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Entry
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- *602229 - SRY-BOX 10; SOX10
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- OMIM
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<p>
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<span class="h4">*602229</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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<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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<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="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602229">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 role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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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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<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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</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=ENSG00000100146;t=ENST00000396884" 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=6663" 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=602229" 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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<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=ENSG00000100146;t=ENST00000396884" 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_006941" 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_006941" 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=602229" 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=03752&isoform_id=03752_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/SOX10" 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/2909360,5902104,6175075,12803953,14043213,47678699,49168626,54696920,119580608,119580609,194374919" 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/P56693" 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=6663" 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=ENSG00000100146;t=ENST00000396884" 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=SOX10" 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=SOX10" 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+6663" 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/SOX10" 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:6663" 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/6663" 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=chr22&hgg_gene=ENST00000396884.8&hgg_start=37972312&hgg_end=37984555&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:11190" 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:11190" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=602229[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=602229[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/SOX10/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/ENSG00000100146" 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=SOX10" 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=SOX10" 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=SOX10" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/SOX10" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">SOX10 database at LOVD</a></div><div style="margin-left: 0.5em;"><a href="http://www.molgen.ua.ac.be/CMTMutations/" title="Inherited Peripheral Neuropathies Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Inherited Peripheral Neuro…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SOX10&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/PA36027" 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:11190" 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:98358" 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/SOX10#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:98358" 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/6663/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/results?search_type=advanced&omia_id=001569,002190,002453" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=6663" 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-011207-1" 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://reactome.org/content/query?q=SOX10&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> 765325002<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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602229
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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 10; SOX10
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SRY-RELATED HMG-BOX GENE 10<br />
|
|
DOMINANT MEGACOLON, MOUSE, HOMOLOG OF; DOM
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SOX10" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SOX10</a></em></strong>
|
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/22/264?start=-3&limit=10&highlight=264">22q13.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr22:37972312-37984555&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'})">22:37,972,312-37,984,555</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=609136,611584,613266" 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>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/22/264?start=-3&limit=10&highlight=264">
|
|
22q13.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
PCWH syndrome
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/609136"> 609136 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Waardenburg syndrome, type 2E, with or without neurologic involvement
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/611584"> 611584 </a>
|
|
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<p>The testis-determining gene SRY (<a href="/entry/480000">480000</a>) encodes a transcription factor characterized by a DNA-binding motif known as the HMG (high mobility group) domain. The SOX gene family, which includes SOX10, consists of genes related to SRY, with a sequence identity of more than 60% to the SRY HMG box. SOX10 is a transcription factor that functions in neural crest and oligodendrocyte development (<a href="#40" class="mim-tip-reference" title="Pusch, C., Hustert, E., Pfeifer, D., Sudbeck, P., Kist, R., Roe, B., Wang, Z., Balling, R., Blin, N., Scherer, G. <strong>The SOX10/Sox10 gene from human and mouse: sequence, expression, and transactivation by the encoded HMG domain transcription factor.</strong> Hum. Genet. 103: 115-123, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9760192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9760192</a>] [<a href="https://doi.org/10.1007/s004390050793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9760192">Pusch et al., 1998</a>; <a href="#8" class="mim-tip-reference" title="Chaoui, A., Kavo, A., Baral, V., Watanabe, Y., Lecerf, L., Colley, A., Mendoza-Londono, R., Pingault, V., Bondurand, N. <strong>Subnuclear re-localization of SOX10 and p54NRB correlates with a unique neurological phenotype associated with SOX10 missense mutations.</strong> Hum. Molec. Genet. 24: 4933-4947, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26060192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26060192</a>] [<a href="https://doi.org/10.1093/hmg/ddv215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26060192">Chaoui et al., 2015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26060192+9760192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using a rat SOX10 cDNA probe to screen a human brain cDNA library, <a href="#34" class="mim-tip-reference" title="Pingault, V., Bondurand, N., Kuhlbrodt, K., Goerich, D. E., Prehu, M.-O., Puliti, A., Herbarth, B., Hermans-Borgmeyer, I., Legius, E., Matthijs, G., Amiel, J., Lyonnet, S., Ceccherini, I., Romeo, G., Smith, J. C., Read, A. P., Wegner, M., Goossens, M. <strong>SOX10 mutations in patients with Waardenburg-Hirschsprung disease.</strong> Nature Genet. 18: 171-173, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462749</a>] [<a href="https://doi.org/10.1038/ng0298-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462749">Pingault et al. (1998)</a> isolated a human SOX10 cDNA predicted to encode a 466-amino acid protein with a highly conserved HMG domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462749" 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="Pusch, C., Hustert, E., Pfeifer, D., Sudbeck, P., Kist, R., Roe, B., Wang, Z., Balling, R., Blin, N., Scherer, G. <strong>The SOX10/Sox10 gene from human and mouse: sequence, expression, and transactivation by the encoded HMG domain transcription factor.</strong> Hum. Genet. 103: 115-123, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9760192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9760192</a>] [<a href="https://doi.org/10.1007/s004390050793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9760192">Pusch et al. (1998)</a> cloned and sequenced the human SOX10 and the mouse Sox10 genes, which share 98% amino acid identity. Sequence analysis suggested that SOX9 (<a href="/entry/608160">608160</a>) and SOX10 have a common evolutionary origin. Northern blot analysis detected a 2.9-kb SOX10 mRNA in fetal brain and in adult heart, brain, small intestine, and colon. Low-level expression was seen in prostate and testis. In mouse embryos, Sox10 expression was detected in the developing peripheral nervous system, most prominent in the trigeminal, geniculate, and acoustic ganglia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9760192" 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="Kuhlbrodt, K., Herbarth, B., Sock, E., Hermans-Borgmeyer, I., Wegner, M. <strong>Sox10, a novel transcriptional modulator in glial cells.</strong> J. Neurosci. 18: 237-250, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9412504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9412504</a>] [<a href="https://doi.org/10.1523/JNEUROSCI.18-01-00237.1998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9412504">Kuhlbrodt et al. (1998)</a> cloned the rat SOX10 gene, which encodes a 466-amino acid protein with a molecular mass of approximately 50 kD. Northern blot analysis detected a 3-kb SOX10 mRNA transcript that was largely restricted to glial cells in the adult nervous system. During development, SOX10 first appeared in the forming neural crest and continued to be expressed as these cells contributed to the forming peripheral nervous system and finally differentiated into Schwann cells. In the central nervous system, SOX10 transcripts were originally confined to glial precursors and later detected in oligodendrocytes of the adult brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9412504" 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="#33" class="mim-tip-reference" title="Pingault, V., Bodereau, V., Baral, V., Marcos, S., Watanabe, Y., Chaoui, A., Fouveaut, C., Leroy, C., Verier-Mine, O., Francannet, C., Dupin-Deguine, D., Archambeaud, F., Kurtz, F.-J., Young, J., Bertherat, J., Marlin, S., Goossens, M., Hardelin, J.-P., Dode, C., Bondurand, N. <strong>Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness.</strong> Am. J. Hum. Genet. 92: 707-724, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643381</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643381[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/10.1016/j.ajhg.2013.03.024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643381">Pingault et al. (2013)</a> demonstrated expression of SOX10 in olfactory ensheathing cells during development of the peripheral olfactory system in mice and humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23643381" 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="#34" class="mim-tip-reference" title="Pingault, V., Bondurand, N., Kuhlbrodt, K., Goerich, D. E., Prehu, M.-O., Puliti, A., Herbarth, B., Hermans-Borgmeyer, I., Legius, E., Matthijs, G., Amiel, J., Lyonnet, S., Ceccherini, I., Romeo, G., Smith, J. C., Read, A. P., Wegner, M., Goossens, M. <strong>SOX10 mutations in patients with Waardenburg-Hirschsprung disease.</strong> Nature Genet. 18: 171-173, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462749</a>] [<a href="https://doi.org/10.1038/ng0298-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462749">Pingault et al. (1998)</a> determined that the SOX10 gene contains 5 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462749" 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="#25" class="mim-tip-reference" title="Lane, P. W., Liu, H. M. <strong>Association of megacolon with a new dominant spotting gene (Dom) in the mouse.</strong> J. Hered. 75: 435-439, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6512238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6512238</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jhered.a109980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6512238">Lane and Liu (1984)</a> determined that a mouse model of Hirschsprung disease (HSCR; <a href="/entry/142623">142623</a>), dominant megacolon (Dom), mapped to a mid-terminal region of mouse chromosome 15 (see ANIMAL MODEL). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6512238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Pingault, V., Puliti, A., Prehu, M.-O., Samadi, A., Bondurand, N., Goossens, M. <strong>Human homology and candidate genes for the dominant megacolon locus, a mouse model of Hirschsprung disease.</strong> Genomics 39: 86-89, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9027489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9027489</a>] [<a href="https://doi.org/10.1006/geno.1996.4476" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9027489">Pingault et al. (1997)</a> noted that, in mice, natural and in vitro-induced mutations affecting the Ret (<a href="/entry/164761">164761</a>), Ednrb (<a href="/entry/131242">131242</a>), and Edn3 (<a href="/entry/131244">131244</a>) genes generated phenotypes similar to human Hirschsprung disease. Using polymorphisms for conserved human/mouse genes, <a href="#37" class="mim-tip-reference" title="Pingault, V., Puliti, A., Prehu, M.-O., Samadi, A., Bondurand, N., Goossens, M. <strong>Human homology and candidate genes for the dominant megacolon locus, a mouse model of Hirschsprung disease.</strong> Genomics 39: 86-89, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9027489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9027489</a>] [<a href="https://doi.org/10.1006/geno.1996.4476" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9027489">Pingault et al. (1997)</a> established homology between the Dom locus and human chromosome 22q12-q13. Two genes, Smstr3 and Adsl (<a href="/entry/608222">608222</a>), not previously mapped in the mouse genome, were also mapped to mouse chromosome 15. The investigators stated that 3 genes, Smstr3, Lgals1 (<a href="/entry/150570">150570</a>), and Pdgfb (<a href="/entry/190040">190040</a>), are possible Dom candidates, as they did not recombine with the Dom mutation in a backcross. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9027489" 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="#24" class="mim-tip-reference" title="Kuhlbrodt, K., Schmidt, C., Sock, E., Pingault, V., Bondurand, N., Goossens, M., Wegner, M. <strong>Functional analysis of Sox10 mutations found in human Waardenburg-Hirschsprung patients.</strong> J. Biol. Chem. 273: 23033-23038, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9722528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9722528</a>] [<a href="https://doi.org/10.1074/jbc.273.36.23033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9722528">Kuhlbrodt et al. (1998)</a> studied 4 SOX10 mutations found in patients with Waardenburg-Shah syndrome (WS4; <a href="/entry/277580">277580</a>). Unlike the rat SOX10 protein, which failed to show transcriptional activity on its own, wildtype human SOX10 displayed a weak, but reproducible, activity as a transcriptional activator. All mutant SOX10 proteins, including the 1 that lacked only the last 106 amino acids, were deficient in this capacity, indicating that the C terminus of human SOX10 carries a transactivation domain. Whereas all 4 mutants failed to transactivate, only 2 failed to enhance synergistically the activity of other transcription factors. Synergy required the ability to bind to DNA and a region in the N-terminal part of SOX10. Those mutants that failed to synergize were unable to bind to DNA. Analysis of the naturally occurring SOX10 mutations not only helped to dissect SOX10 structure, but also allowed limited predictions on the severity of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9722528" 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 evaluate further the role of Sox10 in development and disease, <a href="#41" class="mim-tip-reference" title="Southard-Smith, E. M., Angrist, M., Ellison, J. S., Agarwala, R., Baxevanis, A. D., Chakravarti, A., Pavan, W. J. <strong>The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome.</strong> Genome Res. 9: 215-225, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077527</a>]" pmid="10077527">Southard-Smith et al. (1999)</a> performed comparative genomic analyses. An essential role for the SOX10 gene in neural crest development was supported by zoo blot hybridizations that revealed extensive conservation throughout vertebrate evolution and by similar Northern blot expression profiles between mouse and man. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077527" 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="#39" class="mim-tip-reference" title="Potterf, S. B., Furumura, M., Dunn, K. J., Arnheiter, H., Pavan, W. J. <strong>Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3.</strong> Hum. Genet. 107: 1-6, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10982026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10982026</a>] [<a href="https://doi.org/10.1007/s004390000328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10982026">Potterf et al. (2000)</a> elucidated the hierarchical relationship of 3 transcription factors, MITF (<a href="/entry/156845">156845</a>), PAX3 (<a href="/entry/606597">606597</a>), and SOX10, that are capable of producing several different forms of Waardenburg syndrome, WS2A (<a href="/entry/193510">193510</a>), WS1 (<a href="/entry/193500">193500</a>), and WS4 (<a href="/entry/277580">277580</a>), respectively. SOX10 was able to transactivate the MITF promoter 100-fold, and the transactivation was further stimulated by PAX3. By promoter deletion and mutation analyses, <a href="#39" class="mim-tip-reference" title="Potterf, S. B., Furumura, M., Dunn, K. J., Arnheiter, H., Pavan, W. J. <strong>Transcription factor hierarchy in Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3.</strong> Hum. Genet. 107: 1-6, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10982026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10982026</a>] [<a href="https://doi.org/10.1007/s004390000328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10982026">Potterf et al. (2000)</a> showed that SOX10 can activate MITF expression through binding to a region that is evolutionarily conserved between the mouse and human MITF promoters. A SOX10 mutant that models C-terminal truncations in patients with WS can reduce wildtype SOX10 induction of MITF, suggesting that these mutations may act in a dominant-negative fashion. The data support a model in which the hypopigmentation of WS results from a disruption in function of the central melanocyte transcription factor MITF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10982026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Bondurand, N., Pingault, V., Goerich, D. E., Lemort, N., Sock, E., Le Caignec, C., Wegner, M., Goossens, M. <strong>Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.</strong> Hum. Molec. Genet. 9: 1907-1917, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10942418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10942418</a>] [<a href="https://doi.org/10.1093/hmg/9.13.1907" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10942418">Bondurand et al. (2000)</a> also showed that SOX10, in synergy with PAX3, strongly activates MITF expression in transfection assays. Transfection experiments revealed that PAX3 and SOX10 interact directly by binding to a proximal region of the MITF promoter containing binding sites for both factors. Mutant SOX10 or PAX3 proteins failed to transactivate this promoter, providing further evidence that the 2 genes act in concert to directly regulate expression of MITF. In situ hybridization experiments carried out in the dominant megacolon (Dom) mouse confirmed that SOX10 dysfunction impaired Mitf expression as well as melanocytic development and survival. The authors hypothesized that interaction between 3 of the genes that are altered in WS could explain the auditory/pigmentary symptoms of this disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10942418" 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="#27" class="mim-tip-reference" title="Lee, M., Goodall, J., Verastegui, C., Ballotti, R., Goding, C. R. <strong>Direct regulation of the microphthalmia promoter by Sox10 links Waardenburg-Shah syndrome (WS4)-associated hypopigmentation and deafness to WS2.</strong> J. Biol. Chem. 275: 37978-37983, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973953</a>] [<a href="https://doi.org/10.1074/jbc.M003816200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973953">Lee et al. (2000)</a> demonstrated that wildtype SOX10 directly binds and activates transcription of the MITF promoter, whereas a mutant form of the SOX10 protein (<a href="#0001">602229.0001</a>) associated with Waardenburg-Shah syndrome acts as a dominant-negative repressor of MITF expression and reduces endogenous MITF protein levels. The ability of SOX10 to activate transcription of the MITF promoter implicates SOX10 in the regulation of melanocyte development and provides a molecular basis for the hypopigmentation and deafness associated with WS4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10973953" 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>Connexin-32 (CX32, GJB1; <a href="/entry/304040">304040</a>) is a major protein of peripheral myelin. Mutations in CX32 have been characterized in patients with the X-linked form of Charcot-Marie-Tooth disease (CMTX1; <a href="/entry/302800">302800</a>), a peripheral neuropathy. <a href="#3" class="mim-tip-reference" title="Bondurand, N., Girard, M., Pingault, V., Lemort, N., Dubourg, O., Goossens, M. <strong>Human connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10.</strong> Hum. Molec. Genet. 10: 2783-2795, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11734543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11734543</a>] [<a href="https://doi.org/10.1093/hmg/10.24.2783" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11734543">Bondurand et al. (2001)</a> showed that SOX10, in synergy with EGR2 (<a href="/entry/129010">129010</a>), strongly activates CX32 expression in vitro by directly binding to its promoter. In agreement with this finding, SOX10 and EGR2 mutants identified in patients with peripheral myelin defects failed to transactivate the CX32 promoter. In addition, some CMTX1 patients harbored a T-to-G transversion at position -528 of the CX32 promoter (<a href="/entry/304040#0015">304040.0015</a>). The authors demonstrated that this mutation eliminates binding and activation by SOX10. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11734543" 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>SOX10 acts as a critical transactivator of tyrosinase-related protein-1 (TYRP1; <a href="/entry/115501">115501</a>) during melanoblast development and as a potent transactivator of MITF, which is considered to be a master gene that controls the development and postnatal survival of melanocytes. <a href="#22" class="mim-tip-reference" title="Khong, H. T., Rosenberg, S. A. <strong>The Waardenburg syndrome type 4 gene, SOX10, is a novel tumor-associated antigen identified in a patient with a dramatic response to immunotherapy.</strong> Cancer Res. 62: 3020-3023, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12036907/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12036907</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12036907[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="12036907">Khong and Rosenberg (2002)</a> identified, for the first time, the presence of de novo cellular immune reactivity against SOX10, using tumor-infiltrating lymphocytes obtained from a 63-year-old woman with metastases of melanoma refractory to chemotherapy, who was started on a 4-peptide vaccination protocol. Most of her tumors completely regressed after 2 cycles of immunotherapy, including complete resolution of a large tumor in her left thigh, an intrapelvic mass, a liver lesion, and most of the nodules in her lungs. She also developed vitiligo on the dorsal areas of her hand and distal forearm bilaterally. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12036907" 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 Sox10 and Pax3 transcription factors can directly regulate both MITF and RET (<a href="/entry/164761">164761</a>) in a synergistic fashion. <a href="#26" class="mim-tip-reference" title="Lang, D., Epstein, J. A. <strong>Sox10 and Pax3 physically interact to mediate activation of a conserved c-RET enhancer.</strong> Hum. Molec. Genet. 12: 937-945, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668617</a>] [<a href="https://doi.org/10.1093/hmg/ddg107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12668617">Lang and Epstein (2003)</a> showed that Pax3 and Sox10 can physically interact; this interaction contributes to synergistic activation of a conserved RET enhancer, and it explains why Sox10 mutants that cannot bind DNA still retain the ability to activate this enhancer in the presence of Pax3. However, in the context of the MITF gene, Pax3 and Sox10 must each bind independently to DNA in order to achieve synergy. These observations appear to explain the phenotype in the mild form of Waardenburg syndrome (WS2E; <a href="/entry/611584">611584</a>) caused by a specific SOX10 mutation (S135T; <a href="#0005">602229.0005</a>) in the HMG box that abrogates DNA binding without disrupting association with PAX3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668617" 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 gene expression profiling, <a href="#19" class="mim-tip-reference" title="Iwashita, T., Kruger, G. M., Pardal, R., Kiel, M. J., Morrison, S. J. <strong>Hirschsprung disease is linked to defects in neural crest stem cell function.</strong> Science 301: 972-976, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920301</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12920301[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1085649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12920301">Iwashita et al. (2003)</a> determined that genes associated with Hirschsprung disease were highly upregulated in rat gut neural crest stem cells relative to whole-fetus RNA. The genes with highest expression were GDNF (<a href="/entry/600837">600837</a>), SOX10, GFRA1 (<a href="/entry/601496">601496</a>), and EDNRB. The highest expression was seen in RET (<a href="/entry/164761">164761</a>), which was found to be necessary for neural crest stem cell migration in the gut. GDNF promoted the migration of neural crest stem cells in culture but did not affect their survival or proliferation. The observations made by <a href="#19" class="mim-tip-reference" title="Iwashita, T., Kruger, G. M., Pardal, R., Kiel, M. J., Morrison, S. J. <strong>Hirschsprung disease is linked to defects in neural crest stem cell function.</strong> Science 301: 972-976, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920301</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12920301[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1085649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12920301">Iwashita et al. (2003)</a> were confirmed by quantitative RT-PCR, flow cytometry, and functional analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920301" 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 in early Xenopus embryos, <a href="#45" 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>Ciliary neurotrophic factor (CNTF; <a href="/entry/118945">118945</a>) is a major mediator of the protective effects of Schwann cells, both under physiologic and pathologic conditions. <a href="#18" class="mim-tip-reference" title="Ito, Y., Wiese, S., Funk, N., Chittka, A., Rossoll, W., Bommel, H., Watabe, K., Wegner, M., Sendtner, M. <strong>Sox10 regulates ciliary neurotrophic factor gene expression in Schwann cells.</strong> Proc. Nat. Acad. Sci. 103: 7871-7876, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16684879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16684879</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16684879[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.0602332103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16684879">Ito et al. (2006)</a> identified SOX10 as a key regulator of CNTF expression. Overexpression of Sox10 in cultured primary Schwann cells from rat sciatic nerves upregulated Cntf protein levels more than 100-fold. In addition, Cntf expression was significantly lower in sciatic nerves of Sox10 +/- mice, suggesting that SOX10 acts as a physiologic regulator of CNTF gene expression in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16684879" 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 specificity of NFAT complexes on target genes arises from assembly of NFATc family members (see <a href="/entry/600489">600489</a>) with nuclear partner proteins. Purification of Nfat protein complexes from mouse neural tubes showed that Sox10 is an Nfat nuclear partner and synergizes with Nfatc4 (<a href="/entry/602699">602699</a>) to activate Krox20 (<a href="/entry/129010">129010</a>), which regulates genes necessary for myelination. Protein domain deletion studies indicated that Sox10 bound to the Rel homology domain of Nfatc4. Using oligonucleotide affinity purification, <a href="#21" class="mim-tip-reference" title="Kao, S.-C., Wu, H., Xie, J., Chang, C.-P., Ranish, J. A., Graef, I. A., Crabtree, G. R. <strong>Calcineurin/NFAT signaling is required for neuregulin-regulated Schwann cell differentiation.</strong> Science 323: 651-654, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19179536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19179536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19179536[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1166562" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19179536">Kao et al. (2009)</a> found that Nfatc4 facilitated Sox10 binding to the NRE4 region of the Krox20 myelin-specific enhancer. <a href="#21" class="mim-tip-reference" title="Kao, S.-C., Wu, H., Xie, J., Chang, C.-P., Ranish, J. A., Graef, I. A., Crabtree, G. R. <strong>Calcineurin/NFAT signaling is required for neuregulin-regulated Schwann cell differentiation.</strong> Science 323: 651-654, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19179536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19179536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19179536[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1166562" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19179536">Kao et al. (2009)</a> concluded that NFATc4 and Sox10 cooperate in myelin gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19179536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Chaoui, A., Kavo, A., Baral, V., Watanabe, Y., Lecerf, L., Colley, A., Mendoza-Londono, R., Pingault, V., Bondurand, N. <strong>Subnuclear re-localization of SOX10 and p54NRB correlates with a unique neurological phenotype associated with SOX10 missense mutations.</strong> Hum. Molec. Genet. 24: 4933-4947, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26060192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26060192</a>] [<a href="https://doi.org/10.1093/hmg/ddv215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26060192">Chaoui et al. (2015)</a> found that the nuclear paraspeckle protein p54NRB (NONO; <a href="/entry/300084">300084</a>) interacted with SOX10 to enhance expression of SOX10 target genes. However, p54NRB did not activate SOX10 target genes without SOX10. Overexpression of p54NRB caused redistribution of SOX10 to nuclear bodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26060192" 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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Based on the finding that Sox10 underlies the Dom mouse model (see ANIMAL MODEL), <a href="#42" class="mim-tip-reference" title="Southard-Smith, E. M., Kos, L., Pavan, W. J. <strong>Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model.</strong> Nature Genet. 18: 60-64, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9425902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9425902</a>] [<a href="https://doi.org/10.1038/ng0198-60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9425902">Southard-Smith et al. (1998)</a> and <a href="#12" class="mim-tip-reference" title="Herbarth, B., Pingault, V., Bondurand, N., Kuhlbrodt, K., Hermans-Borgmeyer, I., Puliti, A., Lemort, N., Goossens, M., Wegner, M. <strong>Mutation of the Sry-related Sox10 gene in dominant megacolon, a mouse model for human Hirschsprung disease.</strong> Proc. Nat. Acad. Sci. 95: 5161-5165, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9560246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9560246</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9560246[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.95.9.5161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9560246">Herbarth et al. (1998)</a> considered SOX10 to be a likely candidate for the site of mutations in individuals with Hirschsprung disease or Waardenburg syndrome whose disease had not been related to mutations in other genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9425902+9560246" 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>Waardenburg-Shah syndrome, also known as Waardenburg syndrome type 4 (see WS4C; <a href="/entry/613266">613266</a>) is characterized by deafness, pigmentary abnormalities, and Hirschsprung disease. These features are all caused by defects in the embryonic neural crest. In 4 patients with Waardenburg-Shah syndrome, <a href="#34" class="mim-tip-reference" title="Pingault, V., Bondurand, N., Kuhlbrodt, K., Goerich, D. E., Prehu, M.-O., Puliti, A., Herbarth, B., Hermans-Borgmeyer, I., Legius, E., Matthijs, G., Amiel, J., Lyonnet, S., Ceccherini, I., Romeo, G., Smith, J. C., Read, A. P., Wegner, M., Goossens, M. <strong>SOX10 mutations in patients with Waardenburg-Hirschsprung disease.</strong> Nature Genet. 18: 171-173, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462749</a>] [<a href="https://doi.org/10.1038/ng0298-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462749">Pingault et al. (1998)</a> identified heterozygous mutations in the SOX10 gene (<a href="#0001">602229.0001</a>-<a href="#0004">602229.0004</a>). Each mutation was predicted to result in loss of function, suggesting that the pathologic mechanism is haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with WS4, <a href="#41" class="mim-tip-reference" title="Southard-Smith, E. M., Angrist, M., Ellison, J. S., Agarwala, R., Baxevanis, A. D., Chakravarti, A., Pavan, W. J. <strong>The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome.</strong> Genome Res. 9: 215-225, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077527</a>]" pmid="10077527">Southard-Smith et al. (1999)</a> identified mutations in the SOX10 gene (<a href="#0009">602229.0009</a>-<a href="#0010">602229.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077527" 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="#35" class="mim-tip-reference" title="Pingault, V., Girard, M., Bondurand, N., Dorkins, H., Van Maldergem, L., Mowat, D., Shimotake, T., Verma, I., Baumann, C., Goossens, M. <strong>SOX10 mutations in chronic intestinal pseudo-obstruction suggest a complex physiopathological mechanism.</strong> Hum. Genet. 111: 198-206, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189494</a>] [<a href="https://doi.org/10.1007/s00439-002-0765-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12189494">Pingault et al. (2002)</a> identified SOX10 mutations in patients with WS4 with Hirschsprung disease and in patients with WS and intestinal pseudoobstruction without frank aganglionosis. These results showed that chronic intestinal pseudoobstruction may be a manifestation associated with WS, and indicated that aganglionosis is not the only mechanism underlying the intestinal dysfunction of patients with SOX10 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12189494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Morin, M., Vinuela, A., Rivera, T., Villamar, M., Moreno-Pelayo, M. A., Moreno, F., del Castillo, I. <strong>A de novo missense mutation in the gene encoding the SOX10 transcription factor in a Spanish sporadic case of Waardenburg syndrome type IV. (Letter)</strong> Am. J. Med. Genet. 146A: 1032-1037, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18348274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18348274</a>] [<a href="https://doi.org/10.1002/ajmg.a.32181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18348274">Morin et al. (2008)</a> described a de novo missense mutation (<a href="#0016">602229.0016</a>) in the gene encoding the SOX10 transcription factor in a Spanish patient with sporadic WS4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18348274" 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="Bondurand, N., Dastot-Le Moal, F., Stanchina, L., Collot, N., Baral, V., Marlin, S., Attie-Bitach, T., Giurgea, I., Skopinski, L., Reardon, W., Toutain, A., Sarda, P., Echaieb, A., Lackmy-Port-Lis, M., Touraine, R., Amiel, J., Goossens, M., Pingault, V. <strong>Deletions at the SOX10 gene locus gene Waardenburg syndrome types 2 and 4.</strong> Am. J. Hum. Genet. 81: 1169-1185, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17999358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17999358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17999358[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/10.1086/522090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17999358">Bondurand et al. (2007)</a> used a combination of semiquantitative fluorescent multiplex polymerase chain reaction and fluorescence in situ hybridization to search for SOX10 heterozygous deletions in cases of Waardenburg syndrome. They described the first characterization of SOX10 deletions (see, e.g., <a href="#0012">602229.0012</a>) in patients presenting with WS4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17999358" 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>Peripheral Demyelinating Neuropathy, Central Dysmyelination, Waardenburg Syndrome, and Hirschsprung Disease</em></strong></p><p>
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Of 12 unrelated Waardenburg-Shah syndrome patients recruited by the Genetic Center at the Necker Hospital in Paris, <a href="#46" class="mim-tip-reference" title="Touraine, R. L., Attie-Bitach, T., Manceau, E., Korsch, E., Sarda, P., Pingault, V., Encha-Razavi, F., Pelet, A., Auge, J., Nivelon-Chevallier, A., Holschneider, A. M., Munnes, M., Doerfler, W., Goossens, M., Munnich, A., Vekemans, M., Lyonnet, S. <strong>Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain.</strong> Am. J. Hum. Genet. 66: 1496-1503, 2000. Note: Erratum: Am. J. Hum. Genet. 66: 2020 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10762540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10762540</a>] [<a href="https://doi.org/10.1086/302895" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10762540">Touraine et al. (2000)</a> described 3 patients with growth retardation and a previously unreported neurologic phenotype with impairment of both the central and autonomic nervous systems and occasionally neonatal hypotonia and arthrogryposis (PCWH; <a href="/entry/609136">609136</a>). Each of the 3 patients was heterozygous for a SOX10 truncating mutation: tyr313 to ter (Y313X; <a href="#0006">602229.0006</a>) or ser251 to ter (S251X; <a href="#0007">602229.0007</a>). The extended spectrum of the WS4 phenotype was considered relevant to the brain expression of SOX10 during human embryonic and fetal development. The expression of SOX10 in human embryo was not restricted to the neural crest-derived cells but also involved fetal brain cells, most likely of glial origin. The data emphasized the important role of SOX10 in early development of both neural crest-derived tissues, namely melanocytes and autonomic and enteric nervous systems, and glial cells of the central nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10762540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Pingault, V., Guiochon-Mantel, A., Bondurand, N., Faure, C., Lacroix, C., Lyonnet, S., Goossens, M., Landrieu, P. <strong>Peripheral neuropathy with hypomyelination, chronic intestinal pseudo-obstruction and deafness: a developmental 'neural crest syndrome' related to a SOX10 mutation.</strong> Ann. Neurol. 48: 671-676, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11026454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11026454</a>]" pmid="11026454">Pingault et al. (2000)</a> described a patient with a heterozygous mutation in the SOX10 gene (<a href="#0019">602229.0019</a>) who had peripheral neuropathy with hypomyelination, deafness, and chronic intestinal pseudoobstruction, but not Hirschsprung disease or pigmentary abnormalities. Chronic intestinal pseudoobstruction is defined by repetitive episodes or continuous symptoms of bowel obstruction in the absence of a mechanical occluding lesion. It differs from Hirschsprung disease by the persistence of ganglionic cells and nervous plexus in the submucosal compartments of the bowel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11026454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an infant with pigmentary abnormalities, deafness, and decreased myenteric and submucosal ganglion cells in the colon and small bowel, <a href="#15" class="mim-tip-reference" title="Inoue, K., Shilo, K., Boerkoel, C. F., Crowe, C., Sawady, J., Lupski, J. R., Agamanolis, D. P. <strong>Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: phenotypes linked by SOX10 mutation.</strong> Ann. Neurol. 52: 836-842, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447940</a>] [<a href="https://doi.org/10.1002/ana.10404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447940">Inoue et al. (2002)</a> identified a heterozygous truncating mutation in the SOX10 gene (<a href="#0011">602229.0011</a>). In addition, the patient had little spontaneous respiratory or other movement, severe hypotonia, multiple contractures, undetectable tendon reflexes, and tongue fasciculations. Histopathologic studies showed an absence of peripheral nerve myelin despite normal numbers of Schwann cells, and profound dysmyelination in the CNS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12447940" 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>Waardenburg Syndrome Type 2E</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Bondurand, N., Dastot-Le Moal, F., Stanchina, L., Collot, N., Baral, V., Marlin, S., Attie-Bitach, T., Giurgea, I., Skopinski, L., Reardon, W., Toutain, A., Sarda, P., Echaieb, A., Lackmy-Port-Lis, M., Touraine, R., Amiel, J., Goossens, M., Pingault, V. <strong>Deletions at the SOX10 gene locus gene Waardenburg syndrome types 2 and 4.</strong> Am. J. Hum. Genet. 81: 1169-1185, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17999358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17999358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17999358[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/10.1086/522090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17999358">Bondurand et al. (2007)</a> found 5 different SOX10 deletions (see, e.g., <a href="#0013">602229.0013</a>) in 5 patients with WS2E (<a href="/entry/611584">611584</a>), making SOX10 a new gene for that form of Waardenburg syndrome. No SOX10 point mutations were identified by DNA sequencing of the 3 SOX10 coding exons. Neurologic phenotypes reminiscent of that observed in variant WS4, i.e., PCWH syndrome (peripheral demyelinating neuropathy, central demyelination, WS, and Hirschsprung disease; <a href="/entry/609136">609136</a>) were observed in some WS2-affected patients with SOX10 deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17999358" 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 boy with synophrys, vivid blue eyes, white matter anomalies, impaired intellectual development with autistic-like behavior, and bilateral complete agenesis of the semicircular canals without Hirschsprung disease, <a href="#44" class="mim-tip-reference" title="Sznajer, Y., Coldea, C., Meire, F., Delpierre, I., Sekhara, T., Touraine, R. L. <strong>A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease.</strong> Am. J. Med. Genet. 146A: 1038-1041, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18348267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18348267</a>] [<a href="https://doi.org/10.1002/ajmg.a.32247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18348267">Sznajer et al. (2008)</a> described a de novo splice site mutation in SOX10 (<a href="#0017">602229.0017</a>). <a href="#44" class="mim-tip-reference" title="Sznajer, Y., Coldea, C., Meire, F., Delpierre, I., Sekhara, T., Touraine, R. L. <strong>A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease.</strong> Am. J. Med. Genet. 146A: 1038-1041, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18348267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18348267</a>] [<a href="https://doi.org/10.1002/ajmg.a.32247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18348267">Sznajer et al. (2008)</a> classified the patient as having atypical type 4 Waardenburg syndrome (277580); however, given the absence of Hirschsprung disease, the patient appears to have a type 2E Waardenburg syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18348267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#49" class="mim-tip-reference" title="Zhang, H., Chen, H., Luo, H., An, J., Sun, L., Mei, L., He, C., Jiang, L., Jiang, W., Xia, K., Li, J.-D., Feng, Y. <strong>Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II.</strong> Hum. Genet. 131: 491-503, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21965087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21965087</a>] [<a href="https://doi.org/10.1007/s00439-011-1098-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21965087">Zhang et al. (2012)</a> performed functional analysis of 4 different heterozygous truncating mutations in the SOX10 gene, 3 reported by <a href="#9" class="mim-tip-reference" title="Chen, H., Jiang, L., Xie, Z., Mei, L., He, C., Hu, Z., Xia, K., Feng, Y. <strong>Novel mutations of PAX3, MITF, and SOX10 genes in Chinese patients with type I or type II Waardenburg syndrome.</strong> Biochem. Biophys. Res. Commun. 397: 70-74, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20478267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20478267</a>] [<a href="https://doi.org/10.1016/j.bbrc.2010.05.066" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20478267">Chen et al. (2010)</a> (e.g., <a href="#0021">602229.0021</a>) and 1 novel (<a href="#0022">602229.0022</a>). In vitro functional expression studies showed that the mutant proteins lacked the ability to transactivate the MITF promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20478267+21965087" 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="#33" class="mim-tip-reference" title="Pingault, V., Bodereau, V., Baral, V., Marcos, S., Watanabe, Y., Chaoui, A., Fouveaut, C., Leroy, C., Verier-Mine, O., Francannet, C., Dupin-Deguine, D., Archambeaud, F., Kurtz, F.-J., Young, J., Bertherat, J., Marlin, S., Goossens, M., Hardelin, J.-P., Dode, C., Bondurand, N. <strong>Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness.</strong> Am. J. Hum. Genet. 92: 707-724, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643381</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643381[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/10.1016/j.ajhg.2013.03.024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643381">Pingault et al. (2013)</a> analyzed the SOX10 gene in 17 patients with hypogonadotropic hypogonadism and anosmia who had been diagnosed with Kallmann syndrome (see <a href="/entry/147950">147950</a>) but who also exhibited at least 1 Waardenburg-like feature, and identified heterozygous SOX10 mutations in 6 of them (see, e.g., <a href="#0023">602229.0023</a>). Analysis of SOX10 in 86 more patients with hypogonadotropic hypogonadism and anosmia, 20 of whom had various nonolfactory, nonreproductive associated anomalies, revealed heterozygous mutations in 2 patients; 1 of the 2 had hypoacusis and the other had normal hearing but showed macroscelia. <a href="#33" class="mim-tip-reference" title="Pingault, V., Bodereau, V., Baral, V., Marcos, S., Watanabe, Y., Chaoui, A., Fouveaut, C., Leroy, C., Verier-Mine, O., Francannet, C., Dupin-Deguine, D., Archambeaud, F., Kurtz, F.-J., Young, J., Bertherat, J., Marlin, S., Goossens, M., Hardelin, J.-P., Dode, C., Bondurand, N. <strong>Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness.</strong> Am. J. Hum. Genet. 92: 707-724, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643381</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643381[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/10.1016/j.ajhg.2013.03.024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643381">Pingault et al. (2013)</a> stated that there was no evidence to indicate why a given SOX10 mutation might be associated with hypogonadotropic hypogonadism and anosmia, and also noted that anosmia and hypogonadism might be underestimated in Waardenburg syndrome because individuals usually do not spontaneously complain of anosmia and WS is often diagnosed in childhood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23643381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 4 patients with the neurologic variant of Waardenburg-Shah syndrome, which is also known by the acronym PCWH (peripheral demyelinating neuropathy, central demyelination, Waardenburg syndrome, and Hirschsprung disease; <a href="/entry/609136">609136</a>), <a href="#13" class="mim-tip-reference" title="Inoue, K., Khajavi, M., Ohyama, T., Hirabayashi, S., Wilson, J., Reggin, J. D., Mancias, P., Butler, I. J., Wilkinson, M. F., Wegner, M., Lupski, J. R. <strong>Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations.</strong> Nature Genet. 36: 361-369, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15004559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15004559</a>] [<a href="https://doi.org/10.1038/ng1322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15004559">Inoue et al. (2004)</a> identified truncating mutations in the SOX10 gene; 2 patients, including 1 who had previously been reported by <a href="#20" class="mim-tip-reference" title="Jacobs, J. M., Wilson, J. <strong>An unusual demyelinating neuropathy in a patient with Waardenburg's syndrome.</strong> Acta Neuropath. 83: 670-674, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1636383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1636383</a>] [<a href="https://doi.org/10.1007/BF00299420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1636383">Jacobs and Wilson (1992)</a>, had the Y313X mutation (<a href="#0006">602229.0006</a>). All the mutations were located in the last exon (exon 5) in the 3-prime region of the SOX10 gene. Functional analysis showed that the truncating mutations suppressed the transcriptional activity of cotransfected wildtype SOX10 in a dose-dependent manner, suggesting that PCWH is caused by dominant-negative mutations. However, 2 truncating mutations (E189X; <a href="#0001">602229.0001</a> and Y207X; <a href="#0009">602229.0009</a>) associated with the less severe WS4C phenotype ultimately showed different effects. Northern blot analysis demonstrated that WS4C-associated mutations, but not PCWH-associated mutations, lead to a reduction in mRNA via the nonsense-mediated decay (NMD) pathway, thereby causing haploinsufficiency and preventing a dominant-negative effect. <a href="#13" class="mim-tip-reference" title="Inoue, K., Khajavi, M., Ohyama, T., Hirabayashi, S., Wilson, J., Reggin, J. D., Mancias, P., Butler, I. J., Wilkinson, M. F., Wegner, M., Lupski, J. R. <strong>Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations.</strong> Nature Genet. 36: 361-369, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15004559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15004559</a>] [<a href="https://doi.org/10.1038/ng1322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15004559">Inoue et al. (2004)</a> noted that the results were consistent with the NMD RNA surveillance pathway, which typically degrades only transcripts containing nonsense mutations that are followed by at least 1 intron (<a href="#7" class="mim-tip-reference" title="Carter, M. S., Li, S., Wilkinson, M. F. <strong>A splicing-dependent regulatory mechanism that detects translation signals.</strong> EMBO J. 15: 5965-5975, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8918474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8918474</a>]" pmid="8918474">Carter et al., 1996</a>; <a href="#30" class="mim-tip-reference" title="Nagy, E., Maquat, L. E. <strong>A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance.</strong> Trends Biochem. Sci. 23: 198-199, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9644970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9644970</a>] [<a href="https://doi.org/10.1016/s0968-0004(98)01208-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9644970">Nagy and Maquat, 1998</a>), as usually occurs with WS4C-associated mutations. Accordingly, the PCWH-associated mutations that occur in SOX10 exon 5 are not followed by an intron, may escape NMD, and express large amounts of dominant-negative protein. Similar results were obtained for truncating mutations in the myelin protein zero gene (MPZ; <a href="/entry/159440">159440</a>) that cause distinct myelinopathies. <a href="#13" class="mim-tip-reference" title="Inoue, K., Khajavi, M., Ohyama, T., Hirabayashi, S., Wilson, J., Reggin, J. D., Mancias, P., Butler, I. J., Wilkinson, M. F., Wegner, M., Lupski, J. R. <strong>Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations.</strong> Nature Genet. 36: 361-369, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15004559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15004559</a>] [<a href="https://doi.org/10.1038/ng1322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15004559">Inoue et al. (2004)</a> suggested that, in general, the NMD mechanism may function protectively to convert dominant-negative effects to haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15004559+1636383+8918474+9644970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Chaoui, A., Kavo, A., Baral, V., Watanabe, Y., Lecerf, L., Colley, A., Mendoza-Londono, R., Pingault, V., Bondurand, N. <strong>Subnuclear re-localization of SOX10 and p54NRB correlates with a unique neurological phenotype associated with SOX10 missense mutations.</strong> Hum. Molec. Genet. 24: 4933-4947, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26060192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26060192</a>] [<a href="https://doi.org/10.1093/hmg/ddv215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26060192">Chaoui et al. (2015)</a> found that many SOX10 mutations induced redistribution of SOX10 to nuclear foci and caused redistribution of p54NRB to these foci. However, only foci-forming SOX10 mutants exclusively localized in nucleus altered the ability of p54NRB to enhance SOX10 transactivation activity, and this dominant-negative activity correlated with the more severe PCWH or PCW without HSCR phenotypes observed in patients harboring these mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26060192" 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 mouse model of Hirschsprung disease (HSCR; <a href="/entry/142623">142623</a>), dominant megacolon (Dom), arose spontaneously at the Jackson Laboratory (<a href="#25" class="mim-tip-reference" title="Lane, P. W., Liu, H. M. <strong>Association of megacolon with a new dominant spotting gene (Dom) in the mouse.</strong> J. Hered. 75: 435-439, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6512238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6512238</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jhered.a109980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6512238">Lane and Liu, 1984</a>). Megacolon was associated with dominantly inherited spotting. Dom/+ heterozygous mice displayed regional deficiencies of neural crest-derived enteric ganglia in the distal colon, whereas Dom/Dom homozygous animals were embryonic lethal. The Dom locus mapped to a mid-terminal region of mouse chromosome 15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6512238" 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 positional cloning strategy, <a href="#42" class="mim-tip-reference" title="Southard-Smith, E. M., Kos, L., Pavan, W. J. <strong>Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model.</strong> Nature Genet. 18: 60-64, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9425902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9425902</a>] [<a href="https://doi.org/10.1038/ng0198-60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9425902">Southard-Smith et al. (1998)</a> identified Sox10 as the gene underlying the Dom Hirschsprung mouse model. BLAST analysis of the EST database identified the candidate transcript as Sox10 on the basis of its homology with the 163-bp sequence of the SRY-like HMG box transcription factor Sox10 (<a href="#43" class="mim-tip-reference" title="Stock, D. W., Buchanan, A. V., Zhao, Z., Weiss, K. M. <strong>Numerous members of the Sox family of HMG box-containing genes are expressed in developing mouse teeth.</strong> Genomics 37: 234-237, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8921394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8921394</a>] [<a href="https://doi.org/10.1006/geno.1996.0548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8921394">Stock et al., 1996</a>; <a href="#48" class="mim-tip-reference" title="Wright, E. M., Snopek, B., Koopman, P. <strong>Seven new members of the Sox gene family expressed during mouse development.</strong> Nucleic Acids Res. 21: 744 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8441686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8441686</a>] [<a href="https://doi.org/10.1093/nar/21.3.744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8441686">Wright et al., 1993</a>). The finding was consistent with Sox10 expression in the 2 principal cell types affected in Dom/+ mice, neural crest-derived melanocytes and enteric ganglia. In Dom mice, <a href="#42" class="mim-tip-reference" title="Southard-Smith, E. M., Kos, L., Pavan, W. J. <strong>Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model.</strong> Nature Genet. 18: 60-64, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9425902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9425902</a>] [<a href="https://doi.org/10.1038/ng0198-60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9425902">Southard-Smith et al. (1998)</a> identified a premature termination mutation of Sox10 underlying the absence of neural crest derivatives. They demonstrated Sox10 expression in normal neural crest cells, disrupted expression of both Sox10 and the HSCR disease gene Ednrb in Dom mutant embryos, and loss of neural crest derivatives due to apoptosis. The authors concluded that Sox10 is essential for proper peripheral nervous system development. <a href="#12" class="mim-tip-reference" title="Herbarth, B., Pingault, V., Bondurand, N., Kuhlbrodt, K., Hermans-Borgmeyer, I., Puliti, A., Lemort, N., Goossens, M., Wegner, M. <strong>Mutation of the Sry-related Sox10 gene in dominant megacolon, a mouse model for human Hirschsprung disease.</strong> Proc. Nat. Acad. Sci. 95: 5161-5165, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9560246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9560246</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9560246[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.95.9.5161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9560246">Herbarth et al. (1998)</a> also showed that the Dom mutant mouse is caused by a defect in the Sox10 gene and that Sox10 is an essential factor in mouse neural crest development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9425902+8921394+8441686+9560246" 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>Variability in the disease phenotype of patients with WS4 suggests the influence of genetic modifier loci in the disorder. Mice heterozygous for the Sox10(Dom) allele exhibit variability of aganglionosis and hypopigmentation influenced by genetic background similar to that observed in WS4 patients. <a href="#41" class="mim-tip-reference" title="Southard-Smith, E. M., Angrist, M., Ellison, J. S., Agarwala, R., Baxevanis, A. D., Chakravarti, A., Pavan, W. J. <strong>The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome.</strong> Genome Res. 9: 215-225, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077527</a>]" pmid="10077527">Southard-Smith et al. (1999)</a> constructed Sox10(Dom)/+ congenic lines to segregate loci that modify the neural crest defects in the heterozygous mice. Consistent with previous studies, increased lethality in the heterozygous mice resulted from a C57BL/6J locus; also, an increase in hypopigmentation was noted in conjunction with a locus in another strain. Linkage analysis localized a hypopigmentation modifier of the Dom phenotype to mouse chromosome 10 in close proximity to a modifier of hypopigmentation for the EDNRB (<a href="/entry/131244">131244</a>) mouse model of WS4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077527" 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="Paratore, C., Eichenberger, C., Suter, U., Sommer, L. <strong>Sox10 haploinsufficiency affects maintenance of progenitor cells in a mouse model of Hirschsprung disease.</strong> Hum. Molec. Genet. 11: 3075-3085, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12417529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12417529</a>] [<a href="https://doi.org/10.1093/hmg/11.24.3075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12417529">Paratore et al. (2002)</a> used mice with a targeted deletion of the Sox10 gene to study the etiology of Hirschsprung disease. Neural crest-derived enteric progenitors that were heterozygous for the Sox10 mutation colonized the proximal intestine but were unaffected in their survival capacity. However, unlike their wildtype counterparts, mutant enteric neural crest-derived cells were unable to maintain their progenitor state and acquired preneuronal traits, which resulted in a reduction of the progenitor pool size. Thus, the cells that normally colonize the hindgut were depleted in the Sox10 mutant, causing the distal bowel to become aganglionic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12417529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Cantrell, V. A., Owens, S. E., Chandler, R. L., Airey, D. C., Bradley, K. M., Smith, J. R., Southard-Smith, E. M. <strong>Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10(Dom) mouse model of Hirschsprung disease.</strong> Hum. Molec. Genet. 13: 2289-2301, 2004. Note: Erratum: Hum. Molec. Genet. 13: 3241 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15294878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15294878</a>] [<a href="https://doi.org/10.1093/hmg/ddh243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15294878">Cantrell et al. (2004)</a> tested for association between genes in the endothelin signaling pathway and severity of aganglionosis in an extended pedigree of B6C3FeLe.Sox10(Dom) mice. Single-locus association analysis identified interaction between EdnrB (<a href="/entry/131244">131244</a>) and Sox10. Additional analysis of F2 intercross progeny confirmed a highly significant effect of EdnrB alleles on the Sox10(Dom/+) phenotype. The presence of C57BL/6J alleles at EdnrB was associated with increased penetrance and more severe aganglionosis in Sox10(Dom) mutants. Crosses between EdnrB and Sox10 mutants corroborated this gene interaction, with double-mutant progeny exhibiting significantly more severe aganglionosis. The background strain of the EdnrB mutant further influenced the phenotype of Sox10/EdnrB double-mutant progeny, implying the action of additional modifiers on this phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15294878" 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="#31" class="mim-tip-reference" title="Owens, S. E., Broman, K. W., Wiltshire, T., Elmore, J. B., Bradley, K. M., Smith, J. R., Southard-Smith, E. M. <strong>Genome-wide linkage identifies novel modifier loci of aganglionosis in the Sox10(Dom) model of Hirschsprung disease.</strong> Hum. Molec. Genet. 14: 1549-1558, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15843399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15843399</a>] [<a href="https://doi.org/10.1093/hmg/ddi163" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15843399">Owens et al. (2005)</a> focused on enteric ganglia deficits in Sox10(Dom) mice and defined aganglionosis as a quantitative trait in Sox10(Dom) intercross progeny to investigate the contribution of strain background to variation in enteric nervous system deficits. The phenotype of Sox10(Dom/+) mutants ranged over a continuum from severe aganglionosis to no detectable phenotype in the gut. A SNP-based genome scan in Sox10(Dom/+) F1 intercross progeny revealed modifier loci on mouse chromosomes 3, 5, 8, 11, and 14 with distinct effects on penetrance and severity of aganglionosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15843399" 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 an N-ethyl-N-nitrosourea mutagenesis screen, <a href="#28" class="mim-tip-reference" title="Matera, I., Watkins-Chow, D. E., Loftus, S. K., Hou, L., Incao, A., Silver, D. L., Rivas, C., Elliott, E. C., Baxter, L. L., Pavan, W. J. <strong>A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy.</strong> Hum. Molec. Genet. 17: 2118-2131, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18397875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18397875</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18397875[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/hmg/ddn110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18397875">Matera et al. (2008)</a> identified Gli3 (<a href="/entry/165240">165240</a>) as a modifier of Sox10 neurocristopathy. Heterozygosity for a null mutation of Gli3 increased the penetrance and severity of the hypopigmentation phenotype of Sox10 +/- mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18397875" 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="#38" class="mim-tip-reference" title="Polanco, J. C., Wilhelm, D., Davidson, T.-L., Knight, D., Koopman, P. <strong>Sox10 gain-of-function causes XX sex reversal in mice: implications for human 22q-linked disorders of sex development.</strong> Hum. Molec. Genet. 19: 506-516, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19933217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19933217</a>] [<a href="https://doi.org/10.1093/hmg/ddp520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19933217">Polanco et al. (2010)</a> showed that transgenic expression of Sox10, a close relative of Sox9 (<a href="/entry/608160">608160</a>), in gonads of XX mice resulted in development of testes and male physiology. The degree of sex reversal correlated with levels of Sox10 expression in different transgenic lines. Sox10 was expressed at low levels in primordial gonads of both sexes during normal mouse development, becoming male-specific during testis differentiation. SOX10 protein was able to activate transcriptional targets of SOX9, explaining at a mechanistic level its ability to direct male development. Overexpression of SOX10 alone was able to mimic human 46,XX disorder of sexual development (DSD) phenotypes associated with duplication of chromosome 22q13. Given that human SOX10 maps to chromosome 22q13.1, <a href="#38" class="mim-tip-reference" title="Polanco, J. C., Wilhelm, D., Davidson, T.-L., Knight, D., Koopman, P. <strong>Sox10 gain-of-function causes XX sex reversal in mice: implications for human 22q-linked disorders of sex development.</strong> Hum. Molec. Genet. 19: 506-516, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19933217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19933217</a>] [<a href="https://doi.org/10.1093/hmg/ddp520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19933217">Polanco et al. (2010)</a> implicated SOX10 in the etiology of chromosome 22q13-related DSD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19933217" 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="#10" class="mim-tip-reference" title="Cossais, F., Wahlbuhl, M., Kriesch, J., Wegner, M. <strong>SOX10 structure-function analysis in the chicken neural tube reveals important insights into its role in human neurocristopathies.</strong> Hum. Molec. Genet. 19: 2409-2420, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20308050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20308050</a>] [<a href="https://doi.org/10.1093/hmg/ddq124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20308050">Cossais et al. (2010)</a> used in ovo electroporation in the developing neural tube of chicken to determine which regions and properties of SOX10 are required for early neural crest development. There was a strict reliance on the DNA-binding activity and the presence of the C-terminal transactivation domain, and a lesser influence of the dimerization function and a conserved domain in the center of the protein. Dominant-negative effects on early neural crest development were mostly observed for truncated SOX10 proteins, whose production in patients may be prevented by nonsense-mediated decay. In contrast, mutant SOX10 proteins that occurred in patients were usually inactive. The authors proposed that any dominant-negative activity that some mutants may possess must therefore be restricted to single neural crest-derived cell lineages or oligodendrocytes at later times. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20308050" 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 SOX10-null mice, <a href="#33" class="mim-tip-reference" title="Pingault, V., Bodereau, V., Baral, V., Marcos, S., Watanabe, Y., Chaoui, A., Fouveaut, C., Leroy, C., Verier-Mine, O., Francannet, C., Dupin-Deguine, D., Archambeaud, F., Kurtz, F.-J., Young, J., Bertherat, J., Marlin, S., Goossens, M., Hardelin, J.-P., Dode, C., Bondurand, N. <strong>Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness.</strong> Am. J. Hum. Genet. 92: 707-724, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643381</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643381[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/10.1016/j.ajhg.2013.03.024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643381">Pingault et al. (2013)</a> observed an almost complete absence of olfactory ensheathing cells along the olfactory nerve pathway, as well as defasciculation and misrouting of the nerve fibers, impaired migration of GnRH cells, and disorganization of the olfactory nerve layer of the olfactory bulbs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23643381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=602229[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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<p>In a child with bilateral profound hearing loss, short segment Hirschsprung disease, and pigmentary abnormalities, including white hair, blue irides with gray speckles, and depigmented skin patches, all features consistent with WS4C (<a href="/entry/613266">613266</a>), <a href="#34" class="mim-tip-reference" title="Pingault, V., Bondurand, N., Kuhlbrodt, K., Goerich, D. E., Prehu, M.-O., Puliti, A., Herbarth, B., Hermans-Borgmeyer, I., Legius, E., Matthijs, G., Amiel, J., Lyonnet, S., Ceccherini, I., Romeo, G., Smith, J. C., Read, A. P., Wegner, M., Goossens, M. <strong>SOX10 mutations in patients with Waardenburg-Hirschsprung disease.</strong> Nature Genet. 18: 171-173, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462749</a>] [<a href="https://doi.org/10.1038/ng0298-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462749">Pingault et al. (1998)</a> identified a heterozygous glu189-to-ter mutation (E189X) in the SOX10 gene. The de novo mutation truncated the SOX10 protein, leaving the HMG binding domain intact. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a boy with WS4C (<a href="/entry/613266">613266</a>) characterized by bilateral profound hearing loss (treated by a cochlear implant), fair hair and vivid blue eyes, and chronic bowel problems, <a href="#34" class="mim-tip-reference" title="Pingault, V., Bondurand, N., Kuhlbrodt, K., Goerich, D. E., Prehu, M.-O., Puliti, A., Herbarth, B., Hermans-Borgmeyer, I., Legius, E., Matthijs, G., Amiel, J., Lyonnet, S., Ceccherini, I., Romeo, G., Smith, J. C., Read, A. P., Wegner, M., Goossens, M. <strong>SOX10 mutations in patients with Waardenburg-Hirschsprung disease.</strong> Nature Genet. 18: 171-173, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462749</a>] [<a href="https://doi.org/10.1038/ng0298-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462749">Pingault et al. (1998)</a> identified a heterozygous de novo nonsense tyr83-to-ter mutation (Y83X) in the SOX10 gene. Rectal biopsy showed that the number of ganglia was dramatically reduced. The de novo mutation was located upstream of the HMG domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient with deafness and short segment aganglionosis (<a href="/entry/613266">613266</a>), <a href="#34" class="mim-tip-reference" title="Pingault, V., Bondurand, N., Kuhlbrodt, K., Goerich, D. E., Prehu, M.-O., Puliti, A., Herbarth, B., Hermans-Borgmeyer, I., Legius, E., Matthijs, G., Amiel, J., Lyonnet, S., Ceccherini, I., Romeo, G., Smith, J. C., Read, A. P., Wegner, M., Goossens, M. <strong>SOX10 mutations in patients with Waardenburg-Hirschsprung disease.</strong> Nature Genet. 18: 171-173, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462749</a>] [<a href="https://doi.org/10.1038/ng0298-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462749">Pingault et al. (1998)</a> found a heterozygous 6-bp insertion (GCTCCT) between nucleotides 482 and 483 in exon 4 of the SOX10 gene. The mutation resulted in duplication of arg161leu162 in the middle of helix 3 of the HMG domain. This duplication changed the spacing between 2 highly conserved residues and was likely to disrupt the structure of the DNA-binding domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462749" 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">rs397515367 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515367;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=rs397515367" 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=rs397515367" 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=RCV000007820 OR RCV002512880" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007820, RCV002512880" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007820...</a>
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<p>In a patient with HSCR, deafness, and hypopigmentation (<a href="/entry/613266">613266</a>), <a href="#34" class="mim-tip-reference" title="Pingault, V., Bondurand, N., Kuhlbrodt, K., Goerich, D. E., Prehu, M.-O., Puliti, A., Herbarth, B., Hermans-Borgmeyer, I., Legius, E., Matthijs, G., Amiel, J., Lyonnet, S., Ceccherini, I., Romeo, G., Smith, J. C., Read, A. P., Wegner, M., Goossens, M. <strong>SOX10 mutations in patients with Waardenburg-Hirschsprung disease.</strong> Nature Genet. 18: 171-173, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462749</a>] [<a href="https://doi.org/10.1038/ng0298-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462749">Pingault et al. (1998)</a> identified a heterozygous 2-bp deletion (1076delGA) in exon 5 of the SOX10 gene, resulting in a frameshift that altered the mRNA sequence and introduced a premature termination codon at position 400. This and the other 3 mutations identified by <a href="#34" class="mim-tip-reference" title="Pingault, V., Bondurand, N., Kuhlbrodt, K., Goerich, D. E., Prehu, M.-O., Puliti, A., Herbarth, B., Hermans-Borgmeyer, I., Legius, E., Matthijs, G., Amiel, J., Lyonnet, S., Ceccherini, I., Romeo, G., Smith, J. C., Read, A. P., Wegner, M., Goossens, M. <strong>SOX10 mutations in patients with Waardenburg-Hirschsprung disease.</strong> Nature Genet. 18: 171-173, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9462749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9462749</a>] [<a href="https://doi.org/10.1038/ng0298-171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9462749">Pingault et al. (1998)</a> were likely to result in a loss of function, suggesting that the pathologic mechanism in Waardenburg-Shah syndrome is haploinsufficiency and that the developmental process is sensitive to the exact level of the SOX10 product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9462749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 WAARDENBURG SYNDROME, TYPE 2E, WITHOUT NEUROLOGIC INVOLVEMENT</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315515 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315515;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/rs74315515?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=rs74315515" 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=rs74315515" 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=RCV000007821" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007821" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007821</a>
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<p>In a girl with a mild form of Waardenburg syndrome type 2E (<a href="/entry/611584">611584</a>), reported by <a href="#11" class="mim-tip-reference" title="Hennekam, R. C. M., Gorlin, R. J. <strong>Confirmation of Yemenite (Warburg) deaf-blind hypopigmentation syndrome.</strong> Am. J. Med. Genet. 65: 146-148, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8911608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8911608</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19961016)65:2<146::AID-AJMG13>3.0.CO;2-Q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8911608">Hennekam and Gorlin (1996)</a>, <a href="#4" class="mim-tip-reference" title="Bondurand, N., Kuhlbrodt, K., Pingault, V., Enderich, J., Sajus, M., Tommerup, N., Warburg, M., Hennekam, R. C. M., Read, A. P., Wegner, M., Goossens, M. <strong>A molecular analysis of the Yemenite deaf-blind hypopigmentation syndrome: SOX10 dysfunction causes different neurocristopathies.</strong> Hum. Molec. Genet. 8: 1785-1789, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441344</a>] [<a href="https://doi.org/10.1093/hmg/8.9.1785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441344">Bondurand et al. (1999)</a> identified a heterozygous ser135-to-thr (S135T) mutation in the SOX10 gene. She had cutaneous hypo- and hyperpigmented regions and hearing loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10441344+8911608" 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="0006" class="mim-anchor"></a>
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<strong>.0006 PERIPHERAL DEMYELINATING NEUROPATHY, CENTRAL DYSMYELINATION, WAARDENBURG SYNDROME, AND HIRSCHSPRUNG DISEASE</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">rs74315516 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315516;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=rs74315516" 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=rs74315516" 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=RCV000007822" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007822" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007822</a>
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<p>In 2 unrelated patients (one living in Germany and the second in France), <a href="#46" class="mim-tip-reference" title="Touraine, R. L., Attie-Bitach, T., Manceau, E., Korsch, E., Sarda, P., Pingault, V., Encha-Razavi, F., Pelet, A., Auge, J., Nivelon-Chevallier, A., Holschneider, A. M., Munnes, M., Doerfler, W., Goossens, M., Munnich, A., Vekemans, M., Lyonnet, S. <strong>Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain.</strong> Am. J. Hum. Genet. 66: 1496-1503, 2000. Note: Erratum: Am. J. Hum. Genet. 66: 2020 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10762540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10762540</a>] [<a href="https://doi.org/10.1086/302895" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10762540">Touraine et al. (2000)</a> observed a neurologic variant of Waardenburg-Shah syndrome (<a href="/entry/609136">609136</a>) associated with a tyr313-to-ter (Y313X) mutation in the SOX10 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10762540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with a neurologic variant of Waardenburg-Shah syndrome, one of whom had previously been reported by <a href="#20" class="mim-tip-reference" title="Jacobs, J. M., Wilson, J. <strong>An unusual demyelinating neuropathy in a patient with Waardenburg's syndrome.</strong> Acta Neuropath. 83: 670-674, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1636383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1636383</a>] [<a href="https://doi.org/10.1007/BF00299420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1636383">Jacobs and Wilson (1992)</a>, <a href="#13" class="mim-tip-reference" title="Inoue, K., Khajavi, M., Ohyama, T., Hirabayashi, S., Wilson, J., Reggin, J. D., Mancias, P., Butler, I. J., Wilkinson, M. F., Wegner, M., Lupski, J. R. <strong>Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations.</strong> Nature Genet. 36: 361-369, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15004559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15004559</a>] [<a href="https://doi.org/10.1038/ng1322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15004559">Inoue et al. (2004)</a> identified a tyr313-to-ter (Y313X) mutation in the SOX10 gene. In the 27-year-old male previously reported by <a href="#20" class="mim-tip-reference" title="Jacobs, J. M., Wilson, J. <strong>An unusual demyelinating neuropathy in a patient with Waardenburg's syndrome.</strong> Acta Neuropath. 83: 670-674, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1636383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1636383</a>] [<a href="https://doi.org/10.1007/BF00299420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1636383">Jacobs and Wilson (1992)</a>, the Y313X mutation was the result of a 1-bp insertion (938insA); in the other patient, an 18-year-old male, the Y313X mutation was the result of a 939C-G transversion. Both patients had muscle wasting/atrophy, pes cavus, and areflexia/hyporeflexia, indicating peripheral neuropathy. Both had developmental delay and hypotonia, indicative of dysmyelination, with nystagmus and spastic diplegia also present in the younger patient. Both patients had hypopigmentation and neurosensory deafness, indicating dysmyelinating Waardenburg syndrome, and both had long segment Hirschsprung disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15004559+1636383" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 PERIPHERAL DEMYELINATING NEUROPATHY, CENTRAL DYSMYELINATION, WAARDENBURG SYNDROME, AND HIRSCHSPRUNG DISEASE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs74315518 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315518;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/rs74315518?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=rs74315518" 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=rs74315518" 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=RCV000007823 OR RCV005089203" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007823, RCV005089203" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007823...</a>
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<p><a href="#46" class="mim-tip-reference" title="Touraine, R. L., Attie-Bitach, T., Manceau, E., Korsch, E., Sarda, P., Pingault, V., Encha-Razavi, F., Pelet, A., Auge, J., Nivelon-Chevallier, A., Holschneider, A. M., Munnes, M., Doerfler, W., Goossens, M., Munnich, A., Vekemans, M., Lyonnet, S. <strong>Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain.</strong> Am. J. Hum. Genet. 66: 1496-1503, 2000. Note: Erratum: Am. J. Hum. Genet. 66: 2020 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10762540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10762540</a>] [<a href="https://doi.org/10.1086/302895" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10762540">Touraine et al. (2000)</a> found a ser251-to-ter (S251X) truncating mutation of the SOX10 gene in a child in France with a neurologic variant of Waardenburg-Shah syndrome (<a href="/entry/609136">609136</a>). There was no history of either WS or Hirschsprung disease (<a href="/entry/142623">142623</a>) in other members of the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10762540" 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 PERIPHERAL DEMYELINATING NEUROPATHY, CENTRAL DYSMYELINATION, WAARDENBURG SYNDROME, AND HIRSCHSPRUNG DISEASE</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">rs397515368 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515368;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=rs397515368" 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=rs397515368" 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=RCV000007824" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007824" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007824</a>
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<p><a href="#16" class="mim-tip-reference" title="Inoue, K., Tanabe, Y., Lupski, J. R. <strong>Myelin deficiencies in both the central and the peripheral nervous systems associated with a SOX10 mutation.</strong> Ann. Neurol. 46: 313-318, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10482261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10482261</a>] [<a href="https://doi.org/10.1002/1531-8249(199909)46:3<313::aid-ana6>3.0.co;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10482261">Inoue et al. (1999)</a> described a patient presenting with a neurologic variant of Waardenburg-Shah syndrome (PCWH; <a href="/entry/609136">609136</a>) characterized by severe dysmyelination compatible with Pelizaeus-Merzbacher disease (see <a href="/entry/312080">312080</a>) and peripheral neuropathy consistent with Charcot-Marie-Tooth disease type I (see <a href="/entry/118200">118200</a>), in addition to Waardenburg-Hirschsprung syndrome (<a href="/entry/277580">277580</a>). In the patient, <a href="#16" class="mim-tip-reference" title="Inoue, K., Tanabe, Y., Lupski, J. R. <strong>Myelin deficiencies in both the central and the peripheral nervous systems associated with a SOX10 mutation.</strong> Ann. Neurol. 46: 313-318, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10482261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10482261</a>] [<a href="https://doi.org/10.1002/1531-8249(199909)46:3<313::aid-ana6>3.0.co;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10482261">Inoue et al. (1999)</a> identified a novel heterozygous 12-bp deletion in exon 5 of the SOX10 gene that did not disrupt the coding region, but extended the peptide and hence was thought to act as a dominant-negative allele. There was a 6-bp direct repeat in the wildtype SOX10 sequence that flanked the deletion, suggesting that the deletion may have been mediated by DNA polymerase slippage between these direct repeats. The healthy parents and sibs did not have this deletion, indicating that this was a de novo mutation. Deletion started at the second nucleotide of the TAA stop codon, resulting in disruption of the stop codon, and, by conceptual translation, an extension of 82 amino acids on the carboxy terminus without any other alterations in the putative SOX10 protein. The 12-bp deletion converted the carboxy-terminal codon from TAA (stop) to TGT (cys). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10482261" 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 in vitro functional expression assays, <a href="#14" class="mim-tip-reference" title="Inoue, K., Ohyama, T., Sakuragi, Y., Yamamoto, R., Inoue, N. A., Yu, L.-H., Goto, Y., Wegner, M., Lupski, J. R. <strong>Translation of SOX10 3-prime untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain.</strong> Hum. Molec. Genet. 16: 3037-3046, 2007. Note: Erratum: Hum. Molec. Genet. 17: 1705 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17855451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17855451</a>] [<a href="https://doi.org/10.1093/hmg/ddm262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17855451">Inoue et al. (2007)</a> showed that the 12-bp deletion led to severely diminished transcription and DNA-binding activity of SOX10. However, the mutant protein did not show dominant-negative interference with wildtype SOX10 in vitro. Within the additional 82-amino acid tail, an 11-amino acid region (termed the WR domain) presumably formed an alpha-helix structure and inhibited SOX10 transcription activity if inserted in the C-terminal half of the protein. The WR domain also affected other transcription factors with a graded effect when fused to the C terminus, suggesting that it elicited a toxic functional activity. <a href="#14" class="mim-tip-reference" title="Inoue, K., Ohyama, T., Sakuragi, Y., Yamamoto, R., Inoue, N. A., Yu, L.-H., Goto, Y., Wegner, M., Lupski, J. R. <strong>Translation of SOX10 3-prime untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain.</strong> Hum. Molec. Genet. 16: 3037-3046, 2007. Note: Erratum: Hum. Molec. Genet. 17: 1705 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17855451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17855451</a>] [<a href="https://doi.org/10.1093/hmg/ddm262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17855451">Inoue et al. (2007)</a> concluded that the molecular pathology caused by the 12-bp deletion and its resulting extension was distinct from that of more common premature termination mutations. Failure to properly terminate SOX10 translation resulted in the generation of a deleterious functional domain and a gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17855451" 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>.0009 WAARDENBURG SYNDROME, TYPE 4C</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">rs281797260 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281797260;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=rs281797260" 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=rs281797260" 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=RCV000007825" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007825" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007825</a>
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<p><a href="#41" class="mim-tip-reference" title="Southard-Smith, E. M., Angrist, M., Ellison, J. S., Agarwala, R., Baxevanis, A. D., Chakravarti, A., Pavan, W. J. <strong>The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome.</strong> Genome Res. 9: 215-225, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077527</a>]" pmid="10077527">Southard-Smith et al. (1999)</a> described heterozygosity for a tyr207-to-ter (Y207X) mutation in a patient with Waardenburg syndrome type 4C (<a href="/entry/613266">613266</a>) manifested by short segment Hirschsprung disease, profound sensorineural hearing loss, and hypopigmentation on the abdomen and neck. Both parents were phenotypically normal and neither carried the mutation. The mutation was in exon 4, 27 residues downstream of the carboxyl end of the HMG box and 14 residues downstream of the corresponding site in the Sox10(Dom) mouse where the single basepair insertion is located. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077527" 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">rs74315520 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315520;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=rs74315520" 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=rs74315520" 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=RCV000007826 OR RCV000007827 OR RCV000760372" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007826, RCV000007827, RCV000760372" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007826...</a>
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<p>In a boy with Waardenburg syndrome type 4C (<a href="/entry/613266">613266</a>), <a href="#41" class="mim-tip-reference" title="Southard-Smith, E. M., Angrist, M., Ellison, J. S., Agarwala, R., Baxevanis, A. D., Chakravarti, A., Pavan, W. J. <strong>The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome.</strong> Genome Res. 9: 215-225, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077527</a>]" pmid="10077527">Southard-Smith et al. (1999)</a> found a gln377-to-ter (Q377X) mutation that truncated the SOX10 protein within the transcription modulation domain. The heterozygous proband had sensorineural deafness and variable diagnoses of enteric function ranging from hypoganglionosis to long segment Hirschsprung disease. He also had nystagmus and ataxic cerebral palsy. His sister was also profoundly deaf and had nystagmus and cerebral palsy, but did not have Hirschsprung disease (WS2E; <a href="/entry/611584">611584</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077527" 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>.0011 PERIPHERAL DEMYELINATING NEUROPATHY, CENTRAL DYSMYELINATION, WAARDENBURG SYNDROME, AND HIRSCHSPRUNG DISEASE</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">rs74315521 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315521;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=rs74315521" 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=rs74315521" 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=RCV000007828" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007828" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007828</a>
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<p><a href="#15" class="mim-tip-reference" title="Inoue, K., Shilo, K., Boerkoel, C. F., Crowe, C., Sawady, J., Lupski, J. R., Agamanolis, D. P. <strong>Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: phenotypes linked by SOX10 mutation.</strong> Ann. Neurol. 52: 836-842, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12447940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12447940</a>] [<a href="https://doi.org/10.1002/ana.10404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12447940">Inoue et al. (2002)</a> reported a male infant with peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (PCWH; <a href="/entry/609136">609136</a>) who was heterozygous for a 748C-T transition in the SOX10 gene, resulting in a gln250-to-ter (Q250X) substitution. The patient presented at birth with a white forelock and hyperpigmented and hypopigmented patches on the face, body, and limbs, deafness, and chronic ileus. He never passed meconium and required repeated segmental small and large bowel resections. Myenteric and submucosal ganglion cells were severely diminished throughout the entire colon and much of the small bowel. In addition, he had little spontaneous respiratory or other movement, severe hypotonia, multiple contractures, undetectable tendon reflexes, and tongue fasciculations. Histopathologic studies showed an absence of peripheral nerve myelin despite normal numbers of Schwann cells, and profound dysmyelination in the CNS. He remained ventilator-dependent his entire life and died at 83 days of age of Pseudomonas aeruginosa sepsis. The observations suggested that some SOX10 mutations, such as Q250X, may allow Schwann cells and oligodendrocytes to proliferate but interfere with further differentiation to form myelin. In contrast to SOX10 loss-of-function mutations causing only WS4C (<a href="/entry/613266">613266</a>), mutations associated with both peripheral and central dysmyelination may affect pathology through a dominant-negative mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12447940" 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 WAARDENBURG SYNDROME, TYPE 4C</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007829" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007829" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007829</a>
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<p>In a 1-year-old boy with Waardenburg syndrome type 4C (<a href="/entry/613266">613266</a>), <a href="#2" class="mim-tip-reference" title="Bondurand, N., Dastot-Le Moal, F., Stanchina, L., Collot, N., Baral, V., Marlin, S., Attie-Bitach, T., Giurgea, I., Skopinski, L., Reardon, W., Toutain, A., Sarda, P., Echaieb, A., Lackmy-Port-Lis, M., Touraine, R., Amiel, J., Goossens, M., Pingault, V. <strong>Deletions at the SOX10 gene locus gene Waardenburg syndrome types 2 and 4.</strong> Am. J. Hum. Genet. 81: 1169-1185, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17999358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17999358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17999358[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/10.1086/522090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17999358">Bondurand et al. (2007)</a> identified a heterozygous deletion that removed part of exon 5 of the SOX10 gene. The mutation comprised a 1,128-bp deletion encompassing 740 bp of intron 4 and 388 bp of exon 5, and a 3-bp insertion (697-740_1085del ins CCT). The patient had short-segment Hirschsprung disease, bilateral sensorineural deafness, hair and skin hypopigmentation, and bilateral cryptorchidism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17999358" 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">rs1555939381 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555939381;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=rs1555939381" 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=rs1555939381" 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=RCV000007830" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007830" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007830</a>
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<p>In a 9-year-old boy with Waardenburg syndrome type 2 (WS2E; <a href="/entry/611584">611584</a>) and in his similarly affected brother, <a href="#2" class="mim-tip-reference" title="Bondurand, N., Dastot-Le Moal, F., Stanchina, L., Collot, N., Baral, V., Marlin, S., Attie-Bitach, T., Giurgea, I., Skopinski, L., Reardon, W., Toutain, A., Sarda, P., Echaieb, A., Lackmy-Port-Lis, M., Touraine, R., Amiel, J., Goossens, M., Pingault, V. <strong>Deletions at the SOX10 gene locus gene Waardenburg syndrome types 2 and 4.</strong> Am. J. Hum. Genet. 81: 1169-1185, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17999358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17999358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17999358[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/10.1086/522090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17999358">Bondurand et al. (2007)</a> identified a heterozygous 253-bp deletion in the SOX10 gene (219_428+43del). The deletion removed 210 bp of exon 3 and 43 bp of intron 3. The proband had profound deafness, pigmentation abnormalities of the skin and eyes, but no Hirschsprung disease or mental retardation. The patient's mother exhibited somatic mosaicism for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17999358" 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 WAARDENBURG SYNDROME, TYPE 2E, WITHOUT NEUROLOGIC INVOLVEMENT</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007831" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007831" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007831</a>
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<p>In an 8-year-old boy with Waardenburg syndrome type 2 (WS2E; <a href="/entry/611584">611584</a>), <a href="#2" class="mim-tip-reference" title="Bondurand, N., Dastot-Le Moal, F., Stanchina, L., Collot, N., Baral, V., Marlin, S., Attie-Bitach, T., Giurgea, I., Skopinski, L., Reardon, W., Toutain, A., Sarda, P., Echaieb, A., Lackmy-Port-Lis, M., Touraine, R., Amiel, J., Goossens, M., Pingault, V. <strong>Deletions at the SOX10 gene locus gene Waardenburg syndrome types 2 and 4.</strong> Am. J. Hum. Genet. 81: 1169-1185, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17999358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17999358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17999358[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/10.1086/522090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17999358">Bondurand et al. (2007)</a> identified heterozygosity for a 1,777-bp deletion in the SOX10 gene that removed the whole exon 4, 1,112 bp of intron 3, and 396 bp of intron 4 (429-1112_697+396del). The mutation was inherited from the mother, who also had WS2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17999358" 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 WAARDENBURG SYNDROME, TYPE 2E, WITHOUT NEUROLOGIC INVOLVEMENT</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">rs397515369 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515369;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=rs397515369" 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=rs397515369" 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=RCV000007832" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007832" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007832</a>
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<p>In a Japanese girl with Waardenburg syndrome type 2E (<a href="/entry/611584">611584</a>), <a href="#17" class="mim-tip-reference" title="Iso, M., Fukami, M., Horikawa, R., Azuma, N., Kawashiro, N., Ogata, T. <strong>SOX10 mutation in Waardenburg syndrome type II. (Letter)</strong> Am. J. Med. Genet. 146A: 2162-2163, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18627047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18627047</a>] [<a href="https://doi.org/10.1002/ajmg.a.32403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18627047">Iso et al. (2008)</a> identified a heterozygous 1-bp deletion (506delC) in exon 4 of the SOX10 gene, predicted to result in a frameshift and premature termination that would remove the C-terminal part of the HMG domain and the whole transactivation domain. She had ocular albinism, a white forelock, and sensorineural deafness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18627047" 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 WAARDENBURG SYNDROME, TYPE 4C</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">rs121909117 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909117;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=rs121909117" 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=rs121909117" 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=RCV000007833 OR RCV002273922" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007833, RCV002273922" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007833...</a>
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<p>In an 18-month-old Spanish boy with severe sensorineural hearing loss, Hirschsprung disease, and heterochromia iridis but neither pigmentary abnormalities in the skin nor white forelock (<a href="/entry/613266">613266</a>), <a href="#29" class="mim-tip-reference" title="Morin, M., Vinuela, A., Rivera, T., Villamar, M., Moreno-Pelayo, M. A., Moreno, F., del Castillo, I. <strong>A de novo missense mutation in the gene encoding the SOX10 transcription factor in a Spanish sporadic case of Waardenburg syndrome type IV. (Letter)</strong> Am. J. Med. Genet. 146A: 1032-1037, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18348274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18348274</a>] [<a href="https://doi.org/10.1002/ajmg.a.32181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18348274">Morin et al. (2008)</a> identified a 470C-T transition in the SOX10 gene, resulting in an ala157-to-val (A157V) change in the predicted polypeptide. The mutation affects the alanine at position 56 in the highly conserved HMG domain. The side chain of ala56 participates in interactions between the N-terminal end of helix 1 and helix 3. <a href="#29" class="mim-tip-reference" title="Morin, M., Vinuela, A., Rivera, T., Villamar, M., Moreno-Pelayo, M. A., Moreno, F., del Castillo, I. <strong>A de novo missense mutation in the gene encoding the SOX10 transcription factor in a Spanish sporadic case of Waardenburg syndrome type IV. (Letter)</strong> Am. J. Med. Genet. 146A: 1032-1037, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18348274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18348274</a>] [<a href="https://doi.org/10.1002/ajmg.a.32181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18348274">Morin et al. (2008)</a> proposed that the A157V mutation could disturb these interactions through steric hindrance, destabilizing the HMG domain. The mutation was not present in the patient's parents, his brother, or in 95 unrelated Spanish controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18348274" 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">rs397515370 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515370;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=rs397515370" 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=rs397515370" 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=RCV000007834" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007834" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007834</a>
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<p>In a boy with Waardenburg syndrome type 2E (<a href="/entry/611584">611584</a>), <a href="#44" class="mim-tip-reference" title="Sznajer, Y., Coldea, C., Meire, F., Delpierre, I., Sekhara, T., Touraine, R. L. <strong>A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease.</strong> Am. J. Med. Genet. 146A: 1038-1041, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18348267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18348267</a>] [<a href="https://doi.org/10.1002/ajmg.a.32247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18348267">Sznajer et al. (2008)</a> identified a heterozygous de novo A-to-C transversion in intron 4 of the SOX10 gene. In addition to sensorineural deafness and vivid blue eyes, he had neurologic abnormalities, including white matter anomalies, mental retardation with autistic-like behavior, hypotonia, and a generalized peripheral neuropathy. Brain imaging showed complete agenesis of the semicircular canals. Hirschsprung disease was absent. <a href="#44" class="mim-tip-reference" title="Sznajer, Y., Coldea, C., Meire, F., Delpierre, I., Sekhara, T., Touraine, R. L. <strong>A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease.</strong> Am. J. Med. Genet. 146A: 1038-1041, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18348267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18348267</a>] [<a href="https://doi.org/10.1002/ajmg.a.32247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18348267">Sznajer et al. (2008)</a> hypothesized that the mutation decreased the strength of the acceptor splice site and increased the strength of at least 1 cryptic site 5 nucleotides downstream. Utilization of this cryptic site would cause a frameshift and premature termination 46 residues downstream. The mutation was not present in either parent or in 300 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18348267" 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 WAARDENBURG SYNDROME, TYPE 2E, WITH NEUROLOGIC INVOLVEMENT</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">rs267607081 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607081;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=rs267607081" 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=rs267607081" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 21-month-old boy with Waardenburg syndrome type 2E (<a href="/entry/611584">611584</a>), <a href="#1" class="mim-tip-reference" title="Barnett, C. P., Mendoza-Londono, R., Blaser, S., Gillis, J., Dupuis, L., Levin, A. V., Chiang, P. W., Spector, E., Reardon, W. <strong>Aplasia of cochlear nerves and olfactory bulbs in association with SOX10 mutation.</strong> Am. J. Med. Genet. 149A: 431-436, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19208381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19208381</a>] [<a href="https://doi.org/10.1002/ajmg.a.32657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19208381">Barnett et al. (2009)</a> identified a heterozygous 521A-C transversion in exon 4 of the SOX10 gene, resulting in a gln174-to-pro (Q174P) substitution in the highly conserved HMG domain. He had sensorineural deafness, fair skin and hair pigmentation, multiple tiny lentigines, cafe-au-lait spots, and light blue irides, but no evidence of Hirschsprung disease. He also showed neurologic involvement, with hypotonia, poor vision with intermittent nystagmus in early life, inability to fix or follow, and increased muscle tone. Brain imaging showed absence of the cochlear nerves, absence of the olfactory bulbs, and brain hypomyelination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19208381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0019 PERIPHERAL DEMYELINATING NEUROPATHY, CENTRAL DYSMYELINATION, WAARDENBURG SYNDROME, AND HIRSCHSPRUNG DISEASE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397515371 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515371;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/rs397515371?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=rs397515371" 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=rs397515371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a girl with a phenotype consistent with PCWH (<a href="/entry/609136">609136</a>), <a href="#36" class="mim-tip-reference" title="Pingault, V., Guiochon-Mantel, A., Bondurand, N., Faure, C., Lacroix, C., Lyonnet, S., Goossens, M., Landrieu, P. <strong>Peripheral neuropathy with hypomyelination, chronic intestinal pseudo-obstruction and deafness: a developmental 'neural crest syndrome' related to a SOX10 mutation.</strong> Ann. Neurol. 48: 671-676, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11026454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11026454</a>]" pmid="11026454">Pingault et al. (2000)</a> identified a de novo heterozygous 1-bp deletion (795delG) in the SOX10 gene, resulting in a frameshift and premature termination. She had peripheral neuropathy with marked slowing of nerve conduction velocities resulting in delayed motor development, chronic intestinal pseudoobstruction, hypolacrimation, absence of sweating, and deafness. The peripheral nerve histologic features were more consistent with a developmental dysregulation defect than a degenerative process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11026454" 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">rs397515372 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515372;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=rs397515372" 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=rs397515372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Spanish boy with PCWH (<a href="/entry/609136">609136</a>), <a href="#47" class="mim-tip-reference" title="Vinuela, A., Morin, M., Villamar, M., Morera, C., Lavilla, M. J., Cavalle, L., Moreno-Pelayo, M. A., Moreno, F., del Castillo, I. <strong>Genetic and phenotypic heterogeneity in two novel cases of Waardenburg syndrome type IV. (Letter)</strong> Am. J. Med. Genet. 149A: 2296-2302, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19764030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19764030</a>] [<a href="https://doi.org/10.1002/ajmg.a.33026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19764030">Vinuela et al. (2009)</a> identified a de novo heterozygous 1-bp deletion (915delG) in exon 5 of the SOX10 gene, resulting in a frameshift and premature termination at residue 306. The patient had Hirschsprung disease since birth and progressive sensorineural hearing loss associated with hypoplasia of the cochlea. He had blue eyes, but no pigmentary anomalies of the skin or white forelock. Neurologic findings included congenital nystagmus and delayed motor development due to hypotonia and spasticity. Brain MRI showed central dysmyelinization. <a href="#47" class="mim-tip-reference" title="Vinuela, A., Morin, M., Villamar, M., Morera, C., Lavilla, M. J., Cavalle, L., Moreno-Pelayo, M. A., Moreno, F., del Castillo, I. <strong>Genetic and phenotypic heterogeneity in two novel cases of Waardenburg syndrome type IV. (Letter)</strong> Am. J. Med. Genet. 149A: 2296-2302, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19764030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19764030</a>] [<a href="https://doi.org/10.1002/ajmg.a.33026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19764030">Vinuela et al. (2009)</a> noted that the location of this mutation would cause an escape from nonsense-mediated decay and generate a dominant-negative effect resulting in neurologic features, consistent with the findings of <a href="#13" class="mim-tip-reference" title="Inoue, K., Khajavi, M., Ohyama, T., Hirabayashi, S., Wilson, J., Reggin, J. D., Mancias, P., Butler, I. J., Wilkinson, M. F., Wegner, M., Lupski, J. R. <strong>Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations.</strong> Nature Genet. 36: 361-369, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15004559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15004559</a>] [<a href="https://doi.org/10.1038/ng1322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15004559">Inoue et al. (2004)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15004559+19764030" 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">rs397515386 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515386;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=rs397515386" 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=rs397515386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Chinese father and daughter with WS2E (<a href="/entry/611584">611584</a>), <a href="#49" class="mim-tip-reference" title="Zhang, H., Chen, H., Luo, H., An, J., Sun, L., Mei, L., He, C., Jiang, L., Jiang, W., Xia, K., Li, J.-D., Feng, Y. <strong>Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II.</strong> Hum. Genet. 131: 491-503, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21965087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21965087</a>] [<a href="https://doi.org/10.1007/s00439-011-1098-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21965087">Zhang et al. (2012)</a> identified a heterozygous 2-bp deletion, 743delAG, in exon 5 of the SOX10 gene, resulting in a frameshift and premature termination at codon 248 (Glu248fsTer30). The truncated protein lacked the transactivation domain but retained the DNA-binding domain. In vitro functional expression studies in human cells showed that the mutant protein was expressed and localized only to the nucleus, but did not transactivate the MITF (<a href="/entry/156845">156845</a>) promoter and acted in a dominant-negative manner. However, the mutant protein was degraded faster than wildtype SOX10, which <a href="#49" class="mim-tip-reference" title="Zhang, H., Chen, H., Luo, H., An, J., Sun, L., Mei, L., He, C., Jiang, L., Jiang, W., Xia, K., Li, J.-D., Feng, Y. <strong>Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II.</strong> Hum. Genet. 131: 491-503, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21965087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21965087</a>] [<a href="https://doi.org/10.1007/s00439-011-1098-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21965087">Zhang et al. (2012)</a> postulated may have resulted in haploinsufficiency and the somewhat mild phenotype. Both patients had bilateral profound hearing loss and bilateral heterochromia iridis, but no additional features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21965087" 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>.0022 WAARDENBURG SYNDROME, TYPE 2E, WITHOUT NEUROLOGIC INVOLVEMENT</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397515387 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515387;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/rs397515387?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=rs397515387" 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=rs397515387" 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=RCV000023179" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023179" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023179</a>
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<p>In a Chinese boy with WS2E (<a href="/entry/611584">611584</a>), <a href="#9" class="mim-tip-reference" title="Chen, H., Jiang, L., Xie, Z., Mei, L., He, C., Hu, Z., Xia, K., Feng, Y. <strong>Novel mutations of PAX3, MITF, and SOX10 genes in Chinese patients with type I or type II Waardenburg syndrome.</strong> Biochem. Biophys. Res. Commun. 397: 70-74, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20478267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20478267</a>] [<a href="https://doi.org/10.1016/j.bbrc.2010.05.066" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20478267">Chen et al. (2010)</a> identified a heterozygous 1-bp deletion (113delG) in exon 3 of the SOX10 gene, resulting in a frameshift and premature termination (Gly38fsTer69). In functional studies, <a href="#49" class="mim-tip-reference" title="Zhang, H., Chen, H., Luo, H., An, J., Sun, L., Mei, L., He, C., Jiang, L., Jiang, W., Xia, K., Li, J.-D., Feng, Y. <strong>Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II.</strong> Hum. Genet. 131: 491-503, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21965087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21965087</a>] [<a href="https://doi.org/10.1007/s00439-011-1098-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21965087">Zhang et al. (2012)</a> demonstrated that the truncated protein was expressed and lacked the nuclear localization signal; it showed localization in both the nucleus and cytoplasm, but did not transactivate the MITF (<a href="/entry/156845">156845</a>) promoter, consistent with haploinsufficiency. The patient had bilateral profound hearing loss and bilateral heterochromia iridis, but no additional features. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20478267+21965087" 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>.0023 WAARDENBURG SYNDROME, TYPE 2E, WITHOUT NEUROLOGIC INVOLVEMENT</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">rs397515457 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515457;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=rs397515457" 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=rs397515457" 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=RCV000055673" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000055673" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000055673</a>
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<p>In a 26-year-old man with unilateral deafness, white hair, anosmia, cryptorchidism, and micropenis (WSE2; <a href="/entry/611584">611584</a>), <a href="#33" class="mim-tip-reference" title="Pingault, V., Bodereau, V., Baral, V., Marcos, S., Watanabe, Y., Chaoui, A., Fouveaut, C., Leroy, C., Verier-Mine, O., Francannet, C., Dupin-Deguine, D., Archambeaud, F., Kurtz, F.-J., Young, J., Bertherat, J., Marlin, S., Goossens, M., Hardelin, J.-P., Dode, C., Bondurand, N. <strong>Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness.</strong> Am. J. Hum. Genet. 92: 707-724, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643381</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643381[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/10.1016/j.ajhg.2013.03.024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643381">Pingault et al. (2013)</a> identified heterozygosity for a c.2T-G transversion in the SOX10 gene. Luciferase reporter-gene analysis in transfected HeLa cells showed reduced or absent transactivation capacity with the mutant compared to wildtype. The proband's mother also had unilateral deafness, and his sister was anosmic; their mutation status was unknown. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23643381" 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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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>REFERENCES</strong>
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Barnett, C. P., Mendoza-Londono, R., Blaser, S., Gillis, J., Dupuis, L., Levin, A. V., Chiang, P. W., Spector, E., Reardon, W.
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<strong>Aplasia of cochlear nerves and olfactory bulbs in association with SOX10 mutation.</strong>
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Am. J. Med. Genet. 149A: 431-436, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19208381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19208381</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19208381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32657" target="_blank">Full Text</a>]
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Bondurand, N., Dastot-Le Moal, F., Stanchina, L., Collot, N., Baral, V., Marlin, S., Attie-Bitach, T., Giurgea, I., Skopinski, L., Reardon, W., Toutain, A., Sarda, P., Echaieb, A., Lackmy-Port-Lis, M., Touraine, R., Amiel, J., Goossens, M., Pingault, V.
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<strong>Deletions at the SOX10 gene locus gene Waardenburg syndrome types 2 and 4.</strong>
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Am. J. Hum. Genet. 81: 1169-1185, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17999358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17999358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17999358[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=17999358" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/522090" target="_blank">Full Text</a>]
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Bondurand, N., Girard, M., Pingault, V., Lemort, N., Dubourg, O., Goossens, M.
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<strong>Human connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10.</strong>
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Hum. Molec. Genet. 10: 2783-2795, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11734543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11734543</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11734543" 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/10.24.2783" target="_blank">Full Text</a>]
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<a id="Bondurand1999" class="mim-anchor"></a>
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Bondurand, N., Kuhlbrodt, K., Pingault, V., Enderich, J., Sajus, M., Tommerup, N., Warburg, M., Hennekam, R. C. M., Read, A. P., Wegner, M., Goossens, M.
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<strong>A molecular analysis of the Yemenite deaf-blind hypopigmentation syndrome: SOX10 dysfunction causes different neurocristopathies.</strong>
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Hum. Molec. Genet. 8: 1785-1789, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441344</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441344" 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/8.9.1785" target="_blank">Full Text</a>]
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Bondurand, N., Pingault, V., Goerich, D. E., Lemort, N., Sock, E., Le Caignec, C., Wegner, M., Goossens, M.
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<strong>Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.</strong>
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Hum. Molec. Genet. 9: 1907-1917, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10942418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10942418</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10942418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Cantrell, V. A., Owens, S. E., Chandler, R. L., Airey, D. C., Bradley, K. M., Smith, J. R., Southard-Smith, E. M.
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<strong>Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10(Dom) mouse model of Hirschsprung disease.</strong>
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Hum. Molec. Genet. 13: 2289-2301, 2004. Note: Erratum: Hum. Molec. Genet. 13: 3241 only, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15294878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15294878</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15294878" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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EMBO J. 15: 5965-5975, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8918474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8918474</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8918474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Chaoui, A., Kavo, A., Baral, V., Watanabe, Y., Lecerf, L., Colley, A., Mendoza-Londono, R., Pingault, V., Bondurand, N.
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<strong>Subnuclear re-localization of SOX10 and p54NRB correlates with a unique neurological phenotype associated with SOX10 missense mutations.</strong>
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Hum. Molec. Genet. 24: 4933-4947, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26060192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26060192</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26060192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Chen, H., Jiang, L., Xie, Z., Mei, L., He, C., Hu, Z., Xia, K., Feng, Y.
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<strong>Novel mutations of PAX3, MITF, and SOX10 genes in Chinese patients with type I or type II Waardenburg syndrome.</strong>
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Biochem. Biophys. Res. Commun. 397: 70-74, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20478267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20478267</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20478267" 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.bbrc.2010.05.066" target="_blank">Full Text</a>]
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</p>
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<a id="43" class="mim-anchor"></a>
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<a id="Stock1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stock, D. W., Buchanan, A. V., Zhao, Z., Weiss, K. M.
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|
<strong>Numerous members of the Sox family of HMG box-containing genes are expressed in developing mouse teeth.</strong>
|
|
Genomics 37: 234-237, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8921394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8921394</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8921394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1996.0548" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="44" class="mim-anchor"></a>
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<a id="Sznajer2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sznajer, Y., Coldea, C., Meire, F., Delpierre, I., Sekhara, T., Touraine, R. L.
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|
<strong>A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease.</strong>
|
|
Am. J. Med. Genet. 146A: 1038-1041, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18348267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18348267</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18348267" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32247" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="45" class="mim-anchor"></a>
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<a id="Taylor2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Taylor, K. M., LaBonne, C.
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|
<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.
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.devcel.2005.09.016" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="46" class="mim-anchor"></a>
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<a id="Touraine2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Touraine, R. L., Attie-Bitach, T., Manceau, E., Korsch, E., Sarda, P., Pingault, V., Encha-Razavi, F., Pelet, A., Auge, J., Nivelon-Chevallier, A., Holschneider, A. M., Munnes, M., Doerfler, W., Goossens, M., Munnich, A., Vekemans, M., Lyonnet, S.
|
|
<strong>Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain.</strong>
|
|
Am. J. Hum. Genet. 66: 1496-1503, 2000. Note: Erratum: Am. J. Hum. Genet. 66: 2020 only, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10762540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10762540</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10762540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/302895" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="47" class="mim-anchor"></a>
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<a id="Vinuela2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vinuela, A., Morin, M., Villamar, M., Morera, C., Lavilla, M. J., Cavalle, L., Moreno-Pelayo, M. A., Moreno, F., del Castillo, I.
|
|
<strong>Genetic and phenotypic heterogeneity in two novel cases of Waardenburg syndrome type IV. (Letter)</strong>
|
|
Am. J. Med. Genet. 149A: 2296-2302, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19764030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19764030</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19764030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.33026" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="48" class="mim-anchor"></a>
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<a id="Wright1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wright, E. M., Snopek, B., Koopman, P.
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<strong>Seven new members of the Sox gene family expressed during mouse development.</strong>
|
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Nucleic Acids Res. 21: 744 only, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8441686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8441686</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8441686" 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/nar/21.3.744" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="49" class="mim-anchor"></a>
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<a id="Zhang2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, H., Chen, H., Luo, H., An, J., Sun, L., Mei, L., He, C., Jiang, L., Jiang, W., Xia, K., Li, J.-D., Feng, Y.
|
|
<strong>Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II.</strong>
|
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Hum. Genet. 131: 491-503, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21965087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21965087</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21965087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-011-1098-2" target="_blank">Full Text</a>]
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</p>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 02/24/2016
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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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Marla J. F. O'Neill - updated : 9/27/2013<br>George E. Tiller - updated : 8/5/2013<br>Cassandra L. Kniffin - updated : 3/26/2012<br>George E. Tiller - updated : 1/5/2011<br>Cassandra L. Kniffin - updated : 10/14/2010<br>Ada Hamosh - updated : 5/25/2010<br>Cassandra L. Kniffin - updated : 3/8/2010<br>Patricia A. Hartz - updated : 10/5/2009<br>Cassandra L. Kniffin - updated : 9/2/2009<br>Kelly A. Przylepa - updated : 2/2/2009<br>Cassandra L. Kniffin - updated : 10/20/2008<br>George E. Tiller - updated : 6/5/2008<br>Victor A. McKusick - updated : 11/28/2007<br>George E. Tiller - updated : 4/5/2007<br>Patricia A. Hartz - updated : 6/8/2006<br>Patricia A. Hartz - updated : 12/20/2005<br>George E. Tiller - updated : 2/21/2005<br>Victor A. McKusick - updated : 12/16/2004<br>Cassandra L. Kniffin - reorganized : 3/30/2004<br>Cassandra L. Kniffin - updated : 3/17/2004<br>Ada Hamosh - updated : 8/26/2003<br>Victor A. McKusick - updated : 1/22/2003<br>Victor A. McKusick - updated : 10/2/2002<br>Victor A. McKusick - updated : 9/12/2002<br>Victor A. McKusick - updated : 9/11/2002<br>George E. Tiller - updated : 6/10/2002<br>Victor A. McKusick - updated : 2/1/2001<br>George E. Tiller - updated : 10/20/2000<br>Victor A. McKusick - updated : 9/12/2000<br>Victor A. McKusick - updated : 7/13/2000<br>Victor A. McKusick - updated : 5/18/2000<br>Victor A. McKusick - updated : 10/13/1999<br>Victor A. McKusick - updated : 10/13/1998<br>Victor A. McKusick - updated : 6/26/1998<br>Victor A. McKusick - updated : 1/26/1998
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 12/30/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/10/2020
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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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carol : 06/06/2018<br>carol : 09/21/2016<br>mgross : 02/24/2016<br>carol : 10/26/2015<br>alopez : 4/10/2015<br>carol : 4/10/2015<br>alopez : 4/9/2015<br>mcolton : 2/6/2015<br>carol : 9/27/2013<br>carol : 9/27/2013<br>carol : 9/6/2013<br>alopez : 8/5/2013<br>terry : 3/28/2013<br>alopez : 4/3/2012<br>terry : 3/28/2012<br>ckniffin : 3/26/2012<br>wwang : 1/18/2011<br>terry : 1/5/2011<br>wwang : 10/19/2010<br>ckniffin : 10/14/2010<br>alopez : 5/25/2010<br>ckniffin : 3/15/2010<br>carol : 3/11/2010<br>ckniffin : 3/8/2010<br>mgross : 10/5/2009<br>terry : 10/5/2009<br>wwang : 9/10/2009<br>ckniffin : 9/2/2009<br>carol : 2/4/2009<br>terry : 2/4/2009<br>terry : 2/2/2009<br>ckniffin : 12/3/2008<br>wwang : 10/23/2008<br>ckniffin : 10/20/2008<br>wwang : 6/12/2008<br>terry : 6/5/2008<br>carol : 12/11/2007<br>alopez : 12/10/2007<br>alopez : 12/10/2007<br>terry : 11/28/2007<br>alopez : 4/13/2007<br>terry : 4/5/2007<br>mgross : 6/15/2006<br>mgross : 6/15/2006<br>terry : 6/8/2006<br>wwang : 12/20/2005<br>wwang : 3/2/2005<br>terry : 2/21/2005<br>carol : 1/7/2005<br>carol : 1/6/2005<br>tkritzer : 1/5/2005<br>terry : 12/16/2004<br>tkritzer : 8/24/2004<br>ckniffin : 6/28/2004<br>alopez : 4/2/2004<br>tkritzer : 3/30/2004<br>ckniffin : 3/17/2004<br>cwells : 11/10/2003<br>ckniffin : 11/6/2003<br>alopez : 8/26/2003<br>terry : 8/26/2003<br>tkritzer : 6/13/2003<br>cwells : 1/28/2003<br>tkritzer : 1/22/2003<br>tkritzer : 10/7/2002<br>terry : 10/2/2002<br>carol : 9/19/2002<br>tkritzer : 9/12/2002<br>tkritzer : 9/12/2002<br>tkritzer : 9/11/2002<br>tkritzer : 9/11/2002<br>cwells : 6/12/2002<br>cwells : 6/10/2002<br>carol : 1/8/2002<br>mcapotos : 12/21/2001<br>mcapotos : 2/7/2001<br>mcapotos : 2/6/2001<br>terry : 2/1/2001<br>mcapotos : 11/1/2000<br>mcapotos : 10/20/2000<br>mcapotos : 10/20/2000<br>carol : 9/14/2000<br>terry : 9/12/2000<br>alopez : 7/20/2000<br>terry : 7/13/2000<br>mcapotos : 6/8/2000<br>mcapotos : 5/31/2000<br>terry : 5/18/2000<br>mgross : 10/22/1999<br>mgross : 10/21/1999<br>terry : 10/13/1999<br>dkim : 12/4/1998<br>carol : 10/18/1998<br>terry : 10/13/1998<br>carol : 7/8/1998<br>terry : 6/26/1998<br>carol : 5/27/1998<br>mark : 1/26/1998<br>terry : 1/26/1998<br>alopez : 1/22/1998<br>alopez : 1/7/1998
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 602229
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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 10; SOX10
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
SRY-RELATED HMG-BOX GENE 10<br />
|
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DOMINANT MEGACOLON, MOUSE, HOMOLOG OF; DOM
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SOX10</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> 765325002;
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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: 22q13.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 22:37,972,312-37,984,555 </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="3">
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<span class="mim-font">
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22q13.1
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</span>
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</td>
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<td>
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<span class="mim-font">
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PCWH syndrome
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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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609136
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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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Waardenburg syndrome, type 2E, with or without neurologic involvement
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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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611584
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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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Waardenburg syndrome, type 4C
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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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613266
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The testis-determining gene SRY (480000) encodes a transcription factor characterized by a DNA-binding motif known as the HMG (high mobility group) domain. The SOX gene family, which includes SOX10, consists of genes related to SRY, with a sequence identity of more than 60% to the SRY HMG box. SOX10 is a transcription factor that functions in neural crest and oligodendrocyte development (Pusch et al., 1998; Chaoui et al., 2015). </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>Using a rat SOX10 cDNA probe to screen a human brain cDNA library, Pingault et al. (1998) isolated a human SOX10 cDNA predicted to encode a 466-amino acid protein with a highly conserved HMG domain. </p><p>Pusch et al. (1998) cloned and sequenced the human SOX10 and the mouse Sox10 genes, which share 98% amino acid identity. Sequence analysis suggested that SOX9 (608160) and SOX10 have a common evolutionary origin. Northern blot analysis detected a 2.9-kb SOX10 mRNA in fetal brain and in adult heart, brain, small intestine, and colon. Low-level expression was seen in prostate and testis. In mouse embryos, Sox10 expression was detected in the developing peripheral nervous system, most prominent in the trigeminal, geniculate, and acoustic ganglia. </p><p>Kuhlbrodt et al. (1998) cloned the rat SOX10 gene, which encodes a 466-amino acid protein with a molecular mass of approximately 50 kD. Northern blot analysis detected a 3-kb SOX10 mRNA transcript that was largely restricted to glial cells in the adult nervous system. During development, SOX10 first appeared in the forming neural crest and continued to be expressed as these cells contributed to the forming peripheral nervous system and finally differentiated into Schwann cells. In the central nervous system, SOX10 transcripts were originally confined to glial precursors and later detected in oligodendrocytes of the adult brain. </p><p>Pingault et al. (2013) demonstrated expression of SOX10 in olfactory ensheathing cells during development of the peripheral olfactory system in mice and humans. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Pingault et al. (1998) determined that the SOX10 gene contains 5 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lane and Liu (1984) determined that a mouse model of Hirschsprung disease (HSCR; 142623), dominant megacolon (Dom), mapped to a mid-terminal region of mouse chromosome 15 (see ANIMAL MODEL). </p><p>Pingault et al. (1997) noted that, in mice, natural and in vitro-induced mutations affecting the Ret (164761), Ednrb (131242), and Edn3 (131244) genes generated phenotypes similar to human Hirschsprung disease. Using polymorphisms for conserved human/mouse genes, Pingault et al. (1997) established homology between the Dom locus and human chromosome 22q12-q13. Two genes, Smstr3 and Adsl (608222), not previously mapped in the mouse genome, were also mapped to mouse chromosome 15. The investigators stated that 3 genes, Smstr3, Lgals1 (150570), and Pdgfb (190040), are possible Dom candidates, as they did not recombine with the Dom mutation in a backcross. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Kuhlbrodt et al. (1998) studied 4 SOX10 mutations found in patients with Waardenburg-Shah syndrome (WS4; 277580). Unlike the rat SOX10 protein, which failed to show transcriptional activity on its own, wildtype human SOX10 displayed a weak, but reproducible, activity as a transcriptional activator. All mutant SOX10 proteins, including the 1 that lacked only the last 106 amino acids, were deficient in this capacity, indicating that the C terminus of human SOX10 carries a transactivation domain. Whereas all 4 mutants failed to transactivate, only 2 failed to enhance synergistically the activity of other transcription factors. Synergy required the ability to bind to DNA and a region in the N-terminal part of SOX10. Those mutants that failed to synergize were unable to bind to DNA. Analysis of the naturally occurring SOX10 mutations not only helped to dissect SOX10 structure, but also allowed limited predictions on the severity of the disease. </p><p>To evaluate further the role of Sox10 in development and disease, Southard-Smith et al. (1999) performed comparative genomic analyses. An essential role for the SOX10 gene in neural crest development was supported by zoo blot hybridizations that revealed extensive conservation throughout vertebrate evolution and by similar Northern blot expression profiles between mouse and man. </p><p>Potterf et al. (2000) elucidated the hierarchical relationship of 3 transcription factors, MITF (156845), PAX3 (606597), and SOX10, that are capable of producing several different forms of Waardenburg syndrome, WS2A (193510), WS1 (193500), and WS4 (277580), respectively. SOX10 was able to transactivate the MITF promoter 100-fold, and the transactivation was further stimulated by PAX3. By promoter deletion and mutation analyses, Potterf et al. (2000) showed that SOX10 can activate MITF expression through binding to a region that is evolutionarily conserved between the mouse and human MITF promoters. A SOX10 mutant that models C-terminal truncations in patients with WS can reduce wildtype SOX10 induction of MITF, suggesting that these mutations may act in a dominant-negative fashion. The data support a model in which the hypopigmentation of WS results from a disruption in function of the central melanocyte transcription factor MITF. </p><p>Bondurand et al. (2000) also showed that SOX10, in synergy with PAX3, strongly activates MITF expression in transfection assays. Transfection experiments revealed that PAX3 and SOX10 interact directly by binding to a proximal region of the MITF promoter containing binding sites for both factors. Mutant SOX10 or PAX3 proteins failed to transactivate this promoter, providing further evidence that the 2 genes act in concert to directly regulate expression of MITF. In situ hybridization experiments carried out in the dominant megacolon (Dom) mouse confirmed that SOX10 dysfunction impaired Mitf expression as well as melanocytic development and survival. The authors hypothesized that interaction between 3 of the genes that are altered in WS could explain the auditory/pigmentary symptoms of this disease. </p><p>Lee et al. (2000) demonstrated that wildtype SOX10 directly binds and activates transcription of the MITF promoter, whereas a mutant form of the SOX10 protein (602229.0001) associated with Waardenburg-Shah syndrome acts as a dominant-negative repressor of MITF expression and reduces endogenous MITF protein levels. The ability of SOX10 to activate transcription of the MITF promoter implicates SOX10 in the regulation of melanocyte development and provides a molecular basis for the hypopigmentation and deafness associated with WS4. </p><p>Connexin-32 (CX32, GJB1; 304040) is a major protein of peripheral myelin. Mutations in CX32 have been characterized in patients with the X-linked form of Charcot-Marie-Tooth disease (CMTX1; 302800), a peripheral neuropathy. Bondurand et al. (2001) showed that SOX10, in synergy with EGR2 (129010), strongly activates CX32 expression in vitro by directly binding to its promoter. In agreement with this finding, SOX10 and EGR2 mutants identified in patients with peripheral myelin defects failed to transactivate the CX32 promoter. In addition, some CMTX1 patients harbored a T-to-G transversion at position -528 of the CX32 promoter (304040.0015). The authors demonstrated that this mutation eliminates binding and activation by SOX10. </p><p>SOX10 acts as a critical transactivator of tyrosinase-related protein-1 (TYRP1; 115501) during melanoblast development and as a potent transactivator of MITF, which is considered to be a master gene that controls the development and postnatal survival of melanocytes. Khong and Rosenberg (2002) identified, for the first time, the presence of de novo cellular immune reactivity against SOX10, using tumor-infiltrating lymphocytes obtained from a 63-year-old woman with metastases of melanoma refractory to chemotherapy, who was started on a 4-peptide vaccination protocol. Most of her tumors completely regressed after 2 cycles of immunotherapy, including complete resolution of a large tumor in her left thigh, an intrapelvic mass, a liver lesion, and most of the nodules in her lungs. She also developed vitiligo on the dorsal areas of her hand and distal forearm bilaterally. </p><p>The Sox10 and Pax3 transcription factors can directly regulate both MITF and RET (164761) in a synergistic fashion. Lang and Epstein (2003) showed that Pax3 and Sox10 can physically interact; this interaction contributes to synergistic activation of a conserved RET enhancer, and it explains why Sox10 mutants that cannot bind DNA still retain the ability to activate this enhancer in the presence of Pax3. However, in the context of the MITF gene, Pax3 and Sox10 must each bind independently to DNA in order to achieve synergy. These observations appear to explain the phenotype in the mild form of Waardenburg syndrome (WS2E; 611584) caused by a specific SOX10 mutation (S135T; 602229.0005) in the HMG box that abrogates DNA binding without disrupting association with PAX3. </p><p>Using gene expression profiling, Iwashita et al. (2003) determined that genes associated with Hirschsprung disease were highly upregulated in rat gut neural crest stem cells relative to whole-fetus RNA. The genes with highest expression were GDNF (600837), SOX10, GFRA1 (601496), and EDNRB. The highest expression was seen in RET (164761), which was found to be necessary for neural crest stem cell migration in the gut. GDNF promoted the migration of neural crest stem cells in culture but did not affect their survival or proliferation. The observations made by Iwashita et al. (2003) were confirmed by quantitative RT-PCR, flow cytometry, and functional analysis. </p><p>By expression of Sox9 or Sox10 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>Ciliary neurotrophic factor (CNTF; 118945) is a major mediator of the protective effects of Schwann cells, both under physiologic and pathologic conditions. Ito et al. (2006) identified SOX10 as a key regulator of CNTF expression. Overexpression of Sox10 in cultured primary Schwann cells from rat sciatic nerves upregulated Cntf protein levels more than 100-fold. In addition, Cntf expression was significantly lower in sciatic nerves of Sox10 +/- mice, suggesting that SOX10 acts as a physiologic regulator of CNTF gene expression in vivo. </p><p>The specificity of NFAT complexes on target genes arises from assembly of NFATc family members (see 600489) with nuclear partner proteins. Purification of Nfat protein complexes from mouse neural tubes showed that Sox10 is an Nfat nuclear partner and synergizes with Nfatc4 (602699) to activate Krox20 (129010), which regulates genes necessary for myelination. Protein domain deletion studies indicated that Sox10 bound to the Rel homology domain of Nfatc4. Using oligonucleotide affinity purification, Kao et al. (2009) found that Nfatc4 facilitated Sox10 binding to the NRE4 region of the Krox20 myelin-specific enhancer. Kao et al. (2009) concluded that NFATc4 and Sox10 cooperate in myelin gene expression. </p><p>Chaoui et al. (2015) found that the nuclear paraspeckle protein p54NRB (NONO; 300084) interacted with SOX10 to enhance expression of SOX10 target genes. However, p54NRB did not activate SOX10 target genes without SOX10. Overexpression of p54NRB caused redistribution of SOX10 to nuclear bodies. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Waardenburg Syndrome Type 4C</em></strong></p><p>
|
|
Based on the finding that Sox10 underlies the Dom mouse model (see ANIMAL MODEL), Southard-Smith et al. (1998) and Herbarth et al. (1998) considered SOX10 to be a likely candidate for the site of mutations in individuals with Hirschsprung disease or Waardenburg syndrome whose disease had not been related to mutations in other genes. </p><p>Waardenburg-Shah syndrome, also known as Waardenburg syndrome type 4 (see WS4C; 613266) is characterized by deafness, pigmentary abnormalities, and Hirschsprung disease. These features are all caused by defects in the embryonic neural crest. In 4 patients with Waardenburg-Shah syndrome, Pingault et al. (1998) identified heterozygous mutations in the SOX10 gene (602229.0001-602229.0004). Each mutation was predicted to result in loss of function, suggesting that the pathologic mechanism is haploinsufficiency. </p><p>In 2 patients with WS4, Southard-Smith et al. (1999) identified mutations in the SOX10 gene (602229.0009-602229.0010). </p><p>Pingault et al. (2002) identified SOX10 mutations in patients with WS4 with Hirschsprung disease and in patients with WS and intestinal pseudoobstruction without frank aganglionosis. These results showed that chronic intestinal pseudoobstruction may be a manifestation associated with WS, and indicated that aganglionosis is not the only mechanism underlying the intestinal dysfunction of patients with SOX10 mutations. </p><p>Morin et al. (2008) described a de novo missense mutation (602229.0016) in the gene encoding the SOX10 transcription factor in a Spanish patient with sporadic WS4. </p><p>Bondurand et al. (2007) used a combination of semiquantitative fluorescent multiplex polymerase chain reaction and fluorescence in situ hybridization to search for SOX10 heterozygous deletions in cases of Waardenburg syndrome. They described the first characterization of SOX10 deletions (see, e.g., 602229.0012) in patients presenting with WS4. </p><p><strong><em>Peripheral Demyelinating Neuropathy, Central Dysmyelination, Waardenburg Syndrome, and Hirschsprung Disease</em></strong></p><p>
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|
Of 12 unrelated Waardenburg-Shah syndrome patients recruited by the Genetic Center at the Necker Hospital in Paris, Touraine et al. (2000) described 3 patients with growth retardation and a previously unreported neurologic phenotype with impairment of both the central and autonomic nervous systems and occasionally neonatal hypotonia and arthrogryposis (PCWH; 609136). Each of the 3 patients was heterozygous for a SOX10 truncating mutation: tyr313 to ter (Y313X; 602229.0006) or ser251 to ter (S251X; 602229.0007). The extended spectrum of the WS4 phenotype was considered relevant to the brain expression of SOX10 during human embryonic and fetal development. The expression of SOX10 in human embryo was not restricted to the neural crest-derived cells but also involved fetal brain cells, most likely of glial origin. The data emphasized the important role of SOX10 in early development of both neural crest-derived tissues, namely melanocytes and autonomic and enteric nervous systems, and glial cells of the central nervous system. </p><p>Pingault et al. (2000) described a patient with a heterozygous mutation in the SOX10 gene (602229.0019) who had peripheral neuropathy with hypomyelination, deafness, and chronic intestinal pseudoobstruction, but not Hirschsprung disease or pigmentary abnormalities. Chronic intestinal pseudoobstruction is defined by repetitive episodes or continuous symptoms of bowel obstruction in the absence of a mechanical occluding lesion. It differs from Hirschsprung disease by the persistence of ganglionic cells and nervous plexus in the submucosal compartments of the bowel. </p><p>In an infant with pigmentary abnormalities, deafness, and decreased myenteric and submucosal ganglion cells in the colon and small bowel, Inoue et al. (2002) identified a heterozygous truncating mutation in the SOX10 gene (602229.0011). In addition, the patient had little spontaneous respiratory or other movement, severe hypotonia, multiple contractures, undetectable tendon reflexes, and tongue fasciculations. Histopathologic studies showed an absence of peripheral nerve myelin despite normal numbers of Schwann cells, and profound dysmyelination in the CNS. </p><p><strong><em>Waardenburg Syndrome Type 2E</em></strong></p><p>
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|
Bondurand et al. (2007) found 5 different SOX10 deletions (see, e.g., 602229.0013) in 5 patients with WS2E (611584), making SOX10 a new gene for that form of Waardenburg syndrome. No SOX10 point mutations were identified by DNA sequencing of the 3 SOX10 coding exons. Neurologic phenotypes reminiscent of that observed in variant WS4, i.e., PCWH syndrome (peripheral demyelinating neuropathy, central demyelination, WS, and Hirschsprung disease; 609136) were observed in some WS2-affected patients with SOX10 deletions. </p><p>In a boy with synophrys, vivid blue eyes, white matter anomalies, impaired intellectual development with autistic-like behavior, and bilateral complete agenesis of the semicircular canals without Hirschsprung disease, Sznajer et al. (2008) described a de novo splice site mutation in SOX10 (602229.0017). Sznajer et al. (2008) classified the patient as having atypical type 4 Waardenburg syndrome (277580); however, given the absence of Hirschsprung disease, the patient appears to have a type 2E Waardenburg syndrome. </p><p>Zhang et al. (2012) performed functional analysis of 4 different heterozygous truncating mutations in the SOX10 gene, 3 reported by Chen et al. (2010) (e.g., 602229.0021) and 1 novel (602229.0022). In vitro functional expression studies showed that the mutant proteins lacked the ability to transactivate the MITF promoter. </p><p>Pingault et al. (2013) analyzed the SOX10 gene in 17 patients with hypogonadotropic hypogonadism and anosmia who had been diagnosed with Kallmann syndrome (see 147950) but who also exhibited at least 1 Waardenburg-like feature, and identified heterozygous SOX10 mutations in 6 of them (see, e.g., 602229.0023). Analysis of SOX10 in 86 more patients with hypogonadotropic hypogonadism and anosmia, 20 of whom had various nonolfactory, nonreproductive associated anomalies, revealed heterozygous mutations in 2 patients; 1 of the 2 had hypoacusis and the other had normal hearing but showed macroscelia. Pingault et al. (2013) stated that there was no evidence to indicate why a given SOX10 mutation might be associated with hypogonadotropic hypogonadism and anosmia, and also noted that anosmia and hypogonadism might be underestimated in Waardenburg syndrome because individuals usually do not spontaneously complain of anosmia and WS is often diagnosed in childhood. </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>Genotype/Phenotype Correlations</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>In 4 patients with the neurologic variant of Waardenburg-Shah syndrome, which is also known by the acronym PCWH (peripheral demyelinating neuropathy, central demyelination, Waardenburg syndrome, and Hirschsprung disease; 609136), Inoue et al. (2004) identified truncating mutations in the SOX10 gene; 2 patients, including 1 who had previously been reported by Jacobs and Wilson (1992), had the Y313X mutation (602229.0006). All the mutations were located in the last exon (exon 5) in the 3-prime region of the SOX10 gene. Functional analysis showed that the truncating mutations suppressed the transcriptional activity of cotransfected wildtype SOX10 in a dose-dependent manner, suggesting that PCWH is caused by dominant-negative mutations. However, 2 truncating mutations (E189X; 602229.0001 and Y207X; 602229.0009) associated with the less severe WS4C phenotype ultimately showed different effects. Northern blot analysis demonstrated that WS4C-associated mutations, but not PCWH-associated mutations, lead to a reduction in mRNA via the nonsense-mediated decay (NMD) pathway, thereby causing haploinsufficiency and preventing a dominant-negative effect. Inoue et al. (2004) noted that the results were consistent with the NMD RNA surveillance pathway, which typically degrades only transcripts containing nonsense mutations that are followed by at least 1 intron (Carter et al., 1996; Nagy and Maquat, 1998), as usually occurs with WS4C-associated mutations. Accordingly, the PCWH-associated mutations that occur in SOX10 exon 5 are not followed by an intron, may escape NMD, and express large amounts of dominant-negative protein. Similar results were obtained for truncating mutations in the myelin protein zero gene (MPZ; 159440) that cause distinct myelinopathies. Inoue et al. (2004) suggested that, in general, the NMD mechanism may function protectively to convert dominant-negative effects to haploinsufficiency. </p><p>Chaoui et al. (2015) found that many SOX10 mutations induced redistribution of SOX10 to nuclear foci and caused redistribution of p54NRB to these foci. However, only foci-forming SOX10 mutants exclusively localized in nucleus altered the ability of p54NRB to enhance SOX10 transactivation activity, and this dominant-negative activity correlated with the more severe PCWH or PCW without HSCR phenotypes observed in patients harboring these mutations. </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>A mouse model of Hirschsprung disease (HSCR; 142623), dominant megacolon (Dom), arose spontaneously at the Jackson Laboratory (Lane and Liu, 1984). Megacolon was associated with dominantly inherited spotting. Dom/+ heterozygous mice displayed regional deficiencies of neural crest-derived enteric ganglia in the distal colon, whereas Dom/Dom homozygous animals were embryonic lethal. The Dom locus mapped to a mid-terminal region of mouse chromosome 15. </p><p>Using a positional cloning strategy, Southard-Smith et al. (1998) identified Sox10 as the gene underlying the Dom Hirschsprung mouse model. BLAST analysis of the EST database identified the candidate transcript as Sox10 on the basis of its homology with the 163-bp sequence of the SRY-like HMG box transcription factor Sox10 (Stock et al., 1996; Wright et al., 1993). The finding was consistent with Sox10 expression in the 2 principal cell types affected in Dom/+ mice, neural crest-derived melanocytes and enteric ganglia. In Dom mice, Southard-Smith et al. (1998) identified a premature termination mutation of Sox10 underlying the absence of neural crest derivatives. They demonstrated Sox10 expression in normal neural crest cells, disrupted expression of both Sox10 and the HSCR disease gene Ednrb in Dom mutant embryos, and loss of neural crest derivatives due to apoptosis. The authors concluded that Sox10 is essential for proper peripheral nervous system development. Herbarth et al. (1998) also showed that the Dom mutant mouse is caused by a defect in the Sox10 gene and that Sox10 is an essential factor in mouse neural crest development. </p><p>Variability in the disease phenotype of patients with WS4 suggests the influence of genetic modifier loci in the disorder. Mice heterozygous for the Sox10(Dom) allele exhibit variability of aganglionosis and hypopigmentation influenced by genetic background similar to that observed in WS4 patients. Southard-Smith et al. (1999) constructed Sox10(Dom)/+ congenic lines to segregate loci that modify the neural crest defects in the heterozygous mice. Consistent with previous studies, increased lethality in the heterozygous mice resulted from a C57BL/6J locus; also, an increase in hypopigmentation was noted in conjunction with a locus in another strain. Linkage analysis localized a hypopigmentation modifier of the Dom phenotype to mouse chromosome 10 in close proximity to a modifier of hypopigmentation for the EDNRB (131244) mouse model of WS4. </p><p>Paratore et al. (2002) used mice with a targeted deletion of the Sox10 gene to study the etiology of Hirschsprung disease. Neural crest-derived enteric progenitors that were heterozygous for the Sox10 mutation colonized the proximal intestine but were unaffected in their survival capacity. However, unlike their wildtype counterparts, mutant enteric neural crest-derived cells were unable to maintain their progenitor state and acquired preneuronal traits, which resulted in a reduction of the progenitor pool size. Thus, the cells that normally colonize the hindgut were depleted in the Sox10 mutant, causing the distal bowel to become aganglionic. </p><p>Cantrell et al. (2004) tested for association between genes in the endothelin signaling pathway and severity of aganglionosis in an extended pedigree of B6C3FeLe.Sox10(Dom) mice. Single-locus association analysis identified interaction between EdnrB (131244) and Sox10. Additional analysis of F2 intercross progeny confirmed a highly significant effect of EdnrB alleles on the Sox10(Dom/+) phenotype. The presence of C57BL/6J alleles at EdnrB was associated with increased penetrance and more severe aganglionosis in Sox10(Dom) mutants. Crosses between EdnrB and Sox10 mutants corroborated this gene interaction, with double-mutant progeny exhibiting significantly more severe aganglionosis. The background strain of the EdnrB mutant further influenced the phenotype of Sox10/EdnrB double-mutant progeny, implying the action of additional modifiers on this phenotype. </p><p>Owens et al. (2005) focused on enteric ganglia deficits in Sox10(Dom) mice and defined aganglionosis as a quantitative trait in Sox10(Dom) intercross progeny to investigate the contribution of strain background to variation in enteric nervous system deficits. The phenotype of Sox10(Dom/+) mutants ranged over a continuum from severe aganglionosis to no detectable phenotype in the gut. A SNP-based genome scan in Sox10(Dom/+) F1 intercross progeny revealed modifier loci on mouse chromosomes 3, 5, 8, 11, and 14 with distinct effects on penetrance and severity of aganglionosis. </p><p>Using an N-ethyl-N-nitrosourea mutagenesis screen, Matera et al. (2008) identified Gli3 (165240) as a modifier of Sox10 neurocristopathy. Heterozygosity for a null mutation of Gli3 increased the penetrance and severity of the hypopigmentation phenotype of Sox10 +/- mice. </p><p>Polanco et al. (2010) showed that transgenic expression of Sox10, a close relative of Sox9 (608160), in gonads of XX mice resulted in development of testes and male physiology. The degree of sex reversal correlated with levels of Sox10 expression in different transgenic lines. Sox10 was expressed at low levels in primordial gonads of both sexes during normal mouse development, becoming male-specific during testis differentiation. SOX10 protein was able to activate transcriptional targets of SOX9, explaining at a mechanistic level its ability to direct male development. Overexpression of SOX10 alone was able to mimic human 46,XX disorder of sexual development (DSD) phenotypes associated with duplication of chromosome 22q13. Given that human SOX10 maps to chromosome 22q13.1, Polanco et al. (2010) implicated SOX10 in the etiology of chromosome 22q13-related DSD. </p><p>Cossais et al. (2010) used in ovo electroporation in the developing neural tube of chicken to determine which regions and properties of SOX10 are required for early neural crest development. There was a strict reliance on the DNA-binding activity and the presence of the C-terminal transactivation domain, and a lesser influence of the dimerization function and a conserved domain in the center of the protein. Dominant-negative effects on early neural crest development were mostly observed for truncated SOX10 proteins, whose production in patients may be prevented by nonsense-mediated decay. In contrast, mutant SOX10 proteins that occurred in patients were usually inactive. The authors proposed that any dominant-negative activity that some mutants may possess must therefore be restricted to single neural crest-derived cell lineages or oligodendrocytes at later times. </p><p>In SOX10-null mice, Pingault et al. (2013) observed an almost complete absence of olfactory ensheathing cells along the olfactory nerve pathway, as well as defasciculation and misrouting of the nerve fibers, impaired migration of GnRH cells, and disorganization of the olfactory nerve layer of the olfactory bulbs. </p>
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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>23 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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<h4>
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<span class="mim-font">
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<strong>.0001 WAARDENBURG SYNDROME, TYPE 4C</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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SOX10, GLU189TER
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<br />
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SNP: rs74315514,
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ClinVar: RCV000007817, RCV004700200
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</span>
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<span class="mim-text-font">
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<p>In a child with bilateral profound hearing loss, short segment Hirschsprung disease, and pigmentary abnormalities, including white hair, blue irides with gray speckles, and depigmented skin patches, all features consistent with WS4C (613266), Pingault et al. (1998) identified a heterozygous glu189-to-ter mutation (E189X) in the SOX10 gene. The de novo mutation truncated the SOX10 protein, leaving the HMG binding domain intact. </p>
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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 WAARDENBURG SYNDROME, TYPE 4C</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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SOX10, TYR83TER
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<br />
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SNP: rs73415876,
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gnomAD: rs73415876,
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ClinVar: RCV000007818
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a boy with WS4C (613266) characterized by bilateral profound hearing loss (treated by a cochlear implant), fair hair and vivid blue eyes, and chronic bowel problems, Pingault et al. (1998) identified a heterozygous de novo nonsense tyr83-to-ter mutation (Y83X) in the SOX10 gene. Rectal biopsy showed that the number of ganglia was dramatically reduced. The de novo mutation was located upstream of the HMG domain. </p>
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</span>
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</div>
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<br />
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</div>
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</div>
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<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 WAARDENBURG SYNDROME, TYPE 4C</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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SOX10, 6-BP INS, NT482
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<br />
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SNP: rs397515366,
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ClinVar: RCV000007819
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</div>
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<span class="mim-text-font">
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<p>In a patient with deafness and short segment aganglionosis (613266), Pingault et al. (1998) found a heterozygous 6-bp insertion (GCTCCT) between nucleotides 482 and 483 in exon 4 of the SOX10 gene. The mutation resulted in duplication of arg161leu162 in the middle of helix 3 of the HMG domain. This duplication changed the spacing between 2 highly conserved residues and was likely to disrupt the structure of the DNA-binding domain. </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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<h4>
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<span class="mim-font">
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<strong>.0004 WAARDENBURG SYNDROME, TYPE 4C</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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SOX10, 2-BP DEL, 1076GA
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<br />
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SNP: rs397515367,
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ClinVar: RCV000007820, RCV002512880
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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 patient with HSCR, deafness, and hypopigmentation (613266), Pingault et al. (1998) identified a heterozygous 2-bp deletion (1076delGA) in exon 5 of the SOX10 gene, resulting in a frameshift that altered the mRNA sequence and introduced a premature termination codon at position 400. This and the other 3 mutations identified by Pingault et al. (1998) were likely to result in a loss of function, suggesting that the pathologic mechanism in Waardenburg-Shah syndrome is haploinsufficiency and that the developmental process is sensitive to the exact level of the SOX10 product. </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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<h4>
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<span class="mim-font">
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<strong>.0005 WAARDENBURG SYNDROME, TYPE 2E, WITHOUT NEUROLOGIC INVOLVEMENT</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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SOX10, SER135THR
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<br />
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SNP: rs74315515,
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gnomAD: rs74315515,
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ClinVar: RCV000007821
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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 girl with a mild form of Waardenburg syndrome type 2E (611584), reported by Hennekam and Gorlin (1996), Bondurand et al. (1999) identified a heterozygous ser135-to-thr (S135T) mutation in the SOX10 gene. She had cutaneous hypo- and hyperpigmented regions and hearing loss. </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 PERIPHERAL DEMYELINATING NEUROPATHY, CENTRAL DYSMYELINATION, WAARDENBURG SYNDROME, AND HIRSCHSPRUNG DISEASE</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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SOX10, TYR313TER
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<br />
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SNP: rs74315516,
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ClinVar: RCV000007822
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated patients (one living in Germany and the second in France), Touraine et al. (2000) observed a neurologic variant of Waardenburg-Shah syndrome (609136) associated with a tyr313-to-ter (Y313X) mutation in the SOX10 gene. </p><p>In 2 patients with a neurologic variant of Waardenburg-Shah syndrome, one of whom had previously been reported by Jacobs and Wilson (1992), Inoue et al. (2004) identified a tyr313-to-ter (Y313X) mutation in the SOX10 gene. In the 27-year-old male previously reported by Jacobs and Wilson (1992), the Y313X mutation was the result of a 1-bp insertion (938insA); in the other patient, an 18-year-old male, the Y313X mutation was the result of a 939C-G transversion. Both patients had muscle wasting/atrophy, pes cavus, and areflexia/hyporeflexia, indicating peripheral neuropathy. Both had developmental delay and hypotonia, indicative of dysmyelination, with nystagmus and spastic diplegia also present in the younger patient. Both patients had hypopigmentation and neurosensory deafness, indicating dysmyelinating Waardenburg syndrome, and both had long segment Hirschsprung disease. </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>.0007 PERIPHERAL DEMYELINATING NEUROPATHY, CENTRAL DYSMYELINATION, WAARDENBURG SYNDROME, AND HIRSCHSPRUNG DISEASE</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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SOX10, SER251TER
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<br />
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SNP: rs74315518,
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gnomAD: rs74315518,
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ClinVar: RCV000007823, RCV005089203
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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>Touraine et al. (2000) found a ser251-to-ter (S251X) truncating mutation of the SOX10 gene in a child in France with a neurologic variant of Waardenburg-Shah syndrome (609136). There was no history of either WS or Hirschsprung disease (142623) in other members of 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>.0008 PERIPHERAL DEMYELINATING NEUROPATHY, CENTRAL DYSMYELINATION, WAARDENBURG SYNDROME, AND HIRSCHSPRUNG DISEASE</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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SOX10, 12-BP DEL, EXON 5
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<br />
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SNP: rs397515368,
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ClinVar: RCV000007824
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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>Inoue et al. (1999) described a patient presenting with a neurologic variant of Waardenburg-Shah syndrome (PCWH; 609136) characterized by severe dysmyelination compatible with Pelizaeus-Merzbacher disease (see 312080) and peripheral neuropathy consistent with Charcot-Marie-Tooth disease type I (see 118200), in addition to Waardenburg-Hirschsprung syndrome (277580). In the patient, Inoue et al. (1999) identified a novel heterozygous 12-bp deletion in exon 5 of the SOX10 gene that did not disrupt the coding region, but extended the peptide and hence was thought to act as a dominant-negative allele. There was a 6-bp direct repeat in the wildtype SOX10 sequence that flanked the deletion, suggesting that the deletion may have been mediated by DNA polymerase slippage between these direct repeats. The healthy parents and sibs did not have this deletion, indicating that this was a de novo mutation. Deletion started at the second nucleotide of the TAA stop codon, resulting in disruption of the stop codon, and, by conceptual translation, an extension of 82 amino acids on the carboxy terminus without any other alterations in the putative SOX10 protein. The 12-bp deletion converted the carboxy-terminal codon from TAA (stop) to TGT (cys). </p><p>By in vitro functional expression assays, Inoue et al. (2007) showed that the 12-bp deletion led to severely diminished transcription and DNA-binding activity of SOX10. However, the mutant protein did not show dominant-negative interference with wildtype SOX10 in vitro. Within the additional 82-amino acid tail, an 11-amino acid region (termed the WR domain) presumably formed an alpha-helix structure and inhibited SOX10 transcription activity if inserted in the C-terminal half of the protein. The WR domain also affected other transcription factors with a graded effect when fused to the C terminus, suggesting that it elicited a toxic functional activity. Inoue et al. (2007) concluded that the molecular pathology caused by the 12-bp deletion and its resulting extension was distinct from that of more common premature termination mutations. Failure to properly terminate SOX10 translation resulted in the generation of a deleterious functional domain and a gain-of-function effect. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 WAARDENBURG SYNDROME, TYPE 4C</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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SOX10, TYR207TER
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<br />
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SNP: rs281797260,
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ClinVar: RCV000007825
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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>Southard-Smith et al. (1999) described heterozygosity for a tyr207-to-ter (Y207X) mutation in a patient with Waardenburg syndrome type 4C (613266) manifested by short segment Hirschsprung disease, profound sensorineural hearing loss, and hypopigmentation on the abdomen and neck. Both parents were phenotypically normal and neither carried the mutation. The mutation was in exon 4, 27 residues downstream of the carboxyl end of the HMG box and 14 residues downstream of the corresponding site in the Sox10(Dom) mouse where the single basepair insertion is located. </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>.0010 WAARDENBURG SYNDROME, TYPE 4C</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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WAARDENBURG SYNDROME, TYPE 2E, WITH NEUROLOGIC INVOLVEMENT, 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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SOX10, GLN377TER
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<br />
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SNP: rs74315520,
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ClinVar: RCV000007826, RCV000007827, RCV000760372
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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 boy with Waardenburg syndrome type 4C (613266), Southard-Smith et al. (1999) found a gln377-to-ter (Q377X) mutation that truncated the SOX10 protein within the transcription modulation domain. The heterozygous proband had sensorineural deafness and variable diagnoses of enteric function ranging from hypoganglionosis to long segment Hirschsprung disease. He also had nystagmus and ataxic cerebral palsy. His sister was also profoundly deaf and had nystagmus and cerebral palsy, but did not have Hirschsprung disease (WS2E; 611584). </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>.0011 PERIPHERAL DEMYELINATING NEUROPATHY, CENTRAL DYSMYELINATION, WAARDENBURG SYNDROME, AND HIRSCHSPRUNG DISEASE</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SOX10, GLN250TER
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<br />
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SNP: rs74315521,
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|
|
ClinVar: RCV000007828
|
|
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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>Inoue et al. (2002) reported a male infant with peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (PCWH; 609136) who was heterozygous for a 748C-T transition in the SOX10 gene, resulting in a gln250-to-ter (Q250X) substitution. The patient presented at birth with a white forelock and hyperpigmented and hypopigmented patches on the face, body, and limbs, deafness, and chronic ileus. He never passed meconium and required repeated segmental small and large bowel resections. Myenteric and submucosal ganglion cells were severely diminished throughout the entire colon and much of the small bowel. In addition, he had little spontaneous respiratory or other movement, severe hypotonia, multiple contractures, undetectable tendon reflexes, and tongue fasciculations. Histopathologic studies showed an absence of peripheral nerve myelin despite normal numbers of Schwann cells, and profound dysmyelination in the CNS. He remained ventilator-dependent his entire life and died at 83 days of age of Pseudomonas aeruginosa sepsis. The observations suggested that some SOX10 mutations, such as Q250X, may allow Schwann cells and oligodendrocytes to proliferate but interfere with further differentiation to form myelin. In contrast to SOX10 loss-of-function mutations causing only WS4C (613266), mutations associated with both peripheral and central dysmyelination may affect pathology through a dominant-negative mechanism. </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>.0012 WAARDENBURG SYNDROME, TYPE 4C</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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SOX10, 1128-BP DEL/3-BP INS
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<br />
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ClinVar: RCV000007829
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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 1-year-old boy with Waardenburg syndrome type 4C (613266), Bondurand et al. (2007) identified a heterozygous deletion that removed part of exon 5 of the SOX10 gene. The mutation comprised a 1,128-bp deletion encompassing 740 bp of intron 4 and 388 bp of exon 5, and a 3-bp insertion (697-740_1085del ins CCT). The patient had short-segment Hirschsprung disease, bilateral sensorineural deafness, hair and skin hypopigmentation, and bilateral cryptorchidism. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 WAARDENBURG SYNDROME, TYPE 2E, WITHOUT NEUROLOGIC INVOLVEMENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
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SOX10, 253-BP DEL
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<br />
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|
|
SNP: rs1555939381,
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|
|
ClinVar: RCV000007830
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 9-year-old boy with Waardenburg syndrome type 2 (WS2E; 611584) and in his similarly affected brother, Bondurand et al. (2007) identified a heterozygous 253-bp deletion in the SOX10 gene (219_428+43del). The deletion removed 210 bp of exon 3 and 43 bp of intron 3. The proband had profound deafness, pigmentation abnormalities of the skin and eyes, but no Hirschsprung disease or mental retardation. The patient's mother exhibited somatic mosaicism for the mutation. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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|
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|
<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 WAARDENBURG SYNDROME, TYPE 2E, WITHOUT NEUROLOGIC INVOLVEMENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
SOX10, 1,777-BP DEL
|
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<br />
|
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|
|
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ClinVar: RCV000007831
|
|
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|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 8-year-old boy with Waardenburg syndrome type 2 (WS2E; 611584), Bondurand et al. (2007) identified heterozygosity for a 1,777-bp deletion in the SOX10 gene that removed the whole exon 4, 1,112 bp of intron 3, and 396 bp of intron 4 (429-1112_697+396del). The mutation was inherited from the mother, who also had WS2. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 WAARDENBURG SYNDROME, TYPE 2E, WITHOUT NEUROLOGIC INVOLVEMENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX10, 1-BP DEL, 506C
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs397515369,
|
|
|
|
|
|
|
|
ClinVar: RCV000007832
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese girl with Waardenburg syndrome type 2E (611584), Iso et al. (2008) identified a heterozygous 1-bp deletion (506delC) in exon 4 of the SOX10 gene, predicted to result in a frameshift and premature termination that would remove the C-terminal part of the HMG domain and the whole transactivation domain. She had ocular albinism, a white forelock, and sensorineural deafness. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 WAARDENBURG SYNDROME, TYPE 4C</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX10, ALA157VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909117,
|
|
|
|
|
|
|
|
ClinVar: RCV000007833, RCV002273922
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 18-month-old Spanish boy with severe sensorineural hearing loss, Hirschsprung disease, and heterochromia iridis but neither pigmentary abnormalities in the skin nor white forelock (613266), Morin et al. (2008) identified a 470C-T transition in the SOX10 gene, resulting in an ala157-to-val (A157V) change in the predicted polypeptide. The mutation affects the alanine at position 56 in the highly conserved HMG domain. The side chain of ala56 participates in interactions between the N-terminal end of helix 1 and helix 3. Morin et al. (2008) proposed that the A157V mutation could disturb these interactions through steric hindrance, destabilizing the HMG domain. The mutation was not present in the patient's parents, his brother, or in 95 unrelated Spanish controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 WAARDENBURG SYNDROME, TYPE 2E, WITH NEUROLOGIC INVOLVEMENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX10, IVS4AS, A-C, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397515370,
|
|
|
|
|
|
|
|
ClinVar: RCV000007834
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy with Waardenburg syndrome type 2E (611584), Sznajer et al. (2008) identified a heterozygous de novo A-to-C transversion in intron 4 of the SOX10 gene. In addition to sensorineural deafness and vivid blue eyes, he had neurologic abnormalities, including white matter anomalies, mental retardation with autistic-like behavior, hypotonia, and a generalized peripheral neuropathy. Brain imaging showed complete agenesis of the semicircular canals. Hirschsprung disease was absent. Sznajer et al. (2008) hypothesized that the mutation decreased the strength of the acceptor splice site and increased the strength of at least 1 cryptic site 5 nucleotides downstream. Utilization of this cryptic site would cause a frameshift and premature termination 46 residues downstream. The mutation was not present in either parent or in 300 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 WAARDENBURG SYNDROME, TYPE 2E, WITH NEUROLOGIC INVOLVEMENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX10, GLN174PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607081,
|
|
|
|
|
|
|
|
ClinVar: RCV000007835
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 21-month-old boy with Waardenburg syndrome type 2E (611584), Barnett et al. (2009) identified a heterozygous 521A-C transversion in exon 4 of the SOX10 gene, resulting in a gln174-to-pro (Q174P) substitution in the highly conserved HMG domain. He had sensorineural deafness, fair skin and hair pigmentation, multiple tiny lentigines, cafe-au-lait spots, and light blue irides, but no evidence of Hirschsprung disease. He also showed neurologic involvement, with hypotonia, poor vision with intermittent nystagmus in early life, inability to fix or follow, and increased muscle tone. Brain imaging showed absence of the cochlear nerves, absence of the olfactory bulbs, and brain hypomyelination. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 PERIPHERAL DEMYELINATING NEUROPATHY, CENTRAL DYSMYELINATION, WAARDENBURG SYNDROME, AND HIRSCHSPRUNG DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX10, 1-BP DEL, 795G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397515371,
|
|
|
|
|
|
gnomAD: rs397515371,
|
|
|
|
|
|
ClinVar: RCV000007836, RCV000789612
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with a phenotype consistent with PCWH (609136), Pingault et al. (2000) identified a de novo heterozygous 1-bp deletion (795delG) in the SOX10 gene, resulting in a frameshift and premature termination. She had peripheral neuropathy with marked slowing of nerve conduction velocities resulting in delayed motor development, chronic intestinal pseudoobstruction, hypolacrimation, absence of sweating, and deafness. The peripheral nerve histologic features were more consistent with a developmental dysregulation defect than a degenerative process. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 PERIPHERAL DEMYELINATING NEUROPATHY, CENTRAL DYSMYELINATION, WAARDENBURG SYNDROME, AND HIRSCHSPRUNG DISEASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX10, 1-BP DEL, 915G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397515372,
|
|
|
|
|
|
|
|
ClinVar: RCV000007837
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Spanish boy with PCWH (609136), Vinuela et al. (2009) identified a de novo heterozygous 1-bp deletion (915delG) in exon 5 of the SOX10 gene, resulting in a frameshift and premature termination at residue 306. The patient had Hirschsprung disease since birth and progressive sensorineural hearing loss associated with hypoplasia of the cochlea. He had blue eyes, but no pigmentary anomalies of the skin or white forelock. Neurologic findings included congenital nystagmus and delayed motor development due to hypotonia and spasticity. Brain MRI showed central dysmyelinization. Vinuela et al. (2009) noted that the location of this mutation would cause an escape from nonsense-mediated decay and generate a dominant-negative effect resulting in neurologic features, consistent with the findings of Inoue et al. (2004). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 WAARDENBURG SYNDROME, TYPE 2E, WITHOUT NEUROLOGIC INVOLVEMENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX10, 2-BP DEL, 743AG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397515386,
|
|
|
|
|
|
|
|
ClinVar: RCV000023178
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Chinese father and daughter with WS2E (611584), Zhang et al. (2012) identified a heterozygous 2-bp deletion, 743delAG, in exon 5 of the SOX10 gene, resulting in a frameshift and premature termination at codon 248 (Glu248fsTer30). The truncated protein lacked the transactivation domain but retained the DNA-binding domain. In vitro functional expression studies in human cells showed that the mutant protein was expressed and localized only to the nucleus, but did not transactivate the MITF (156845) promoter and acted in a dominant-negative manner. However, the mutant protein was degraded faster than wildtype SOX10, which Zhang et al. (2012) postulated may have resulted in haploinsufficiency and the somewhat mild phenotype. Both patients had bilateral profound hearing loss and bilateral heterochromia iridis, but no additional features. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 WAARDENBURG SYNDROME, TYPE 2E, WITHOUT NEUROLOGIC INVOLVEMENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX10, 1-BP DEL, 113G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397515387,
|
|
|
|
|
|
gnomAD: rs397515387,
|
|
|
|
|
|
ClinVar: RCV000023179
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Chinese boy with WS2E (611584), Chen et al. (2010) identified a heterozygous 1-bp deletion (113delG) in exon 3 of the SOX10 gene, resulting in a frameshift and premature termination (Gly38fsTer69). In functional studies, Zhang et al. (2012) demonstrated that the truncated protein was expressed and lacked the nuclear localization signal; it showed localization in both the nucleus and cytoplasm, but did not transactivate the MITF (156845) promoter, consistent with haploinsufficiency. The patient had bilateral profound hearing loss and bilateral heterochromia iridis, but no additional features. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 WAARDENBURG SYNDROME, TYPE 2E, WITHOUT NEUROLOGIC INVOLVEMENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SOX10, 2T-G
|
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<br />
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SNP: rs397515457,
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ClinVar: RCV000055673
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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 26-year-old man with unilateral deafness, white hair, anosmia, cryptorchidism, and micropenis (WSE2; 611584), Pingault et al. (2013) identified heterozygosity for a c.2T-G transversion in the SOX10 gene. Luciferase reporter-gene analysis in transfected HeLa cells showed reduced or absent transactivation capacity with the mutant compared to wildtype. The proband's mother also had unilateral deafness, and his sister was anosmic; their mutation status was unknown. </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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Barnett, C. P., Mendoza-Londono, R., Blaser, S., Gillis, J., Dupuis, L., Levin, A. V., Chiang, P. W., Spector, E., Reardon, W.
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<strong>Aplasia of cochlear nerves and olfactory bulbs in association with SOX10 mutation.</strong>
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Am. J. Med. Genet. 149A: 431-436, 2009.
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[PubMed: 19208381]
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[Full Text: https://doi.org/10.1002/ajmg.a.32657]
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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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Bondurand, N., Dastot-Le Moal, F., Stanchina, L., Collot, N., Baral, V., Marlin, S., Attie-Bitach, T., Giurgea, I., Skopinski, L., Reardon, W., Toutain, A., Sarda, P., Echaieb, A., Lackmy-Port-Lis, M., Touraine, R., Amiel, J., Goossens, M., Pingault, V.
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<strong>Deletions at the SOX10 gene locus gene Waardenburg syndrome types 2 and 4.</strong>
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Am. J. Hum. Genet. 81: 1169-1185, 2007.
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[PubMed: 17999358]
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[Full Text: https://doi.org/10.1086/522090]
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<p class="mim-text-font">
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Bondurand, N., Girard, M., Pingault, V., Lemort, N., Dubourg, O., Goossens, M.
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<strong>Human connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10.</strong>
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Hum. Molec. Genet. 10: 2783-2795, 2001.
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[PubMed: 11734543]
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[Full Text: https://doi.org/10.1093/hmg/10.24.2783]
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</p>
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<li>
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<p class="mim-text-font">
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Bondurand, N., Kuhlbrodt, K., Pingault, V., Enderich, J., Sajus, M., Tommerup, N., Warburg, M., Hennekam, R. C. M., Read, A. P., Wegner, M., Goossens, M.
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<strong>A molecular analysis of the Yemenite deaf-blind hypopigmentation syndrome: SOX10 dysfunction causes different neurocristopathies.</strong>
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Hum. Molec. Genet. 8: 1785-1789, 1999.
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[PubMed: 10441344]
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[Full Text: https://doi.org/10.1093/hmg/8.9.1785]
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</p>
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<li>
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<p class="mim-text-font">
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Bondurand, N., Pingault, V., Goerich, D. E., Lemort, N., Sock, E., Le Caignec, C., Wegner, M., Goossens, M.
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<strong>Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.</strong>
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Hum. Molec. Genet. 9: 1907-1917, 2000.
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[PubMed: 10942418]
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[Full Text: https://doi.org/10.1093/hmg/9.13.1907]
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Cantrell, V. A., Owens, S. E., Chandler, R. L., Airey, D. C., Bradley, K. M., Smith, J. R., Southard-Smith, E. M.
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<strong>Interactions between Sox10 and EdnrB modulate penetrance and severity of aganglionosis in the Sox10(Dom) mouse model of Hirschsprung disease.</strong>
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Hum. Molec. Genet. 13: 2289-2301, 2004. Note: Erratum: Hum. Molec. Genet. 13: 3241 only, 2004.
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[PubMed: 15294878]
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[Full Text: https://doi.org/10.1093/hmg/ddh243]
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<p class="mim-text-font">
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Carter, M. S., Li, S., Wilkinson, M. F.
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<strong>A splicing-dependent regulatory mechanism that detects translation signals.</strong>
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EMBO J. 15: 5965-5975, 1996.
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[PubMed: 8918474]
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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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Chaoui, A., Kavo, A., Baral, V., Watanabe, Y., Lecerf, L., Colley, A., Mendoza-Londono, R., Pingault, V., Bondurand, N.
|
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<strong>Subnuclear re-localization of SOX10 and p54NRB correlates with a unique neurological phenotype associated with SOX10 missense mutations.</strong>
|
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Hum. Molec. Genet. 24: 4933-4947, 2015.
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[PubMed: 26060192]
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[Full Text: https://doi.org/10.1093/hmg/ddv215]
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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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Chen, H., Jiang, L., Xie, Z., Mei, L., He, C., Hu, Z., Xia, K., Feng, Y.
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<strong>Novel mutations of PAX3, MITF, and SOX10 genes in Chinese patients with type I or type II Waardenburg syndrome.</strong>
|
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Biochem. Biophys. Res. Commun. 397: 70-74, 2010.
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[PubMed: 20478267]
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[Full Text: https://doi.org/10.1016/j.bbrc.2010.05.066]
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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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Cossais, F., Wahlbuhl, M., Kriesch, J., Wegner, M.
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<strong>SOX10 structure-function analysis in the chicken neural tube reveals important insights into its role in human neurocristopathies.</strong>
|
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Hum. Molec. Genet. 19: 2409-2420, 2010.
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[PubMed: 20308050]
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[Full Text: https://doi.org/10.1093/hmg/ddq124]
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<p class="mim-text-font">
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Hennekam, R. C. M., Gorlin, R. J.
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<strong>Confirmation of Yemenite (Warburg) deaf-blind hypopigmentation syndrome.</strong>
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Am. J. Med. Genet. 65: 146-148, 1996.
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[PubMed: 8911608]
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[Full Text: https://doi.org/10.1002/(SICI)1096-8628(19961016)65:2<146::AID-AJMG13>3.0.CO;2-Q]
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<p class="mim-text-font">
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Herbarth, B., Pingault, V., Bondurand, N., Kuhlbrodt, K., Hermans-Borgmeyer, I., Puliti, A., Lemort, N., Goossens, M., Wegner, M.
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<strong>Mutation of the Sry-related Sox10 gene in dominant megacolon, a mouse model for human Hirschsprung disease.</strong>
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Proc. Nat. Acad. Sci. 95: 5161-5165, 1998.
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[PubMed: 9560246]
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[Full Text: https://doi.org/10.1073/pnas.95.9.5161]
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<li>
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<p class="mim-text-font">
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Inoue, K., Khajavi, M., Ohyama, T., Hirabayashi, S., Wilson, J., Reggin, J. D., Mancias, P., Butler, I. J., Wilkinson, M. F., Wegner, M., Lupski, J. R.
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<strong>Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations.</strong>
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Nature Genet. 36: 361-369, 2004.
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[PubMed: 15004559]
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[Full Text: https://doi.org/10.1038/ng1322]
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<p class="mim-text-font">
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Inoue, K., Ohyama, T., Sakuragi, Y., Yamamoto, R., Inoue, N. A., Yu, L.-H., Goto, Y., Wegner, M., Lupski, J. R.
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<strong>Translation of SOX10 3-prime untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain.</strong>
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Hum. Molec. Genet. 16: 3037-3046, 2007. Note: Erratum: Hum. Molec. Genet. 17: 1705 only, 2008.
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[PubMed: 17855451]
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[Full Text: https://doi.org/10.1093/hmg/ddm262]
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<p class="mim-text-font">
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Inoue, K., Shilo, K., Boerkoel, C. F., Crowe, C., Sawady, J., Lupski, J. R., Agamanolis, D. P.
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<strong>Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: phenotypes linked by SOX10 mutation.</strong>
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Ann. Neurol. 52: 836-842, 2002.
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[PubMed: 12447940]
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[Full Text: https://doi.org/10.1002/ana.10404]
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<p class="mim-text-font">
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Inoue, K., Tanabe, Y., Lupski, J. R.
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<strong>Myelin deficiencies in both the central and the peripheral nervous systems associated with a SOX10 mutation.</strong>
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Ann. Neurol. 46: 313-318, 1999.
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[PubMed: 10482261]
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[Full Text: https://doi.org/10.1002/1531-8249(199909)46:3<313::aid-ana6>3.0.co;2-7]
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Iso, M., Fukami, M., Horikawa, R., Azuma, N., Kawashiro, N., Ogata, T.
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<strong>SOX10 mutation in Waardenburg syndrome type II. (Letter)</strong>
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[PubMed: 18627047]
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[Full Text: https://doi.org/10.1002/ajmg.a.32403]
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<p class="mim-text-font">
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Ito, Y., Wiese, S., Funk, N., Chittka, A., Rossoll, W., Bommel, H., Watabe, K., Wegner, M., Sendtner, M.
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<strong>Sox10 regulates ciliary neurotrophic factor gene expression in Schwann cells.</strong>
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|
Proc. Nat. Acad. Sci. 103: 7871-7876, 2006.
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[PubMed: 16684879]
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[Full Text: https://doi.org/10.1073/pnas.0602332103]
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<p class="mim-text-font">
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Iwashita, T., Kruger, G. M., Pardal, R., Kiel, M. J., Morrison, S. J.
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<strong>Hirschsprung disease is linked to defects in neural crest stem cell function.</strong>
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Science 301: 972-976, 2003.
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[PubMed: 12920301]
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[Full Text: https://doi.org/10.1126/science.1085649]
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</p>
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<li>
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<p class="mim-text-font">
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Jacobs, J. M., Wilson, J.
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<strong>An unusual demyelinating neuropathy in a patient with Waardenburg's syndrome.</strong>
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Acta Neuropath. 83: 670-674, 1992.
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[PubMed: 1636383]
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[Full Text: https://doi.org/10.1007/BF00299420]
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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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Kao, S.-C., Wu, H., Xie, J., Chang, C.-P., Ranish, J. A., Graef, I. A., Crabtree, G. R.
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<strong>Calcineurin/NFAT signaling is required for neuregulin-regulated Schwann cell differentiation.</strong>
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Science 323: 651-654, 2009.
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[PubMed: 19179536]
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[Full Text: https://doi.org/10.1126/science.1166562]
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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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Khong, H. T., Rosenberg, S. A.
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<strong>The Waardenburg syndrome type 4 gene, SOX10, is a novel tumor-associated antigen identified in a patient with a dramatic response to immunotherapy.</strong>
|
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Cancer Res. 62: 3020-3023, 2002.
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[PubMed: 12036907]
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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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Kuhlbrodt, K., Herbarth, B., Sock, E., Hermans-Borgmeyer, I., Wegner, M.
|
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<strong>Sox10, a novel transcriptional modulator in glial cells.</strong>
|
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J. Neurosci. 18: 237-250, 1998.
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[PubMed: 9412504]
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[Full Text: https://doi.org/10.1523/JNEUROSCI.18-01-00237.1998]
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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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Kuhlbrodt, K., Schmidt, C., Sock, E., Pingault, V., Bondurand, N., Goossens, M., Wegner, M.
|
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<strong>Functional analysis of Sox10 mutations found in human Waardenburg-Hirschsprung patients.</strong>
|
|
J. Biol. Chem. 273: 23033-23038, 1998.
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[PubMed: 9722528]
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[Full Text: https://doi.org/10.1074/jbc.273.36.23033]
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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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Lane, P. W., Liu, H. M.
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<strong>Association of megacolon with a new dominant spotting gene (Dom) in the mouse.</strong>
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J. Hered. 75: 435-439, 1984.
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[PubMed: 6512238]
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[Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a109980]
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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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Lang, D., Epstein, J. A.
|
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<strong>Sox10 and Pax3 physically interact to mediate activation of a conserved c-RET enhancer.</strong>
|
|
Hum. Molec. Genet. 12: 937-945, 2003.
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[PubMed: 12668617]
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[Full Text: https://doi.org/10.1093/hmg/ddg107]
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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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Lee, M., Goodall, J., Verastegui, C., Ballotti, R., Goding, C. R.
|
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<strong>Direct regulation of the microphthalmia promoter by Sox10 links Waardenburg-Shah syndrome (WS4)-associated hypopigmentation and deafness to WS2.</strong>
|
|
J. Biol. Chem. 275: 37978-37983, 2000.
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[PubMed: 10973953]
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[Full Text: https://doi.org/10.1074/jbc.M003816200]
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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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Matera, I., Watkins-Chow, D. E., Loftus, S. K., Hou, L., Incao, A., Silver, D. L., Rivas, C., Elliott, E. C., Baxter, L. L., Pavan, W. J.
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<strong>A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy.</strong>
|
|
Hum. Molec. Genet. 17: 2118-2131, 2008.
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[PubMed: 18397875]
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[Full Text: https://doi.org/10.1093/hmg/ddn110]
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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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Morin, M., Vinuela, A., Rivera, T., Villamar, M., Moreno-Pelayo, M. A., Moreno, F., del Castillo, I.
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<strong>A de novo missense mutation in the gene encoding the SOX10 transcription factor in a Spanish sporadic case of Waardenburg syndrome type IV. (Letter)</strong>
|
|
Am. J. Med. Genet. 146A: 1032-1037, 2008.
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[PubMed: 18348274]
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[Full Text: https://doi.org/10.1002/ajmg.a.32181]
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</p>
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<li>
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<p class="mim-text-font">
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Nagy, E., Maquat, L. E.
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<strong>A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance.</strong>
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Trends Biochem. Sci. 23: 198-199, 1998.
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[PubMed: 9644970]
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[Full Text: https://doi.org/10.1016/s0968-0004(98)01208-0]
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</p>
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<li>
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<p class="mim-text-font">
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