
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Hum. Molec. Genet. 16: 1143-1156, 2007.
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[PubMed: 17409199]
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[Full Text: https://doi.org/10.1093/hmg/ddm061]
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<li>
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<p class="mim-text-font">
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Bishop, C. E., Whitworth, D. J., Qin, Y., Agoulnik, A. I., Agoulnik, I. U., Harrison, W. R., Behringer, R. R., Overbeek, P. A.
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<strong>A transgenic insertion upstream of Sox9 is associated with dominant XX sex reversal in the mouse.</strong>
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Nature Genet. 26: 490-494, 2000.
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[PubMed: 11101852]
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[Full Text: https://doi.org/10.1038/82652]
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<li>
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<p class="mim-text-font">
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Blache, P., van de Wetering, M., Duluc, I., Domon, C., Berta, P., Freund, J.-N., Clevers, H., Jay, P.
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<strong>SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes.</strong>
|
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J. Cell Biol. 166: 37-47, 2004.
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[PubMed: 15240568]
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[Full Text: https://doi.org/10.1083/jcb.200311021]
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<p class="mim-text-font">
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Cameron, F. J., Hageman, R. M., Cooke-Yarborough, C., Kwok, C., Goodwin, L. L., Sillence, D. O., Sinclair, A. H.
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<strong>A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal.</strong>
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Hum. Molec. Genet. 5: 1625-1630, 1996.
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[PubMed: 8894698]
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[Full Text: https://doi.org/10.1093/hmg/5.10.1625]
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<p class="mim-text-font">
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Cheung, M., Chaboissier, M.-C., Mynett, A., Hirst, E., Schedl, A., Briscoe, J.
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<strong>The transcriptional control of trunk neural crest induction, survival, and delamination.</strong>
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Dev. Cell 8: 179-192, 2005.
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<p class="mim-text-font">
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Chikuda, H., Kugimiya, F., Hoshi, K., Ikeda, T., Ogasawara, T., Shimoaka, T., Kawano, H., Kamekura, S., Tsuchida, A., Yokoi, N., Nakamura, K., Komeda, K., Chung, U., Kawaguchi, H.
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<strong>Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.</strong>
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Genes Dev. 18: 2418-2429, 2004.
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[PubMed: 15466490]
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[Full Text: https://doi.org/10.1101/gad.1224204]
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<p class="mim-text-font">
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Cox, J. J., Willatt, L., Homfray, T., Woods, C. G.
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<strong>A SOX9 duplication and familial 46,XX developmental testicular disorder. (Letter)</strong>
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New Eng. J. Med. 364: 91-93, 2011.
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[PubMed: 21208124]
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[Full Text: https://doi.org/10.1056/NEJMc1010311]
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<li>
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<p class="mim-text-font">
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Ebensperger, C., Jager, R. J., Lattermann, U., Dagna Bricarelli, F., Keutel, J., Lindsten, J., Rehder, H., Muller, U., Wolf, U.
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<strong>No evidence of mutations in four candidate genes for male sex determination/differentiation in sex-reversed XY females with campomelic dysplasia.</strong>
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Ann. Genet. 34: 233-238, 1991.
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[PubMed: 1809232]
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<li>
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<p class="mim-text-font">
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Fantauzzo, K. A., Kurban, M., Levy, B., Christiano, A. M.
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<strong>Trps1 and its target gene Sox9 regulate epithelial proliferation in the developing hair follicle and are associated with hypertrichosis.</strong>
|
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PLoS Genet. 8: e1003002, 2012. Note: Electronic Article.
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[PubMed: 23133399]
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[Full Text: https://doi.org/10.1371/journal.pgen.1003002]
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</p>
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<li>
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<p class="mim-text-font">
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Foster, J. W., Dominguez-Steglich, M. A., Guioli, S., Kwok, C., Weller, P. A., Stevanovic, M., Weissenbach, J., Mansour, S., Young, I. D., Goodfellow, P. N., Brook, J. D., Schafer, A. J.
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<strong>Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.</strong>
|
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Nature 372: 525-530, 1994.
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[PubMed: 7990924]
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[Full Text: https://doi.org/10.1038/372525a0]
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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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|
Furuyama, K., Kawaguchi, Y., Akiyama, H., Horiguchi, M., Kodama, S., Kuhara, T., Hosokawa, S., Elbahrawy, A., Soeda, T., Koizumi, M., Masui, T., Kawaguchi, M., Takaori, K., Doi, R., Nishi, E., Kakinoki, R., Deng, J. M., Behringer, R. R., Nakamura, T., Uemoto, S.
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<strong>Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine.</strong>
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Nature Genet. 43: 34-41, 2011.
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[PubMed: 21113154]
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[Full Text: https://doi.org/10.1038/ng.722]
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</p>
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<li>
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<p class="mim-text-font">
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Gasca, S., Canizares, J., de Santa Barbara, P., Mejean, C., Poulat, F., Berta, P., Boizet-Bonhoure, B.
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<strong>A nuclear export signal within the high mobility group domain regulates the nucleocytoplasmic translocation of SOX9 during sexual determination.</strong>
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Proc. Nat. Acad. Sci. 99: 11199-11204, 2002.
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[PubMed: 12169669]
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[Full Text: https://doi.org/10.1073/pnas.172383099]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
German, J., Simpson, J. L., Chaganti, R. S. K.
|
|
<strong>Genetically determined sex-reversal in 46,XY humans.</strong>
|
|
Science 202: 53-56, 1978.
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|
|
[PubMed: 567843]
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[Full Text: https://doi.org/10.1126/science.567843]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gonen, N., Futtner, C. R., Wood, S., Garcia-Moreno, S. A., Salamone, I. M., Samson, S. C., Sekido, R., Poulat, F., Maatouk, D. M., Lovell-Badge, R.
|
|
<strong>Sex reversal following deletion of a single distal enhancer of Sox9.</strong>
|
|
Science 360: 1469-1473, 2018.
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[PubMed: 29903884]
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[Full Text: https://doi.org/10.1126/science.aas9408]
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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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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 11/20/2020<br>Ada Hamosh - updated : 09/22/2020<br>Ada Hamosh - updated : 09/04/2018<br>Marla J. F. O'Neill - updated : 08/03/2016<br>Marla J. F. O'Neill - updated : 5/18/2016<br>Ada Hamosh - updated : 6/23/2015<br>Marla J. F. O'Neill - updated : 6/17/2015<br>Ada Hamosh - updated : 11/17/2014<br>Ada Hamosh - updated : 9/30/2014<br>Marla J. F. O'Neill - updated : 7/3/2014<br>Patricia A. Hartz - updated : 1/15/2014<br>Marla J. F. O'Neill - updated : 11/9/2012<br>Patricia A. Hartz - updated : 3/9/2011<br>Ada Hamosh - updated : 1/19/2011<br>Patricia A. Hartz - updated : 3/18/2010<br>Marla J. F. O'Neill - updated : 1/29/2010<br>Patricia A. Hartz - updated : 12/8/2009<br>Patricia A. Hartz - updated : 9/21/2009<br>Cassandra L. Kniffin - updated : 9/15/2009<br>Cassandra L. Kniffin - updated : 8/11/2009<br>Marla J. F. O'Neill - updated : 4/30/2009<br>Patricia A. Hartz - updated : 10/28/2008<br>Ada Hamosh - updated : 7/11/2008<br>George E. Tiller - updated : 5/19/2008<br>Patricia A. Hartz - updated : 2/29/2008<br>Marla J. F. O'Neill - updated : 3/9/2007<br>Marla J. F. O'Neill - updated : 10/30/2006<br>Patricia A. Hartz - updated : 12/20/2005<br>Patricia A. Hartz - updated : 11/9/2005<br>Cassandra L. Kniffin - updated : 9/7/2005<br>Marla J. F. O'Neill - updated : 7/5/2005<br>George E. Tiller - updated : 3/22/2005<br>Victor A. McKusick - updated : 3/11/2005<br>Patricia A. Hartz - updated : 2/23/2005<br>Patricia A. Hartz - updated : 12/9/2004<br>George E. Tiller - updated : 8/18/2004
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Cassandra L. Kniffin : 10/10/2003
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mgross : 11/20/2020<br>alopez : 09/22/2020<br>alopez : 07/16/2019<br>alopez : 09/04/2018<br>alopez : 08/03/2016<br>alopez : 06/09/2016<br>alopez : 5/18/2016<br>alopez : 6/23/2015<br>alopez : 6/22/2015<br>mcolton : 6/17/2015<br>alopez : 11/17/2014<br>alopez : 9/30/2014<br>joanna : 9/2/2014<br>alopez : 7/8/2014<br>mcolton : 7/3/2014<br>mgross : 1/17/2014<br>mcolton : 1/15/2014<br>carol : 11/12/2012<br>terry : 11/9/2012<br>terry : 8/22/2012<br>carol : 6/4/2012<br>carol : 6/1/2011<br>mgross : 3/9/2011<br>terry : 3/9/2011<br>terry : 3/9/2011<br>alopez : 3/4/2011<br>alopez : 2/24/2011<br>alopez : 1/31/2011<br>terry : 1/19/2011<br>mgross : 3/22/2010<br>terry : 3/18/2010<br>wwang : 2/1/2010<br>terry : 1/29/2010<br>mgross : 1/25/2010<br>joanna : 1/25/2010<br>mgross : 1/4/2010<br>terry : 12/8/2009<br>carol : 9/22/2009<br>terry : 9/21/2009<br>wwang : 9/21/2009<br>ckniffin : 9/15/2009<br>carol : 8/19/2009<br>carol : 8/12/2009<br>ckniffin : 8/11/2009<br>wwang : 5/5/2009<br>terry : 4/30/2009<br>alopez : 2/9/2009<br>mgross : 10/28/2008<br>mgross : 10/28/2008<br>terry : 9/26/2008<br>alopez : 7/15/2008<br>terry : 7/11/2008<br>wwang : 5/22/2008<br>terry : 5/19/2008<br>wwang : 4/30/2008<br>mgross : 2/29/2008<br>carol : 7/26/2007<br>wwang : 3/13/2007<br>terry : 3/9/2007<br>wwang : 10/30/2006<br>wwang : 10/30/2006<br>wwang : 12/20/2005<br>mgross : 12/6/2005<br>terry : 11/9/2005<br>mgross : 9/7/2005<br>ckniffin : 9/7/2005<br>joanna : 9/6/2005<br>wwang : 7/11/2005<br>wwang : 7/8/2005<br>terry : 7/5/2005<br>wwang : 6/8/2005<br>terry : 5/23/2005<br>alopez : 3/22/2005<br>wwang : 3/18/2005<br>wwang : 3/15/2005<br>terry : 3/11/2005<br>mgross : 2/23/2005<br>mgross : 12/9/2004<br>alopez : 8/18/2004<br>carol : 2/23/2004<br>carol : 10/15/2003<br>ckniffin : 10/14/2003
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